1. health and fitness
2. disease
3. cancer

Protocol Update #04
03/07/2014
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY
_________________________________________
PROTOCOL UPDATE TO ALLIANCE A091102
_________________________________________
PHASE II STUDY OF MLN8237 IN ADVANCED/METASTATIC SARCOMA
Clinicaltrials.gov Identifier: NCT01653028
Investigational Agent: MLN8237 (NSC # 747888; IND 116565) supplied by the NCI
Update:
Status Change:
Eligibility changes
Activation
Therapy / Dose Modifications / Study Calendar changes
Closure
X Informed Consent changes
Suspension / temporary closure
Scientific / Statistical Considerations changes
Reactivation
Data Submission / Forms changes
X Editorial / Administrative changes
X Other: MLN8237 CAEPR Update
The changes included in this update to Alliance A091102 have been made in response to the NCI
Request for Amendment for MLN8237 from Dr. Richard Piekarz, dated January 6, 2014. Please note
an action letter will not follow and there is no new risk information.
IRB review of this update is required within 90 days. Expedited review is allowed. Please follow your
local IRB guidelines.
Patients currently enrolled on Alliance A091102 need not be re-consented.
PROTOCOL UPDATES:
References to the “Adverse Event Expedited Reporting System (AdEERS)” have been changed to
“CTEP Adverse Event Reporting System (CTEP-AERS)” throughout the protocol.
Cover Page:
• The “Activation Date” and “Includes Update” have been moved to the newly added “Document
History Table” under the “Protocol Resources table”.
1
• In keeping with the new CTEP policy the following sentence has been removed under the title “An
Alliance trial conducted by CALGB*, NCCTG, and ACOSOG”. In addition, the “* Lead Group” has
been removed from the bottom left corner.
• The clinicaltrials.gov identifier has been added.
• The telephone contact information for the Study Chair has changed from “212-639-5218” to “646-8884164”.
• The data manager has been moved from the protocol resources page.
• In the bottom left corner, the following has been added “Participating NCTN Groups: Alliance”.
Protocol Resources:
• Under the bolded title “Expedited Adverse Event Reporting,” the website has been updated to reflect
the change from AdEERS to CTEP-AERS.
•
Within the “Protocol-related questions may be directed as follows” table, in the last column, the
contact has been updated to “Alliance Regulatory: [email protected]”.
Section 4.2 (OPEN Registration Procedures):
The PMB number has been updated to “240-276-6575”, this change has been made throughout the
protocol.
Section 6.0 (Dosing Delays/Dose Modifications):
• The ANC and Platelet Count criterion has been revised to reflect the number “9” as a superscript and
the number “1” after the slash has been revised to the letter “l”. In addition the value “109/l” has been
placed within parenthesis.
• The following sentence has been added after the last sentence in this section: “Amylase, lipase,
phosphorus or magnesium and not required to be routinely checked.”
Section 7.1.1.1 (CAEPR for MLN8237):
An updated CAEPR for MLN8237 (Version 2.2, November 27, 2013) has replaced the previous version.
Section 7.2 (Expedited Adverse Event Reporting):
The second paragraph has been removed, as it is not applicable: “In the rare event when Internet
connectivity is disrupted, a 24 hour notification is to be made to the NCI by telephone at 301-879-7497.
An electronic report MUST be submitted upon re-establishment of Internet connection.”
Section 9.2 (Methods):
The first sentence of the paragraph has been revised to, “Patients treated at MSKCC may have two
optional biopsies: one pretreatment and the second 1-4 weeks after the start of treatment.”
Section 9.3.1 ([F-18]FLT Administration):
The first sentence has been revised to read, “An FLT-PET scan may be performed at baseline and 1-4
weeks after starting treatment for up to 20 patients treated with MLN8237 at MSKCC only in connection
with [F-18]FLT CIP IND #71,260.”
Appendix B (Pill Diary for Alliance A091102
The first sentence has been revised from, “Please remember to take your pills without food (except for
water and prescribed medications at least 1 hour before and 2 hours after eating)” to “Please remember to
2
take your pills without food (except for water and prescribed medications at least 1 hour before and 2
hours after)”.
MODEL CONSENT UPDATES
What side effects or risks can I except from being in the study?:
• The following has been placed above the Risk list for MLN8237:
“If you choose to take part in this study, there is a risk that:
• You may lose time at work or home and spend more time in the hospital or doctor’s
office than usual
• You may be asked sensitive or private questions which you normally do not discuss
The MLN 8237 used in this study may affect how different parts of your body work such as your
liver, kidneys, heart, and blood. The study doctor will be testing your blood and will let you know
if changes occur that may affect your health.
There is also a risk that you could have side effects from the study drug(s)/study approach.
Here are important points about side effects:
• The study doctors do not know who will or will not have side effects.
• Some side effects may go away soon, some may last a long time, or some may never go
away.
• Some side effects may interfere with your ability to have children.
• Some side effects may be serious and may even result in death.
Here are important points about how you and the study doctor can make side effects less of a
problem:
• Tell the study doctor if you notice or feel anything different so they can see if you are
having a side effect.
• The study doctor may be able to treat some side effects.
• The study doctor may adjust the study drugs to try to reduce side effects.
The tables below show the most common and the most serious side effects that researchers know
about. There might be other side effects that researchers do not yet know about. If important new
side effects are found, the study doctor will discuss these with you.”
Risks and side effects related to MLN8237 include those which are:
• The risk list for MLN8237 has been updated to reflect the NCI’s new condensed risk profile format.
The former “Likely” category has been replaced with “Common, Some May Be Serious,” the former
“Less Likely” category has been replaced with “Occasional, Some May Be Serious,” and the former
“Rare but Serious” has been replaced with “Rare, and Serious.”
• The following changes have been made within “Common, Some May Be Serious” to be consistent
with CTEP’s new condensed risk format for MLN8237:
• The new condensed term “Anemia which may require blood transfusion” replaces the
previous term “Lack of enough red blood cells (anemia)”.
• The new condensed term “Diarrhea, nausea, vomiting” replaces the following old terms
“Diarrhea, Nausea or the urge to vomit, Vomiting”.
• The new term “Sores in mouth which may cause difficulty swallowing” replaces the
following old term “Irritation or sores in the lining of the mouth”.
3
•
•
•
•
The new condensed term “Tiredness” replaces the following term “Fatigue or tiredness”.
The new condensed term “Bruising, bleeding” has been added to be consistent with the
CTEP condensed risk list.
• The term “Infection, especially when white blood cell count is low” has been revised and
moved from the “Occasional, some may be serious” category.
• The following terms have been removed to be consistent with the new CTEP condensed
risk list:
 Decreased number of a type of white blood cell (lymphocyte)
 Decreased number of a type of white blood cell (neutrophil/granulocyte)
 Decreased number of a type of blood cell that helps to clot blood (platelet)
 Decrease in the total number of white blood cells (leukocytes)
 Sleepiness, feeling drowsy, ready to fall asleep
The following changes have been made within “Occasional, Some May be Serious” to be consistent
with CTEP’s new condensed risk format for MLN8237:
• The new term “Pain” replaces the following terms “Belly pain, Mouth pain, Back Pain”
• The new term “Fever” replaces the following term “Fever associated with dangerously
low levels of a type of white blood cell (neutrophils), Fever”
• The new term “Swelling of arms, legs” replaces the following term “Swelling of the arms
and/or legs”
• The new term “Dehydration” replaces the following term “Dehydration (when your body
does not have as much water and fluid as it should)”
• The new term “Dizziness, headache” replaces the following terms “Dizziness (or
sensation of lightheadedness, unsteadiness, or giddiness, Headache or head pain”
• The new term “Cough, shortness of breath” replaces the following terms “Shortness of
breath, Cough”
• The following terms have been removed to be consistent with the new CTEP condensed
risk list:
 Increased blood level of a liver enzyme (ALT/SGPT)
 Increased blood level of a liver or bone enzyme (alkaline phosphatase)
 Increased blood level of a liver enzyme (AST/SGOT)
 Increased blood level of a liver pigment (bilirubin) often a sign of liver problems
 Increased blood level of creatinine (a substance normally eliminated by the
kidneys into the urine)
 Low blood pressure
The following changes have been made within “Rare, And Serious” to be consistent with CTEP’s
new condensed risk format for MLN8237:
• The new term “Blisters on skin” replaces the following term “Skin condition with fluidfilled blisters”
• The new term “Redness, pain or peeling of palms and soles” replaces the following term
“Swelling and redness of the skin on the palms of the hands and soles of the feet”
A replacement protocol and Model Consent documents has been issued
____________________________________________________________
ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL
____________________________________________________________
4
ALLIANCE A091102
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY
ALLIANCE A091102
PHASE II STUDY OF MLN8237 IN ADVANCED/METASTATIC SARCOMA
Clinicaltrials.gov Identifier: NCT01653028
Investigational Agent: MLN8237 (NSC # 747888; IND 116565) supplied by the NCI
Study Chair
Mark A. Dickson MD
Memorial Sloan-Kettering Cancer Center
1275 York Ave
New York, NY 10065
Tel: 646-888-4164 Fax: 646-888-3231
[email protected]
Experimental Therapeutics Committee Co-Chairs
Charles Erlichman MD
Tel: 507-266-3200 Fax: 507-538-6290
[email protected]
Gary Schwartz, MD
Tel: 212-639-8324 Fax: 212-717-3085
[email protected]
Community Oncologist
Roscoe F. Morton, M.D.,FACP
Tel: 515-282-2921 Fax: 515-282-1035
[email protected]
Primary Statistician
Michelle R. Mahoney, M.S
Tel: 507-266-4456 Fax: 507-266-2477
[email protected]
Protocol Coordinator
Guadalupe Aquino
Tel: 773-702-0956 Fax: 312-345-0117
[email protected]
Data Manager
Carla Hilton
Tel: 507-284-1370 Fax: 507-284-1902
[email protected]
Participating NCTN Groups: Alliance and French Sarcoma Cosortium
1
Version Date 02/20/2014
Update #04
ALLIANCE A091102
Alliance Central Protocol Operations Office
230 West Monroe Street, Suite 2050
Chicago, IL 60606
Tel: 773-702-9171 Fax: 312-345-0117
www.alliance-website.org
Alliance Statistical Data Center
Mayo Clinic
200 First St. SW
Rochester MN 55905
Expedited Adverse Event Reporting
https://eapps-ctep.nci.nih.gov/ctepaers/
Medidata Rave iMedidata portal
https://login.imedidata.com
OPEN (Oncology Patient Enrollment Network)
https://open.ctsu.org
Protocol Resources:
A091102 Nursing Contact
Ms. Mercedes Condy R.N. ANP
300 East 66th Street-10th Floor
New York City, NY 10065
Tel: 646-888-4158 Fax: 646-888-4250
[email protected]
Alliance Pathology Coordinating Office
The Ohio State University
Innovation Centre
2001 Polaris Parkway
Columbus, OH 43240
Tel: 614-293-7073 Fax: 614-293-7967
[email protected]
Protocol-related questions may be directed as follows:
Questions
Questions regarding patient eligibility, treatment,
and dose modification:
Questions related to data submission, RAVE or
patient follow-up:
Questions regarding the protocol document:
Questions related to IRB issues and model
consent revisions:
Questions regarding CTEP-AERS reporting:
Contact (via email)
Study Chair, Nursing Contact, Protocol
Coordinator, or Data Manager
Data Manager
Protocol Coordinator
Regulatory Affairs Manager:
[email protected]
Alliance Regulatory:
[email protected]
Document History
Activation Date
Update #01
Update #02
Version Date 02/20/2014
Effective Date:
08/22/2012
12/08/2012
12/08/2012
Update #03
Update #04
2
05/29/2013
03/07/2014
Update #04
ALLIANCE A091102
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION
To submit site registration For patient enrollments: Submit study data directly to the Lead
documents:
Cooperative Group unless otherwise
specified in the protocol:
CTSU Regulatory Office
Please refer to the patient All participating sites will submit study data
1818 Market Street, Suite
enrollment section for
via Medidata Rave System.
1100
instructions on using the
Philadelphia, PA 19103
OPEN system.
Do not submit study data or forms to CTSU
Phone – 1-866-651-CTSU
Data Operations. Do not copy the CTSU on
Fax – 215-569-0206
data submissions
The study protocol and all related forms and documents must be downloaded from the protocolspecific Web page of the CTSU Member Web site located at https://www.ctsu.org. Sites must use the
current form version and adhere to the instructions and submission schedule outlined in the protocol.
CTSU sites should follow procedures outlined in the protocol for Site registration, Patient Enrollment,
Adverse Event Reporting, Data Submission (including ancillary studies), and Drug Procurement.
For patient eligibility or treatment-related questions contact the Study PI of the Coordinating Group
For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU Help
Desk by phone or e-mail:
CTSU General Information Line – 1-888-823-5923, or [email protected]. All calls and
correspondence will be triaged to the appropriate CTSU representative.
For detailed information on the regulatory and monitoring procedures for CTSU sites please
review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ website
https://www.ctsu.org
The CTSU Web site is located at https://www.ctsu.org
French Sarcoma Consortium
French Sarcoma Consortium Site:
Institut Bergonié, Bordeaux
Centre Léon Bérard, Lyon
Institut Gustave Roussy, Villejuif,
Centre Oscar Lambret, Lille
Institut Curie, Paris
Hôpital La Timone, Marseille
Centre René Gauducheau, Saint
Herblain
Centre Georges François Leclerc, Dijon
Institut Claudius Régaud, Toulouse
Version Date 02/20/2014
3
Principal Investigator
Dr Antoine Italiano
Pr Jean Yves Blay
A Le Cesne
Dr F Watelle
Dr Piperno-Neuman
Dr Duffaud
Dr E Bompas
Dr N Isambert
Dr C Chevreau
Update #04
ALLIANCE A091102
PHASE II STUDY OF MLN8237 IN ADVANCED/METASTATIC SARCOMA
SCHEMA
MLN8237
50 mg PO BID
d1-7, q21d
Patient will be assigned to a cohort depending on the histologic
sub-type of sarcoma, as described in section 3.1.1.
Restage every 6 weeks***
CR, PR, SD: *
Continue until
Progression* or
toxicity
PD or Unacceptable
toxicity: **
Stop therapy
Off treatment
*
Patients who are in CR, PR or SD will continue on therapy until PD, or unacceptable adverse events
occur (see section 5.2.1.1).
** Upon PD, patients will begin the Survival and Disease Status Follow-Up phase of the study (see
section 5.2.1.1)
*** Scans are repeated every 6 weeks, regardless of dose delays, ±8 days, starting timing from the first
day of therapy. After 24 weeks (approximately 8 cycles), patients should be re-evaluated for response
every 12 weeks (approximately every 4 cycles, ±8 days).
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ALLIANCE A091102
TABLE OF CONTENT
1.0
OBJECTIVES ................................................................................................................... 7
1.1.
Primary Objectives ............................................................................................................. 7
1.2.
Secondary Objectives ......................................................................................................... 7
1.3
Correlative Objectives/ Translational Objectives ............................................................... 7
2.0
BACKGROUND ............................................................................................................... 7
2.1
Soft tissue sarcoma ............................................................................................................. 7
2.2
CTEP and CIP IND Agents ................................................................................................ 7
2.3
Rationale ........................................................................................................................... 16
3.0
PATIENT SELECTION ................................................................................................ 20
3.1
Eligibility Criteria ............................................................................................................. 20
3.2
Exclusion Criteria ............................................................................................................. 21
3.3
Inclusion of Women and Minorities ................................................................................. 22
4.0
REGISTRATION ........................................................................................................... 22
4.1
Registration Requirements ................................................................................................ 22
4.2
OPEN Registration Procedures ......................................................................................... 23
5.0
TREATMENT ................................................................................................................. 24
5.1
Agent Administration ....................................................................................................... 24
5.2
End of Treatment/Intervention.......................................................................................... 24
5.3
General Concomitant Medication and Supportive Care Guidelines ................................. 25
5.4
Definitions of Ineligible and canceled patients, and major protocol violations ................ 25
5.5
Extraordinary Medical Circumstances:............................................................................. 25
5.6
Criteria for Removal from Protocol Therapy.................................................................... 26
5.7
Clinical Benefit in the Setting of Apparent Radiological Progression ............................. 26
6.0
DOSING DELAYS/DOSE MODIFICATIONS ........................................................... 26
6.1
Dose adjustments: general principles................................................................................ 26
6.2
Dose Modifications for Hematologic Toxicity ................................................................. 27
6.3
Dose Modifications for Non-Hematologic Toxicity ........................................................ 27
6.4
Other non-hematologic Toxcity ........................................................................................ 27
7.0
Adverse Events: List and Reporting Requirements .................................................... 28
7.1
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs)............................. 28
7.2
Expedited Adverse Event Reporting................................................................................. 31
7.3 Additional Instructions or Exclusions to CTEP-AERS ........................................................... 34
8.0
PHARMACEUTICAL and IMAGING AGENT INFORMATION .......................... 34
8.1
CTEP and CIP IND Agent ................................................................................................ 34
8.2
FLT-PET ........................................................................................................................... 38
9.0
CORRELATIVE STUDIES FOR MSKCC PATIENTS ............................................ 44
9.1
Background ....................................................................................................................... 44
9.2 Methods ................................................................................................................................... 44
9.3
A091102-IM1 ................................................................................................................... 46
10.0
STUDY CALENDAR ..................................................................................................... 48
11.0
MEASUREMENT OF EFFECT ................................................................................... 49
11.1
Schedule of Evaluations.................................................................................................... 49
11.2
Definitions of Measurable................................................................................................. 49
11.3
Guidelines for Evaluation of Measurable Disease ............................................................ 49
11.4
Measurement of Effect...................................................................................................... 51
11.5
Formal Definitions of Variables ....................................................................................... 54
12.0
DATA REPORTING ...................................................................................................... 54
12.1
Data Reporting .................................................................................................................. 54
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ALLIANCE A091102
13.0
STATISTICAL CONSIDERATIONS .......................................................................... 54
13.1
Study Design/Endpoints ................................................................................................... 54
13.2
Sample Size/Accrual Rate................................................................................................. 55
13.3
Grouping Factors .............................................................................................................. 56
13.4
Analysis of Secondary Endpoints & Correlative End Points ............................................ 57
13.5
Reporting and Exclusions ................................................................................................. 57
14.0 REFERENCES .............................................................................................................................. 59
APPENDIX A ........................................................................................................................................ 63
APPENDIX B ........................................................................................................................................ 64
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ALLIANCE A091102
1.0 OBJECTIVES
1.1. Primary Objectives
The primary objective is to determine the response rate (CR + PR) assessed for patients within
each cohort:
•
•
•
•
•
Cohort 1: liposarcoma
Cohort 2: leiomyosarcoma (non-uterine)
Cohort 3: undifferentiated sarcoma (including pleiomorphic undifferentiated sarcoma,
formerly known as malignant fibrous histiocytoma, and myxofibrosarcoma)
Cohort 4: malignant peripheral nerve sheath tumor
Cohort 5: other sarcomas
1.2. Secondary Objectives
The Secondary objective is:
•
To estimate the PFS and OS for patients treated with MLN8237 in each cohort
•
To assess the adverse events associated with patients treated with MLN8237 in each
cohort
1.3 Correlative Objectives/ Translational Objectives
The correlative objectives are:
•
To correlate potential clinical benefit with markers of aurora kinase inhibition in pre- and
post-treatment tumor biopsies
•
To correlate clinical outcome with change in FLT-PET uptake at baseline versus after one
week of treatment (ie, Week 2 of Cycle 1)
2.0 BACKGROUND
2.1 Soft tissue sarcoma
Soft tissue sarcomas (STS) are heterogeneous malignant tumors of mesenchymal origin.
Approximately 13,000 cases of soft tissue and bone are diagnosed annually in the US. Surgery,
often with adjuvant radiation therapy for larger tumors, is the mainstay of treatment. Despite
primary combined modality therapy, between 30-80% of patients develop recurrent and/or
metastatic disease. The standard of care for metastatic disease for many years has been
doxorubicin or a doxorubicin combination. Response rates, however, are low [1]. Another
chemotherapy option for metastatic disease is gemcitabine with docetaxel, however activity is
limited [2]. Recent phase II studies of the targeted agents imatinib, sunitinib, and sorafenib
have also been disappointing. Thus, there is a dearth of active agents and an unmet medical
need.
2.2 CTEP and CIP IND Agents
2.2.1
MLN8237
Background
The aurora kinase family of serine/threonine kinases consists of three members,
designated aurora kinases A, B, and C [3]. Aurora kinases A and B are expressed
in many different cell types, whereas the expression of aurora kinase C is
Version Date 02/20/2014
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Update #04
ALLIANCE A091102
restricted to testicular tissue. Aurora kinase A is located at the centrosome and
required for centrosome maturation and division as well as the formation of the
mitotic spindle. In a number of different experimental systems, aurora kinase A
inhibition leads to mitotic delays and severe chromosome congression, and
segregation defects followed by cell death [4-7]. By the G2 phase of the cell
cycle through anaphase, it can be detected in the pericentriolar material, and
spreads to mitotic spindle poles and midzone microtubules during mitosis [8] . In
addition to its primary effects on the cell cycle, aurora kinase A appears to have a
role in oncogenic signaling, including the activity of myc [9].
Aurora kinase A overexpression results in centrosome amplification,
chromosome instability, and oncogenic transformation in mammalian cells [3].
Overexpression or amplification of the aurora kinase A gene has been identified
in several malignancies including breast [10, 11], colon [12], lung [13], and head
and neck cancers [14]. In some tumor types, aurora kinase A overexpression was
associated with poorly differentiated tumors [13] and a poor prognosis [10, 14].
In addition, overexpression was found in aggressive lymphomas [15], ovarian
cancer, specifically primary ovarian tumors and high-grade serous carcinoma
[16-18], head and neck squamous cell carcinoma [14, 19], gastrointestinal
adenocarcinomas [20], colorectal cancer [21], myelodyplastic syndromes and
acute myeloid leukemia (AML) [22], and Barrett’s carcinogenesis [23].
Several polymorphisms in the aurora kinase A gene have been identified.
Specifically, the polymorphic substitution of isoleucine for phenylalanine at
residue 31 (F31I) has been correlated with an increased risk of developing breast
cancer [24].
Preclinical Evaluations of MLN8237
MLN8237 is an adenosine triphosphate (ATP)-competitive and reversible
inhibitor of aurora kinase A with an inhibition constant (Ki) of 0.43 nM [25].
MLN8237 inhibited aurora kinase A activity in HCT-116 human colon cancer
cells with a half-maximal inhibitory concentration (IC50) of 6.7 nM and was
approximately 200-fold more selective for aurora kinase A than aurora kinase B
(IC50=1534 nM). In addition, MLN8237 was at least 250-fold more selective for
aurora kinase A when compared to other kinases tested in vitro.
In Vitro Activity
Antiproliferative effect of MLN8237 has been noted in cell lines derived from a
variety of malignancies (Table 1) including colon, lung, breast, prostate, ovary,
pancreas, and lymphoid [25].
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ALLIANCE A091102
Table 1. Growth Inhibition Induced by MLN8237 in Cultured Tumor Cells
Cell Line
HCT-116
SW480
DLD-1
H460
MD-MB-231
PC3
SKOV3
HPAC
LY-3
Origin
MLN8237 GI50 (nM)
Colon Tumor
34 ± 10 (8)a
Colon Tumor
431 ± 159 (8)
Colon Tumor
469 (1)
Lung Tumor
17 (1)
Breast Tumor
190 (1)
Prostate Tumor
54 (1)
Ovarian Tumor
111 (1)
Pancreatic Tumor
130 (1)
Lymphoma
43 (1)
GI50 = concentration required to achieve 50% cell growth inhibition.
a
Numbers represent average GI50 ± standard deviation derived from the
bromodeoxyuridine (BrdU) cell proliferation ELISA. Numbers in parentheses
represent the number of experiments completed.
MLN8237 was tested against the Pediatric Preclinical Testing Program (PPTP) in
vitro panel at concentrations ranging from 1.0 nM to 10 μM [26]. The cell lines
included AML, anaplastic large cell lymphoma (ALCL), acute lymphoblastic
leukemia (ALL) B-precursor and T-cell, non-Hodgkin’s lymphoma (NHL),
neuroblastoma (NB), and Ewing’s as well as rhabdoid and rhabdomyosarcoma.
MLN8237 had a median IC50 of 61 nM. Specifically, the ALL cell lines were
more sensitive and the rhabdomyosarcoma cell lines were less sensitive than the
remaining PPTP cell lines. In a further confirmation of these results, MLN8237
demonstrated significant activity in vivo against solid tumor models (6 of them
neuroblastoma) at the MTD of 20.8 mg/kg; however, only 2 of 6 neuroblastoma
models had objective responses at 0.25 of the MTD [27]. In three ALL models,
MLN8237 induced objective responses at its MTD and at 0.5 of the MTD, and in
two out of three models at 0.25 of the MTD. PK studies at the MTD
demonstrated a time to peak plasma concentration (Tmax) of 0.5 hours, maximum
plasma concentration (Cmax) of 42.5 μM, area under the curve from zero to 24
hours (AUC0–24 hr) of 78.4 μM·h, and 12-hour trough level of 1.8 μM. Mitotic
indices increased 6–12 hours after MLN8237 administration. In addition,
objective responses were more frequent in tumors with decreased AURKA copy
number (5/8) compared to those with increased gene copy number (2/14).
MLN8237 inhibited the in vitro growth and survival of human chronic myeloid
leukemia (CML) cell lines as well as primary CML cells from patients (Kelly et
al., 2010). Activity was noted in imatinib-sensitive and -resistant CML cells as
well as cells expressing unmutated and mutated BCR-ABL. MLN8237 induced
apoptosis in AML cell lines and leukemia cells from patients with either newly
diagnosed or relapsed AML [28]. Treatment with MLN8237 and cytarabine
resulted in greater apoptosis and tumor regression than treatment with either
agent alone. In addition, MLN8237 strongly inhibited the viability and
proliferation of both primary multiple myeloma (MM) cells and MM cell lines in
the presence of stroma cells, interleukin (IL)-6, and insulin growth factor-1 (IGF1) [29].
In Vivo Activity
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ALLIANCE A091102
In several experimental solid and hematologic human xenograft models in mice,
MLN8237 demonstrated tumor growth inhibition (TGI) >90% when
administered orally on a daily basis for approximately 21 days [30]. Less
frequent dosing (e.g., 5 days of treatment followed by 5 days of rest) was also
efficacious, demonstrating that continuous dosing may not be necessary for
antitumor activity [31].
MLN8237 was tested against the PPTP in vivo panels at a dose of 20 mg/kg
administered orally BID for 5 days (Maris et al., 2010). Solid tumor xenografts
were treated for 6 weeks and ALL xenografts for 3 weeks. MLN8237 induced
differences in event-free survival (EFS) distributions in 32/40 (80%) solid tumor
models and all (6/6) ALL models compared to controls. All six evaluable ALL
xenografts achieved complete responses (CR; n=4) or maintained CR status
(n=2); maintained CRs were observed in three of seven NB xenografts. There did
not appear to be a correlation between aurora kinase A copy number or
expression with kinase activity level in the xenografts suggesting that other
cofactors of aurora kinase A may have a role in the response to MLN8237.
Other xenograft models included MM [29] and diffuse large B-cell lymphoma
(DLBCL) [32, 33].
Combination studies were also conducted in xenograft models. In DLBCL
xenografts, MLN8237 administered 3 or 10 mg/kg QD for 21 days with
rituximab (10 mg/kg; every 7 days [Q7D]) demonstrated additive activity or
better, and resulted in complete regression of disease in some animals with the
mean survival endpoint significantly longer than either agent alone [33]. In
addition, MLN8237 in combination with docetaxel was studied in multiple
human tumor xenografts, including breast, non-small cell lung cancer (NSCLC),
and prostate models [30]. MLN8237 demonstrated either additive or synergistic
antitumor activity in all combination studies, and long-term benefit was
observed, as shown by increased tumor growth delay after terminating treatment.
Antitumor activity was also observed when MLN8237 treatment was
administered on an intermittent dosing schedule, including the 3 days on/4 days
off combined with weekly taxane schedule [34]. This latter MLN8237 schedule
of administration supports clinical evaluation of alternative schedules, including
regimens designed to administer MLN8237 in combinations with other agents. In
the clinic, protocol C14008 has been initiated in which MLN8237 is administered
on Days 1, 2, 3, 8, 9, 10, 15, 16, and 17, and combined with paclitaxel
administered weekly on Days 1, 8, and 15; the combination regimen is repeated
in 28-day cycles (NCT01091428).
Pharmacokinetics
Rats and dogs were administered MLN8237 for 6 cycles with each cycle
consisting of daily dosing for 21 consecutive days separated by a 7-day nondosing period [30]. For animals treated at 2 mg/kg, the Cmax and AUC0-24hr was
0.88 μM and 6.67 hr▪μM, respectively, for males, and 2.00 μM and 13.90 hr▪μM,
respectively, for females on day 160. The Cmax and AUC0-24hr for the dose of 0.75
mg/kg on Day 160 in dogs was 1.34 μM and 14.4 hr▪μM, respectively.
Toxicology
The dose limiting toxicities (DLTs) were evaluated in both rats and dogs after
repeat daily oral dosing for 2 cycles (each cycle consisted of 7 consecutive days
separated by a 14-day dose rest) [30]. The DLT in rats was reversible
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myelosuppression (which resulted in secondary infections). The DLT in dogs
was reversible gastrointestinal (GI) mucosal damage and myelosuppression.
Principal findings included GI signs (stomatitis/mucositis/oral pain, nausea,
vomiting, anorexia, abdominal pain, dyspepsia, diarrhea, and dehydration),
decreased reticulocyte counts, and panleukopenia.
Pharmacodynamics/Biomarkers
MLN8237 decreases phosphorylation of aurora kinase A at the T288 amino acid
residue and increases phosphorylation of histone H3 at Ser10 [29, 35]. In an
asynchronous population of cells, mitotic delay manifested as an increase in the
mitotic index (MI), which was used as a pharmacodynamic marker for MLN8237
in vivo [36]. The MI in HCT116 xenografts increased substantially in response to
treatment. Maximally elevated MI levels in HCT116 tumors were observed at
plasma concentrations ≥1 μM. The TGI was proportional to the average steadystate plasma concentration of MLN8237 and found to be saturated at higher
steady-state plasma concentrations. The TGI at 12 days of continuous exposure
was found to be proportional to the MI at 8 hours. Biomarker studies
demonstrated that maintaining a plasma exposure in the vicinity of 1 μM led to
maximal elevation of histone H3 phosphorylation and TGI [37] . Below 1 μM,
both the histone H3 phosphorylation and TGI were dose-dependent. Notably, oral
doses of MLN8237 that led to profound TGI maintained the critical 1 μM plasma
exposure for 8–12 hours a day.
Increased nuclear and cell body size, as well as staining for β-galactosidase (a
molecular marker of cell senescence), revealed that aurora kinase A inhibitors
(MLN8054 in this study) induced cellular senescence aside from apoptosis under
some circumstances [38].
FDG (deoxy-2-[18F]-fluoro-D-glucose)-PET (positron emission technology)
imaging demonstrated an acute change that appropriately predicted for the extent
of chronic tumor volume response in CWR22RV1 SC xenografts [39].
Furthermore, FLT (fluorothymidine)-PET imaging in HCT-116 SC xenografts
demonstrated an acute decrease preceding a significant change in tumor volume
(unpublished data, Millennium Pharmaceuticals, Inc.). Further preclinical work
to expand on the FLT-PET data is warranted and could support clinical
evaluation of FLT-PET as a biomarker for pharmacodynamics or patient
selection.
Clinical Development of MLN8237
As of January 2011, there are ten completed or ongoing clinical studies of
MLN8237 as listed in Table 2 below [30]. Another phase 1/2 study is planned to
evaluate the combination of MLN8237 with rituximab and vincristine.
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Study
Number
C14001
C14002
C14003
C14004
C14005
C14006
C14007
C14008
with
paclitaxel
C14009
with
docetaxel
C14010
Table 2. Clinical Studies Sponsored by Millennium Pharmaceuticals, Inc.
Phase
Patient Population
Dose and Schedule
(All Adults)
1
Advanced solid tumors (U.S.)
21-, 14-, and 7-day schedules
evaluated. Maximum tolerated dose (
MTD) was 50 mg BID for 7-days in a
21-day cycle.
1
Advanced malignancies (Spain)
21-, 14-, and 7-day schedules; MTD
was 50 mg BID for 7 days in a 21-day
cycle.
1
Relapsed or refractory advanced
14- and 7-day schedules; MTD was
hematologic malignancies.
45 mg QD x 14 days in a 28-day
cycle.
Amended to evaluate MTD using
Enteric Coated Tablet (ECT)
Using ECT, MTD was 50 mg BID for
formulation in 7-day schedule.
7 days in a 21-day cycle.
2
Aggressive non-Hodgkin’s lymphoma
50 mg BID for 7 days in a 21-day
cycle.
2
Acute myelogenous leukemia; high50 mg BID for 7 days in a 21-day
grade myelodysplastic syndrome
cycle.
2
Platinum-refractory or -resistant
Starting dose: 50 mg BID for 7 days
fallopian tube, epithelial ovarian, or
in a 21-day cycle.
primary peritoneal carcinoma
1/2
Phase 1: nonhematological
Enteric coated tablet.
malignancies.
Phase 1 doses studied: 10–60 mg
BID.
Phase 2: non-small cell lung (NSCLC),
small cell lung (SCLC), breast, head and MTD and the Phase 2 dose 50 mg
neck, or gastroesophageal malignancies. BID; for 7 days in a 21-day cycle.
1/2
Phase 1: ovarian or breast cancers.
Phase 1 doses started with 10 mg BID
Phase 2: relapsed ovarian cancer.
on Days 1-3, 8-11, and 15-17, and
Combination with weekly paclitaxel.
paclitaxel on Days 1, 8, and 15 in a
28-day cycle.
1/2
Phase 1: solid tumors including castrate- Phase 1 doses started with 10 mg BID
resistant prostate cancer.
for 7 days; docetaxel on Day 1 in a
21-day cycle.
Combination with Q3week docetaxel.
1
Advanced solid tumors
Pill and oral solution; bioavailability
and food effects.
Pharmacokinetics
Preliminary PK results were reported from two phase 1 studies in over 100 patients
with advanced solid tumors receiving the powder in capsule (PIC) formulation or the
newer ECT formulation [40, 41]. Using the PIC formulation, MLN8237 was
administered orally QD or BID for 7, 14, or 21 days with a 14-day rest between
cycles. MLN8237 was absorbed rapidly with a median Tmax of 2 hours. Mean
terminal half-life (t1/2) was ~23 hours. Steady-state exposures were achieved by 7
days and were dose-proportional over 5–200 mg/day. The overall mean peak/trough
ratios were 5.2 and 2.5 for QD and BID dosing, respectively (Investigator's Brochure,
2010). The overall mean accumulation ratios were 1.8 and 2.9 for QD and BID
dosing, respectively.
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Using the ECT formulation (protocol C14007), MLN8237 was absorbed well with an
overall median Tmax of 3 hours and dose-related increase in exposure over 10–50 mg
BID. Mean t1/2 was ~20 hours following multiple dosing.
Pharmacodynamics/Biomarkers
Pharmacodynamic evaluations were performed in patient skin and tumor biopsies
with PK evaluation of potential associations to the levels of MLN8237 exposures.
These analyses have demonstrated that pharmacodynamics effects are dose- and/or
exposure-dependent [40]. In phase 1 studies in patients with advanced solid tumors,
at steady-state exposures, skin mitotic and apoptotic indices and tumor MI increased,
while tumor mitotic cell chromosome alignment and spindle bipolarity decreased, all
consistent with inhibition of aurora kinase A. In evaluable patients with paired tumor
biopsies (n=8), exposure-related changes were observed by Day 7, including
decreases in chromosome alignment and spindle bipolarity.
In adults with advanced solid tumors, the recommended phase 2 dose (RP2D) was
equivalent with the PIC and ECT formulations, e.g., 50 mg BID ×7 days in 21-day
cycles. This dosing produced steady-state average plasma concentrations exceeding
the target 1 μM concentration, estimated preclinically to be associated with
pharmacodynamic effects.
Safety
In adult patients enrolled in phase 1-2 studies, the most frequent grade 3 or greater
toxicities related to MLN8237 included blood and lymphatic system disorders such
as neutropenia, leukopenia, and thrombocytopenia; gastrointestinal disorders
including mucositis and diarrhea; and skin disorders (alopecia). These latter toxicities
likely represent anti-proliferative effects in normal tissues which generally appear
after completion of the dosing period in the first treatment cycles, and they are
managed and monitored during the treatment-free period to allow recovery (except
for alopecia) prior to the start of a new treatment cycle.
Reflecting the benzodiazepine chemical structure of MLN8237, central nervous
system (CNS) effects (such as somnolence, dizziness, confusion, gait disturbance,
memory impairment) or other benzodiazepine-like effects were observed, and
sometimes reported during initial drug administration. MLN8237 is structurally
related to the benzodiazepines (e.g., diazepam, lorazepam, etc.) and has activity
against the GABA receptor. The frequency and/or severity of benzodiazepineassociated CNS toxicities may be reduced in adult patients enrolled to recent
protocols, which administered MLN8237 with divided doses (e.g., BID), a schedule
designed to reduce peak plasma levels while maintaining overall AUC. However,
some patients continued to report intermittent CNS events, including some serious
adverse events (SAEs) after administration of the BID schedule. Overall, CNS effects
were generally reversible and manageable by dose delay or reduction, and some
patients have been managed by reduced dosing of other sedative medications, or coadministration of CNS stimulants such as methylphenidate. If a patient experiences
sedation or any benzodiazepine-like effect after MLN8237 administration, it is
recommended that the patient should not drive, operate dangerous tools or
machinery, or engage in any other potentially hazardous activity that requires full
alertness and coordination. Differential diagnosis of observed CNS effects should
also be considered, such as co-morbidities associated with the patient’s oncologic
diagnosis, concomitant medications, infection, metabolic abnormalities, etc.
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The initial phase 1-2 studies employed a PIC formulation of MLN8237. Recent
studies have employed an ECT formulation, which will be administered in newer
studies. In the phase 1 part of C14007, MLN8237 ECT was administered BID for 7
days followed by a 14-day treatment-free period (21-day cycle) [41]. Doses were
escalated in a 3+3 design based on dose-limiting toxicities in cycle 1 until the
maximum tolerated dose (MTD). AEs were graded according to NCI-CTCAE v4.0.
Neutropenia was the most common grade ≥3 AE, and was generally reversible. Table
3 below lists treatment-emergent across all dose levels evaluated in the study,
including any grade reported in ≥20% or grade ≥3 in ≥10% of patients. At the
maximum administered dose of 60 mg BID, 3 patients experienced grade 4
neutropenia, and this dose level was determined to be above the MTD. The MTD was
determined to be 50 mg BID for 7 days in a 21-day cycle.
Table 3. Adverse Events Profile of MLN8237 Administered to Adult Patients with
Nonhematologic Malignancies
Adverse Event
No. (%) of Patients (N=17)
Any Grade
Grade ≥3
Fatigue
12 (42)
3 (13)
Alopecia
10 (43)
-Anorexia
10 (43)
-Diarrhea
10 (43)
3 (13)
Neutropenia
10 (43)
9 (39)
Leukopenia
8 (35)
6 (26)
Vomiting
8 (35)
4 (17)
Nausea
7 (39)
5 (22)
Stomatitis
7 (30)
-Abdominal pain
6 (26)
3 (13)
Hypersomnia (Somnolence)
5 (22)
Thrombocytopenia
5 (22)
-Febrile neutropenia
3 (13)
3 (13)
White blood cell decreased
3 (13)
3 (13)
Anemia
2 (12)
3 (13)
The appearance of toxicities on days 8–15, some of which were dose limiting at
higher dose levels, favored a 7-day administration schedule followed by a 2-week
treatment-free period to allow recovery with safety monitoring prior to start of a new
cycle. In addition, an alternative multi-day schedule is supported by results in
preclinical xenograft models [34], in which MLN8237 is administered BID for 3
consecutive days in 3 out of 4 weeeks, e.g., 3 days on/4 days off, given alone or in
combination with another agent given weekly, e.g., Days 1, 8, and 15 in a 28-day
cycle to allow overlapping exposures. After administration of multi-day schedules,
the dominant toxicities observed to date included reversible hematologic and GI
events (mucositis, diarrhea), likely reflecting the anti-proliferative mechanism of
action.
Safety data from the C14001 study were reported at the American Society of Clinical
Oncology (ASCO) 2010 meeting [42]. In that study, sixty-five patients with solid
tumors received the PIC formulation of 5–150 mg MLN8237, orally QD for 7 days or
25–70 mg QD for 14 or 21 days. DLTs included grades 3–4 neutropenia with fever
(n=4), thrombocytopenia (n=3), somnolence (n=2), and mucositis (n=1), and were
seen at doses ≥40 mg BID x 14 days, ≥110 mg/day x 7 days, and 50 mg BID x 7
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days. The reversibility of alopecia has not been established; however, other prevalent
toxicities (myelotoxicities and GI disorders) are largely manageable by dose
reduction, interruption of the planned dosing schedule, or supportive care. The AE
profile is listed in Table 4 below [42]. At 75 mg BID for 7 days in a 21-day cycle,
one patient experienced neutropenia lasting more than 7 days, and another patient
experienced stomatitis/oral mucositis with neutropenia requiring dose reduction in
cycle 2 [30]. Grade 4 thrombocytopenia, grade 4 neutropenic fever, and grade 3
somnolence were observed in patients treated with 60 mg BID.
Table 4. Adverse Events Profile of MLN8237 Administered to Patients with Solid
Tumors
Most Frequent
No. (%) of Patients (N=65)
Drug-Related AEs
Any Grade
Grade ≥3
Nausea
33 (51)
1 (2)
Fatigue
28 (43)
3 (5)
Diarrhea
24 (40)
6 (9)
Somnolence
25 (38)
2 (3)
Alopecia
24 (37)
-Neutropenia
24 (37)
16 (25)
Anemia
21 (32)
5 (8)
Vomiting
20 (31)
1 (2)
Anorexia
19 (29)
-Stomatitis
14 (22)
1 (2)
Thrombocytopenia
10 (15)
5 (8)
Febrile neutropenia
6 (9)
6 (9)
8 patients (12%) discontinued due to AEs across all dose levels.
Other common AEs (grades 1-4) include: (1) reversible myelosuppression including
leukopenia, lymphopenia, and neutropenia; (2) GI toxicity including abdominal pain,
dehydration, and dyspepsia; (3) confusion and disorientation, sedation, and
associated memory loss and gait disturbances; (4) fever; (5) infection; (6) alopecia;
(7) asthenia/fatigue; (8) fever, (9) infection, (10) abnormal liver function tests
(including alanine transaminase [ALT], aspartate aminotransferase [AST], bilirubin,
alkaline phosphatase, and gamma-glutamyl transpeptidase [GGT]); (11) rash, which
may include bullous dermatitis or palmar-plantar erythrodysaesethesia syndrome
(hand and foot syndrome); and (12) dehydration [30]. However, because of limited
human experience with MLN8237, it is possible that other toxicities that have not
been observed/predicted in rats and dogs, and from ongoing studies in humans, will
occur. SAEs included effects related to MLN8237 and those attributable to disease
progression in the advanced malignancy patient population.
In a phase 2 trial, patients with advanced AML or intermediate-2/high-risk
myelodysplastic syndrome (MDS) received 50 mg of MLN8237 for 7 days followed
by a 14-day rest in 21-day cycles (Goldberg et al., 2010). Treatment-related grade 3/4
AEs were seen in 24 (42%) patients and included febrile neutropenia (11%), anemia
(9%), thrombocytopenia (9%), neutropenia (7%), and fatigue (7%). Treatmentemergent somnolence was identified in 14 (25%) patients; grade 3/4 somnolence was
reported in 2 (4%) patients.
Efficacy
Partial (PR) or CRs have been observed in multiple hematologic malignancies and
solid tumors. In a phase 1 study of patients with solid tumors, durable response was
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seen in a patient with platinum-refractory ovarian cancer who continued to tolerate
the treatment over 2 years (>30 cycles) [42]. Eight patients continued ≥6 cycles with
stable disease (3 head and neck, 2 lung, and 3 others). With single agent MLN8237
treatment, objective responses were also observed in a phase 2 study that enrolled
patients with relapsed ovarian, fallopian tube, or primary peritoneal carcinoma [43].
Objective antitumor activity has been observed in patients with relapsed lymphoma
and myeloma. In a phase 2 study that enrolled 48 patients with mixed types of
aggressive B- or T- cell lymphomas, responses (PR and CR) were reported in patients
with multiple lymphoma histologies (peripheral T-cell lymphoma [PTCL], DLBCL,
mantle cell, transformed follicular, and Burkitt’s lymphoma) and some responses
have been durable over 1 year with continued treatment cycles [44].
Six (13%) responses were observed (all AML patients) in 45 evaluable patients who
received 50 mg of MLN8237 for 7 days followed by a 14-day rest in 21-day cycles
[45]. One CR was documented in a 79-year-old female with AML and no prior
therapy, while 5 patients had a PR. Seventeen (49%) AML and 2 MDS (20%)
patients achieved stable disease.
Pediatric Studies
In children with refractory solid tumors, MLN8237 was administered orally as the
PIC formulation QD or BID for 7 days, every 21 days [46]. Using the rolling-six
design, four dose levels (45, 60, 80, and 100 mg/m2/day) were evaluated on the QD
regimen and two dose levels (60 and 80 mg/m2/day) on the BID regimen. On the QD
regimen, 1/6 patients developed DLT (grade 3 mucositis) at 45 mg/m2 and 1/6
developed DLT (grade 4 mood alteration) at 80 mg/m2. At 100 mg/m2, 3/4 patients
developed DLT (neutropenia/thrombocytopenia), thus exceeding the MTD. On the
BID regimen, 2/6 patients developed dose-limiting myelosuppression at 80 mg/m2;
one of these patients also experienced grade 3 mucositis. One out of five patients
experienced DLT (grade 3 alkaline phosphatase) at 60 mg/m2. Of note, 5/11 patients
experienced hand-foot-skin syndrome (grades 1–3) versus 1/21 (grade 2) on the QD
schedule. Although the BID regimen appeared to be well tolerated in adults, children
experienced more myelosuppression and hand-foot-skin syndrome with BID versus
QD dosing. Therefore, the recommended pediatric phase 2 dose and schedule of
MLN8237 is 80 mg/m2/day administered QD for 7 days, followed by a 2-week
treatment-free period.
2.3 Rationale
Several lines of evidence suggest that an inhibitor of Aurora Kinase A (AURKA) represents a
promising new treatment for soft tissue sarcoma. Our group has studied AURKA expression
and inhibition in multiple STS subtypes. We have shown that AURKA is commonly
overexpressed in STS, and that inhibition of AURKA by shRNA or by a specific AURKA
inhibitor inhibits proliferation of STS cells. These observations provide a strong rationale for a
clinical trial of an AURKA inhibitor in multiple STS subtypes.
Beginning with liposarcoma, we applied a microarray-based gene-expression profiling
approach to identify molecular signatures that distinguish liposarcoma subtypes (welldifferentiated/de-differentiated; myxoid/round cell; and pleomorphic). Differentially expressed
genes for each liposarcoma subtype compared to normal fat were used to identify histologyspecific signaling pathways and candidate genes important to liposarcoma pathogenesis and
progression. We postulated that these differentially expressed genes may serve as potential
therapeutic targets. Among the most strongly overexpressed genes in liposarcoma is AURKA,
which is both overexpressed and amplified. Specifically, we have found a 3-fold increase in
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AURKA in dedifferentiated liposarcoma (p<0.0002) and 10-fold increase in pleomorphic
liposarcoma (p<0.00005), when each is compared to normal fat. In vitro, shRNA knockdown
of AURKA inhibits proliferation of dedifferentiated liposarcoma cell lines.
Preclinical development of AURKA inhibitors for treatment of liposarcoma: We next
sought to determine whether liposarcoma cell lines could be growth inhibited with a specific
AURKA inhibitor. Using a small molecule AURKA inhibitor (AURKAi), we first confirmed
target specificity in an in vitro kinase assay using purified AURKA and biotinylated Polo like
kinase 1 (PLK1) peptide, known substrates of AURKA. As shown in figure 1 (i)
phosphorylation of PLK1 peptide (Ser137) was inhibited when the kinase assay was done in
the presence AURKAi (500 nM). T-288, an auto-phosphorylation site of AURKA, was also
inhibited (Figure 1 (ii)) upon incubation with AURKAi. As a negative control, the experiment
was repeated using Aurora B kinase and histone H3 as substrate. No inhibition of
phosphorylation of AURKB or histone H3 was observed upon incubation with AURKAi
(Figure 1 (iii)), indicating the specificity of AURKAi for AURKA and not AURKB.
Figure 1. AURKAi inhibits the phosphoryl-ation of AURKA substrate
PLK1 (i) and AURKA auto-phosphorylation (ii) but not the Aurora B
substrate H3 (iii).
Figure 2. Growth inhibition of three liposarcoma cell lines treated for 6
days with 5 and 10 µM of AURKAi. Growth inhibition was determined
with the CCK-8 cell counting kit and is represented as proliferation as a
percentage of untreated controls.
With AURKA specificity established, we next treated a panel of liposarcoma cell lines with
either 5 or 10 µM of AURKAi. As shown in Figure 2, all the cell lines were inhibited by the
drug. Interestingly, this was also observed in LS141 cells, which we have reported shows
increased AURKA protein expression relative to normal fat, but in which the gene is not
amplified [47]. We reported similar results with shRNA such that all the cell lines could be
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inhibited by shRNA, including LS141. Thus, amplification of AURKA is not an absolute
requirement for growth inhibition by an AURKA inhibitor.
Figure 3. Growth inhibition of two malignant peripheral nerve
sheath tumor (MPNST) cell lines treated for 6 days with 5 and 10
µM of AURKAi.
We next extended this observation to other subtypes of sarcoma. We treated two malignant
peripheral nerve sheath tumor (MPNST) cell lines (MPNST and ST88) with AURKAi. As
shown in figure 3, these cells are also exquisitely sensitive to AURKA inhibition, suggesting
that sensitivity to AURKA inhibitors may be a property of several subtypes of STS. Indeed,
we have tested other sarcoma cell lines, including Ewing sarcoma, synovial sarcoma, and
rhabdomyosarcoma, and have observed similar results (data not shown). Collectively, this data
supports the clinical testing of AURKA inhibitors in multiple STS subtypes.
We have also begun to examine the effect of AURKAi on the cell cycle. Figure 4 shows the
flow cytometry results of liposarcoma cells treated with 5 µM of AURKAi. Drug treatment
induces a G2/M peak with a time dependent increase in the mitotic population (figure 4).
Western blot confirms AURKA protein expression in the cell lines. Interestingly, AURKA
expression increases with drug therapy, as a result of cells accumulating in the M phase of the
cell cycle.
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Figure 4. Flow cytometry of DDLS and LS141 cells treated
with 5 µM of AURKAi for 24 hours indicates the induction of
a G2/M peak with an increase in the mitotic population as
reflected by an increase in MPM-2 labeling (upper right
boxes). Western blot shows AURKA expression increases with
drug therapy as cells accumulate in M phase.
Our colleagues in France have also studied the role of AURKA in STS. Through gene
expression profiling, they identified AURKA as a key component of the CINSARC
(complexity index in sarcomas) signature, a group of genes related to mitosis and chromosome
management [48]. This data supports the oncogenic role of AURKA in STS, particularly those
subtypes with complex genetic changes such as leiomyosarcoma and undifferentiated sarcoma
(also called malignant fibrous histiocytoma or MFH).
Thus, multiple lines of preclinical evidence support the selective targeting of AURKA in STS
subtypes. MLN8237 is a novel, oral, ATP-competitive, selective small-molecule inhibitor of
AURKA currently in clinical development. It was designed as a second generation AURKA
inhibitor so as to reduce the benzodiazepine-like central nervous system effects observed with
the parent compound MLN8054. MLN8054 has broad anti-tumor activity both in tumor cell
lines and in xenografts.(Manfredi et al., 2008) In preclinical studies MLN8237 is more potent
than MLN8054.
Clinical development of AURKA inhibitors: A phase I trial examining the safety and
efficacy of MLN8237 has been completed [40, 42].Grade 3 and 4 neutropenia with stomatitis
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was dose-limiting and the recommended phase II dose was 50 mg BID. Pre and post treatment
skin biopsies showed an increase in the number of mitotic cells, by measuring MPM2 and
phospho-ser10 Histone H3 as mitotic markers, at doses ≥ 50 mg BID, suggesting effective
target inhibition. A partial response was observed in a patient with pleomorphic liposarcoma
who had failed prior chemotherapy. This patient remained on study for over one year without
evidence of disease progression. This clinical result is especially remarkable considering the
natural history of the disease. Historical data show that the prognosis for advanced sarcoma
patients who have failed at least one prior therapy is poor, with 90% experiencing disease
progression within 6 months (i.e., the 6-month progression-free survival is 10%) [49]. Thus,
we consider the prolonged progression-free survival in this patient a meaningful result.
3.0 PATIENT SELECTION
3.1 Eligibility Criteria
3.1.1 Patients must have histologically or cytologically confirmed sarcoma that is
metastatic and/or locally advanced or locally recurrent and unresectable.
Confirmation of pathologic diagnosis will be performed at the registering site.
Patients will be enrolled on one of five cohorts of the study:
•
Cohort 1: liposarcoma
•
Cohort 2: leiomyosarcoma (non-uterine)
•
Cohort 3: undifferentiated sarcoma (including malignant fibrous histiocytoma
and myxofibrosarcoma)
•
Cohort 4: malignant peripheral nerve sheath tumor
•
Cohort 5: other sarcomas
3.1.2 Patients must have measurable disease per RECIST 1.1 Note: defined as at least
one lesion that can be accurately measured in at least one dimension (longest
diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥
2 cm with conventional techniques or as ≥ 1 cm with spiral CT scan, MRI, or
calipers by clinical exam. See Section 11 for the evaluation of measurable disease.
3.1.3 Any number of prior therapies is permitted. Note: The last dose of systemic therapy
(including tyrosine kinase inhibitors) must have been given ≥ 4 weeks prior to
initiation of therapy. Patients receiving BCNU or mitomycin C must have received
their last dose of such therapy at least 6 weeks prior to initiation of therapy.
3.1.4
Age ≥ 18 years.
3.1.5
ECOG PS ≤ 2 (Please refer to appendix A)
3.1.6
Patients must have normal organ and marrow function as defined below:
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-leukocytes
≥3,000/mcL
-absolute neutrophil count
≥1,500/mcL
-platelet count
≥100,000/mcL
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≤1.5X institutional upper limit of normal
-total bilirubin
-SGOT(AST) and SGPT(ALT) <3X institutional upper limit of normal if no
liver metastases or <5X institutional upper limit of normal if liver metastases
present
≤ 1.5 X ULN
-creatinine
OR
-creatinine clearance
≥60 mL/min/1.73 m2 for patients with creatinine levels
above institutional normal.
3.1.7
Women of childbearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to
study entry and for the duration of study participation. Note: The effects of
MLN8237 on the developing human fetus are teratogenic. Should a woman
become pregnant or suspect she is pregnant while she or her partner is
participating in this study, she should inform her treating physician immediately.
Men treated or enrolled on this protocol must also agree to use adequate
contraception prior to the study, for the duration of study participation, and 4
months after completion of MLN8237 administration.
3.1.8
Ability to understand and the willingness to sign a written informed consent
document.
3.1.9
According to current guidelines, patients must be able to take oral medication
and to maintain a fast as required for approximately one hour before and two
hours after MLN8237 administration.
3.2 Exclusion Criteria
3.2.1
Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks
for nitrosoureas or mitomycin C) prior to entering the study or those who have
not recovered from adverse events due to agents administered more than 4 weeks
earlier. Patients who have had radiation therapy to more than 25% of the bone
marrow. Whole pelvic radiation is considered to be over 25%.
3.2.2
Patients who are receiving any other investigational agents.
3.2.3
Patients with known brain metastases. Note: These patients should be excluded
from this clinical trial because of their poor prognosis and because they often
develop progressive neurologic dysfunction that would confound the evaluation
of neurologic and other adverse events.
3.2.4
History of allergic reactions attributed to compounds of similar chemical or
biologic composition to MLN8237, including but not limited to established
allergic reaction to benzodiazepines.
3.2.5
Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, NYHA Class II-IV heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance
with study requirements.
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3.2.6
Pregnant women. Note: Women of child bearing potential must have a negative
serum or urine pregnancy test within 7 days prior to registration. This is because
MLN8237 is an aurora kinase A inhibitor with the potential for teratogenic or
abortifacient effects.
• Because there is an unknown but potential risk for adverse events in nursing
infants secondary to treatment of the mother with MLN8237, breastfeeding
should be discontinued if the mother is treated with MLN8237. These potential
risks may also apply to other agents used in this study.
3.2.7
Leiomyosarcoma of the uterus
3.2.8
Patients known to be HIV-positive on antiretroviral therapy. Note: These patients
are ineligible because of the potential for pharmacokinetic interactions with
MLN8237. In addition, these patients are at increased risk of lethal infections
when treated with marrow-suppressive therapy. Appropriate studies will be
undertaken in patients receiving antiretroviral therapy when indicated.
3.2.9
Prior allogeneic bone marrow or organ transplantation.
3.2.10
Known history of uncontrolled sleep apnea syndrome and other conditions that
could result in excessive daytime sleepiness, such as severe chronic obstructive
pulmonary disease; requirement for supplemental oxygen; or any conditions that
could result in excessive toxicity associated with the benzodiazepine-like effects
of MLN8237.
3.2.11
Requirement for constant administration of proton pump inhibitor, H2 antagonist,
or pancreatic enzymes. Note: Intermittent uses of antacids or H2 antagonists are
allowed as described in Section 8.1.1.
3.2.12
Inability to swallow oral medication or to maintain a required fast for
approximately one hour before and two hours after MLN8237 administration or
any condition that would modify small bowel absorption of oral medications,
including malabsorption, or resection of pancreas or upper bowel.
3.2.13
Treatment with clinically significant enzyme inducers, such as the enzymeinducing antiepileptic drugs phenytoin, carbamazepine, oxcarbazepine,
primidone or phenobarbital, or rifampin, rifabutin, rifapentine, or St. John's wort
within 14 days prior to the first dose of MLN8237 and during the study.
3.3 Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial.
4.0 REGISTRATION
4.1 Registration Requirements
Informed Consent: the patient must be aware of the neoplastic nature of his/her disease and
willingly consent after being informed of the procedure to be followed, the experimental
nature of the therapy, alternatives, potential benefits, side- effects, risks, and discomforts.
Human subjects protection committee approval of this protocol and a consent form are
required.
Registration must occur prior to the initiation of therapy.
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Registration to the optional correlative studies will be performed at the time registration occurs
to the treatment study. Registration to both the treatment study and the companion study will
not be completed if eligibility requirements are not met for both trials.
4.2 OPEN Registration Procedures
This study is supported by the NCI Cancer Trials Support Unit (CTSU).
Prior to the recruitment of a patient for this study, investigators must be registered members of
a Cooperative Group. Each investigator must have an NCI investigator number and must
maintain an “active” investigator registration status through the annual submission of a
complete investigator registration packet (FDA Form 1572 with original signature, current CV,
Supplemental Investigator Data Form with signature, and Financial Disclosure Form with
original signature) to the Pharmaceutical Management Branch, CTEP, DCTD, NCI. These
forms are available on the CTSU Web site (enter credentials at https://www.ctsu.org; then
click on the Register tab) or by calling the PMB at 240-276-6575 Monday through Friday
between 8:30 a.m. and 4:30 p.m. Eastern time.
Each investigator or group of investigators at a clinical site must obtain IRB approval for this
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory
Office before they can enroll patients. Study centers can check the status of their registration
packets by querying the Regulatory Support System (RSS) site registration status page of the
CTSU member web site by entering credentials at https://www.ctsu.org.
Requirements for Alliance 091102 site registration:
•
CTSU IRB Certification
•
CTSU IRB/Regulatory Approval Transmittal Sheet
Please note: Patient enrollment will be facilitated using the CTSU Slot Reservation System
in conjunction with the Oncology Patient Enrollment Network (OPEN). Prior to discussing
protocol entry with prospective patients, site staff must use the CTSU OPEN Slot
Reservation System to ensure that a slot for the study is available to the patient. Once a slot
reservation confirmation is obtained, site staff may then proceed to enroll patients to this
study. Please note that a slot reservation will only be held for up to seven calendar days.
Patient registration can occur only after pre-treatment evaluation is complete, eligibility
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS. Patients
must have signed and dated all applicable consents and authorization forms.
All site staff (Lead Group and CTSU Sites) will use OPEN to enroll patients to this study.
OPEN can be accessed at https://open.ctsu.org or from the OPEN tab on the CTSU members’
side of the website at https://www.ctsu.org.
Prior to accessing OPEN site staff should verify the following:
All eligibility criteria has been met within the protocol stated timeframes. Site staff should use
the registration forms provided on the group or CTSU web site as a tool to verify eligibility.
All patients have signed an appropriate consent form and HIPAA authorization form (if
applicable).
Access requirements for OPEN:
Site staff will need to be registered with CTEP and have a valid and active CTEP-IAM
account. This is the same account (user id and password) used for the CTSU members' web
site.
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To perform registrations, the site user must have been assigned the 'Registrar' role on the
relevant Group or CTSU roster.
To perform registrations on protocols for which you are a member of the Lead Group, you
must have an equivalent 'Registrar' role on the Lead Group roster. Role assignments are
handled through the Groups in which you are a member
To perform registrations to trials accessed via the CTSU mechanism (i.e., non-Lead Group
registrations) you must have the role of Registrar on the CTSU roster. Site and/or Data
Administrators can manage CTSU roster roles via the new Site Roles maintenance feature
under RSS on the CTSU members' web site. This will allow them to assign staff the
"Registrar" role.
Note: The OPEN system will provide the site with a printable confirmation of registration and
treatment information. Please print this confirmation for your records.
Further instructional information is provided on the OPEN tab of the CTSU members’ side of
the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any additional
questions contact the CTSU Help Desk at 1-888-823-5923 or [email protected].
Please note : PMB will not provide MLN8237 to the international sites.
5.0 TREATMENT
5.1 Agent Administration
5.1.1
MLN8237
MLN8237 50 mg orally twice daily on day 1-7, every 21 days until the patient
meets any of the criteria in Section 5.2, 5.4 or 5.5.
Treatment will be administered on an outpatient basis. No investigational or
commercial agents or therapies other than those described below may be
administered with the intent to treat the patient's malignancy.
The study drug MLN8237 will be administered on an empty stomach with the
patient remaining NPO (nothing by mouth), except for water and prescribed
medications, for approximately one hour before and two hours after each dose.
Patients will be instructed to take each oral dose of MLN8237 with 8 ounces (1
cup, 240 mL) of water.
The patient will be requested to maintain a medication diary of each dose of
medication. The medication diary will be returned to clinic staff at the end of
each course. See Appendix B for an example of the medication diary.
5.2 End of Treatment/Intervention
5.2.1
5.2.1.1
Duration of Treatment
Clinical Follow-Up Phase:
Patients who are in CR, PR or SD will continue on therapy until PD, or unacceptable
adverse events occur. There is no limit to the number of cycles of therapy patient
may receive on study, assuming availability of agents and no change in the status
regarding commercialization of MLN8237 with respect to sarcoma. Upon PD,
patients will begin the Survival and Disease Status Follow-Up phase of the study.
Patients discontinuing for reasons other than PD will return in 4 weeks (+/- 7 days)
for an assessment of adverse events associated with the last cycle of treatment.
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Thereafter, they will begin the Survival and Disease Status Follow-Up phase of the
study. Subsequent off-study treatment is at the discretion of their attending physician.
5.2.1.2
Survival and Disease Status Follow-Up Phase:
During the Survival and Disease Status Follow-Up Phase, patients are monitored for
off-treatment PD, long-term adverse events, new primaries, and survival. Here,
patients should be followed per standard of care. Submit the appropriate form(s) per
forms packet, every 6 months until a period of 18 months following registration.
5.3 General Concomitant Medication and Supportive Care Guidelines
See Section 6.1 for guidelines in managing drug toxicity.
5.4 Definitions of Ineligible and canceled patients, and major protocol violations
5.4.1
A patient is deemed ineligible if after registration, it is determined that at the time
of registration, the patient did not satisfy each and every eligibility criteria for
study entry. The patient may continue treatment off-protocol at the discretion of
the physician as long as there are no safety concerns, and the patient was
properly registered. The patient will go directly to the Survival and Disease
Status Follow-Up phase of the study (or off study, if applicable).
• If the patient received treatment, all data up until the point of confirmation of
ineligibility must be submitted.
•
If the patient never received treatment, on-study material must be submitted.
5.4.2
A patient’s registration is deemed a major violation if protocol requirements
regarding treatment in cycle 1 of the initial therapy are severely violated that
evaluability for primary end point is questionable. The patient may continue
therapy at the discretion of the treating physician as long as there are no safety
concerns and the patient was properly registered. If the patient continues on
treatment, all scans, tests, and data submission will continue per protocol. If the
patient does not continue therapy, all data until the patient stops therapy will be
submitted, and the patient will go to the Survival and Disease Status Follow-Up
phase of the study, or off-study if applicable.
5.4.3
A patient’s registration is deemed a cancel if s/he is removed from the study for
any reason before any study treatment is given. On-study material and the End of
Active Treatment/Cancel Notification Form must be submitted. No further data
submission is necessary.
5.5 Extraordinary Medical Circumstances:
If, at any time the constraints of this protocol are detrimental to the patient's health and/or the
patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued.
In this event:
•
Notify the Study Chair.
•
Document the reason(s) for discontinuation of therapy on Case Report Forms.
•
Follow the patient for survival or secondary malignancy for a minimum of 18 months
following registration.
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5.6 Criteria for Removal from Protocol Therapy
Patients will be removed from protocol therapy when any of the criteria listed in Section 5.2,
5.3, or 5.4 apply. The reason for removal from protocol therapy and the date the patient was
removed must be documented in the Case Report Form.
5.7 Clinical Benefit in the Setting of Apparent Radiological Progression
In exceptional cases there may be evidence of clinical benefit in the setting of progression by
imaging studies. For example, with the use of imatinib in metastatic GIST, apparent
progression was noted in liver metastases after exposure to imatinib. In retrospect, this
radiological finding represented necrosis of occult lesions in the liver, not overt progression of
disease.
If a patient has evidence of clinical benefit in the setting of progression on imaging studies, the
participating site investigator may petition to continue the patient on study. The patient will
continue therapy pending a review of the imaging by the PI and discussion with CTEP as to
whether to continue or not. The patient will come off study therapy if it is decided that the
changes represent tumor progression instead of response, using a date of the measurement of
the tumor as the date of progression. A patient allowed to continue on study therapy will
maintain the follow up as defined in the study, and the Study Chair will remain involved in the
decision making for continuation of the patient on study, incorporating the advice of CTEP
staff.
6.0 DOSING DELAYS/DOSE MODIFICATIONS
Therapy may be administered provided that the patient meets the following criteria at the beginning
of each cycle:
ANC > 1 x (109/l)
Platelet Count > 50 x (109/l)
Non-hematologic toxicity recovered to ≤ grade 1 (or tolerable grade 2); the following laboratory
evaluations are excluded, which must recover to within one grade toxicity of their baseline:
elevated lipase and/or amylase without pancreatitis, and lymphopenia. Patients who experience
grade ≥ 3 hypophosphatemia or hypomagnesemia must recover to ≤ grade 2 before resuming
treatment.
No evidence of progressive disease
Amylase, lipase, phosphorus or magnesium and not required to be routinely checked.
6.1 Dose adjustments: general principles
•
•
•
•
Grading of AEs for dose modification is based on NCI-CTCAE (Version 4.0), unless
otherwise indicated
The maximum delay of starting a cycle of treatment for any reason is 2 weeks. If treatment
is withheld for more than 2 continuous weeks due to a treatment-related toxicity that does
not resolve, the patient will be withdrawn from the protocol treatment.
AEs that can be managed with supportive care (anti-emetics, anti-diarrheals, GCSF, etc.)
may not require dose reduction.
The maximum number of dose reductions is 2.
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Dose Level
-2
-1
0
MLN8237 Dose
30 mg PO BID d1-7, q21d
40 mg PO BID d1-7, q21d
50 mg PO BID d1-7, q21d
6.2 Dose Modifications for Hematologic Toxicity
•
For grade 3 or 4 neutrophil count decresed on day 1 of a cycle, delay MLN8237 until ANC
improves to ≤ grade 2, then resume treatment with one dose level reducation for all
subsequent cycles.
•
For febrile neutropenia, grade 4 neutropenia lasting longer than 7 days, or infection, at any
time during a cycle, decrease MLN8237 by one dose level for all subsequent cycles.
•
For grade 3 or 4 platelet count on day 1 of a cycle, delay MLN8237 until platelets improve
to ≤ grade 2, then resume treatment with one dose level reduction for all subsequent
cycles.
•
For platelet count decrease complicated by bleeding at any time during a cycle decrease
MLN8237 by one dose level for all subsequent cycles.
•
Myeloid growth factors may be used according to ASCO guidelines.
6.3 Dose Modifications for Non-Hematologic Toxicity
6.3.1
Dose Modifications for GI Toxicity
Nausea and Vomiting
•
For grade 2 nausea or vomiting that the patient finds intolerable, delay (day
1) or interrupt MLN8237 until symptoms improve to ≤ grade 1, then resume
treatment at the previous dose.
•
For grade 3 nausea or vomiting, or for grade 4 vomiting, delay (day 1) or
interrupt MLN8237 until symptoms improve to ≤ tolerable grade 2, then
resume treatment with one dose level reduction for all subsequent cycles.
•
Manage nausea and vomiting according to institutional procedures.
Diarrhea
•
For grade 2 diarrhea that the patient finds intolerable, or grade 3 or 4
diarrhea, delay (day 1) or interrupt MLN8237 until diarrhea improves to ≤
tolerable grade 2, then resume treatment with one dose level reduction for all
subsequent cycles.
•
Manage diarrhea with loperamide ( 4mg at onset, then 2mg with each loose
bowel movement, until diarrhea free for 12 hours) or according to instutional
guidelines.
6.4 Other non-hematologic Toxcity
•
For other grade 2 non-hematologic toxicity that the patient finds intolerable and that is
considered at least possibly related to MLN8237, delay (day 1) or interrupt MLN8237
until toxicity improves to ≤ grade 1, then resume treatment at the previous dose.
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•
For other grade 3 or 4 non-hematologic toxicity considered at least possibly related to
MLN8237, delay ( day 1) or interrupt MLN8237 until toxicity improves to ≤ tolerable
grade 2, then resume treatment with one dose level reduction for all subsequent cycles.
7.0 ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The following
list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will determine
whether the event requires expedited reporting (via CTEP-AERS) in addition to routine reporting.
Adverse Events are required to be reported once the patient has been registered to treatment.
7.1 Comprehensive Adverse Events and Potential Risks Lists (CAEPRs)
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of
reported and/or potential adverse events (AE) associated with an agent using a uniform
presentation of events by body system. In addition to the comprehensive list, a subset of AEs,
the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate
column and is identified with bold and italicized text. The SPEER is a list of events that are
protocol specific exceptions to expedited reporting to NCI via CTEP-AERS (except as noted
below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements:
http://ctep.info.nih.gov/protocolDevelopment/default.htm - adverse_events_adeers for further
clarification.
The CAEPR may not provide frequency data; if not, refer to the Investigator’s Brochure for
this information.
7.1.1
7.1.1.1
CAEPRs for CTEP IND Agent
CAEPR for MLN8237
Comprehensive Adverse Events and Potential Risks list (CAEPR) for MLN 8237
(NSC 747888)
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a
single list of reported and/or potential adverse events (AE) associated with an agent
using a uniform presentation of events by body system. In addition to the
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited
Reporting (SPEER), appears in a separate column and is identified with bold and
italicized text. This subset of AEs (SPEER) is a list of events that are protocol
specific exceptions to expedited reporting to NCI via CTEP-AERS (except as noted
below).
Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting
Requirements'
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelin
es.pdf for further clarification. Frequency is provided based on 640 patients. Below
is the CAEPR for MLN 8237.
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in
parentheses next to the AE in the SPEER. If this CAEPR is part of a combination
protocol using multiple investigational agents and has an AE listed on different
SPEERs, use the lower of the grades to determine if expedited reporting is required.
Version 2.2, November 27, 20131
Adverse Events with Possible
Relationship to MLN 8237
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ALLIANCE A091102
(CTCAE 4.0 Term)
[n= 640]
Likely (>20%)
(SPEER)
Rare but Serious
(<3%)
Less Likely (<=20%)
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Anemia (Gr 3)
Febrile neutropenia (Gr 3)
Anemia
Febrile neutropenia
GASTROINTESTINAL DISORDERS
Abdominal pain (Gr 2)
Constipation (Gr 2)
Diarrhea (Gr 2)
Mucositis oral (Gr 3)
Nausea (Gr 2)
Oral pain (Gr 2)
Vomiting (Gr 2)
Abdominal pain
Constipation
Diarrhea
Mucositis oral
Nausea
Oral pain
Vomiting
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
Edema limbs (Gr 2)
Fatigue (Gr 2)
Fever (Gr 2)
Edema limbs
Fatigue
Fever
INFECTIONS AND INFESTATIONS
Infection2
Infection2 (Gr 2)
Alanine aminotransferase
increased
Alkaline phosphatase
increased
Aspartate
aminotransferase
increased
Blood bilirubin increased
Creatinine increased
Lymphocyte count
decreased
Alanine aminotransferase
increased (Gr 2)
Alkaline phosphatase increased
(Gr 2)
Aspartate aminotransferase
increased (Gr 2)
INVESTIGATIONS
Blood bilirubin increased (Gr 2)
Creatinine increased (Gr 2)
Lymphocyte count decreased (Gr
4)
Neutrophil count decreased (Gr 3)
Neutrophil count
decreased
Platelet count
decreased
White blood cell
decreased
Platelet count decreased (Gr 3)
White blood cell decreased (Gr 4)
METABOLISM AND NUTRITION DISORDERS
Anorexia (Gr 2)
Dehydration (Gr 2)
Anorexia
Dehydration
NERVOUS SYSTEM DISORDERS
Dizziness
Headache
Somnolence
Headache (Gr 2)
Somnolence (Gr 2)
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
Cough
Dyspnea
Dyspnea (Gr 2)
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Alopecia (Gr 2)
Alopecia
Bullous dermatitis
Palmar-plantar
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erythrodysesthesia
syndrome
1
This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all
Principal Investigators at the time of revision. The current version can be obtained by contacting
[email protected]. Your name, the name of the investigator, the protocol and the agent should
be included in the e-mail.
2Infection
includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC.
Also reported on MLN 8237 trials but with the relationship to MLN 8237 still undetermined:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Bone marrow hypocellular; Leukocytosis
CARDIAC DISORDERS - Left ventricular systolic dysfunction; Restrictive cardiomyopathy; Sinus
tachycardia
EAR AND LABYRINTH DISORDERS - Hearing impaired
EYE DISORDERS - Eye pain; Flashing lights; Floaters; Keratitis; Photophobia
GASTROINTESTINAL DISORDERS - Anal mucositis; Colitis; Dry mouth; Dyspepsia; Dysphagia;
Enterocolitis; Esophagitis; Flatulence; Hemorrhoids; Typhlitis
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Flu like symptoms; Gait
disturbance; General disorders and administration site conditions - Other (systemic inflammatory
response syndrome); Localized edema; Multi-organ failure; Pain
HEPATOBILIARY DISORDERS - Hepatobiliary disorders - Other (venoocclusive liver disease)
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall
INVESTIGATIONS - CD4 lymphocytes decreased; Ejection fraction decreased; GGT increased;
Investigations - Other (pancytopenia); Weight loss
METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; Hypernatremia; Hypoalbuminemia;
Hypocalcemia; Hypokalemia; Hyponatremia; Hypophosphatemia; Metabolism and nutrition disorders Other (failure to thrive)
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Generalized
muscle weakness; Muscle weakness lower limb; Musculoskeletal and connective tissue disorder - Other
(rhabdomyolysis); Pain in extremity
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) Myelodysplastic syndrome
NERVOUS SYSTEM DISORDERS - Ataxia; Depressed level of consciousness; Dysgeusia; Lethargy;
Memory impairment; Nervous system disorders - Other (bradyphrenia); Paresthesia; Sinus pain; Syncope
PSYCHIATRIC DISORDERS - Agitation; Confusion; Euphoria; Insomnia
RENAL AND URINARY DISORDERS - Acute kidney injury; Proteinuria
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage;
Epistaxis; Nasal congestion; Pharyngolaryngeal pain
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Periorbital edema; Pruritus; Rash
maculo-papular; Skin hyperpigmentation
VASCULAR DISORDERS - Hypotension; Vascular disorders - Other (shock)
Note: MLN 8237 in combination with other agents could cause an exacerbation of any adverse event
currently known to be caused by the other agent, or the combination may result in events never
previously associated with either agent.
7.1.1.2
Comprehensive Adverse Events and Potential Risks List (CAEPR) for 3'deoxy-3'-[F-18]fluorothymidine (NSC 743144)
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a
single list of reported and/or potential adverse events (AE) associated with an agent
using a uniform presentation of events by body system. In addition to the
comprehensive list, a subset, the Agent Specific Adverse Event List (ASAEL),
appears in a separate column and is identified with bold and italicized text. This
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ALLIANCE A091102
subset of AEs (ASAEL) contains events that are considered 'expected' for expedited
reporting purposes only. Refer to the 'CTEP, NCI Guidelines: Adverse Event
Reporting
Requirements'
http://ctep.info.nih.gov/protocolDevelopment/default.htm#adverse_events_adeers
for further clarification. The CAEPR does not provide frequency data; refer to the
Investigator's Brochure for this information. Below is the CAEPR for 3'-deoxy-3'[F-18]fluorothymidine.
Version 1.0, July 1, 2010 1
Category
(Body
System)
Adverse Events2 with Possible
Relationship to 3'-deoxy-3'-[F18]fluorothymidine
(CTCAE v4.0 Term)
EXPECTED AEs FOR CTEP-AERS
REPORTING
Agent Specific Adverse Event List
(ASAEL)
No AEs reported in human studies2,3.
1
This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to
all Principal Investigators at the time of revision. The current version can be obtained by contacting
[email protected]. Your name, the name of the investigator, the protocol, and the agent
should be included in the e-mail.
2
No adverse events have been attributed to Positron-Emission Tomography (PET) imaging/diagnostic
administration of [3'-deoxy-3'-[F-18] fluorothymidine at the levels described in the Investigators
Brochure. Therefore, no adverse events are expected as a result of the intravenous (IV) administration
of 3'-deoxy-3'-[F-18] fluorothymidine for typical PET imaging applications.
3
As with many intravenously administered agents, 3'-deoxy-3'-[F-18] fluorothymidine could cause an
allergic reaction that could potentially pose a threat to life (anaphylaxis). This has not been observed
in limited human exposure to date. Reasonable precautions should be taken, consistent with normal
radiologic and clinical facility practice. The patient should be monitored until the PET procedure is
completed, and trained personnel and emergency equipment should be available per facility
standards.
For purposes of informed consent regarding reasonably foreseeable risks to subjects in trials
utilizing 3’-deoxy-3’-[F-18]fluorothymidine, the following potential adverse events are considered
extremely rare:
 Injection-related risks that may include infection, or accidental extravasation of the dose that
may lead to discomfort, localized pain, or infection.
 Risks related to allergic reaction/anaphylaxis that may be life threatening.
Note: As with all PET imaging agents, 3'-deoxy-3'-[F-18]fluorothymidine is a radiopharmaceutical that
decays with positron emission. As such, it poses an intrinsic radiation exposure risk. However, when
administered in accordance with the Investigator’s Brochure as a PET imaging agent, this risk is felt to be
extremely small. The organ and total body doses associated with FLT PET imaging are comparable to or
lower than those associated with other widely used clinical nuclear medicine procedures.
Note: 3'-deoxy-3'-[F-18]fluorothymidine in combination with other agents could cause an exacerbation of
any adverse event currently known to be caused by the other agent, or the combination may result in
events never previously associated with either agent.
7.2 Expedited Adverse Event Reporting
Investigators are required by Federal Regulations to report serious adverse events as defined
below. Investigators are required to notify the Alliance Protocol Operations Office the Study
Chair, and their Institutional Review Board if a patient has an adverse event requiring
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expedited reporting. All such events must be reported in an expedited manner using the NCI
CTEP Adverse Event Reporting System (CTEP-AERS). The descriptions and grading scales
found in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
will be utilized for reporting. All treatment areas should have access to a copy of the CTCAE
version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP website
(http//ctep.cancer.gov).
The Alliance requires investigators to route all expedited adverse event reports through the
Alliance Protocol Operations Office for Alliance –coordinated studies.
Be sure to read this entire protocol section, as requirements are described in both the table and
bullet points following the table. Note that the table and the Additional instructions or
exclusions may conflict. The additional instructions or exclusions are protocol-specific, and in
the case of a conflict, the additional instructions or exclusions supersede the table. Most
exclusions cover “expected” events that the sponsor would not be required to report to the
FDA in an expedited manner.
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Late Phase 2: Expedited Reporting Requirements for Adverse Events that Occur on Studies
under an IND within 30 Days of the Last Administration Agent(s) 1, 2
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)
An adverse event is considered serious if it results in ANY of the following outcomes:
1) Death
2) A life-threatening adverse event
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥
24 hours
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life
functions
5) A congenital anomaly/birth defect.
6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization
may be considered serious when, based upon medical judgment, they may jeopardize the patient or
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6).
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via
CTEP-AERS within the timeframes detailed in the table below.
Grade 1
Grade 2
Grade 3
Grade 4 & 5
Hospitalization
Timeframe
Timeframes
Timeframes
Timeframes
s
Resulting in
Hospitalization
10 Calendar Days
≥ 24 hrs
24-Hour 5 Calendar Days
Not resulting in
Hospitalization
Not required
10 Calendar Days
≥ 24 hrs
Expedited AE reporting timelines are defined as:
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours
of learning of the AE, followed by a complete expedited report within 5 calendar days of the
initial 24-hour report.
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10
calendar days of learning of the AE.
1Serious
adverse events that occur more than 30 days after the last administration of the Agent(s)
require reporting as follows:
Expedited 24-hour notification followed by complete report within 5 calendar days for:
•
All Grade 4, and Grade 5 Aes that are at least possibly related to treatment
Expedited 10 calendar day reports for:
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization, and that
are at least possibly related to treatment.
• Grade 3 adverse events
2
For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half
lives, rounded UP to the nearest whole day, after the agent/intervention was last administered.
Footnote “1” above applies after this reporting period.
NOTE: Deaths clearly due to progressive disease should NOT be reported via CTEP-AERS but rather
should be reported via routine reporting methods (e.g., CDUS and/or CTMS).
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7.3 Additional Instructions or Exclusions to CTEP-AERS
Additional instructions or exclusions to CTEP-AERS expedited reporting requirements for
A091102
•
All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also be
forwarded to your local IRB.
•
Treatment expected adverse events include those listed in Section 2.2, in the Investigator’s
Brochure for MLN8237, in the CAEPR for MLN8237 and in the CAEPR for (3'-deoxy-3'[F-18] fluorothymidine. Note that the ASAEL column of the CAEPR has been replaced with
the Specific Protocol Exceptions to Expedited Reporting (SPEER) column. The SPEER
includes “expected” severity grades in addition to event terms. Events listed in the SPEER
only require expedited reporting if the severity grade is above the grade noted in the SPEER.
•
All new malignancies should be reported through CTEP-AERS whether or not they are
thought to be related to either previous or current treatment. All new malignancies should be
reported including solid tumors (including non-melanoma skin malignancies), hematologic
malignancies, myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML), and
in situ tumors. In CTCAE version 4.0, the new malignancies (both second and secondary)
may be reported as one of the following (1) Leukemia secondary to oncology chemotherapy,
(2) Myelodysplastic syndrome, (3) Treatment-related secondary malignancy, or (4)
Neoplasm other, malignant (grade 3 or 4). Whenever possible, the CTEP-AERS reports for
new malignancies should include, tumor pathology, history of prior tumors, prior
treatment/current treatment including duration, any associated risk factors or evidence
regarding how long the new malignancy may have been present, when and how the new
malignancy was detected, molecular characterization or cytogenetics of the original tumor
(if available) and of any new tumor, and new malignancy treatment and outcome, if
available.
•
Patients who become pregnant on study risk intrauterine exposure of the fetus to agents,
which may be teratogenic. For this reason, pregnancy occurring on study or within 6
months following the last dose of study therapy should be reported in an expedited manner
via CTEP-AERS as “Pregnancy, puerperium and perinatal conditions - Other
(Pregnancy) under the Pregnancy, puerperium and perinatal conditions SOC and
reported as Grade 3.
•
Pregnancy should be followed up until the outcome of the pregnancy is known at intervals
deemed appropriate by the investigator and the outcome reported via CTEP-AERS. .
•
All Adverse Events must be reported in routine study data submissions. AEs reported
through CTEP-AERS must also be reported in routine study data submissions.
•
Deaths due to progressive disease do not require CTEP-AERS, but must be reported as part
of study results via routine reporting.
8.0 PHARMACEUTICAL AND IMAGING AGENT INFORMATION
A list of the adverse events and potential risks associated with the investigational agent
administered in this study can be found in Section 7.1.
8.1 CTEP and CIP IND Agent
8.1.1
MLN8237 (NSC 747888)
Chemical Name: sodium 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4d][25]benzazepin-2-yl]amino}-2-methoxybenzoate
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Other Names: MLN8237-004, ML00653668
Classification: Aurora A kinase inhibitor
CAS Registry Number: 1208255-63-3
Molecular Formula: C27H19ClFN4NaO4.H2O
M.W.: 558.92 (sodium salt)
518.92 (free acid)
Approximate Solubility: MLN8237’s solubility in water (pH = 8.4) is 8.5 mg/mL.
Mode of Action: MLN8237 inhibits aurora A kinase activity; the aurora A kinase gene is
amplified, overexpressed, or both in many tumors, and results in transformation of normal
cells.
Description: In its solid state, MLN8237-004 drug substance is an off-white to yellow
solid.
How Supplied: Millennium supplies and the Pharmaceutical Management Branch, CTEP,
DCTD, distributes MLN8237 as enteric coated 10 mg tablets (expressed as MLN8237 free
acid). Excipients include a buffer (sodium bicarbonate), surfactant (sodium lauryl sulfate),
enteric coating, binder (povidone), filler (microcrystalline cellulose), disintegrant
(croscarmellose sodium), and lubricant (sodium stearyl fumarate). Each bottle contains 10
tablets.
Storage: Store MLN8237 at controlled room temperature (20oC-25ºC).
Excursions from 15°C to 30°C are permitted.
Stability: Stability testing is ongoing.
Route of Administration: Oral
Method of Administration: Patients will take nothing by mouth (NPO) except for water
and prescribed medications for approximately one hour before and two hours after each
dose. Patients will be instructed to take each oral dose of MLN8237 with 8 ounces (1 cup,
240 mL) of water. All tablets are to be ingested whole; patients who have difficulty
swallowing tablets should not be registered to the trial.
Potential Drug Interactions: Agents that alter gastric pH may
MLN8237absorption. The following concomitant medications are not permitted:
change
Proton pump inhibitors (PPI are not permitted). Patients must stop using the PPI for at
least 4 days prior to the first dose of MLN8237.
Histamine-2 (H2) receptor antagonists are not permitted from the day prior (Day -1)
through to the end of the MLN8237 dosing period in a cycle.
Antacid preparations are not permitted for 2 hours before or 2 hours after administration of
MLN8237.
The effect of drug-metabolizing enzyme inducers on the clinical PK of MLN8237 has not
been characterized, so decreased systemic exposures of MLN8237 in patients receiving
clinically significant enzyme inducers is possible. Co-administration of enzyme-inducing
antiepileptic drugs, rifampin, rifabutin, rifapentine, or St. John’s wort is not permitted.
Patient Care Implications: Concurrent bisphosphonate therapy is allowed if it was
started before study entry and is maintained at recommended dosing intervals. If
bisphosphonate therapy is initiated after study entry, bone lesions will not be considered
evaluable for disease responses.
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If a patient experiences excessive sedation or other benzodiazepine-like effects, they
should not drive, operate dangerous tools or machinery, or engage in any other potentially
hazardous activity that requires full alertness and coordination. Differential diagnosis of
observed CNS effects should also be considered, such as co-morbidities associated with
the patient’s oncologic diagnosis, concomitant medications, infection, metabolic
abnormalities, etc. If excessive sedation is believed to be related to MLN8237, treatment
with MLN8237 should be delayed or the doses modified as described in Section 6.
Patients must limit alcohol consumption to no more than 1 standard unit of alcohol [12 oz
beer (350 mL), 1.5 oz (45 mL) of 80-proof alcohol, or one 6-oz (175 mL) glass of wine]
per day during the study and for 30 days from the last dose of MLN8237.
Minimize the use of agents with CNS effects. Because of their structural and
pharmacological similarity to MLN8237, benzodiazepine use is discouraged but not
prohibited.
Availability
MLN8237 is an investigational agent supplied to investigators by the Division of Cancer
Treatment and Diagnosis (DCTD), NCI.
MLN8237 is provided to the NCI under a Collaborative Agreement between the
Pharmaceutical Collaborator and the DCTD, NCI
8.1.2
Agent Ordering and Agent Accountability
8.1.2.1
NCI-supplied agents may be requested by the Principal Investigator (or their
authorized designee) at each participating institution. Pharmaceutical Management
Branch (PMB) policy requires that agent be shipped directly to the institution where
the patient is to be treated. PMB does not permit the transfer of agents between
institutions (unless prior approval from PMB is obtained). The CTEP-assigned
protocol number must be used for ordering all CTEP-supplied investigational agents.
The responsible investigator at each participating institution must be registered with
CTEP, DCTD, through an annual submission of FDA Form 1572 (Statement of
Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and
Financial Disclosure Form (FDF). If there are several participating investigators at
one institution, CTEP-supplied investigational agents for the study should be ordered
under the name of one lead investigator at that institution. Active CTEP-registered
investigators and investigator-designated shipping designees and ordering designees
can submit agent requests through the PMB Online Agent Order Processing (OAOP)
application (https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx). Access to OAOP
requires the establishment of a CTEP Identity and Access Management (IAM)
account (https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an “active”
account status and a “current” password. For questions about drug orders, transfers,
returns, or accountability, call (240) 276-6575 Monday through Friday between 8:30
am and 4:30 pm (ET) or email [email protected] anytime.
8.1.2.2
Agent Inventory Records – The investigator, or a responsible party designated by
the investigator, must maintain a careful record of the inventory and disposition of all
agents received from DCTD using the NCI Drug Accountability Record Form
(DARF). (See the NCI Investigator’s Handbook for Procedures for Drug
Accountability and Storage.)
Please note : PMB will not supply MLN8237 to the French Sarcoma Consortium.
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8.1.3
Collaborative Agreements Language
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to
the NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the
Pharmaceutical Company (ies) (hereinafter referred to as “Collaborator(s)”) and the
NCI Division of Cancer Treatment and Diagnosis. Therefore, the following
obligations/guidelines, in addition to the provisions in the “Intellectual Property
Option
to
Collaborator”
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained
within the terms of award, apply to the use of the Agent(s) in this study:
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor
can Agent(s) be transferred or licensed to any party not participating in the clinical
study. Collaborator(s) data for Agent(s) are confidential and proprietary to
Collaborator(s) and shall be maintained as such by the investigators. The protocol
documents for studies utilizing Agents contain confidential information and should
not be shared or distributed without the permission of the NCI. If a copy of this
protocol is requested by a patient or patient’s family member participating on the
study, the individual should sign a confidentiality agreement. A suitable model
agreement can be downloaded from: http://ctep.cancer.gov.
2. For a clinical protocol where there is an investigational Agent used in
combination with (an)other Agent(s), each the subject of different Collaborative
Agreements, the access to and use of data by each Collaborator shall be as follows
(data pertaining to such combination use shall hereinafter be referred to as "MultiParty Data”):
a. NCI will provide all Collaborators with prior written notice regarding the
existence and nature of any agreements governing their collaboration with NCI, the
design of the proposed combination protocol, and the existence of any obligations
that would tend to restrict NCI's participation in the proposed combination protocol.
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the
clinical trial by any other Collaborator solely to the extent necessary to allow said
other Collaborator to develop, obtain regulatory approval or commercialize its own
Agent.
c. Any Collaborator having the right to use the Multi-Party Data from these trials
must agree in writing prior to the commencement of the trials that it will use the
Multi-Party Data solely for development, regulatory approval, and commercialization
of its own Agent.
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as
appropriate and unless additional disclosure is required by law or court order as
described
in
the
IP
Option
to
Collaborator
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).
Additionally, all Clinical Data and Results and Raw Data will be collected, used and
disclosed consistent with all applicable federal statutes and regulations for the
protection of human subjects, including, if applicable, the Standards for Privacy of
Individually Identifiable Health Information set forth in 45 C.F.R. Part 164.
4. When a Collaborator wishes to initiate a data request, the request should first be
sent to the NCI, who will then notify the appropriate investigators (Group Chair for
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Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact
them.
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance
with the guidelines and policies of the responsible Data Monitoring Committee
(DMC), if there is a DMC for this clinical trial.
6. Any manuscripts reporting the results of this clinical trial must be provided to
CTEP by the Group office for Cooperative Group studies or by the principal
investigator for non-Cooperative Group studies for immediate delivery to
Collaborator(s) for advisory review and comment prior to submission for publication.
Collaborator(s) will have 30 days from the date of receipt for review. Collaborator
shall have the right to request that publication be delayed for up to an additional 30
days in order to ensure that Collaborator’s confidential and proprietary data, in
addition to Collaborator(s)’s intellectual property rights, are protected. Copies of
abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy
review as soon as possible and preferably at least three (3) days prior to submission,
but in any case, prior to presentation at the meeting or publication in the proceedings.
Press releases and other media presentations must also be forwarded to CTEP prior to
release. Copies of any manuscript, abstract and/or press release/ media presentation
should be sent to:
Email: [email protected]
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No
publication, manuscript or other form of public disclosure shall contain any of
Collaborator’s confidential/ proprietary information.
8.2 FLT-PET
For complete information, please refer to the current Investigator’s Brochure (3'-deoxy-3'-[F18] fluorothymidine: [F-18]FLT: An Investigational Positron Emission Tomography (PET)
Radiopharmaceutical for Injection intended for use as an in vivo diagnostic for imaging active
cellular proliferation of malignant tumors, Edition Number: 8, Edition Date: May 2011).
8.2.1
Pharmacology and Toxicology
The pharmacology of FLT is based on its action as an inhibitor of DNA synthesis
(Langen, 1969; 1972; 1972; Matthes, 1988). Intracellular metabolism of FLT
produces nucleotides that inhibit endogenous DNA polymerases because they
lack a 3'-hydroxyl substituent. This results in premature chain termination of
DNA synthesis (Matthes 1987, Sundseth 1996). These biochemical properties
can account for FLT's prominent hematological and liver toxicity in treatment
studies. The proposed PET tracer studies using approximately 6 µg single dose
[F-18]FLT are significantly lower than the oral 0.125 mg/kg or 2 mg/day multi
dose used in the human studies (Flexner, 1994; Faraj, 1994; Sundseth, 1996;
Katlama, 2004; Ghosn, 2007). The pharmacology of FLT closely parallels that of
the widely used prescription HIV-antiviral drug azidothymidine (AZT)
(Lundgren, 1991; Kong, 1992). Both FLT and AZT are 3'-deoxythymidine
analogs that act as inhibitors of DNA synthesis and are cleared from the body in
the same way. Although FLT is significantly more cytotoxic than AZT in test cell
lines (Faraj, 1994) at comparable levels of exposure, this is not a factor when [F18]FLT exposure is limited to typical PET imaging microdose requirements.
Cellular uptake of FLT and thymidine is greater than that of AZT. Transport of
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FLT and thymidine across cell membranes occurs by active transport and passive
diffusion (Kong, 1992).
8.2.2
Toxicity of [F-18]FLT in Humans
In a study performed at the University of Washington, Turcotte and colleagues
(Turcotte, 2008) assessed the toxicity of [F-18]FLT in twenty patients with
proven or suspected diagnosis of non-small cell lung cancer (Table 5). All
patients gave written informed consent to the [F-18]FLT injection, and
subsequent PET imaging and blood draws. Blood samples were collected for
each patient at multiple times before and after [F-18]FLT-PET. These samples
were assayed for comprehensive metabolic panel, total bilirubin, complete blood
and platelet counts. In addition, a standard neurological examination by a
qualified physician was performed for each patient before and immediately after
[F-18]FLT-PET. All [F-18]FLT doses were calculated based on patient weight
(2.59 MBq/kg = 0.07 mCi/kg) with a maximal dose of 185 MBq (5.0 mCi).
Starting with the [F-18]FLT injection, dynamic PET images were acquired for 90
or 120 minutes. By placing a region-of-interest in the center of the left ventricular
chamber, blood time- activity curves were generated for each patient from the
dynamic PET data and then extrapolated to 720 minutes. This provided a
measure of the area under the [F-18]FLT concentration curve for 12 hours
(AUC12). A separate estimation of the AUC12 was also obtained from sequential
blood samples collected during PET data acquisition. No side effects were
reported by patients or observed. No change was observed in the neurological
status of patients. A neurological examination was performed by an experienced
neurologist prior to [F-18]FLT administration, the day after [F-18]FLT
administration, and at four weeks post [F-18]FLT administration. Only albumin,
red blood cell count, hemoglobin, and hematocrit show a statistically significant
decrease over time (Table 5). These changes were attributed to IV hydration
during PET imaging and to subsequent blood loss at surgery. The AUC12 values
estimated from imaging data are not significantly different from those found
from serial measures of [F-18]FLT blood concentrations (P = 0.66). No
significant neurologic sequelae have been attributed to [F-18]FLT use in pet
imaging to date. As a result, peripheral neuropathy, which had been listed as a
possible risk based upon observations at significantly higher doses in early
therapeutic HIV studies, is no longer considered a risk of [F-18]FLT use in a
micro-dose imaging setting. Screening for peripheral neuropathy is not justified
based upon the available evidence in multiple [F-18]FLT imaging trials.
Table 5. Laboratory Values (mean ± SD) At Each Time Point
Pre[F18]FLT
Immediate <
5 hours
5 – 24
hours
1 – 7 days
> 1 week
P*
Sodium (mEq/L ± SD) 139.4 ± 1.5
138.2 ± 2.1
138.3 ±
2.0
137.5 ± 1.8 138.1 ± 2.3 0.064
Potassium (mEq/L ±S
D)
4.2 ± 0.4
4.1 ± 0.4
4.2 ± 0.3
104.2 ± 3.7
104 ± 3.8
102.3 ± 2.4 101.2 ± 3.1 0.055
4.2 ± 0.5
Chloride (mEq/L ± SD) 102.3 ± 3.3
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Glucose (mEq/L ± SD) 95.1 ± 14.8
96.6 ± 20.7
98.5 ±
23.1
105.4 ±
17.7
109.5 ±
14.6
0.175
Creatinine (mEq/L ±
SD)
0.885 ± 0.198
0.882 ± 0.207
0.881 ±
0.180
0.910 ±
0.190
0.844 ±
0.217
0.949
BUN (mEq/L ± SD)
15.8 ± 5.0
15.1 ± 5.6
15.2 ± 6.3 14.3 ± 5.2
15.3 ± 5.7
0.959
SGOT (U/L ± SD)
20.8 ± 5.0
22.0 ± 5.1
22.0 ± 5.3 22.2 ± 11.4 21.8 ± 6.7
0.973
SGPT (U/L ± SD)
18.7 ± 6.7
18.5 ± 6.6
19.1 ± 6.5 17.6 ± 5.3
17.2 ± 6.5
0.978
Albumin (g/dL ± SD)
3.9 ± 0.5
3.5 ± 0.4
3.44 ± 0.3 3.1 ± 0.6
3.2 ± 0.8
0.003
Alk Phos (U/L ± SD)
73.8 ± 19.4
61.1 ± 14.7
58.3 ±
17.0
59.5 ± 22.7
Bilirubin (mg/dL ± SD) 0.647 ± 1.81
0.573 ± 0.246
0.581 ±
0.263
0.621 ±
0.286
0.752 ±
0.418
0.714
RBC (X109 /ml ± SD) 4.5 ± 0.4
4.3 ± 0.5
4.2 ± 0.5
3.8 ± 0.3
3.7 ± 0.4
<0.000
1
Hematocrit (% ± SD)
39.1 ± 4.4
38.4 ± 4.0 35.2 ± 3.4
35.0 ± 3.4
<0.000
1
WBC (X106/ml ±S D) 7.6 ± 2.1
7.7 ± 3.4
7.9 ± 3.3
9.5 ± 2.8
9.0 ± 3.2
0.262
Platelets (X106/ml ±
SD)
259.1 ± 103.1
255.9 ±
103.0
230.1 ±
76.7
233.5 ±
69.5
0.674
40.9 ± 3.1
278.1 ± 96.9
0.081
*one-way ANOVA P values (from Turcotte et al, 2007)
The single dose AUC12 values derived from blood clearance studies performed at the
University of Washington ranged from 0.22 to 1.34 ng-h/mL with a mean of 0.80 ngh/mL. This range corresponds to 0.46% to 2.7% of the Flexner therapeutic clinical trial
AUC12 of 50 ng-h/mL. In the Flexner trial the only dose-limiting toxicity was
hematologic, either anemia or granulocytopenia, and the threshold for this response was
greater than 50 ng-h/mL. The only adverse event at the 50 ng-h/mL level was a peripheral
neuropathy in 2 of 15 patients that manifested at about 40 days. The peripheral
neuropathy was detected by vibration sensation scores and was not a dose limiting
toxicity. For FLT, the average arterial blood curve (% injected dose per mL of blood)
from 16 University of Washington FLT two hour studies were extrapolated to 12 hours
using the conservative estimation that there would be no more clearance of FLT from the
plasma and that all the radioactivity in the blood was in the form of the unmetabolized
FLT. It was then assumed that 100% of the dose (6.1 µg = 6100 ng) was in a plasma
volume of 3,000 mL. The dose in nanograms was multiplied by the fraction of the
injected dose per mL divided by the plasma volume to obtain ng/mL for each time point.
The area under this curve was 0.5 ng-h/mL. Thus, the AUC12 of a single injected dose of
FLT will be < 1% of the single dose and less than 0.01% of the cumulative 40 day dose
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of the lowest mass associated with any reported toxic effect in humans, 50 ng-h/mL and
will not lead to clinically detectable toxic effects.
An NCI-sponsored study (Spence, 2008) was conducted at University of Washington in
Seattle beginning in 2005. Twelve patients with brain tumors were enrolled. Overall, 2 of
the 12 subjects receiving FLT experienced an elevation in BP from baseline to two hours
post infusion: Subjects 1 (119/56 – 133/66) and 4 (120/78 – 163/74). In Subject 4,
abnormal BP was attributed to discomfort from the head immobilization device. There
were no clinically relevant events reported. All subjects performed consistently on the
pre- and post- neurological exams and there were no changes in status. The clinical
chemistry data are shown in Table 6.
Four of these analytes demonstrated statistically significant changes on one-way
ANOVA: potassium, carbon dioxide, total protein, and albumin. Some of the other values
were above or below normal, but no pattern was seen except that many were lower on the
day of the study. These decreases are attributed to two main factors. Normal saline
infusion, which expands blood volume, and arterial blood sampling for kinetic analysis
are performed during the procedure, both of which will cause a general lowering of the
concentration of blood components. The subsequent recovery of these values to baseline
is consistent with this explanation and consistent with the results obtained by Turcotte
(2008).
The AUC12 values, estimated from assaying arterial blood samples, ranged from 0.004 to
0.035 ng-hr/ml, with a mean of 0.016 ng-hr/ml. These mass levels correspond to 0.008%
to 0.07% of the least toxic single dose of 50 ng-hr/ml in the Flexner trial (a 40 day, 2 dose
per day study). If comparison is made to the cumulative dose, the [F-18]FLT is
at0.0001% to 0.0009% of the therapeutic dose.
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Table 6. Laboratory Values (mean ± SD) At Each Time Point
Analyte
Pre Mean ± SD
Amylase
Na+
K+
ClCO2 total
Ion Gap
Glucose
BUN
Creatinine
Protein total
Albumin
Bilirubin total
Ca++
AST (GOT)
Alk Phos
GPT
GGT
LDH
Phosphate
Prothrombin
INR
PTT
WBC
RBC
Hgb
Hct
MCV
MCH
MCHC
Platelets
ANC
Spec Gravity
pH
75.4 ± 23.1
140.8 ± 2.6
4.27 ± 0.42
106.0 ± 3.7
27.6 ± 2.9
6.29 ± 1.60
121.8 ± 47.7
12.45 ± 4.06
1.00 ± 0.17
6.45 ± 0.38
4.15 ± 0.25
0.68 ± 0.16
9.35 ± 0.19
26.3 ± 5.9
86.0 ± 22.7
39.4 ± 15.8
44.7 ± 21.1
224.9 ± 104.9
3.15 ± 0.55
12.74 ± 1.39
1.02 ± 0.04
26.8 ± 3.1
6.13 ± 1.91
4.65 ± 0.42
14.5 ± 1.1
42.5 ± 3.1
91.5 ± 3.3
31.4 ± 1.6
34.3 ± 0.9
233.9 ± 54.2
4.08 ± 1.42
1.02 ± 0.01
6.05 ± 1.01
Immediately
Pre-Mean ± SD
68.5 ± 27.6
138.4 ± 4.6
3.88* ± 0.20
106.0 ± 4.6
24.6* ± 2.3
7.83 ± 2.29
98.7 ± 33.4
10.58 ± 4.01
0.85 ± 0.17
5.66* ± 0.37
3.66* ± 0.18
0.79 ± 0.24
9.01 ± 0.29
22.5 ± 4.4
78.5 ± 26.4
30.2 ± 9.6
42.3 ± 22.4
151.8 ± 41.9
3.03 ± 0.55
13.59 ± 0.52
1.05 ± 0.05
29.4 ± 5.7
5.75 ± 1.40
4.37 ± 0.39
13.4 ± 0.9
39.9 ± 3.4
91.3 ± 3.5
30.8 ± 1.4
33.7 ± 0.8
226.2 ± 42.7
3.79 ± 1.15
1.01 ± 0.00
6.88 ± 0.80
Day 1
Mean ± SD
77.8 ± 33.9
139.3 ± 3.3
4.20 ± 0.28
104.5 ± 3.6
26.9 ± 2.1
7.70 ± 2.21
125.2 ± 73.5
11.00 ± 3.03
0.97 ± 0.24
6.14 ± 0.57
4.01 ± 0.51
0.79 ± 0.17
9.38 ± 0.39
23.7 ± 5.0
84.3 ± 27.9
32.7 ± 11.2
47.2 ± 23.3
174.9 ± 57.9
3.16 ± 0.59
13.12 ± 0.94
1.01 ± 0.09
30.9 ± 15.8
6.96 ± 3.98
4.50 ± 0.38
13.9 ± 1.1
41.1 ± 3.0
91.3 ± 3.2
31.0 ± 1.4
33.9 ± 0.6
220.9 ± 47.8
5.02 ± 3.34
1.02 ± 0.00
6.60 ± 0.97
Day 28
Mean ± SD
75.4 ± 33.7
141.1 ± 3.1
4.08 ± 0.30
106.5 ± 3.3
26.8 ± 2.5
7.67 ± 3.08
116.9 ± 71.6
13.73 ± 4.63
1.01 ± 0.27
6.33 ± 0.76
3.99 ± 0.50
0.65 ± 0.12
9.24 ± 0.54
26.8 ± 5.1
86.5 ± 30.3
33.0 ± 7.7
44.3 ± 26.0
248.6 ± 205.4
3.07 ± 0.41
12.82 ± 1.39
1.01 ± 0.06
26.3 ± 2.8
5.85 ± 2.10
4.48 ± 0.52
13.9 ± 1.6
41.2 ± 4.5
92.1 ± 3.3
31.2 ± 1.3
33.9 ± 0.8
220.0 ± 52.4
3.89 ± 1.42
1.02 ± 0.00
5.85 ± 1.08
* Statistically significant change (p < 0.05); one-way ANOVA
The published studies on [F-18]FLT are discussed in Section VII of this Investigator’s
Brochure. While none of these studies reported explicit safety information, the majority
of these publications did indicate that Institutional Review Board (IRB) or Ethics
Committee approval was obtained for the study, so the patients would have been observed
for clinically evident adverse events, none of which were reported.
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8.2.3
Dosimetry Table
F18-FLT Patient Dosimetry
Absorbed Doses
1 FLT PET-CT scan
0.9
rad 2 CT +
0.3
rad 3 CT +
rad/8 mCi
rad
0.61
1.81
0.47
1.67
0.10
1.30
0.25
1.45
0.50
1.70
0.49
1.69
1.05
2.25
0.13
1.33
0.37
1.57
0.31
1.51
1.34
2.54
0.30
1.50
0.50
1.70
0.68
1.88
0.71
1.91
0.13
1.33
0.42
1.62
0.42
1.62
0.39
1.59
0.31
1.51
0.37
1.57
F18-FLT1
Target Organ
Adrenals
Bone Surfaces
Brain
Breasts
Gall Bladder Wall
Heart Wall
Kidneys
Large Intestine - Lower Wall
Large Intestine - Upper Wall
Lens of Eye
Liver
Lungs
Muscle / Other tissue
Pancreas
Red Marrow
Skin
Small Intestine
Stomach Wall
Testes
Thyroid
Total Body
Urinary Bladder Wall
2-hr Voiding Interval
Effective Dose Equivalent (rem)
1
2
3
8.2.4
rad/mCi
0.0766
0.0585
0.0125
0.0310
0.0625
0.0618
0.132
0.0168
0.0459
0.0389
0.1680
0.0374
0.0622
0.0851
0.0888
0.0164
0.0525
0.0522
0.0488
0.0385
0.0466
0.2927
0.10
2.34
0.83
3.54
2.03
Vesselle et al. J Nucl Med 44: 1482-1488, 2003.
Wu et al. Eur J Nucl Med Mol Imaging 31:38-43, 2004 Dos estimates scaled to low-dose (90-mA) CT scan
Wu et al. Eur J Nucl Med Mol Imaging 31:38-43, 2004 Dos estimates scaled to ultra-low-dose (30-mA) CT scan
for optional dynamic PET scan at 1 bed position
[F-18]FLT Administered Dose
[F-18]FLT will be administered to subjects over 1 minute by intravenous bolus
injection. Doses will be pre-calibrated to 8 mCi.
8.2.5
Quality Assurance, Quality Control and Storage
In accordance with regulations, the radioisotope vendor conducts several quality
control tests on the [F-18] FLT product prior to release for human administration.
Once delivered to the participating institution, doses will be stored in the
appropriate storage area in the nuclear medicine facility until they are
administered to the patient on the same day.
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8.2.6
Supplier of [F-18]FLT
Drug Ordering:
[F-18] FLT will be purchased from the NCI IND AUTHORIZED commercial
vendor (e.g. PetNet, Cardinal, IBA) under the CIP IND # 71260 cross-referenced
to CTEP IND # 113149. The vendor must be specifically authorized within the
NCI IND. The investigator or appropriate investigator-designee will order subject
doses of [F-18] FLT for this specific trial. The investigational
radiopharmaceutical [F-18] FLT solution will be shipped to the site the same day
the participant is to be injected.
The investigational pharmacist or qualified nuclear medicine technologist at the
participating institution will be the responsible party designated by the
investigator.
Drug Returns:
If for any reason the study imaging is unable to be completed, sites will allow the
radioactivity of the [F-18] FLT solution to decay and then discard it appropriately
per site’s policies and procedures, making a record of the event as required. A
copy of the policy should be available upon request.
Drug Accountability:
The investigator or the investigator-designee must maintain a detailed record of
receipt, disposition, and destruction dates of [F-18]FLT solution.
9.0 CORRELATIVE STUDIES FOR MSKCC PATIENTS
9.1 Background
In preclinical studies, AURKA amplification was not necessary for sensitive to AURKA
inhibition, so we have not made AURKA gene amplification an entry criterion. However, we
will undertake an exploratory analysis to determine whether patients with a gene amplification
have an improved clinical benefit (CR, PR, SD). Similarly, we will determine in the posttreatment biopsies whether the AURKA pathway is being inhibited. These studies may include
staining for the mitotic markers MPM2 and phospho- Histone H3 at Serine10 by IHC and
western blot. We may also examine the tissues for induction of apoptosis by TUNEL and
cleaved caspase 3, inhibition of cell proliferation by Ki67 staining, and changes in cellular
morphology (increase in % of bipolar spindles). Staining intensity by IHC will be graded semiquantitatively, with a five-point scale: 0, no staining; 1+, weak; 2+, moderate; 3+, strong and
4+, intense. Pre and post-treatment protein levels will be compared by Wilcoxon signed-rank
test (for paired samples). The association of response or clinical benefit with the presence or
absence of markers of pathway inhibition in patient tumors will be tested using Fisher’s exact
test. For changes in morphology, the number of mitotic cells at baseline will be counted from 5
randomly selected high powered fields and will be subtracted from those counted on the
second biopsy. A positive result will represent an increase in the mitotic index in the posttreatment biopsy relative to the baseline. These analyses of the correlative endpoints would be
exploratory and hypothesis-generating.
9.2 Methods
Patients treated at MSKCC may have two optional biopsies: one pretreatment and the second 1-4
weeks after the start of treatment. Tissue will be divided with part sent to the Pathology Core for
IHC and FISH and the remainder flash frozen for Western blots. Tissues will be tested at baseline
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for AURKA gene amplification by FISH. This test may be performed by Cytogenetics Core at
Memorial Sloan-Kettering or in the laboratory of Cristina Antonescu, MD. FISH analysis will be
performed by hybridization of bacterial artificial chromosome (BAC) probes, covering AURKA
(RP11-65K20, 20q13.2-13.31) and two reference probes (RP11-380E19 & RP11-713N22, on
20q11.21) onto 4μm sections of formalin-fixed paraffin-embedded tissue from each tumor. BAC
clones are chosen according to their genomic location as defined in the UCSC genome browser
(http://genome.ucsc.edu). The BAC clones will be obtained from BACPAC sources of Children's
Hospital of Oakland Research Institute (CHORI) (Oakland, CA) (http://bacpac.chori.org). BAC
DNA will be isolated according to the manufacturer’s instructions, labeled with different
fluorochromes in a nick translation reaction, denatured, and hybridized to pretreated slides. Slides
will be then incubated, washed, and mounted with DAPI in an antifade solution, as previously
described (Antonescu et al., 2010). The genomic location of each BAC set will be verified by
hybridizing them to normal metaphase chromosomes. Two hundred interphase nuclei from each
tumor will be examined using a Zeiss fluorescence microscope (Zeiss Axioplan, Oberkochen,
Germany), controlled by Isis 5 software (Metasystems). Other tests may include IHC and
Western blot staining for the mitotic markers MPM2 and phospho- Histone H3 at Serine10.
Aurora Kinase A may be assessed by Western blot (Cell signaling # 3092, 1:500 dilution). We
may also examine the tissues for induction of apoptosis by TUNEL and cleaved caspase 3,
inhibition of cell proliferation by Ki67 staining, chromosomal complexity, and changes in cellular
morphology (increase in % of bipolar spindles).
Cryostat-cut frozen tissue sections are used unfixed or fixed for 10 minutes (methanol:acetone or
1% formalin). Formalin-fixed/paraffin-embedded sections are also used. The avidin-biotin
immunoperoxidase technique is our method of choice and will be utilized for the experiments
proposed. For specific epitopes on paraffin sections we utilize antigen retrieval methods (0.01%
citric acid for 15 minutes under microwave treatment) prior to incubation with primary antibodies
or antiserum overnight at 40C. Secondary antibodies are biotinylated horse anti-mouse or goat
anti-rabbit antibodies, which are used at 1:500 dilutions (Vector Laboratories). Diaminobenzidine
will be utilized as the final chromogen and hematoxylin as the nuclear counterstain.
Collection of Specimens
Tumors samples will be collected from patients with accessible material treated at Memorial
Sloan Kettering Cancer Center.
Submission of Specimens
For each sample indicate the unique subject ID number, histology diagnosis, and the date of the
specimen.
Tumors will be sent to:
Grazia Ambrosini, Ph.D.
Memorial Sloan-Kettering Cancer Center
G. Schwartz Laboratory, Z-1841
1275 York Ave
New York, NY 10065
Tel: 646-888-2183
Fax: 646-422-0631
Email: [email protected]
NOTE: Research Tissue Submission Form should accompany all samples sent to the MSKCC.
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9.3 A091102-IM1
9.3.1
[F-18]FLT Administration
An FLT-PET scan may be performed at baseline and 1-4 weeks after starting
treatment for up to 20 patients treated with MLN8237 at MSKCC only in
connection with [F-18]FLT CIP IND # 71,260. These will be optional.
[F-18]FLT will be provided by a vendor authorized within the NCI IND. [F18]FLT will be administered according to the guidance provided in the most
current Investigators Brochure for this IND.
9.3.2
9.3.2.1
[F-18]FLT-PET Imaging
Methods
Patients will not have dietary restriction for FLT imaging. Up to 8 mCi FLT will be
injected IV. Following low dose CT (for attenuation correction and anatomic
localization), PET emission images will be obtained from mid skull to floor of pelvis
for up to 5-minutes/bed position, starting approximately 60 minutes after FLT
injection. Optionally, we may obtain a one field of view dynamic scan for up to 60
minutes over a lesion of interest (e.g. largest lesion seen on prior CT or FDG PET
scans). We may obtain one approx. 3mL venous blood sample at approximately 60
minutes after FLT injection for metabolite analysis (needed for quantitative analysis).
All studies will be obtained on dedicated PET/CT scanners (either DSTE or 690
scanners). Regardless which specific scanner is chosen, baseline and follow up
scans must be obtained on the same scanner.
9.3.2.2
Image Analysis and Interpretation Details
All FLT-PET images will be reviewed and examined by a board-certified nuclear
medicine physician who is experienced in PET interpretation. CT, attenuationcorrected PET, and fusion PET-CT images will be available and reviewed
simultaneously for each patient. Interpretation of the cancer site will be based on the
intensity of the signal, focality of radiotracer uptake, and whether the lesion could be
adequately discriminated from background activity in the surrounding tissues.
9.3.2.3
Imaging Related Procedures
A venous catheter will be placed in a superficial hand or arm vein for administration
of the radiopharmaceuticals. If a central venous catheter is present, it will also be
used for radiopharmaceutical administration.
9.3.2.4
Background
18
F Fluorothymidine PET
3'-deoxy-3'-[(18)F] fluorothymidine 18F FLT is a new investigational PET radiotracer
that can be used to assess tumor cell proliferation [50]. Imaging with FLT takes
advantage of the fact that pyrimidine nucleosides and several of their analogues are
phosphorylated to the respective monophosphate (MP) by thymidine kinase 1 (TK-1)
and are incorporated into DNA. FLT is also substrate for thymidine kinase-1 (TK-1),
which has been demonstrated both in vitro and in vivo [51-54]. TK-1 activity is upregulated in cells entering the S-phase, whereas the protein is nearly undetectable in
growth arrested cells. TK-1 catalyzes the phosphorylation of FLT to FLTmonophosphate. Because it lacks a 3'-hydroxyl group, very little FLT is incorporated
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into DNA. Thus, FLT measures an early event in DNA synthesis, rather than DNA
incorporation. Nevertheless, many reports have shown a positive correlation between
FLT uptake and S-phase fraction of cells in vitro, and the fraction of proliferating
cells in vivo (MIB-1; Ki-67) [52, 55-57]. Accordingly, FLT might be a useful
imaging agent to monitor the early response to therapy in cancer patients. Preclinical
and in vitro studies showed a close correlation between FLT uptake in tumor cell
cultures or xenografts and growth arrest [58, 59]. In particular, changes in the FLT
signal in consecutive imaging studies occur earlier than changes in the FDG signal
(FDG PET is currently the only widely available imaging test for response
assessment).
As MLN8237 is a potent inhibitor of AURKA and induces a mitotic arrest, we would
anticipate that FLT-PET could be used as an early predictive marker of response.
Patients treated with MLN8237 will undergo FLT PET/CT at baseline and after the
first week of therapy. Of note FLT PET/CT is used as an exploratory tool. Data will
not be used to guide treatment decisions. However, retrospective analysis of these
data will demonstrate whether FLT PET/CT can indeed be used as potential
biomarker for response assessment and prediction in the clinic for patients treated
with Aurora Kinase inhibitors. FLT findings will be correlated with FDG PET and
traditional RECIST criteria.
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10.0 STUDY CALENDAR
Pre- study evaluations are to be performed ≤ 7 days prior to registration.
Scans and x-rays must be done ≤ 28 days prior to registration.
Informed consent can be obtained ≤4 weeks prior to the start of treatment and must be re-signed if
the patient falls outside of this treatment window (e.g. to schedule biopsies)
Clinical
Follow-Up
Pre-
Wk
Wk
Wk
Wk
Wk
Wk
Wk
Wk
Wk
Wk
Wk
Wk
Study
1
2
3
1
2
3
1
2
3
1
2
3
Cycle
1
→
→
2
→
→
3
→
→
4
→
→
MLN8237
A
A
A
A
A→
VisitC
5+ f
Informed consent
X
Demographics
X
Medical history
X
Concurrent meds
X
X
X
X
X
X
Physical exam
X
X
X
X
X
X→
X
Vital signs
X
X
X
X
X
X→
X
Height
X
Weight
X
X
X
X
X
X→
X
Performance status
X
X
X
X
X
X→
X
CBC w/diff, plts
X
X
X
X
X
X→
X
Serum chemistry
X
X
X
X
X
X→
X
Adverse event evaluation
X
X
X
X
X
X
X
X
Tumor measurements are repeated every 6 weeks. Documentation (radiologic) must
be provided for patients removed from study for progressive disease.
X→
X
a
Tumor measurements
Radiologic evaluatione
X
B-HCG
Xb
X
X
Radiologic measurements should be performed every 6 weeks.
X
LVEF assessments will be conducted during the study as clinically indicated
Correlative Study A091102-IM1
(MSKCC Patients Only)
See Section 9.2 for collection and submissiond
A: MLN8237: (see section 5.1.1)
a: Comprehensive Metabolic Panel (Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium,
total protein, SGOT [AST], SGPT [ALT], sodium)
b: Serum pregnancy test (women of childbearing potential). Pregnancy test must be done ≤ 7 days prior to registration
c: To be performed ≤4 weeks after removal from active study treatment
d: Only patients at Memorial Sloan-Kettering
e: Scans are repeated every 6 weeks, regardless of dose delays, ±8 days, starting timing from the first day of therapy. After 24 weeks (approximately 8
cycles), patients should be re-evaluated for response every 12 weeks (approximately every 4 cycles, ±8 days).
f: Treatment and assessments are to be completed per cycles 2-4. For scans refer to footnote e.
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11.0 MEASUREMENT OF EFFECT
Response and progression will be evaluated in this study using the new international criteria
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines
(version 1.1) [60]. Changes in the largest diameter (unidimensional measurement) of the tumor
lesions and the short axis measurements in the case of lymph nodes are used in the RECIST
guideline.
11.1 Schedule of Evaluations
For the purposes of this study, patients should be reevaluated every 6 weeks, regardless of
dose delays, ±8 days, starting timing from the first day of therapy. After 24 weeks
(approximately 8 cycles), patients should be re-evaluated for response every 12 weeks
(approximately every 4 cycles, ±8 days). In addition to a baseline scan, confirmatory scans
should also be obtained 6 weeks following initial documentation of objective response.
11.2 Definitions of Measurable
11.2.1
Measurable Disease
11.2.1.1 A non-nodal lesion is considered measurable if its longest diameter can
be accurately measured as ≥2.0 cm with chest x-ray, or as ≥1.0 cm
with CT scan, CT component of a PET/CT, or MRI.
11.2.1.2 A superficial non-nodal lesion is measurable if its longest diameter is ≥
1.0 cm in diameter as assessed using calipers (e.g. skin nodules) or
imaging. In the case of skin lesions, documentation by color
photography, including a ruler to estimate the size of the lesion, is
recommended.
11.2.1.3 A malignant lymph node is considered measurable if its short axis is
>1.5 cm when assessed by CT scan (CT scan slice thickness
recommended to be no greater than 5 mm).
11.3 Guidelines for Evaluation of Measurable Disease
11.3.1
Measurement Methods:
• All measurements should be recorded in metric notation (i.e., decimal
fractions of centimeters) using a ruler or calipers.
• The same method of assessment and the same technique must be used to
characterize each identified and reported lesion at baseline and during followup. For patients having only lesions measuring at least 1 cm to less than 2 cm
must use CT imaging for both pre- and post-treatment tumor assessments.
• Imaging-based evaluation is preferred to evaluation by clinical examination
when both methods have been used at the same evaluation to assess the
antitumor effect of a treatment.
11.3.2
Acceptable Modalities for Measurable Disease:
• Conventional CT and MRI: This guideline has defined measurability of
lesions on CT scan based on the assumption that CT slice thickness is 5 mm
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or less. If CT scans have slice thickness greater than 5 mm, the minimum size
for a measurable lesion should be twice the slice thickness.
• As with CT, if an MRI is performed, the technical specifications of the
scanning sequences used should be optimized for the evaluation of the type
and site of disease. The lesions should be measured on the same pulse
sequence. Ideally, the same type of scanner should be used and the image
acquisition protocol should be followed as closely as possible to prior scans.
Body scans should be performed with breath-hold scanning techniques, if
possible.
• PET-CT: If the site can document that the CT performed as part of a PET-CT
is of identical diagnostic quality to a diagnostic CT (with IV and oral
contrast), then the CT portion of the PET-CT can be used for RECIST
measurements and can be used interchangeably with conventional CT in
accurately measuring cancer lesions over time.
• Chest X-ray: Lesions on chest x-ray are acceptable as measurable lesions
when they are clearly defined and surrounded by aerated lung. However, CT
scans are preferable.
• Physical Examination: For superficial non-nodal lesions, physical examination
is acceptable, but imaging is preferable, if both can be done. In the case of
skin lesions, documentation by color photography, including a ruler to
estimate the size of the lesion, is recommended.
• FDG-PET: FDG-PET scanning is allowed to complement CT scanning in
assessment of progressive disease [PD] and particularly possible 'new' disease.
A ‘positive’ FDG-PET scanned lesion is defined as one which is FDG avid
with an update greater than twice that of the surrounding tissue on the
attenuation corrected image; otherwise, an FDG-PET scanned lesion is
considered ‘negative.’ New lesions on the basis of FDG-PET imaging can be
identified according to the following algorithm:
11.3.3
Version Date 02/20/2014
a.
Negative FDG-PET at baseline with a positive FDG-PET at
follow-up is a sign of PD based on a new lesion.
b.
No FDG-PET at baseline and a positive FDG-PET at follow-up:
i.
If the positive FDG-PET at follow-up corresponds to a new site
of disease confirmed by CT, this is PD.
ii.
If the positive FDG-PET at follow-up is not confirmed as a new
site of disease on CT at the same evaluation, additional followup CT scans (i.e., additional follow-up scans at least 4 weeks
later) are needed to determine if there is truly progression
occurring at that site. In this situation, the date of PD will be the
date of the initial abnormal PDG-PET scan.
iii
If the positive FDG-PET at follow-up corresponds to a preexisting site of disease on CT that is not progressing on the
basis of the anatomic images, it is not classified as PD.
Measurement at Follow-up Evaluation:
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•
A subsequent scan must be obtained 6 weeks following initial documentation
of an objective status of either complete response (CR) or partial response
(PR).
•
In the case of stable disease (SD), follow-up measurements must have met
the SD criteria at least once after study entry at a minimum interval of 6
weeks (see Section 11.4.4).
•
The cytological confirmation of the neoplastic origin of any effusion that
appears or worsens during treatment when the measurable tumor has met
criteria for response or stable disease is mandatory to differentiate between
response or stable disease (an effusion may be a side effect of the treatment)
and progressive disease.
•
Cytologic and histologic techniques can be used to differentiate between PR
and CR in rare cases (e.g., residual lesions in tumor types such as germ cell
tumors, where known residual benign tumors can remain.)
11.4 Measurement of Effect
11.4.1. Target Lesions & Target Lymph Nodes
Measurable lesions (as defined in Section 11.2.1) up to a maximum of 5 lesions,
representative of all involved organs, should be identified as “Target Lesions”
and recorded and measured at baseline. These lesions can be non-nodal or nodal
(as defined in 11.2.1), where no more than 2 lesions are from the same organ and
no more than 2 malignant nodal lesions are selected.
Note: If fewer than 5 (target lesions and target lymph nodes are identified (as
there often will be), there is no reason to perform additional studies beyond those
specified in the protocol to discover new lesions.
Target lesions and target lymph nodes should be selected on the basis of their
size, be representative of all involved sites of disease, but in addition should be
those that lend themselves to reproducible repeated measurements. It may be the
case that, on occasion, the largest lesion (or malignant lymph node) does not lend
itself to reproducible measurements in which circumstance the next largest lesion
(or malignant lymph node) which can be measured reproducibly should be
selected.
Baseline Sum of Dimensions (BSD): A sum of the longest diameter for all target
lesions plus the sum of the short axis of all the target lymph nodes will be
calculated and reported as the baseline sum of dimensions (BSD). The BSD will
be used as reference to further characterize any objective tumor response in the
measurable dimension of the disease.
Post-Baseline Sum of the Dimensions (PBSD): A sum of the longest diameter for
all target lesions plus the sum of the short axis of all the target lymph nodes will
be calculated and reported as the post-baseline sum of dimensions (PBSD). If the
radiologist is able to provide an actual measure for the target lesion (or target
lymph node), that should be recorded, even if it is below 0.5 cm. If the target
lesion (or target lymph node) is believed to be present and is faintly seen but too
small to measure, a default value of 0.5 cm should be assigned. If it is the opinion
of the radiologist that the target lesion or target lymph node has likely
disappeared, the measurement should be recorded as 0 cm.
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The minimum sum of the dimensions (MSD) is the minimum of the BSD and the
PBSD.
11.4.2
Non-Target Lesions & Non-Target Lymph Nodes
Non-measurable sites of disease are classified as non-target lesions or non-target
lymph nodes and should also be recorded at baseline. These lesions and lymph
nodes should be followed in accord with 11.4.3.2.
11.4.3
Response Criteria
All target lesions and target lymph nodes followed by CT/MRI/PET-CT/Chest Xray/physical examination must be measured on re-evaluation at evaluation times
specified in Section 11.1. Specifically, a change in objective status to either a PR
or CR cannot be done without re-measuring target lesions and target lymph
nodes.
Note: Non-target lesions and non-target lymph nodes should be evaluated at each
assessment, especially in the case of first response or confirmation of response.
In selected circumstances, certain non-target organs may be evaluated less
frequently. For example, bone scans may need to be repeated only when
complete response is identified in target disease or when progression in bone is
suspected.
11.4.3.1 Evaluation of Target Lesions
• Complete Response (CR):
All of the following must be true:
o Disappearance of all target lesions.
o Each target lymph node must have reduction in short axis to <1.0 cm.
• Partial Response (PR): At least a 30% decrease in PBSD (sum of the longest
diameter for all target lesions plus the sum of the short axis of all the target lymph
nodes at current evaluation) taking as reference the BSD (see Section 11.4.1).
• Progression (PD):
At least one of the following must be true:
o At least one new malignant lesion, which also includes any lymph node
that was normal at baseline (< 1.0 cm short axis) and increased to ≥ 1.0
cm short axis during follow-up.
o At least a 20% increase in PBSD (sum of the longest diameter for all
target lesions plus the sum of the short axis of all the target lymph nodes
at current evaluation) taking as reference the MSD (Section 11.4.1). In
addition, the PBSD must also demonstrate an absolute increase of at least
0.5 cm from the MSD.
o See Section 11.3.2 for details in regards to the requirements for PD via
FDG-PET imaging.
• Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor sufficient
increase to qualify for PD taking as reference the MSD.
11.4.3.2 Evaluation of Non-Target Lesions & Non-target Lymph Nodes
•
Complete Response (CR): All of the following must be true:
a Disappearance of all non-target lesions.
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b. Each non-target lymph node must have a reduction in short axis to <1.0 cm.
•
Non-CR/Non-PD: Persistence of one or more non-target lesions or non-target
lymph nodes.
•
Progression (PD): At least one of the following must be true:
a. At least one new malignant lesion, which also includes any lymph node
that was normal at baseline (< 1.0 cm short axis) and increased to ≥ 1.0
cm short axis during follow-up.
b. Unequivocal progression of existing non-target lesions and non-target
lymph nodes. (NOTE: Unequivocal progression should not normally
trump target lesion and target lymph node status. It must be
representative of overall disease status change.)
c. See Section 11.3.2 for details in regards to the requirements for PD via
FDG-PET imaging.
11.4.4
Overall Objective Status
The overall objective status for an evaluation is determined by combining the
patient’s status on target lesions, target lymph nodes, non-target lesions, nontarget lymph nodes, and new disease as defined in the following tables:
For Patients with Measurable Disease
Target Lesions &
Target Lymph Nodes
CR
CR
PR
CR/PR
SD
Not all Evaluated
PD
CR/PR/SD/PD/Not
Evaluated
CR/PR/SD/PD/Not
Evaluated
*
all
all
Non-Target Lesions &
Non-Target Lymph Nodes
CR
Non-CR/Non-PD
CR
Non-CR/Non-PD
Not All Evaluated*
CR
Non-CR/Non-PD
Not All Evaluated*
CR
Non-CR/Non-PD
Not All Evaluated*
Unequivocal PD
CR
Non-CR/Non-PD
Not All Evaluated*
Unequivocal PD
New
Sites of Disease
No
No
No
Overall Objective
Status
CR
PR
PR
No
No
PR**
SD
No
Not Evaluated (NE)
Yes or No
PD
Yes or No
PD
CR
Non-CR/Non-PD
Not All Evaluated*
Yes
PD
See Section 11.4.3.1
11.4.5 Symptomatic Deterioration: Patients with global deterioration of health status
requiring discontinuation of treatment without objective evidence of disease
progression at that time, and not either related to study treatment or other medical
conditions, should be reported as PD due to “symptomatic deterioration.” Every
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effort should be made to document the objective progression even after
discontinuation of treatment due to symptomatic deterioration. A patient is classified
as having PD due to “symptomatic deterioration” if any of the following occur that
are not either related to study treatment or other medical conditions:
•
•
•
Weight loss >10% of body weight.
Worsening of tumor-related symptoms.
Decline in performance status of >1 level on ECOG scale.
11.5 Formal Definitions of Variables
Formal definitions of variables used for the statistical analysis appear in Section 13.0.
12.0 DATA REPORTING
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0
(Adverse Events: List and Reporting Requirements).
12.1 Data Reporting
12.1.1
Method
This study will be monitored by the Clinical Data Update System (CDUS)
version 3.0. Cumulative CDUS data will be submitted quarterly to CTEP by
electronic means. Reports are due January 31, April 30, July 31, and October 31.
Instructions for submitting data using the CDUS can be found on the CTEP Web
site
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/cdus.htm)
12.1.2
Data Submission
This study will use Medidata Rave® for remote data capture (RDC) of all study
data. The Rave system can be accessed through the iMedidata portal at
https://login.imedidata.com. For additional information regarding account setup
or training, please visit the training section of the CALGB website.
Common Terminology Criteria for Adverse Events: This study will utilize the
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 for
toxicity and adverse event reporting.
13.0 STATISTICAL CONSIDERATIONS
13.1 Study Design/Endpoints
Overview: This study was originally developed and fully approved by CTEP to be coordinated
through the Memorial Sloan Kettering Cancer Center. In 2012 and due to recent N01 funding
and contract developments, the study was transferred to the Alliance. This study is evaluating
the primary endpoint of confirmed response rate following treatment with MLN8237 in 5
cohorts which are defined by histologic subtype [ie, Cohort 1 -Liposarcoma, Cohort 2 –
Leiomyosarcoma (non-uterine), Cohort 3 – Undifferentiated Sarcoma (including Pleiomorphic
Undifferentiated Sarcoma which is formerly known as Malignant Fibrous Histiocytoma, and
Myxofibrosarcoma), Cohort 4 – Malignant Peripheral Nerve Sheath Tumor, and Cohort 5 –
Other Sarcomas]. Accrual and efficacy will be determined for each cohort and independently
from the other cohorts.
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13.1.1
Primary Endpoint: The confirmed response (CR/PR) rate within each cohort of
patients enrolled to this study.
13.1.2
Secondary Endpoints:
13.1.3
13.1.4
•
To estimate progression-free survival and overall survival
•
To assess adverse events
Correlative/Translational Endpoints:
•
To correlate potential clinical benefit with pre- and post-treatment tumor
biopsies
•
To correlate clinical outcome with change in FLT-PET uptake at baseline
versus after one week of treatment
Study Design
We will use a Simon two-stage design [61] to assess the primary endpoint within
each patient cohort. See section 13.5.2 for the definition of patients to be
included in evaluating this endpoint. We will consider a response rate of 0.05 as
not promising, and a response rate of 0.25 as promising. The type I error rate is
set at 0.1 and the type II error rate at 0.1. In each of the five cohorts, 9 patients
will be accrued initially (ie, Stage 1). If there are no responses, further accrual to
that cohort will be stopped and the treatment will be declared ineffective. If there
is at least one response, then an additional 15 patients (ie, Stage 2) will be
accrued for a total of 24 in that cohort. If at least 3 responses out of the 24
patients are observed, the new treatment would be considered worthy of further
testing in this subtype. The probability of stopping the study earlier is 63% under
the null hypothesis. The overall response rate (CR + PR) will be estimated and a
90% confidence interval provided. The sample size required to address the
primary endpoint will range from 45 patients (ie, 9 patients x 5 cohorts) to 120
patients (24 patients x 5 cohorts, if each cohort proceeds to Stage 2 of the Simon
two-stage study design).
NOTE: Given the expected accrual rate, we will not suspend accrual after
enrolling a sufficient number of patients to the 1st stage noted above and to allow
patients to become evaluable. However, we will suspend accrual to a cohort if we
observe an unexpectedly high accrual rate or excessive toxicity within a cohort.
13.2 Sample Size/Accrual Rate
13.2.1
Sample Size:
The study design requires up to 120 patients. We will accrue an additional 10%
(ie, 15) of patients to account for those who are deemed non-evaluable due to
cancellation, ineligibility, major treatment violation, or not satisfying the
definition of “evaluable” as provided above. Therefore, we anticipate enrolling a
minimum of 50 (ie, 9 for stage 1 of each cohort, plus 1 for replacing those
deemed non-evaluable) to a projected maximum of 135 (ie, 24 for stages 1 and 2
of each cohort, plus 3 for replacing those deemed non-evaluable).
13.2.2
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We are basing our accrual estimates on those provided by Memorial Sloan
Kettering Cancer Center, recognizing that the Alliance (ie, CALGB and NCCTG)
have neither conducted studies in this population and we have no estimates of
expected accrual. Based on estimates from Memorial Sloan Kettering Cancer
Center, it was expected that between their enrolling sites there will be 10 new
patients a month accrued. We are also assuming that each cohort will enroll at the
similar rates (ie, of the 10 patients – two patients will be enrolled for each
cohort). The minimum duration of the study is 5 months if the study is stopped
early for all 5 cohorts and the expected duration is approximately 14 months if
the study fully accrues to completion for all 5 cohorts.
This study will be available to all patients, regardless of gender, race, or
ethnicity. The Alliance (ie, NCCTG and CALGB) has not conducted trials in
this population and therefore do not have an estimate of accrual a rates for these
specific patient groups. The table below represents the estimated accrual based
on the rates provided by Memorial Sloan Kettering Cancer Center for each of the
NCI/CTEP defined categories.
Sex/Gender
Ethnic Category
Females
Males
Total
Hispanic or Latino
8
+
8
=
16
Not Hispanic or Latino
60
+
59
=
119
Ethnic Category: Total of all subjects
68
+
67
=
135
Racial Category
American Indian or Alaskan Native
+
=
Asian
5
+
4
=
9
Black or African American
9
+
9
=
18
Native Hawaiian or other Pacific Islander
+
=
White
54
+
54
=
108
Racial Category: Total of all subjects
68
+
67
=
135
Accrual Rate:
10 pts/month
13.2.3
Total Expected Accrual:
50
Min
135 Max
Requirements for Clinicaltrials.gov
Results Reporting on ClinicalTrials.gov: At study activation, this study will have
been registered within the “ClincialTrails.gov” web site. The Primary and
Secondary Endpoints (ie, “Outcome Measures”) along with other required
information for this study will be reported on ClinicalTrials.gov. For purposes of
timing of the Results Reporting, the initial estimated completion date for the
Primary Endpoint of this study is 20 months after the study opens to accrual. The
definition of “Primary Endpoint Completion Date” (PECD) for this study is the
time the last patient registered has been followed for at least 6 months.
13.3 Grouping Factors
Patient will be assigned to a cohort depending on the histologic sub-type of sarcoma, and
identified administratively as the following.
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•
Cohort 1: Liposarcoma
•
Cohort 2: Leiomyosarcoma (non-uterine)
•
Cohort 3: Undifferentiated Sarcoma (including Pleiomorphic Undifferentiated Sarcoma,
formerly known as Malignant Fibrous Histiocytoma, and Myxofibrosarcoma)
•
Cohort 4: Malignant Peripheral Nerve Sheath Tumor
•
Cohort 5: Other Sarcomas
13.4 Analysis of Secondary Endpoints & Correlative End Points
13.4.1
Progression-free survival (PFS) & Overall Survival (OS): PFS will be
calculated as the time between registration and disease progression or death.
Patients lost to follow-up will be censored at the date of their most recent disease
assessment. Overall Survival (OS) will be calculated as the time between
registration and death. Again, patients lost to follow-up will be censored at their
most recent date last known alive. The distributions of PFS and survival will be
estimated using the methods of Kaplan and Meier [62] . The estimates of PFS and
survival at specific time points will be calculated (eg, median, 1 year PFS, 6
month survival). No direct comparisons across cohorts will be performed as this
study lacks sufficient power to draw meaningful statistical conclusions. All
patients will be followed for a period of 18 months post-registration and for
survival.
13.4.2 Adverse Events: Adverse events will be summaries using summary statistics and
frequency tables for each separate cohort. Analyses will be descriptive in nature.
13.4.3 Correlative Endpoints
Analyses of the correlative endpoints will be exploratory and hypothesisgenerating. For tumor biopsies, pre- and post-treatment protein levels will be
compared by Wilcoxon signed-rank test (for paired samples). The association of
response or clinical benefit with the presence or absence of markers of pathway
inhibition in patient tumors will be tested using Fisher’s exact test. Changes in
FLT-PET uptake at baseline versus after one week of treatment will be compared
by Wilcoxon Rank Sum test between responders and non-responders defined by
RECIST criteria. An exploratory analysis will be performed to identify clinical
meaningful thresholds for classifying patients into FLT-PET responders (high
change in FLT-PET uptake) versus FLT-PET non-responders (low change in
FLT-PET uptake). The receiver operating characteristic (ROC) curve will be
reported using RECIST response status as “gold” standard. Candidate thresholds
in FLT-PET uptake change will be selected based on ROC curve. Each threshold
will classify patients into high vs. low change in FLT-PET uptake subgroups.
Fisher’s exact test will be used to assess the association between dichotomous
change in FLT-PET uptake change and RECIST response status. We acknowledge
the exploratory nature of this analysis. The findings are subject to further
validation in an independent study.
13.5 Reporting and Exclusions
13.5.1
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All patients will be evaluable for adverse events from the time of their first
treatment with MLN8237. Patients determined to be ineligible after having
started treatment will be included in the assessment of toxicity for MLN8237.
Summary statistics and frequencey tables will be used to describe the
distributions of toxicity.
13.5.2
Evaluation of response
Each patient will be assigned one of the following categories: 1) complete
response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early
death from malignant disease, 6) early death from toxicity, 7) early death because
of other cause, or 8) unknown (not assessable, insufficient data). [Note: By
arbitrary convention, category 8 usually designates the “unknown” status of any
type of data in a clinical database.]
We are conducting our analyses using “Per Protocol” (vs Intention to Treat)
principles. That is, our analyses will be performed on the basis of a subset of
patients enrolled to this trial and will exclude patients deemed ineligible,
cancelled, or in major treatment violation. Reasons for excluding patients from
the analysis will be clearly reported. All eligible patients will be classified as
evaluable for assessing the primary endpoint if they have at least one cycle of
treatment and been assessed for response to treatment. Patients in response
categories 4-8 should be considered to have a treatment failure (disease
progression) and are deemed evaluable. Thus, an incorrect treatment schedule or
drug administration does not result in exclusion from the analysis of the response
rate.
The 95% confidence intervals should also be provided and estimated using the
method of Duffy and Santner [62]
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APPENDIX A
Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
100
0
Normal activity. Fully active, able to
carry on all pre-disease performance
without restriction.
1
2
3
4
5
Symptoms, but ambulatory.
Restricted in physically strenuous
activity, but ambulatory and able to
carry out work of a light or sedentary
nature (e.g., light housework, office
work).
In bed <50% of the time. Ambulatory
and capable of all self-care, but
unable to carry out any work
activities. Up and about more than
50% of waking hours.
In bed >50% of the time. Capable of
only limited self-care, confined to bed
or chair more than 50% of waking
hours.
90
80
Normal activity with effort; some signs
or symptoms of disease.
70
Cares for self, unable to carry on
normal activity or to do active work.
60
50
40
30
100% bedridden. Completely
disabled. Cannot carry on any selfcare. Totally confined to bed or chair.
20
Dead.
0
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63
Description
Normal, no complaints, no evidence of
disease.
Able to carry on normal activity; minor
signs or symptoms of disease.
10
Requires occasional assistance, but is
able to care for most of his/her needs.
Requires considerable assistance and
frequent medical care.
Disabled, requires special care and
assistance.
Severely disabled, hospitalization
indicated. Death not imminent.
Very sick, hospitalization indicated.
Death not imminent.
Moribund, fatal processes progressing
rapidly.
Dead.
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ALLIANCE A091102
APPENDIX B
Pill Diary for Alliance A091102:
A Phase 2 Study of MLN8237 in Advanced / Metastatic Sarcoma
Number of Pills Given:___________ Pill Bottle(s) returned: Circle Yes or No
Total Daily Dose:________________ Number of Pills returned:___________
(To be completed by RN)
PLEASE FILL OUT AND BRING THIS SHEET AT YOUR NEXT VISIT.
Please remember to take your pills without food (except for water and prescribed medications
at least 1 hour before and 2 hours after). Pills should be taken at approximately the same time
each day with 8 ounces of water (1 cup). You will be asked to maintain the below pill diary for
each dose of medication.
CYCLE #: _____
DAY
MEDICATION
Example
MLN8237
Day 1
MLN8237
Day 2
MLN8237
Day 3
MLN8237
Day 4
MLN8237
Day 5
MLN8237
Day 6
MLN8237
Day 7
MLN8237
DATE
01/01/2010
TIME
9:00
9:00
NUMBER of 10mg
tablets taken
AM/PM
AM/PM
AM/PM
AM/PM
AM/PM
AM/PM
AM/PM
AM/PM
AM/PM
AM/PM
AM/PM
AM/PM
AM/PM
AM/PM
AM/PM
AM/PM
5
5
Patient Signature: ____________________________________ Date: __________
Consenting Professional/Research RN Signature: ____________________
Date: ______________
Consenting Professional/Research RN
Comments:___________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
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