1. health and fitness
2. therapy

CLINICAL STUDY PROTOCOL
Phase 1 study to evaluate the feasibility and efficacy
of the addition of P1101 (PEG-Proline-Interferon
alpha-2b) to imatinib treatment in patients with
chronic phase chronic myeloid leukaemia
not achieving a complete molecular response
(MR 4.5 or BCR-ABL transcripts not detectable)
AGMT_CML 1
Coordinating Investigator:
Univ.- Prof. Dr. Josef Thaler/ OA Dr. Sonja Burgstaller
Protocol Version: 2, 04-Apr-2013
EudraCT number: 2013-000115-24
An academic clinical trial sponsored by
CONFIDENTIALITY STATEMENT
The information contained in this document is the property of the AGMT and therefore is
provided to you in confidence for review by you, your staff, an applicable Ethics
Committee/Institutional Review Board and regulatory authorities. It is understood that the
information will not be disclosed to others without prior written approval from the AGMT,
except to the extent necessary to obtain informed consent from those persons to whom the
medication may be administered.
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COORDINATING INVESTIGATOR:
Univ.- Prof. Prim. Dr. Josef Thaler
Dept. Internal Medicine IV
Grieskirchnerstr. 42
4600 Wels, Austria
e-mail: [email protected]
COORDINATING INVESTIGATOR AND PROTOCOL CONTACT PERSON:
OA Dr. Sonja Burgstaller
Dept. Internal Medicine
Grieskirchnerstr. 42
4600 Wels, Austria
e-mail: [email protected]
STATISTICS:
Ao. Univ.- Prof. Dr. Mag. Hanno Ulmer
Medizinische Universität Innsbruck
Department für medizinische Statistik, Informatik und Gesundheitsökonomie
Schöpfstraße 41/1, 6020 Innsbruck, Austria
e-mail: [email protected]
SPONSOR:
Arbeitsgemeinschaft medikamentöse Tumortherapie gemeinnützige GmbH
Klinisch-wissenschaftlicher Geschäftsführer: Prim. Univ. Prof. Dr. Richard Greil
Nußdorferplatz 8
1190 Wien, Austria
phone: +43 662/4482 2899
e-mail: [email protected]
STUDY MANAGEMENT:
Arbeitsgemeinschaft medikamentöse Tumortherapie gemeinnützige GmbH
Mag. Alexandra Keuschnig
Universitätsklinik f. Innere Medizin III
Universitätsklinikum der PMU
Müllner Hauptstraße 48, 5020 Salzburg, Austria
phone: +43 664/1648243
e-mail: [email protected]
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Protocol version 2, 04-Apr-2013: Summary of major changes
For detailed description please refer to the amendment tracking log (Appendix 5)
The definition of complete molecular response in this protocol was changed from MR 4 or
below to MR 4.5 or below.
Therefore the protocol title, the exclusion criteria and the description of the efficacy
assessment was adapted.
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AGMT_CML 1
Protokoll Version 2 (04-Apr-2013)
SPONSOR APPROVAL PAGE:
_____________________________
_______________
Univ.- Prof. Dr. Richard Greil
Date
Klinisch-wissenschaftlicher Geschäftsführer der AGMT gGmbH
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AGMT_CML 1
Protokoll Version 2 (04-Apr-2013)
INVESTIGATOR AGREEMENT PAGE
I have thoroughly read and reviewed the study protocol “Phase 1 study to evaluate the
feasibility and efficacy of the addition of P1101 (PEG-Proline-Interferon alpha-2b) to imatinib
treatment in patients with chronic phase chronic myeloid leukaemia not achieving a
complete molecular response (MR 4.5 or BCR-ABL transcripts not detectable)” Version 2, 04Apr-2013. Having read and understood the requirements and conditions of the study
protocol, I agree to perform the clinical study according to the international good clinical
practice principles and regulatory authority requirements.
I understand that changes to the protocol must be made in form of an official amendment.
I agree to report all serious adverse events, whether considered treatment-related or not
within 24 hours.
____________________________
Investigator Name
____________________________
Investigator Signature
AGMT_CML 1
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Date
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Table of Content
1.
ABBREVIATIONS ...................................................................................................................................... 8
2.
STUDY SUMMARY ................................................................................................................................. 10
3.
INTRODUCTION ..................................................................................................................................... 11
4.
5.
6.
3.1.
BACKGROUND AND RATIONAL FOR THE STUDY............................................................................................... 11
3.2.
INTERFERON ALPHA ................................................................................................................................. 12
3.3.
IMATINIB ............................................................................................................................................... 12
3.4.
COMBINATION THERAPY OF IMATINIB AND INTERFERON ALPHA......................................................................... 13
3.5.
P1101 (AOP2014) ............................................................................................................................... 14
INVESTIGATIONAL PLAN........................................................................................................................ 15
4.1.
STUDY OBJECTIVES................................................................................................................................... 15
4.2.
STUDY DESIGN ........................................................................................................................................ 15
4.3.
PREMATURE WITHDRAWAL ....................................................................................................................... 15
4.4.
END OF STUDY........................................................................................................................................ 16
4.5.
STUDY POPULATION................................................................................................................................. 16
4.5.1.
Patient population ......................................................................................................................... 16
4.5.2.
Inclusion criteria ............................................................................................................................ 16
4.5.3.
Exclusion criteria ........................................................................................................................... 16
TREATMENT .......................................................................................................................................... 17
5.1.
GENERAL ............................................................................................................................................... 17
5.2.
IMATINIB ............................................................................................................................................... 17
5.3.
P1101 ................................................................................................................................................. 17
DOSE MODIFICATION ............................................................................................................................ 17
6.1.
GRADE < 2 HAEMATOLOGICAL AND GRADE ≤ 2 NON HAEMATOLOGICAL TOXICITIES .............................................. 17
6.2.
GRADE ≥ 2 HEAMTOLOGICAL AND GRADE 3/4 NON HAEMATOLOGICAL TOXICITIES (DLT) ...................................... 17
7.
CONCOMITANT THERAPY ...................................................................................................................... 18
8.
VISIT SCHEDULES AND ASSESSMENTS ................................................................................................... 19
9.
8.1.
SCREENING ............................................................................................................................................ 19
8.2.
VISITS EVERY 14 DAYS .............................................................................................................................. 19
8.3.
VISITS EVERY 4 WEEKS .............................................................................................................................. 20
8.4.
VISITS EVERY 8 WEEKS .............................................................................................................................. 20
8.5.
VISITS EVERY 12 WEEKS ............................................................................................................................ 20
8.6.
TREATMENT FAILURE ............................................................................................................................... 20
8.7.
FINAL VISIT ............................................................................................................................................ 20
EFFICACY ASSESSMENT ......................................................................................................................... 21
9.1.
MONITORING OF MOLECULAR RESPONSE BY REAL-TIME QUANTITATIVE PCR (RQ-PCR)........................................ 21
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10.
SAFETY .................................................................................................................................................. 21
10.1.
DEFINITION OF AE AND SAE ..................................................................................................................... 21
10.1.1.
Adverse Event (AE) .................................................................................................................... 21
10.1.2.
Serious Adverse Event (SAE): .................................................................................................... 22
10.1.3.
Events not to be treated as SAEs .............................................................................................. 22
10.1.4.
AE and SAE documentation ...................................................................................................... 22
10.2.
SAE REPORTING ..................................................................................................................................... 24
10.3.
REPORTING PREGNANCIES ......................................................................................................................... 24
10.4.
FOLLOW UP OF (S)AES............................................................................................................................. 24
10.5.
REPORTING TO REGULATORY AUTHORITIES AND THE ETHICS COMMITTEES ........................................................... 25
11.
STATISTICAL METHODS ......................................................................................................................... 25
11.1.
STUDY DESIGN ........................................................................................................................................ 25
11.2.
SAMPLE SIZE .......................................................................................................................................... 25
11.3.
POPULATIONS ........................................................................................................................................ 25
11.4.
BACKGROUND AND DEMOGRAPHIC CHARACTERISTICS ..................................................................................... 25
11.5.
EFFICACY EVALUATION ............................................................................................................................. 25
11.6.
SAFETY EVALUATION ................................................................................................................................ 26
12.
ADMINISTRATIVE CONSIDERATIONS ..................................................................................................... 26
12.1.
LOCAL REGULATIONS / DECLARATION OF HELSINKI......................................................................................... 26
12.2.
INFORMED CONSENT ............................................................................................................................... 26
12.3.
INDEPENDENT ETHICS COMMITTEES ............................................................................................................ 26
12.4.
INSURANCE ............................................................................................................................................ 27
12.5.
CONDITIONS FOR TERMINATING THE STUDY .................................................................................................. 27
12.6.
AUDITS AND INSPECTIONS ......................................................................................................................... 27
12.7.
CASE REPORT FORMS ............................................................................................................................... 27
12.8.
CONFIDENTIALITY OF TRIAL DOCUMENTS AND PATIENT RECORDS ....................................................................... 27
12.9.
MONITORING THE STUDY .......................................................................................................................... 27
13.
REFERENCE LIST..................................................................................................................................... 28
APPENDIX 1: VISIT SCHEDULE ......................................................................................................................... 31
APPENDIX 2: ECOG PERFORMANCE STATUS ................................................................................................... 32
APPENDIX 3: ELN RESPONSE CRITERIA ........................................................................................................... 33
APPENDIX 4: DECLARATION OF HELSINKI ....................................................................................................... 35
APPENDIX 5: AMENDMENT TRACKING LOG ................................................................................................... 40
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1.
ABBREVIATIONS
ANA
Anti-nuclear antibodies
AE
Adverse event
ASH
American Society of Hematology
CCyR
Complete cytogenetic response
CHR
Complete haematological response
CML
Chronic myeloid leukaemia
CMR
Complete molecular remission
CRF
Case report form
CTEP
Cancer therapy evaluation program
DLT
Dose limiting toxicity
DNA
Deoxyribonucleic acid
ECOG
Eastern Cooperative Oncology Group
EDTA
Ethylenediaminetetraacetic acid
ELN
European leukemia net
FDA
Food and Drug Administration
FPI
First patient in
HIV
human immunodeficiency virus
IFN
Interferon
IND
Investigational new drug
ITT
Intention to treat
LPO
Last patient out
MCyR
Major cytogenetic response
MIU
Million international units
MMR
Major molecular response
NCI-CTCAE National Cancer Institute – Common Terminology Criteria for
Adverse Events
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OS
Overall survival
PCR
Polymerase chain reaction
PDGF
Platelet-derived growth factor
PEG
Pegylated
Ph
Philadelphia chromosome
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RQ-PCR
Real-time quantitative polymerase chain reaction
SCF
Stem cell factor
SAE
Severe adverse event
TgAb
Thyroglobulin antibodies
TKI
Tyrosin kinase inhibitor
TPOAb
Thyroid peroxidase antibody
TSH
Thyroid stimulating hormone
WBC
White blood cell
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2.
STUDY SUMMARY
Trial ID:
AGMT_CML 1
EudraCT number:
2013-000115-24
Protocol title:
Phase 1 study to evaluate the feasibility and efficacy of the
addition of P1101 (PEG-Proline-Interferon alpha-2b) to
imatinib treatment in patients with chronic phase chronic
myeloid leukaemia not achieving a complete molecular
response (MR 4.5 or BCR-ABL transcripts not detectable)
Protocol version:
Version 2
Date of protocol:
04-Apr-2013
Coordinating Investigator:
Univ.- Prof. Dr. Josef Thaler/ OA Dr. Sonja Burgstaller
Sponsor:
AGMT – Arbeitsgemeinschaft medikamentöse Tumortherapie
gemeinnützige GmbH
Project Phase:
Uncontrolled, open-label phase I pilot study
Indication:
Pretreated BCR-ABL positive chronic myeloid leukaemia in
chronic phase
Objectives:
Primary endpoint: Safety and tolerability
Secondary endpoint: Efficacy
Study design:
Imatinib (at the same dose level as before study entry),
additional P1101 (every 14 days) for 18 months
Planned sample size:
12 patients
Selection criteria:
Imatinib treatment for at least 18 months before study entry;
achievement of a CHR and CCyR; no complete molecular
remission.
Duration of the Study:
19 months (The study duration for each patient will be 18
months treatment plus 1 month AE follow up.)
Recruitment period:
12 months
FPI:
Q2 2013
LPO:
Q4 2015
End of Study:
Last patient last visit. (Final visit 28 days after last
administration of study drug.)
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3.
INTRODUCTION
3.1.
Background and rational for the study
Chronic myeloid leukaemia (CML) is a clonal stem cell disorder characterized by the presence
of the Philadelphia chromosome (Ph). This reciprocal translocation between chromosomes 9
and 22 [t(9;22)(q34;q11)] results in a BCR-ABL fusion protein with a constitutively activated
tyrosine kinase [1,2,3]. The introduction of imatinib, an oral inhibitor targeting the ABL
tyrosine kinase revolutionized therapy of CML. However, up to now allogeneic stem cell
transplantation has been considered the only curative treatment option for patients with
CML. The dependence on age and donor type has limited the offer of stem cell
transplantation to a minority of patients.
The use of imatinib has been approved for the treatment of pretreated and de novo CML
since 2001 and 2003, respectively. Based on the results of the phase 3 International
Randomized Study of Interferon and STI571, imatinib has been recommended as first line
therapy [4]. Seven year data of the IRIS trial report on 82% of patients achieving a complete
cytogenetic response (CCyR), overall survival (OS) at 7 years is 86% [5]. However, complete
molecular remission (CMR) is only achieved in a minority of patients. Moreover, in a subset
of patients the efficacy of imatinib is even not sufficient to induce complete cytogenetic
responses and these patients are then considered as treatment failures.
Interferon (IFN) alpha was introduced into the treatment of CML in the early 1980s and was
recommended as first line treatment until 2001. The activity of IFN alpha is based on a
variety of biological activities including antiproliferative, immunomodulatory and
antiangiogenic effects [6]. Furthermore IFN alpha promotes cycling of dormant malignant
stem cells [7, 8]. Taken all these points into consideration the combination of TKIs with IFN
alpha might be a valuable strategy for optimizing treatment in patients with CML.
The French SPIRIT trial tested the approach of combining imatinib 400mg daily plus
pegylated interferon alpha-2a 90µg and imatinib 400mg daily plus cytarabine against
imatinib 400mg or 600mg daily. The addition of pegylated interferon resulted in significantly
higher rates of major molecular responses and complete molecular responses at 12 months
[9]. Adverse events were higher in the combination treatment arms as well as in the imatinib
600mg arm compared to the imatinib 400mg arm.
The german CML IV study compared imatinib 400mg/d verus imatinib 400mg/d in
combination with IFN-alpha versus imatinib 800mg/d. This investigation was not able to
show a higher response rate for the combination of imatinib and interferon alpha, but early
high dose imatinib therapy increased the rate of MMR at 12 months [10]. In contrast, the
very recent publication by the Nordic CML study group underscores the therapeutic
potential of pegylated interferon in combination with imatinib, as they could increase the
MMR rate at 12 months in the imatinib+Peg-IFN-α2b arm by 28% when compared to the
imatinib monotherapy arm [11]. Of note, the studies used different types of interferon, i.e.
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the French and the Nordic study used pegylated interferon whereas the german study used
conventional interferon. Therefore pegylated interferon might have an advantage over
conventional interferon. A comparison between pegylated and conventional interferon in
patients with CML conducted in the pre-imatinib era showed higher response rates
(haematological and cytogenetic) in patients receiving pegylated interferon alpha [12].
P1101 (PEG-Proline-Interferon alpha-2b) is a long-acting third generation interferon resulting
in a less frequent dosing regimen. The drug has reached IND approval for treatment of
hepatitis B and C by the FDA. A phase I trial (P1101 every two weeks) in patients with
polycythemia vera is ongoing in Austria.
Mainly based on in vivo evidence imatinib alone is not able to eradicate the whole BCR-ABL
clone. In the majority of CML patients BCR-ABL transcripts are still detectable even after
years of imatinib treatment. The addition of P1101 to current imatinib treatment is expected
to deepen molecular remission and increase the rate of complete molecular remission. The
French STIM study tested stopping imatinib treatment in patients who achieved a complete
molecular remission. A certain proportion of patients were able to stay without treatment
for a median follow up of 30 months now. These patients might be cured by conventional
therapy. Therefore achieving a complete molecular remission is the main goal of CML
therapy.
3.2.
Interferon alpha
Interferon alpha has been used to treat different malignant and viral disorders for more than
two decades. The activity of interferon alpha is based on a variety of biological activities
including antiproliferative, immmunomodulatory and antiangiogenic effects [6].
Furthermore interferon alpha promotes cycling of dormant malignant stem cells [7, 8].
Before the introduction of imatinib, interferon alpha based regimens have been used as first
line treatment for patients with CML not eligible for allogeneic stem cell transplantation [1316]. Haematological, cytogenetic and even molecular responses were achieved with
interferon alpha. However, using active dosages of interferon was associated with significant
toxicities including depression and neurologic disturbances. Conventional interferon alpha
needs to be administered daily or two to three times weekly for sustained efficacy. To
overcome this frequent administration 2 forms of pegylated interferon alpha have been
developed with a prolonged half-life. Pegylated forms of interferon alpha need to be
administered only once weekly. This modified administration form led to higher
haematological and cytogenetic responses and improved overall survival [12]. Safety profile
and tolerance are comparable or even slightly better than with conventional interferon
alpha [17]. A synergistic effect of interferon alpha and imatinib has been shown in vitro [18].
3.3.
Imatinib
Imatinib is a protein-tyrosine kinase inhibitor inhibiting the BCR-ABL tyrosine kinase. This
constitutively active tyrosine kinase created by a reciprocal translocation t(9;22)(q34;q11)
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plays the central pathogenetic role in CML. Imatinib inhibits proliferation and induces
apoptosis in BCR-ABL positive cell lines and fresh leukemic cells from PH+ CML. Imatinib
inhibits furthermore receptor tyrosine kinases of platelet-derived growth factor (PDGF) and
stem cell factor (SCF), c-KIT [19].
On the basis of the results of the International Randomized Study of Interferon and STI571
(IRIS) imatinib is recommended as first line treatment for first line treatment of chronic
phase CML [4, 5]. This study compared treatment with either single-agent imatinib or a
combination of interferon alpha plus cytarabine. Patients showing lack of response (loss of
complete haematological response (CHR) at 6 months, increasing WBC nor major
cytogenetic response (MCyR) at 24 months), loss of response or severe intolerance to
treatment were allowed to crossover to the alternative treatment arm. Patients were
treated with 400mg imatinib daily in the imatinib arm and with a target dose of
5 MIU/m²/day interferon alpha subcutaneously in combination with cytarabine
20 mg/m²/day subcutaneously for 10 days/month. A total of 1106 patients have been
randomized. Seven year data of the IRIS trial report on 82% of patients achieving a CCR, OS
at 7 years is 86% [5]. However, long-term data of the IRIS trial also show that not all
patientsare able to maintain long term molecular remissions with imatinib therapy. About
one quarter to one third of the patients become resistant or intolerant [20]. In the meantime
two second generation TKIs gained approval for first line treatment of chronic phase CML.
Nilotinib as well as dasatinib showed higher rates of major molecular response and CCyR
after 12 months compared to imatinib treatment [21, 22]
3.4.
Combination therapy of imatinib and interferon alpha
Considering the facts discussed previously, reincorporation of interferon alpha into
treatment strategies for CML patients becomes more and more reasonable and interesting.
The French SPIRIT trial randomly assigned 636 patients with untreated chonic-phase CML to
receive imatinib alone at a dose 400mg daily, imatinib (400mg daily) plus cytarabine
(20mg/m²/day in days 15 to 28 of each 28 day cyle) or pegylated interferon alfa-2a (90µg
weekly), or imatinib alone at a dose of 600mg daily. The addition on pegylated interferon
resulted in significantly higher rates of molecular responses at 12 months (superior
molecular response 30% in patients receiving imatinib 400mg plus pegylated interferon vs
14% in patients receiving 400mg imatinib alone). Cytogenetic responses were similar in all
groups. Adverse events occurred more frequently in the interferon arm (and imatinib 600mg
and cytarabine arm) than with imatinib 400mg alone. Comparing the imatinib 400mg arm
and the interferon arm higher rates of grade 3 or 4 rash, depression, asthenia and edema
have been reported for the latter one. A high proportion of patients (45%) discontinued
interferon treatment during the first year [9]. Thus first results of the amended protocol with
a reduced dose of pegylated interferon alpha (45µg weekly) were presented at ASH 2011.
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Similar rates of molecular responses have been achieved, while early toxicity was less with
the lower dose of pegylated interferon alpha [23].
The Nordic CML study group reported recently their results of the combination of 50µg
pegylated interferon alpha 2b weekly with 400mg imatinib daily. They also found an
increased rate of molecular responses in the interferon arm at 12 months (82% vs 54%).
Though in this study a lower dose of pegylated interferon than in the french study has been
used, 61% of patients discontinued treatment in the combination arm - mainly due to
toxicity. Therefore the authors of this study concluded that even lower doses of interferon
may enhance tolerability and could be used in future protocols [11].
The german CML IV study included a combination arm of imatinib 400mg daily with
conventional interferon alpha and compared this arm with imatinib 400mg daily alone
versus imatinib 800mg daily alone. This investigation was not able to show higher response
rates for the combination of imatinib and interferon alpha., but early high dose imatinib
increased the rate of MMR at 12 months.
In contrast to the French and Nordic study using pegylated interferon, the german study
used conventional interferon. Therefore pegylated interferon might have an advantage over
conventional interferon as shown in a comparison between those two different types of
interferon by Lipton et al. In patients with CML pegylated interferon achieved higher
haematological and cytogenetic responses than conventional interferon [12].
3.5.
P1101 (AOP2014)
P1101 is a new formulation of pegylated interferon alpha-2b. This agent has only one major
positional isomer, resulting in one single major active compound. Proline-interferon alpha2b (P1040), the starting material used to manufacture P1101, is a water-soluble protein with
a molecular weight of 19362 daltons produced by recombinant DNA techniques. The Prolineinterferon alpha-2b is purified from the bacterial fermentation of an E. coli strain
transformed with a plasmid bearing the genetically- engineered gene coding for human
interferon alpha fused with methionine and proline at the amino-terminus. The aminoterminal methionine residue of the translated product is cleaved by endogenous methionine
aminopeptidase producing the Proline-interferon alpha-2b polypeptide. The result of this
manufacturing process is an improved pegylated molecule coupling procedure resulting in a
PEG-P-IFNalpha-2b molecule with only one major site-specific coupling position with a
molecular weight of 40K, considered the limit for a PEG molecule for administration to
humans.
P1101 will be administered subcutaneously every 14 days. Due to the new formulation a
better tolerability is suspected.
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4.
INVESTIGATIONAL PLAN
4.1.
Study objectives
Primary objective: to determine the safety and tolerability of the addition of P1101 to the
currently established dose of imatinib.
Secondary objective: to determine the rate of achievement of ≥ 1 log reduction from the
initial BCR-ABL transcript level at study entry and the achievement of molecular remission
4.5 or undetectable BCR-ABL transcripts.
4.2.
Study design
This is a phase 1, open label pilot study of adding P1101 to treatment with imatinib in
patients with CML in chronic phase. Patients are eligible, if a molecular remission 4.5 or
below has not been achieved with imatinib therapy alone after at least 18 months of therapy.
Only patients achieving a CHR and a CCyR at study entry will be included. P1101 will be
added in a dose of 50µg subcutaneously every 14 days. In the absence of a dose limiting
toxicity (DLT), i.e. haematological toxicity ≥ grade 2, non haematological toxicity ≥ grade 3,
after 12 weeks of therapy, P1101 will be increased to 100µg subcutaneously every 14 days
(refer to 6.2.). In the absence of a DLT after another 12 weeks of therapy, treatment will be
continued with the same dose level for further 12 months. A dose of 100µg every 14 days is
considered as maximum dose.
Imatinib will be continued at the same dose level as before study entry.
Imatinib (at the same dose level as before study entry)
P1101 100 µg
every 14 days
12 weeks
P1101 50µg every 14 d
12 weeks
P1101 100 µg
every 14 days
further 12 months
MR assessment every 12 weeks
28d
Final Visit
CHR
CCyR
no MR 4.5 or below
Screening
>18 months Imatinib
MR
Figure 1: Study design
4.3.
Premature withdrawal
Study participation/treatment will be discontinued in case of
-
Withdrawal of patients consent
-
Investigators decision in best interest of patient
-
Treatment failure according to ELN criteria (appendix 3) during treatment period
-
Unacceptable toxicity
-
Study termination after DLTs according to 6.2.
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Moreover patients must be withdrawn under the following circumstances:
-
Pregnancy or lack of adequate contraception in women of childbearing potential
-
Major protocol violation considered to be relevant by the Investigator and/or the
sponsor
In case of premature withdrawal of the patient from the study, the patient should attend a
final visit.
End of Study
4.4.
Study end will be at last patient last visit. The study duration for each patient will be 18
months treatment plus 28 days AE follow up.
Study population
4.5.
4.5.1.
Patient population
A total of 12 patients with BCR-ABL positive CML in chronic phase will be included. Patients
must be on imatinib treatment for at least 18 months. The achievement of a CHR and CCyR
are mandatory. A complete molecular remission (molecular remission 4.5 or BCR-ABL
transcripts undetectable) is not allowed.
4.5.2.

Inclusion criteria
Patients ≥ 18 years of age

BCR-ABL positive chronic myeloid leukaemia in chronic phase treated with
imatinib as first line therapy

CHR, CCyR after at least 18 months of imatinib treatment

Adequate organ function, defined as the following:
total bilirubin < 1.5 x ULN, AST and ALT < 2.5 x ULN, creatinine < 1.5 x ULN,
ANC > 1.5 x 109/L, platelets > 100 x 109/L

Written, voluntarily signed informed consent

Exclusion criteria
CMR (molecular remission 4.5 or BCR-ABL transcripts undetectable)
4.5.3.

Patient has received any other investigational treatment within 28 days before
study entry

Treatment with a second generation tyrosine kinase inhibitor (dasatinib, nilotinib)

ECOG performance status ≥ 3

Patients with a primary of a different histological origin than the study indication
(unless relapse-free interval is ≥ 5 years, except cervical carcinoma, basal cell
epithelioma or squamous cell carcinoma of the skin)

Evidence of severe or uncontrolled systemic disease (e.g. unstable or
uncompensated respiratory, cardiac, hepatic or renal disease etc.)
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
Acute chronic infections

Known autoimmune disease (e.g. collagen disease, polyarthritis, immune
thrombocytopenia, thyroiditis, psoriasis, lupus nephritis or any other
autoimmune disorder)

Female patients who are pregnant or breast-feeding

Known diagnosis of HIV
5.
TREATMENT
5.1.
General
Patients with chronic phase chronic myeloid leukaemia are treated with imatinib for at least
18 months. Achievement of CHR and CCyR are mandatory before entering the study.
5.2.
Imatinib
Imatinib will be continued at the same dose level as before study entry. Dose modifications
are limited to interferon therapy.
5.3.
P1101
P1101 will be added in a dose of 50µg subcutaneously every 14 days. In the absence of a
dose limiting toxicity (DLT) at 12 weeks the dose of P1101 will be increased to 100µg
subcutaneously every 14 days. DLT is defined as haematological toxicities grade ≥ 2 or non
haematological toxicities grade ≥ 3. 100µg P1101 is considered as the maximum dose,
further increase of P1101 is not planned. Maximum treatment duration will not expand 18
months.
6.
DOSE MODIFICATION
6.1.
Grade < 2 haematological and grade ≤ 2 non haematological
toxicities
No dose interruptions or reductions are planned for grade 1 haematological and grade 1 or 2
non haematological toxicities.
6.2.
Grade ≥ 2 heamtological and grade 3/4 non haematological
toxicities (DLT)
A dose limiting toxicity (DLT) is defined as grade 2 or more haematological or grade 3 or 4
non haematological toxicity.
If the patient experiences a DLT with 50µg every 14 days, study drug must be withheld until
the toxicity has resolved to ≤ grade 1. P1101 can be reintroduced with 50 µg every 14 days. If
another DLT occurs, P1101 must be stopped and study participation will be discontinued.
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After reintroduction of P1101 with 50µg every 14 days, the dose can be increased to 100µg
every 14 days in the absence of any DLT after another 12 weeks.
If the patient experiences a DLT with 100µg P1101, study drug (P1101) must be withheld
until the toxicity has resolved to ≤ grade 1. After reintroduction of P1101 with 50µg every 14
days, the dose can be increased to 100µg every 14 days in the absence of any DLT after
another 12 weeks. If another DLT (re)occurs with 100µg every 14 days, study drug must be
stopped again until the toxicity resolved to ≤ grade 1. P1101 can be reintroduced with 50µg
every 14 days. Another increase to 100µg every 14 days is not permitted.
50 µg
every 14 days
no DLT
for 12 weeks
100 µg
every 14 days
DLT
Withhold until < grade 1
restart with 50 µg
DLT
no DLT
for 12 weeks
and <2 former
DLT at 100 µg
DLT
Study termination
no DLT
and 2 former
DLT at 100 µg
100 µg
every 14 days
50 µg
every 14 days
Figure 2: Dose modification scheme for P1101 in case of dose limiting toxicities
7.
CONCOMITANT THERAPY
In general, concomitant medications and therapies necessary for supportive care and safety
of the patient are allowed. The administration of any other anticancer agent or other
concurrent investigational drug is not permitted.
All relevant concomitant medication including over the counter drugs must be reported in
the Case Report Form (CRF).
Paracetamol and antihistamines can be used according to local clinical practice for the
prevention and treatment of injection site reactions associated with P1101. Paracetamol (eg
500 - 1000mg p.o.) is highly recommended to be administered 8 - 10 hours, 24 hours and 48
hours after the first administration of P1101 in order to avoid potential flu-like symptoms.
Because of the inherent risk of either reduced activity or enhanced toxicity of the
concomitant medication and/or imatinib, drugs known to interact with the same CYP450
isoenzymes (2D and 3A4) as imatinib should be used with caution (check drug interactions
programs).
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8.
VISIT SCHEDULES AND ASSESSMENTS
Patients must be followed at the study site according to the visit schedule and assessments
outlined in appendix 1.
All assessments have to be performed within ±3 days of the day indicated on the visit
schedule. To avoid weekly visits, assessments 8.2 to 8.5 can be adjusted in case of delay of
P1101.
8.1.
Screening
1. Written informed consent has to be obtained before any study-specific medical
procedures are performed.
2. All responses to inclusion criteria need to be yes, all response to exclusion criteria
need to be no.
3. Demographics and medical history should include previous and current diseases and
all relevant past and current medications (including over the counter medications
and herbal remedies).
4. Complete physical examination including palpation of spleen (size of palpable spleen
in cm below rib)
5. Evaluation of haematologic remission according to ELN criteria (appendix 3; [24])
6. Vital signs including pulse rate, blood pressure, body temperature
7. ECOG performance status (appendix 2)
8. Women of childbearing potential: pregnancy test
9. Laboratory assessment:
haematology parameters: including platelet count, WBC count, differential:
granulocytes, % basophils
blood chemistry: liver values, kidney function tests, electrolytes
immunological parameters: coombs test direct, anti-nuclear antibodies (ANA),
thyroglobulin antibodies (TgAb), thyroid peroxidase antibody (TPOAb), thyroid
stimulating hormone (TSH)
10. Send sample of peripheral blood to central laboratory for molecular assessment
(BCR-ABL ration using the International Scale). For details a separate laboratory
manual is provided.
8.2.
Visits every 14 days
Following assessments need to be obtained during and at the end of treatment:
1. Physical examination
2. Vital signs
3. ECOG performance status (appendix 2).
4. Haematology and blood chemistry as defined in 8.1.
5. Adverse events according to NCI-CTCAE version 4.0 need to be assessed.
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8.3.
Visits every 4 weeks
Following assessments need to be obtained additional to assessments scheduled every 14
days until final visit:
1. Women of childbearing potential: pregnancy test
8.4.
Visits every 8 weeks
Following assessments need to be obtained additional to assessments scheduled every 14
days during treatment:
1. Immunological parameters: coombs test direct, anti-nuclear antibodies (ANA),
thyroglobulin antibodies (TgAb), thyroid peroxidase antibody (TPOAb), thyroid
stimulating hormone (TSH)
8.5.
Visits every 12 weeks
Molecular assessment is done every 12 weeks during and at the end of treatment. BCR-ABL
ratio is determined by a central laboratory using the International scale.
1. Send sample of peripheral blood to central laboratory for molecular assessment.
2. Evaluation of haematologic remission: Haematology and palpation of spleen
according to ELN criteria (appendix 3; [24])
8.6.
Treatment failure
In case of treatment failure and for occurrences of unexplained anemia, leucopenia, or
thrombocytopenia a cytogenetic response evaluation (% Ph+ metaphases according to ELN
criteria appendix 3) should be done according to local standard of care.
8.7.
Final Visit
28 days after discontinuing or completion of study treatment
1. Complete physical examination including palpation of spleen (size of palpable spleen
in cm below rib)
2. Evaluation of haematologic remission according to ELN criteria (appendix 3; [24])
3. Vital signs including pulse rate, blood pressure, body temperature
4. ECOG performance status (appendix 2)
5. Laboratory assessment:
haematology parameters: including platelet count, WBC count, differential:
granulocytes, % basophils
blood chemistry: liver values, kidney function tests, electrolytes
immunological parameters: coombs test direct, anti-nuclear antibodies (ANA),
thyroglobulin antibodies (TgAb), thyroid peroxidase antibody (TPOAb), thyroid
stimulating hormone (TSH)
6. Adverse event assessment according to NCI-CTCAE version 4.0
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7. Send sample of peripheral blood to central laboratory for molecular assessment.
9.
EFFICACY ASSESSMENT
9.1.
Monitoring of molecular response by real-time quantitative PCR
(RQ-PCR)
RQ-PCR monitoring of patients will be carried out using a European standardized approach
established by a European collaborative group [22]. Results of the RQ-PCR are reported
according to the international scale (IS) [23].
A major molecular response (MMR) is defined as a reduction of BCR-ABL transcripts to ≤
0.1% according to the IS. A reduction of BCR-ABL transcripts to ≤ 0.01% is defined as
molecular response 4 (MR 4), a reduction of BCR-ABL transcripts to ≤ 0.0032% is defined as
MR 4.5, and to ≤ 0.001% as MR 5.
In this protocol a complete molecular response is defined as MR 4.5 or BCR-ABL transcripts
not detectable.
10.
SAFETY
10.1.
Definition of AE and SAE
10.1.1.
Adverse Event (AE)
An AE is any untoward medical occurrence in a subject or clinical investigation subject
administered a pharmaceutical product and which does not necessarily have a causal
relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal
laboratory finding, for example), symptom, or disease temporally associated with the use of
a medicinal product, whether or not considered related to the medicinal product.
Pre-existing conditions should be considered AEs if there is either an increase in severity,
frequency or duration of the condition or an association with significantly worse outcomes.
Interventions for pre-existing conditions (e.g. elective cosmetic surgery) or medical
procedures that were planned before study enrolment are not considered AEs.
Laboratory test value abnormalities should not be recorded in the AE section of the CRF as
AEs unless they are considered clinically significant as defined below. Any treatmentemergent abnormal laboratory result that is clinically significant should be recorded as a
single diagnosis in the AE section of the CRF. Clinical significance is defined as meeting one or
more of the following conditions:



Accompanied by clinical symptoms
Leading to a change in study medication (e.g. dose modification, interruption or
permanent discontinuation)
Requiring a change in concomitant therapy (e.g. addition of, interruption of,
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discontinuation of, or any other change in a concomitant medication, therapy or
treatment)
Any laboratory abnormality fulfilling the criteria for an SAE should be reported as such, in
addition to being recorded as an AE in the CRF. Laboratory abnormalities grade 4 according
to NCI-CTCAE without life-threatening clinical symptoms should not be reported as SAE, if no
other SAE criteria applies.
10.1.2.
Serious Adverse Event (SAE):
A Serious Adverse Event is any untoward medical occurrence that at any dose:


resulted in death (was fatal, NOTE: death is an outcome, not an event)
was life-threatening
NOTE: The term ”life-threatening” refers to an event in which the subject was
at immediate risk of death at the time of the event; it does not refer to an
event which could hypothetically have caused death had it been more severe.

required in-subject hospitalization (at least one night stay) or prolongation of existing
hospitalization
resulted in persistent or significant disability/incapacity
is a congenital anomaly/birth defect
is an important medical event, i.e. events that might not be immediately life
threatening or result in death or hospitalisation but might jeopardise the subject or
might require intervention to prevent one or other of the outcomes listed above



Events without underlying AE (e.g. hospitalisation due to elective cosmetic surgery, for social
reasons or rehabilitation stay) are not considered SAEs. The full requirements of the
International Conference on Harmonisation (ICH) Guideline for Clinical Safety Data
Management, Definitions and Standards for Expedited Reporting, Topic E2 will be adhered to.
10.1.3.
Events not to be treated as SAEs
Progression of disease (including death due to the underlying malignant disease) is not to be
regarded as SAE.
Due to the seriousness of the disease in this study, certain conditions defined as SAEs will be
excluded from expedited reporting on a SAE report Form, i.e.:


Elective hospitalization and surgery for treatment of disease
Elective hospitalization to simplify treatment or study procedures
10.1.4.
AE and SAE documentation
All AEs must be documented in the appropriate section of the CRF.
Each AE will be evaluated by the investigator for:



Seriousness
Severity
Causal relationship
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The Severity will be assessed by the investigator according to the definitions in NCI-CTCAE
Version 4.0. AEs not listed in the NCI-CTCAE Version 4.0 should be graded according to the
following five-point scale:
 Grade 1 Mild (Discomfort noticed but no disruption of normal daily activity)
 Grade 2 Moderate (Discomfort sufficient to reduce or affect daily activity; no
treatment or medical intervention is indicated although this could improve the
overall well-being or symptoms of the subject)
 Grade 3 Severe (Inability to work or perform normal daily activity; treatment or
medical intervention is indicated in order to improve the overall well-being or
symptoms; delaying the onset of treatment is not putting the survival of the subject
at direct risk.)
 Grade 4 Life-threatening/disabling (An immediate threat to life or leading to a
permanent mental or physical condition that prevents work or the performing
normal daily activities; treatment or medical intervention is required in order to
maintain survival.)
 Grade 5 Death (AE resulting in death)
The Causal Relationship of any of the study drugs to the AE will be assessed by the
Investigator as either YES (related) or NO (unrelated). If there is a reasonable suspected
causal relationship to the study medication(s), i.e. there are facts (evidence) or arguments to
suggest a causal relationship, the drug-event relationship should be assessed as YES. The
criteria for evaluating drug-event relationship must include consideration of potential
interactions among treatments in a combination therapy regimen.
The following criteria should be considered in order to assess the relationship as YES:





Reasonable temporal association with drug administration.
It may or may not have been produced by the patient’s clinical state, environmental
or toxic factors, or other modes of therapy administered to the subject.
Known response pattern to suspected drug.
Disappears or decreases on cessation or reduction in dose.
Reappears on re-challenge.
The following criteria should be considered in order to assess the relationship as NO:




It does not follow a reasonable temporal sequence from administration of the drug.
It may readily have been produced by the patient’s clinical state, environmental or
toxic factors, or other modes of therapy administered to the subject.
It does not follow a known pattern of response to the suspected drug.
It does not reappear or worsen when the drug is re-administered.
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10.2.
SAE reporting
Any clinical AE which occurs during the course of the study (initial and follow up reports)
must be reported to AGMT within 24 hours after becoming aware of the event by the
Investigator.
Follow-up information on SAEs must also be reported by the Investigator within the same
time frame. SAEs will be reported using standard forms provided by AGMT and must be
documented in the (Serious) Adverse Event section of the CRF. SAEs must be reported by fax
to the number specified on the appropriate form.
In the event of a drug overdose occurring in the course of the present study, this must be
reported as a SAE.
10.3.
Reporting pregnancies
The Investigator should report all pregnancies (initial and follow up report; female subjects
and partner of male subjects) within 24 hours after becoming aware to AGMT using the
forms provided by AGMT.
A female subject must be instructed to stop taking the study medications and immediately
inform the Investigator if she becomes pregnant during the study. The Investigator should
counsel the female subject; discuss the risks of continuing with the pregnancy and the
possible effects on the foetus. Monitoring of the subject should continue until conclusion of
the pregnancy (final follow report). Pregnancies occurring up to 6 months after the last dose
of study medications must also be reported to the Investigator.
Pregnancy occurring in the partner of a male subject participating in the study should be
reported to the Investigator. The partner should be counselled, the risks of continuing the
pregnancy discussed, as well as the possible effects on the foetus. Monitoring of the
patient’s partner should continue until conclusion of the pregnancy (final follow report).
10.4.
Follow up of (S)AEs
All patients having received at least one dose of the study medication must be followed for
adverse events for at least 28 days after discontinuing study treatment or completion of
study treatment. All (serious) adverse events occurring during study treatment will be
collected until 28 days after the end of study treatment.
Follow-up information on the outcome must be recorded on the respective AE page in the
CRF. The outcome “unknown” is not acceptable, except if attempts to collect the
information have been made and documented. All other information has to be documented
in the source documents.
If any SAE persists at study end, the course of the event has to be followed up by the
investigator until its resolution or until the SAE is recognized as permanent condition.
Any AE leading to premature withdrawal of the subject from the study has to be followed up.
It is the responsibility of the investigator that any necessary additional therapeutic measures
and follow-up procedures are performed.
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10.5.
Reporting to regulatory authorities and the ethics committees
The sponsor will inform relevant regulatory authorities and the ethics committee and all
participating investigators:


of all relevant information about serious unexpected adverse events suspected to be
related to the study medication that are fatal or life threatening as soon as possible,
and in any case no later than seven days after knowledge of such a case. Relevant
follow-up information for these cases will subsequently be submitted within an
additional eight days.
of all other serious unexpected adverse events suspected to be related to the study
medication as soon as possible, but within a maximum of fifteen days of first
knowledge by the investigator.
11.
STATISTICAL METHODS
11.1.
Study design
This is a multi-center, uncontrolled, open-labelled phase I pilot study to be performed in
pretreated CML patients.
11.2.
Sample size
Main aim of this phase I pilot study is feasibility and safety. No formal hypothesis testing will
be performed. Therefore, no formal sample size estimation will be applied. It is planned to
include 12 patients into this study.
11.3.
Populations
The ITT Population will include all enrolled patients who received at least one dose of the
study treatment. Patients going off study due to adverse events or toxicity prior to the key
response evaluation will be considered treatment failures.
The Per Protocol Population will consist of all patients who received study medication at
least 12 weeks and who did not violate inclusion or exclusion criteria.
11.4.
Background and demographic characteristics
Baseline characteristics will be summarized for all patients enrolled using appropriate
descriptive statistics, i.e. number (%) of patients for categorical variables and mean, SD
(standard deviation), median, minimum/maximum for continuous variables.
11.5.
Efficacy evaluation
Primary efficacy parameter is the achievement of a molecular response as defined above.
The Kaplan-Meier product limit estimator will be applied to analyse the time to and the
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occurrence of a molecular response. Secondary efficacy parameters will be summarized
using descriptive statistics.
11.6.
Safety evaluation
The assessment of safety will be based mainly on the frequency of adverse events,
particularly adverse events leading to discontinuation of treatment and on the number of
significant laboratory abnormalities.
Adverse events will be summarized by presenting the number and percentage (as
appropriate) of patients having any adverse event by body system, type of adverse event,
and maximum severity. Those adverse events which result in death, discontinuation or are
otherwise classified as dose limiting will be presented separately.
12.
ADMINISTRATIVE CONSIDERATIONS
12.1.
Local regulations / Declaration of Helsinki
The Investigator will ensure that this study is conducted in full conformance with the
principles of the “Declaration of Helsinki” [appendix 4] and with the applicable local laws and
regulations.
12.2.
Informed Consent
It is the responsibility of the Investigator, or a person designated by the Investigator (if
acceptable by local regulations), to obtain written informed consent from each patient
participating in this study, after adequate explanation of the aims, methods, anticipated
benefits, and potential hazards of the study. The Investigator or designee must also explain
that the patients are completely free to refuse to enter the study or to withdraw from it at
any time, for any reason.
12.3.
Independent ethics committees
This protocol and any accompanying material provided to the patient (such as patient
information sheets or descriptions of the study used to obtain informed consent) as well as
any advertising or compensation given to the patient, will be submitted to an Independent
Ethics Committee. Approval from the committee must be obtained before starting the study.
Any modifications made to the protocol after receipt of the Independent Ethics Committee
approval must also be submitted by the Investigator to the Committee in accordance with
local procedures and regulatory requirements.
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12.4.
Insurance
All patients and Investigators will be covered by an insurance contract existing between the
sponsor AGMT gemeinnützige GmbH and HDI Versicherung, according to Austrian
regulations.
12.5.
Conditions for terminating the study
Both the Sponsor and the Investigator reserve the right to terminate the study at any time.
Should this be necessary, both parties will arrange the procedures on an individual study
basis after review and consultation. In terminating the study, Sponsor and Investigator will
assure that adequate consideration is given to the protection of the patient’s interests.
12.6.
Audits and inspections
The Investigator should understand that source documents for this trial should be made
available to appropriately qualified personnel from health authority inspectors after
appropriate notification. The verification of the Case Report Form data must be by direct
inspection of source documents.
12.7.
Case report forms
The Investigator should ensure the accuracy, completeness, legibility, and timeliness of the
data reported to the sponsor in the CRFs and in all required reports.
12.8.
Confidentiality of trial documents and patient records
The Investigator must assure that patients’ anonymity will be maintained and that their
identities are protected from unauthorized parties. On CRFs or other documents submitted
to the Sponsor, patients should not be identified by their names. The Investigator should
keep a patient enrolment log showing codes and names. The Investigator should maintain
documents not for submission to Sponsor, e.g., patients’ written consent forms, in strict
confidence.
12.9.
Monitoring the study
The Monitor will contact and visit the Investigators regularly in accordance with the
monitoring plan. He/she will be allowed to inspect the various records of the trial (provided
that patient confidentiality is maintained) in accordance with local requirements.
The Monitor should have access to laboratory test reports and other patient records needed
to verify the entries on the Case Report Form. The Investigator (or his/her deputy) agrees to
cooperate with the monitor to ensure that any problems detected in the course of these
monitoring visits are resolved.
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13.
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APPENDIX 1: Visit schedule
Screening
Every 14 days
during
treatment
Every 4 weeks Every 8 weeks
during
during
treatment
treatment
Every 12 weeks
during
treatment
Final visit
Written informed consent
X
Demographics and medical history
X
Physical examination including palpation of spleen (size
in cm below rib)
X
X
X
X
X
X
Vital sings (incl. pulse rate, blood pressure, body
temperature)
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
X
1
X
X
X
Pregnancy test (women of childbearing potential)
X
Haematology (incl. platelet count, WBC count,
differential: granulocytes, % basophils)
X
X
X
X
X
X
Blood chemistry (liver values, kidney function tests,
electrolytes)
X
X
X
X
X
X
Immunology (coombs test direct, anti-nuclear antibodies
(ANA), thyroglobulin antibodies (TgAb), thyroid
peroxidase antibody (TPOAb), thyroid stimulating
hormone (TSH))
X
Send blood sample according to laboratory manual
X
Adverse events according to NCI-CTCAE 4.0 (incl.
seriousness, severity, causal relationship)
Evaluation of haematologic remission
1
X
X
X
X
X
X
X
X
X
X
X
X
Perform pregnancy test every 4 weeks until final visit
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APPENDIX 2: ECOG performance status
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APPENDIX 3: ELN response criteria
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APPENDIX 4: Declaration of Helsinki
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by
the:
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996
52nd WMA General Assembly, Edinburgh, Scotland, October 2000
53th WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29
added)
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly, Seoul, October 2008
A. INTRODUCTION
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a
statement of ethical principles for medical research involving human subjects, including
research on identifiable human material and data.
The Declaration is intended to be read as a whole and each of its constituent paragraphs
should not be applied without consideration of all other relevant paragraphs.
2. Although the Declaration is addressed primarily to physicians, the WMA encourages other
participants in medical research involving human subjects to adopt these principles.
3. It is the duty of the physician to promote and safeguard the health of patients, including
those who are involved in medical research. The physician's knowledge and conscience are
dedicated to the fulfillment of this duty.
4. The Declaration of Geneva of the WMA binds the physician with the words, “The health of
my patient will be my first consideration,” and the International Code of Medical Ethics
declares that, “A physician shall act in the patient's best interest when providing medical
care.”
5. Medical progress is based on research that ultimately must include studies involving
human subjects. Populations that are underrepresented in medical research should be
provided appropriate access to participation in research.
6. In medical research involving human subjects, the well-being of the individual research
subject must take precedence over all other interests.
7. The primary purpose of medical research involving human subjects is to understand the
causes, development and effects of diseases and improve preventive, diagnostic and
therapeutic interventions (methods, procedures and treatments). Even the best current
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interventions must be evaluated continually through research for their safety, effectiveness,
efficiency, accessibility and quality.
8. In medical practice and in medical research, most interventions involve risks and burdens.
9. Medical research is subject to ethical standards that promote respect for all human
subjects and protect their health and rights. Some research populations are particularly
vulnerable and need special protection. These include those who cannot give or refuse
consent for themselves and those who may be vulnerable to coercion or undue influence.
10. Physicians should consider the ethical, legal and regulatory norms and standards for
research involving human subjects in their own countries as well as applicable international
norms and standards. No national or international ethical, legal or regulatory requirement
should reduce or eliminate any of the protections for research subjects set forth in this
Declaration.
B. PRINCIPLES FOR ALL MEDICAL RESEARCH
11. It is the duty of physicians who participate in medical research to protect the life, health,
dignity, integrity, right to self-determination, privacy, and confidentiality of personal
information of research subjects.
12. Medical research involving human subjects must conform to generally accepted scientific
principles, be based on a thorough knowledge of the scientific literature, other relevant
sources of information, and adequate laboratory and, as appropriate, animal
experimentation. The welfare of animals used for research must be respected.
13. Appropriate caution must be exercised in the conduct of medical research that may harm
the environment.
14. The design and performance of each research study involving human subjects must be
clearly described in a research protocol. The protocol should contain a statement of the
ethical considerations involved and should indicate how the principles in this Declaration
have been addressed. The protocol should include information regarding funding, sponsors,
institutional affiliations, other potential conflicts of interest, incentives for subjects and
provisions for treating and/or compensating subjects who are harmed as a consequence of
participation in the research study. The protocol should describe arrangements for poststudy access by study subjects to interventions identified as beneficial in the study or access
to other appropriate care or benefits.
15. The research protocol must be submitted for consideration, comment, guidance and
approval to a research ethics committee before the study begins. This committee must be
independent of the researcher, the sponsor and any other undue influence. It must take into
consideration the laws and regulations of the country or countries in which the research is to
be performed as well as applicable international norms and standards but these must not be
allowed to reduce or eliminate any of the protections for research subjects set forth in this
Declaration. The committee must have the right to monitor ongoing studies. The researcher
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must provide monitoring information to the committee, especially information about any
serious adverse events. No change to the protocol may be made without consideration and
approval by the committee.
16. Medical research involving human subjects must be conducted only by individuals with
the appropriate scientific training and qualifications. Research on patients or healthy
volunteers requires the supervision of a competent and appropriately qualified physician or
other health care professional. The responsibility for the protection of research subjects
must always rest with the physician or other health care professional and never the research
subjects, even though they have given consent.
17. Medical research involving a disadvantaged or vulnerable population or community is
only justified if the research is responsive to the health needs and priorities of this
population or community and if there is a reasonable likelihood that this population or
community stands to benefit from the results of the research.
18. Every medical research study involving human subjects must be preceded by careful
assessment of predictable risks and burdens to the individuals and communities involved in
the research in comparison with foreseeable benefits to them and to other individuals or
communities affected by the condition under investigation.
19. Every clinical trial must be registered in a publicly accessible database before recruitment
of the first subject.
20. Physicians may not participate in a research study involving human subjects unless they
are confident that the risks involved have been adequately assessed and can be satisfactorily
managed. Physicians must immediately stop a study when the risks are found to outweigh
the potential benefits or when there is conclusive proof of positive and beneficial results.
21. Medical research involving human subjects may only be conducted if the importance of
the objective outweighs the inherent risks and burdens to the research subjects.
22. Participation by competent individuals as subjects in medical research must be voluntary.
Although it may be appropriate to consult family members or community leaders, no
competent individual may be enrolled in a research study unless he or she freely agrees.
23. Every precaution must be taken to protect the privacy of research subjects and the
confidentiality of their personal information and to minimize the impact of the study on their
physical, mental and social integrity.
24. In medical research involving competent human subjects, each potential subject must be
adequately informed of the aims, methods, sources of funding, any possible conflicts of
interest, institutional affiliations of the researcher, the anticipated benefits and potential
risks of the study and the discomfort it may entail, and any other relevant aspects of the
study. The potential subject must be informed of the right to refuse to participate in the
study or to withdraw consent to participate at any time without reprisal. Special attention
should be given to the specific information needs of individual potential subjects as well as
to the methods used to deliver the information. After ensuring that the potential subject has
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understood the information, the physician or another appropriately qualified individual must
then seek the potential subject’s freely-given informed consent, preferably in writing. If the
consent cannot be expressed in writing, the non-written consent must be formally
documented and witnessed.
25. For medical research using identifiable human material or data, physicians must normally
seek consent for the collection, analysis, storage and/or reuse. There may be situations
where consent would be impossible or impractical to obtain for such research or would pose
a threat to the validity of the research. In such situations the research may be done only
after consideration and approval of a research ethics committee.
26. When seeking informed consent for participation in a research study the physician
should be particularly cautious if the potential subject is in a dependent relationship with the
physician or may consent under duress. In such situations the informed consent should be
sought by an appropriately qualified individual who is completely independent of this
relationship.
27. For a potential research subject who is incompetent, the physician must seek informed
consent from the legally authorized representative. These individuals must not be included
in a research study that has no likelihood of benefit for them unless it is intended to
promote the health of the population represented by the potential subject, the research
cannot instead be performed with competent persons, and the research entails only minimal
risk and minimal burden.
28. When a potential research subject who is deemed incompetent is able to give assent to
decisions about participation in research, the physician must seek that assent in addition to
the consent of the legally authorized representative. The potential subject’s dissent should
be respected.
29. Research involving subjects who are physically or mentally incapable of giving consent,
for example, unconscious patients, may be done only if the physical or mental condition that
prevents giving informed consent is a necessary characteristic of the research population. In
such circumstances the physician should seek informed consent from the legally authorized
representative. If no such representative is available and if the research cannot be delayed,
the study may proceed without informed consent provided that the specific reasons for
involving subjects with a condition that renders them unable to give informed consent have
been stated in the research protocol and the study has been approved by a research ethics
committee. Consent to remain in the research should be obtained as soon as possible from
the subject or a legally authorized representative.
30. Authors, editors and publishers all have ethical obligations with regard to the publication
of the results of research. Authors have a duty to make publicly available the results of their
research on human subjects and are accountable for the completeness and accuracy of their
reports. They should adhere to accepted guidelines for ethical reporting. Negative and
inconclusive as well as positive results should be published or otherwise made publicly
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available. Sources of funding, institutional affiliations and conflicts of interest should be
declared in the publication. Reports of research not in accordance with the principles of this
Declaration should not be accepted for publication.
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH
MEDICAL CARE
31. The physician may combine medical research with medical care only to the extent that
the research is justified by its potential preventive, diagnostic or therapeutic value and if the
physician has good reason to believe that participation in the research study will not
adversely affect the health of the patients who serve as research subjects.
32. The benefits, risks, burdens and effectiveness of a new intervention must be tested
against those of the best current proven intervention, except in the following circumstances:
• The use of placebo, or no treatment, is acceptable in studies where no current proven
intervention exists; or
• Where for compelling and scientifically sound methodological reasons the use of placebo is
necessary to determine the efficacy or safety of an intervention and the patients who
receive placebo or no treatment will not be subject to any risk of serious or irreversible
harm. Extreme care must be taken to avoid abuse of this option.
33. At the conclusion of the study, patients entered into the study are entitled to be
informed about the outcome of the study and to share any benefits that result from it, for
example, access to interventions identified as beneficial in the study or to other appropriate
care or benefits.
34. The physician must fully inform the patient which aspects of the care are related to the
research. The refusal of a patient to participate in a study or the patient’s decision to
withdraw from the study must never interfere with the patient-physician relationship.
35. In the treatment of a patient, where proven interventions do not exist or have been
ineffective, the physician, after seeking expert advice, with informed consent from the
patient or a legally authorized representative, may use an unproven intervention if in the
physician's judgment it offers hope of saving life, re-establishing health or alleviating
suffering. Where possible, this intervention should be made the object of research, designed
to evaluate its safety and efficacy. In all cases, new information should be recorded and,
where appropriate, made publicly available.
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APPENDIX 5: Amendment tracking log
Chapter Original text
Titel and Phase 1 study to evaluate the
feasibility and efficacy of the
2.
addition of P1101 (PEG-ProlineInterferon alpha-2b) to imatinib
treatment in patients with
chronic phase chronic myeloid
leukaemia not achieving a
complete molecular response
(MR 4 or 4.5)
2.
FPI: Q1 2013; LPO: Q3 2015
4.1
Secondary
objective:
to
determine
the
rate
of
achievement of ≥ 1 log
reduction from the initial BCRABL transcript level at study
entry and the achievement of
molecular remission 4 and 4.5
Patients are eligible if a
molecular remission 4 or 4.5 has
not been achieved with imatinib
therapy alone after at least 18
months of therapy.
4.2
Figure 1
4.5.1
A complete molecular remission
(molecular remission 4 and 4.5)
is not allowed.
4.5.3
CMR (molecular remission 4 or
4.5)
9.1
A reduction of BCR-ABL
transcripts to ≤ 0.01% is defined
as molecular response 4 (MR 4)
and a reduction of BCR-ABL
transcripts to ≤ 0.001% is
defined as MR 5.
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Phase 1 study to evaluate the
feasibility and efficacy of the
addition of P1101 (PEG-ProlineInterferon alpha-2b) to imatinib
treatment in patients with chronic
phase chronic myeloid leukaemia
not achieving a complete molecular
response
(MR 4.5 or BCR-ABL transcripts not
detectable)
FPI: Q2 2013; LPO: Q4 2015
Reasons
Secondary objective: to determine
the rate of achievement of ≥ 1 log
reduction from the initial BCR-ABL
transcript level at study entry and
the achievement of molecular
remission 4.5 or undetectable BCRABL transcripts.
Patients are eligible, if a molecular
remission 4.5 or below has not been
achieved with imatinib therapy
alone after at least 18 months of
therapy.
Figure was updated
Definition of
CMR
was
changed.
Definition of
CMR
was
changed.
updated
Definition of
CMR
was
changed.
CMR
definition
A complete molecular remission Definition of
(molecular remission 4.5 or BCR-ABL CMR
was
transcripts undetectable) is not changed.
allowed.
CMR (molecular remission 4.5 or Definition of
BCR-ABL transcripts undetectable)
CMR
was
changed.
A reduction of BCR-ABL transcripts Definition of
to ≤ 0.01% is defined as molecular CMR
was
response 4 (MR 4), a reduction of changed.
BCR-ABL transcripts to ≤ 0.0032% is
defined as MR 4.5, and to ≤ 0.001%
as MR 5.
In this protocol a complete
molecular response is defined as MR
4.5 or BCR-ABL transcripts not
detectable.
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