1. No category

EORTC
&
German Hodgkin Lymphoma Study Group
PVAG
– phase I/II dose finding trial in
elderly patients (> 60 yrs) with
intermediate and advanced stages
Hodgkin´s lymphoma
version 3.0
September 13, 2005 (including amendment #1 and #2)
Writing committee:
M. Hansen; S. Trelle; H. Bredenfeld (editorial board)
Statistics:
J. Franklin
Principal Investigator:
A. Engert
PVAG Study Coordination:
Klinik I für Innere Medizin der Universität zu Köln
Klinisches Studienzentrum Hämatologie
Kerpener Str. 62, Bettenhaus Ebene 4
D-50937 Köln (Cologne)
Tel:
+49 221 478 - 6128 or - 3777 or - 6628
Fax:
+49 221 478 - 3531
E-mail: [email protected]
2
Protocol Synopsis
Title
PVAG – a phase I/II dose finding trial in elderly patients
(> 60 years) with intermediate* and advanced** stages
Hodgkin´s lymphoma
* CS (PS) IA, IB, IIA, and IIB + risk factors
** CS (PS) IIB + risk factors, CS (PS) III and IV
Study Phase
Phase I and II
Objective
The study is designed to test the toxicity, feasibility and
short-term efficacy of PVAG
Regimen
P
V
A
G
Prednisone
Vinblastine
Doxorubicin
Gemcitabine
p.o
i.v.
i.v.
i.v.
40 mg/m2
d1-5
6 mg/m2
d1
50 mg/m2
d1
1000 mg/m2 d1
Recycle on day 22 (platelets have to be > 75.000/mm³
and leukocytes > 2000/mm³ otherwise treatment has to
be delayed for a maximum of 21 days; if platelets or
leukocytes recover between day 14 and 21, dose
reduction as detailed in section 6.1.5 have to be
employed; patients not reaching the specified values
within 21 days have to be withdrawn from the study)
A specific dose reduction scheme will be applied
(section 6.1.5) to patients experiencing grade 4
leukopenia for more than four days or grade 4 nonhematological toxicities.
Study Design
This is an oligocenter, non-randomized, single-arm
trial, run by a collaboration of the GHSG and selected
members of the EORTC. A phase I-part is to evaluate
the safety of the regimen with reasonable certainty.
Subsequently a phase II will determine the short term
efficacy and safety.
Frequent toxicity monitoring is mandatory. First
response evaluation is conducted after 4 cycles,
definitive restaging after end of chemotherapy. Followup examinations are be performed and documented
every 6 months for the first 2 years and once a year in
years 3, 4 and 5.
Primary Endpoints
Phase I: occurrence of dose-limiting toxicities (DLT)
and dose reductions as defined in section 6.1.5.
Phase II: feasibility: adminitration of adequate dose
without excessive delays; efficacy: complete remission
3
Seondary Endpoints
Phase II: occurrence of acute toxicities; administration
of blood concentrates and antibiotics; early progression
Sample Size
26 patients are required for the phase I-part.
Subsequently, 14 patients will be included for the
phase II-part.
Eligibility Criteria
(a) Staging according to protocol
(b) Documented informed consent
(c) Histologically proven HD (Excluded: Lymphocyte
Predominant, Nodular type Hodgkin’s Lymphoma).
(d) Intermediate stage: clinical stage (CS) IA, IB, or IIA
(with risk factors riskfactors bulky mediastinal mass,
extranodal involvement, high ESR, and/or ≥ 3
involved lymphnode areas), IIB (with risk factors
high ESR and/or ≥ 3 involved lymphnode areas) or
Advanced stage: CS IIB (with riskfactors bulky
mediastinal mass and/or extranodal involvement),
CS III and IV.
(e) Age 60 to 75.
(f) Previously untreated patients.
(g) WHO performance status grades 0, 1, or 2
(h) Written informed consent or confirmed informed
consent according to ICH/EU Good Clinical
Practice, and national/local regulations.
(i) Leukocytes > 2.5 x109/L and platelets >100 000
x109/L.
(j) Normal Pulmonary function
4
Table of Contents
1.
INTRODUCTION ....................................................................................................... 7
1.1.
1.2
1.3.
1.4.
1.5.
1.5.1.
1.5.2.
1.6.
PURPOSE .................................................................................................................... 8
STANDARD REGIMEN ................................................................................................... 8
THE IMPACT OF DACARBAZINE IN THE ABVD REGIMEN .................................................. 9
THE IMPACT OF BLEOMYCIN IN THE ABVD REGIMEN .....................................................10
GEMCITABINE AND HD................................................................................................10
SAFETY OF GEMCITABINE ADMINISTERED AS SINGLE-AGENT.......................................11
THE COMBINATION OF GEMCITABINE AND OTHER CYTOSTATICS ..................................12
DEFINITION OF THE EXPERIMENTAL ARM – PVAG.........................................................14
2.
STUDY DESIGN:......................................................................................................16
2.1.
2.2.
2.3.
2.4.
2.5.
2.6.
ENTRY CRITERIA .........................................................................................................16
REGIMEN ...................................................................................................................16
DOSE-FINDING STRATEGY ...........................................................................................17
OBJECTIVES ..............................................................................................................18
ENDPOINTS ................................................................................................................18
STUDY ORGANIZATION ................................................................................................18
3
STATISTICS.............................................................................................................19
3.1.
3.2.
3.3.
PHASE I .....................................................................................................................19
PHASE II ....................................................................................................................19
DATA ANALYSIS ........................................................................................................20
4
REQUIREMENTS FOR PARTICIPATION IN GHSG (AND EORTC) TRIALS ..........20
5
DIAGNOSIS AND RANDOMIZATION ......................................................................21
5.1
5.1.1.
5.2.
5.2.1.
5.2.2.
5.2.3.
5.3.
5.3.1.
5.3.2.
5.3.3.
5.4.
5.5.
VERIFICATION OF DIAGNOSIS BY THE PRIMARY PATHOLOGIST........................................21
PATHOLOGY REVIEW PROCEDURE ............................................................................21
REGISTRATION ...........................................................................................................22
REGISTRATION PROCEDURE ....................................................................................22
ENTRY CRITERIA FOR ENROLMENT ...........................................................................22
EXCLUSION CRITERIA: .............................................................................................22
STAGING (AN AND ST FORM; SEE APPENDIX) ..............................................................23
DIAGNOSIS OF CLINICAL STAGE ................................................................................23
DEFINITION OF LYMPH NODE AREAS .........................................................................25
STAGING CLASSIFICATION OF HODGKIN´S DISEASE (MODIFIED ANN ARBOR) ...............26
PATIENTS CONSENT AND TERMINATION ........................................................................27
RECRUITMENT ............................................................................................................27
6.
PVAG REGIMEN......................................................................................................28
6.1.
CHEMOTHERAPY ........................................................................................................28
6.1.1.
ADMINISTRATION OF CHEMOTHERAPY ......................................................................28
6.1.2.
PVAG SCHEME ......................................................................................................28
6.1.3.
DURATION ..............................................................................................................28
5
6.1.4.
6.1.5.
6.1.6.
6.2.
6.2.1.
6.2.2.
6.3.
6.4.
6.5.
6.6.
LABORATORY CONTROLS DURING CHEMOTHERAPY ...................................................29
THERAPY POSTPONEMENT AND DOSE REDUCTION.....................................................29
DOCUMENTATION OF SIDE-EFFECTS .........................................................................31
RESTAGING ................................................................................................................31
INTERIM RESTAGING ...............................................................................................31
DEFINITIVE RESTAGING ...........................................................................................32
RELAPSE DIAGNOSTICS AND SECOND LINE TREATMENT ................................................32
FOLLOW-UP ...............................................................................................................33
SERIOUS UNFAVORABLE EVENTS (SAE FORMS; SEE APPENDIX) ...................................34
DEATH (FINAL REPORT) ..............................................................................................34
7.
RADIOTHERAPY .....................................................................................................34
7.1.
7.2.
7.3.
7.4.
RADIATION DOSE AND VOLUME ....................................................................................35
BLOOD TESTS AND DOCUMENTATION OF SIDE-EFFECTS .................................................35
RESTAGING ................................................................................................................35
TECHNICAL REQUIREMENTS ........................................................................................36
8.
CRITERIA FOR REMISSION ...................................................................................36
9.
DOCUMENTATION ..................................................................................................38
9.1.
DOCUMENTATION OF DOSE REDUCTIONS .....................................................................38
9.2.
DOCUMENTATION OF ADVERSE EVENTS .......................................................................38
9.2.1.
SEVERE ADVERSE EVENTS (SAE) ............................................................................39
10.
PUBLICATION OF STUDY RESULTS .....................................................................40
11.
REFERENCE LIST ...................................................................................................41
12.
APPENDICES ..........................................................................................................45
12.1
12.2.
12.3.
12.4.
12.5.
12.6.
12.7.
12.8.
12.9.
12.10.
12.11.
12.12.
12.12.
12.13.
12.14.
PATIENT INFORMATION (ENGLISH VERSION)..............................................................46
PATIENT CONSENT FORM........................................................................................49
PATIENTEN INFORMATION (DEUTSCHE FASSUNG, VERSION KÖLN DEUTSCH 2-2005)..50
EINVERSTÄNDNISERKLÄRUNG .................................................................................57
DATENSCHUTZ ...................................................................................................60
DECLARATION OF HELSINKI ....................................................................................61
PERFORMANCE STATUS SCALES .............................................................................65
WHO TOXICITY ......................................................................................................66
ASSESSMENT OF EACH CYCLE .................................................................................67
COURSE OF ASSESSMENTS .....................................................................................68
FLOW-CHART .........................................................................................................69
CERTIFICATE OF INSURANCE ...................................................................................69
CERTIFICATE OF INSURANCE ...................................................................................70
APPROVAL FROM THE ETHICS COMMITTEE OF THE UNIVERSITY OF COLOGNE .............71
APPROVAL FROM THE ETHICS COMMITTEE OF THE UNIVERSITY OF COLOGNE
(AMENDMENT #1)....................................................................................................72
6
12.15.
12.16.
12.17.
12.18.
APPROVAL FROM THE ETHICS COMMITTEE OF THE UNIVERSITY OF COLOGNE
(AMENDMENT #2)....................................................................................................74
CHANGES BY AMENDMENT # 1 ................................................................................76
CHANGES BY AMENDMENT # 2.................................................................................93
CLINICAL REPORT FORMULARS (CRFS) ..................................................................98
7
1.
Introduction
Most patients with Hodgkin’s disease (HD) are under 40 years old, but around 20%
are over 60 and around 7% are over 70 [1;2]. Patients aged 60 to 65 years with early
stage disease have a very good outcome, while advanced stage elderly patients
demonstrate around 50% survival at 3 years. In patients over 70 years old, the
outcome is even worse with a median survival of advanced stages < 6 months [1].
The distribution of the stages between the age-groups is the same [3;4]. With age as
the variable, Guinee et al (1991) reported the following complete remission or relapse
rates in all stages of patients with HD [4]:
Age
40-59
60-79
N
220
136
CR %
88.2
83.8
Relapse % (2-year)
14
26
In the group of patients with advanced disease, Glimelius et al (1996) reported a
reduced outcome with increasing age [5]:
Age
N
CR %
FFP %
40-49
50-59
60-69
70-79
48
39
56
50
88
79
73
50
54
67
55
42
Deaths from
HD %
19
26
41
52
The effect of age on overall survival is mainly caused by poor results of salvage
chemotherapy. Survival rates at 5-years among patients with progression or relapse
of HD decreases with age: 42% in patients < 34 years decreasing to 5% in patients
aged 55-65 years [6]. This has been supported by others [7].
The induction of complete remission following the first line chemotherapy is an
important predicter of long time survival. In a registry-analysis of HD in elderly
patients, 34% received inadequate therapy compared to 2% in younger patients. It
affected the complete remission rates: 61% versus 90%, but the elderly patients with
CR had a relapse free survival that was not significantly different from the younger
patients [8]. This trend has been confirmed by others [3;9-12].
8
The single most important factor for poor prognosis appears to be poor tolerability of
chemotherapy. In one study around 50% of the patients aged over 60 years received
less than 40% of the planned chemotherapy doses due to intolerance of the therapy
[13]. Intolerance due to toxicity has been reported by others in this patient population
[14-17]. This is at least in part due to co-morbidities, which are seen in 56% of elderly
patients with HD, but not related to stage of disease. The main co-morbid conditions
are cardiovascular disease (18%), chronic obstructive pulmonary disease (13%), and
diabetes mellitus (10%) resulting in 50% of the patients were not able to tolerate full
dose of therapy [18].
1.1.
Purpose
The goal is to improve the standard regimen ABVD by lowering the toxicity without
compromising the efficacy (non-inferiority of PVAG compared to ABVD regarding
efficacy). This is achieved by substituting bleomycin and dacarbazine with
prednisolone and gemcitabine (PVAG). The development of a less toxic regimen with
at least an equal efficacy enables elderly patients to receive full scale chemotherapy
resulting in increased CR-rates and thereby improved survival.
1.2
Standard regimen
Two large phase III trials have not shown any advantage of alternating regimens
(such as MOPP/ABVD, MOPP/ABV, COPP/ABVD) over ABVD. In the first large trial
(CALGB; n=361), ABVD showed equality with MOPP/ABVD [19]. The second large
study (CALGB, ECOG, SWOG, NCIC; n=862) resulted in equality between ABVD
and MOPP/ABV, although MOPP/ABV was more toxic in the elderly population [20].
ABVD became the gold standard due to less toxicity.
In the elderly population of HD patients, several regimens has been used, such as
MOPP; BOPP, MVPP, MOPP/ABV, ABVD, ODPEB, LVPP/OEPA [5;16;17;19;21].
The general problem is intolerability to treatment and the need for dose reduction.
9
The superiority of doxorubicin containing regimens is well-established [19;22], but no
large scale studies have been published using ABVD in patients over 60 years of
age.
Glimelius et al (1996) used the doxorubicin containing LVPP/OEPA (chlorambucil,
vinblastine,
procarbazine,
prednisone/vincristine,
etoposide,
prednisone
and
doxorubicin) and the group of patients aged over 60 years showed the following
results at 6 years:
Age
60-69
70-79
80-
N
56
50
3
CR%
73%
50%
0%
FFP
55%
42%
0%
HD death
41%
52%
100%
MacPherson et al (2002) reported in a non-randomised study a DFS of 37% at 5
years using MOPP/ABV variant chemotherapy in 17 patients aged 66-80 years,
median 72 years. OS was 32% at 5 years. Using the doxorubicin containing ODBEP
(vincristine 1.2 mg/m2 day 1, doxorubicin 50 mg/m2 day 1, bleomycin 10 U/m2 day 8,
etoposide 50 mg/m2 day 8 IV and 100 mg/m2 PO day 9-12, prednisone 45 mg/m2 day
1-8 and the every other day. Cycle length 28 days) in 39 patients aged 66-86 years,
median 72 years, OS was 42% and DFS 49% at 5 y. Toxicity was lower with ODBEP
[16].
In 56 patients aged > 60 years of age (73% with advanced disease) received either
ChlVPP or ChlVPP/ABV. The 5 year OS for patients receiving ChlVPP was 30%
compared to 67% for those receiving ChlVPP/ABV. EFS at 2y was 50% versus 75%
using ChlVPP and ChlVPP/ABV, respectively. However, the treatment assignment in
this study was at the choice of the attending physician [23].
1.3.
The impact of dacarbazine in the ABVD regimen
Frei was the first to report that dacarbazine induced remissions in around half of
pretreated patients with HD with a median duration of response of 3 months [24].
This observation has been confirmed by others [25].
10
Dacarbazine has known myelosupression and gastrointestinal toxicity in the majority
of patients and in order to reduce toxicity, dacarbazine was omitted in the
MOPP/ABV regimen and the dose of doxorubicin increased [26]. The dacarbazinefree regimen MOPP/ABV has the same efficacy as the dacarbazine-containing
MOPP/ABVD [27].
Recently, the ABVD regimen has been modified by reducing the dose of dacarbazine
with 33% (ABVd) without loss of efficacy (OS 5y 89%, PFS 5y 75%) [28]. The
Japanese Oncology group is presently conducting a phase II trial of ABV
(dacarbazine-free ABVD) + irradiation in the treatment of advanced HD.
In conclusion, dacarbazine adds little to efficacy with undesirable toxicity.
1.4.
The impact of bleomycin in the ABVD regimen
Single agent studies of bleomycin in HD shows response rates around 40-55% with a
very short duration of response - between one and ten weeks [29;30].
Pulmonary toxicity is a severe and dose-limiting side effect. In general, bleomycin
induced pneumonitis occurs in up to 46% of patients treated with the drug and the
mortality is approximately 3% [31]. After 6 cycles of ABVD, bleomycin related
mortality has been estimated at 1-3% [19;32]
Recently, late pulmonary sequelae after 5 years has been reported in 37.6% of HD
patients following radiation therapy or bleomycin-containing chemotherapy in
combination with radiation therapy [33].
In conclusion, bleomycin adds little to efficacy, but the drug is connected with serious
pulmonary toxicity.
1.5.
Gemcitabine and HD
11
Gemcitabine
(2’,2’-difluorodeoxycytidine,
dFdC)
is
a
prodrog,
that,
despite
resemblance with cytosine arabinoside, possesses specific cellular pharmacology
and mechanism of action. The prodrug is phosphorylated by deoxycytidine kinase,
which is saturable at an extracellular fluid concentration of 10-20 µmol/L [34;35]. The
incorporation of gemcitabine triphosphate (dFdCTP) into DNA results in apoptosis
[36;37].
The use of gemcitabine in HD was reported in 1997 by Santoro [38], where 14 pretreated patients were given gemcitabine 1,250 mg/m2 IV over 30 min days 1, 8, 15
and a 28 days schedule. The overall response rate was 57% (CR/PR: 21%/36%),
median duration of CR 8 months and of PR 6 months.
These data were extended in 2000 [39], where 23 refractory HD patients had been
treated according to the same schedule. The overall response rate was 39% (CR/PR:
9%/30%). The median duration of response was 6.7 months and the median over all
survival time was 10.7 months.
Zinzani (2000) [40] studied 14 heavily pre-treated HD patients (10 relapsed, 4
refractory) with 1,200 mg/m2 IV over 30 min days 1, 8, 15 and a 28 days schedule.
The overall response rate was 43% (CR/PR 15%/28%). At the time of publication, the
CR patients were still in CR (15+ months).
Others have reported an effect of gemcitabine in single patient reports [41;42].
1.5.1. Safety of gemcitabine administered as single-agent
The safety profile of gemcitabine administered in doses of 800-1250 mg/m2 IV over
30 min days 1, 8 and 15 every 28 days is well known and very mild. The tables show
the maximum WHO grades for laboratory and symptomatic toxicity (% of patients)
due to gemcitabine [43]:
Laboratory
toxicity
Haemoglobin
Leukocytes
Neutrophils
Number
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
781
781
766
34.4
38.9
36.2
38.9
24.8
17.2
19.3
27.7
22.2
6.4
8.1
18.7
0.9
0.5
5.7
12
Platelets
Alanine
transferase
Alkaline
phosphatase
Bilirubin
Creatinine
Proteinuria
Symptomatic
Nausea/vomiting
Oral
Diarrhoea
Pulmonary
Fever
Allergic
Cutaneous
Hair
Infection
State of
consciousness
Peripheral
neurotoxicity
Constipation
Pain
Haemorrhage
781
620
79.1
32.4
9.9
37.4
6.3
21.0
3.7
7.4
1.0
1.8
776
49.6
29.0
14.8
4.5
2.1
773
777
748
89.8
91.9
41.4
7.2
7.5
46.9
1.4
0.5
11.1
1.0
0.1
0.5
0.5
0
0
Number
435
435
435
435
435
435
435
435
435
435
Grade 0
34.7
93.1
92.4
91.7
60.5
96.1
74.3
86.7
91.0
89.9
Grade 1
26.9
4.4
4.4
4.8
21.8
3.2
16.1
9.0
6.2
5.3
Grade 2
17.7
2.3
2.8
1.6
17.0
0.5
9.4
3.9
1.6
4.4
Grade 3
19.8
0.2
0.5
1.6
0.7
0.2
0.2
0.5
0.9
0.5
Grade 4
0.9
0
0
0.2
0
0
0
0
0.2
0
435
96.6
3.2
0.2
0
0
435
435
160
93.6
82.3
98.1
5.3
10.6
0.6
0.9
6.0
1.3
0.2
1.1
0
0
0
0
Myelosuppression is the most common toxicity and the toxicity increases in
pretreated patients. In pretreated HD patients grade 3-4 reductions in platelets and
neutrophils have been observed from 3%-60% and 6%-33%, respectively in three
different studies [39;40;42]. The studies differ with regard to dose and administration
but the conclusion is that pre-treatment increases the risk of myelotoxicity and
especially thrombocytopenia.
Pulmonary toxicity is rare using gemcitabine as single agent, but severe pulmonary
toxicity has been reported in a few cases [44-51]. The syndrome is caused by
sudden, reversible capillary hyperpermeability with a rapid extravasation of plasma to
the interstitial space [45]. It is reversible by treatment with corticosteroids. This has
been confirmed I a recent study with ABVG [52]
1.5.2. The combination of gemcitabine and other cytostatics
In PVAG gemcitabine will be combined with doxorubicin, vinblastine and prednisone.
13
In studies of solid tumours, gemcitabine has been combined with several drugs
including doxorubicin [53-55]. There is no published data on the combination of
gemcitabine and vinblastine but in general, gemcitabine-based combinations are
associated with more thrombocytopenia (grade 3 or 4) than single-agent gemcitabine
(40 vs. 7%) [56].
Recently, in a phase II trial comprising 39 patients with breast cancer, the patients
was treated first-line with gemcitabine 1200 mg/m2 days 1+8 and doxorubicin 60
mg/m2 day 1. Grade 3/4 toxicities included neutropenia (14%) and thrombocytopenia
(1.7%) [55].
In a phase II trial comprising 41 patients with metastatic breast cancer, the patients
were treated first-line with doxorubicin 30 mg/m2 day 1, paclitaxel 135 mg/m2 day 2
and gemcitabine 2,500 mg/m2 day 2. Gemcitabine was infused over 30-60 min. The
regimen was administered biweekly for six cycles. Haematologic toxicity was
moderate, with grade 3-4 toxicity as follows: Neutropenia in 44%, thrombocytopenia
in 7% and anemia in 12% of the patients. Non-haematological events were generally
mild [57].
In a phase II study comprising 42 patients with advanced breast cancer, the patients
were treated first-line with gemcitabine 800 or 1000 mg/m2 over standard 30 min
infusion and doxorubicin 25 mg/m2 intravenously days 1, 8 and 15 every 28 days.
Grade 3/4 toxicity of anemia, neutropenia and thrombocytopenia is 2.4%/0%,
45.2%/21.4% and 14.3%/2.4%. Other toxicities included transient increases in
transaminase levels (grade 3 in 3/42 patients) and mucositis (grade 3 in 3/42
patients). Pharmakokinetic analysis showed, that the disposition of the drugs is
unchanged when they are administered on the same day [54].
In a phase I-II study with gemcitabine and doxorubicin in a 21-day schedule. Four
levels of Gem/Dox were administered to patients with hepatocellular carcinoma: (gem
day 1+8 and Dox day 1). Gem/Dox doses were 1000/30 mg/m2, 1250/30 mg/m2,
1250/45 mg/m2, 1250/60 mg/m2. Level 2 (1250/30 mg/m2) was identified as the MTD
dose. Grade ¾ hematological toxicities were anemia in 45.7%, neutropenia in 51,4%
and thrombocytopenia in 25,7%. Non-hematological toxicities were mild [58].
14
The GHSG initiated a study of BAGCOPP where etoposide (in BEACOPP) was
substituted with gemcitabine at a dose of 800 mg/m2 twice per cycle. Severe
pulmonary toxicity appeared in 8/27 patients and all the cases developed after > 3
cycles of BAGCOPP. The pulmonary toxicity were considered to be due to an
interaction of bleomycin and gemcitabine [59].
1.6.
Definition of the experimental arm – PVAG
PVAG is developed from ABVD by substituting bleomycin and dacarbazine with
prednisone and gemcitabine, respectively.
In general and as described above, the risk of toxicity is highest with gemcitabine
based combinations compared to single agent gemcitabine therapy. The toxicity
profile is schedule dependent and all the regimens described are based on a one or
two-weekly dosing schedule.
In order to reduce the risk of toxicity the PVAG schedule is a 21-day regimen with the
doses as seen in the table and compared to ABVD:
PVAG (d1) mg/m2
50
6
40 (d1-5)
1000
Drug
Doxorubicin
Bleomycin
Vinblastine
Dacarbazine
Prednisone
Gemcitabine
ABVD (d1, d15) mg/m2
25
10
6
375
-
The PVAG regimen has increased the dose of doxorubicin, which is an important
drug [19;22], resulting in the same total cumulated dose as in ABVD and with dose
intensity 33% higher in PVAG.
The table below shows the dose intensity (mg/m2/week) and the total cumulated dose
(mg/m2) for each regimen, eight cycles.
PVAG
Prednisone
Vinblastine
Doxorubicine
DI
66.6
2
16.6
ABVD
TD
1600
48
400
DI
3
12.5
TD
96
400
15
Gemcitabine
Bleomycin
Dacarbazine
333
-
8000
-
5
187.5
160
6000
Considering the impact of bleomycin and dacarbazine in ABVD is very limited, the
PVAG is combined of the highly active drugs and with higher dose intensity of
doxorubicin, which is expected to result in a regimen, which is at least as effective as
ABVD. The toxicity is expected to fall due to elimination of the most toxic drugs.
No consolidating irradiation in either arm is planned to patients in complete remission
after chemotherapy. A meta-analysis of chemotherapy versus combined modality
treatment from 1,740 patients concluded that combined modality treatment in
patients with advanced-stage HD overall has a significantly inferior long-term survival
outcome than chemotherapy alone if chemotherapy is given over an appropriate
number of cycles [60]. Recently, it has been shown that consolidative chemotherapy
matches consolidative radiotherapy (subtotal nodal irradiation) in advanced stage HD
patients in CR or good PR after 6 series of chemotherapy [61], and the EORTC
#20884 showed that adjuvant radiotherapy did not improve overall survival or eventfree survival for HD patients in stages III-IV in CR after 6 or 8 MOPP/ABV cycles [62].
Patients not achieving complete remission after the end of chemotherapy do receive
an additional radiation therapy to sites of tumor rest (see 7. ff).
16
2.
Study design:
2.1.
Entry criteria
CS(PS) IA, IB, IIA, IIB with one or more of the risk factors:
a)
bulky mediastinal mass (> 1/3 of maximum transverse thorax diameter)
b)
extranodal involvement
c)
high ESR (≥ 50 mm in IA and IIA; ≥ 30 mm in IB)
d)
≥ 3 involved lymphnode areas
CS(PS) III, IV
Age: 60-75 years
As mentioned in the introduction, elderly patients have a higher intolerance to
chemotherapy than younger patients. In order to ensure the safety is unaffected by
an increased intolerance in the oldest patients, the inclusion is limited to patients
aged 60-75 years. The final analysis will evaluate the results with respect to two
different age groups (60 – 65 years and 66 – 75 years).
2.2.
Regimen
6 - 8 cycles of PVAG
P
Prednisone
p.o
40 mg/m2
d1-5
V
Vinblastine
i.v.
6 mg/m2
d1
A
Doxorubicine
i.v.
50 mg/m2
d1
G
Gemcitabine
i.v.
1000 mg/m2
d1
Recycle on day 22
The clinical response is evaluated after 4 cycles of chemotherapy (the interim staging
procedures must not lead to a delay of cycle No. 5. In case of a complete remission
(CR), two additional series are given to a total of six cycles PVAG. In case of a partial
remission (PR) after 4 cycles, additional 4 series are applied to a total of 8 cycles
PVAG. In case of no change (NC) or progressive disease (PD), the patient is
17
discontinued from the study. Patients with residual disease after completion of
chemotherapy receive radiotherapy (36 Gy) to locoregional sites.
4 cycles PVAG
Interim staging
CR
PR
2 cycles PVAG
4 cycles PVAG
Definitive restaging
CR
End of therapy
2.3.
PR
Radiotherapy
Dose-finding strategy
Phase I: Safety
The phase I part of the study will evaluate the safety profile of 1000 mg/m²
gemcitabine in combination with prednisone, vinblastine and doxorubicin. 26 patients
will be recruited on this dose level to establish the safety with reasonable certainty.
Recruitment will not be stopped during this interim analysis.
Phase II: Efficacy / Feasibility
18
After phase I an additional cohort of 14 patients will be treated to better characterize
the feasibility and efficacy of the regimen. The total sample size of 40 patients will
allow the proportion of complete responders (CR) to be determined within +/- 14%.
.
2.4.
Objectives
This study is designed to test
1) the toxicity, feasibility and short-term efficacy of PVAG
2.5.
Endpoints
Two primary endpoints have been defined, in accordance with the two main aims of
the second phase of the study, i.e. assessment of feasibility and of short-term
efficacy.
1)
For the phase I-part (safety) the endpoint is the occurrence of dose limiting
toxicities (DLT) and dose reductions as defined in section 6.1.5.
2)
For the phase II-part, for assessment of feasibility the primary endpoint is the
administration of adequate dose without excessive delays.
For the assessment of efficacy the primary endpoint is complete remission 3
months after end of protocol therapy.
Secondary endpoints are the occurrence of acute toxicities and the
administration of blood concentrates and antibiotics (feasibility) and the
occurrence of early progression (efficacy)
2.6.
Study organization
The PVAG pilot study is an international trial collaboration of the GERMAN HODGKIN´S
LYMPHOMA STUDY GROUP (GHSG) with participation of selected members of the
EUROPEAN ORGANISATION
FOR
RESEARCH
AND
TREATMENT
OF
CANCER (EORTC).
Participants from both organisations will recruit qualified patients. The study
coordination is organized by the GHSG and takes place at the Klinisches
Studienzentrum Hämatologie in Cologne/Germany. Data collection and evaluation
will be performed by the Klinisches Studienzentrum Hämatologie according to GCPguidelines.
19
3
Statistics
3.1.
Phase I
Phase I of the study is a pragmatic approach to establish the safety of the PVAG
regimen in this selected patient cohort of elderly with Hodgkin lymphoma based on
data about gemcitabine published so far and available data from patients already
entered into the trial (recruited until December 31, 2004; final version of this protocol,
October 28, 2003).
The aim of phase I is to demonstrate that the rate of dose-limiting toxicities is below a
predefined maximum tolerable rate (MTD). Sample size calculations are based on
the following considerations:
−
Maximum tolerable rate of dose-limiting toxicities: 0,33
−
True rate of dose-limiting toxicities: 0,20
−
Probability to consider PVAG by mistake too toxic (rate of DLT > 0,33) although
the true rate of DLTs is acceptable (rate of DLT = 0,20): ≤ 0,2 (β = 0,2
corresponding to a power of 80%)
−
Probability to consider PVAG by mistake promising (rate of DLT ≤ 0,33)
although the true rate of DLTs is unacceptable high (rate of DLT > 0,33): 0,05 (α
= 0,05)
According to these considerations and data from a previous trial (BAGCOPP trial of
the GHSG) 26 patients will be entered in phase I. Analysis will be performed
separately for patients with intermediate and advanced stage disease resulting in 26
+ 26 patients overall.
3.2.
Phase II
Based on the results of 68 advanced stage patients aged 66-75 years treated with 8
cycles COPP/ABVD or BEACOPP (baseline dose) +/- localised radiotherapy in the
GHSG trial HD9 (1993-98), we expect PVAG to achieve a complete remission rate of
70-80%. The requirement that the width of the 90% confidence interval for the
complete remission rate does not exceed 28% is satisfied with a sample size of 40
patients (method: interval width calculated as 1.96 x SE, where SE = SQRT (p (1-p) /
n) is the standard error of a proportion, p is the true value, n is the sample size).
Therefore, overall we aim to recruit 40 patients during the entire study (phases I and
II). Analysis will be performed separately for patients with intermediate and advanced
stage disease resulting in 40 + 40 patients overall.
20
Recruitment for advanced stage patients will be stopped if 40 evaluable patients with
advanced stage disease have been entered or on 31th of December 2006 whichever
comes first. Recruitment for intermediate stage patients will be stopped if 40
evaluable patients with intermediate stage disease have been entered or on 30th of
July 2007 whichever comes first.
3.3.
Data Analysis
The data will be analysed in the German Hodgkin Lymphoma Study Group biometry
unit in Cologne. Results will be reported at two points in time separately for patients
with intermediate and advanced stage disease, as follows.
Firstly, a preliminary description of acute toxicity and dose reductions will be reported
at the end of phase I:
(1) Description of the toxicity profile of PVAG.
Secondly, a final analysis of toxicity, feasibility and short-term efficacy will be
performed following treatment and restaging of all recruited patients:
(1) Repeat of the previous analysis (toxicity) using all received data
(2) Description of treatment administration (number of cycles, reasons for
discontinuation,
given
dose,
treatment
duration
and
delays,
supportive
medication)
(3) Estimation of the rate of early progressions and complete remissions.
4
Requirements for participation in GHSG (and EORTC) trials
•
Patient is eligible as decided by the haematologist/oncologist, the radiotherapist
and the pathologist.
•
Written informed consent of the patient
•
Laboratory results (SI units)
•
Complete and prompt documentation of each visit, event etc.
•
GHSG as the study coordination center assumes responsibility for insurance of
patients.
•
Publication of the data only with agreement of the trial coordinators of GHSG and
EORTC.
21
5
Diagnosis and randomization
5.1
Verification of diagnosis by the primary pathologist
Only patients with histological proven Morbus Hodgkin will be enrolled in the study. A
large-scale biopsy must be taken from a lymph node or a primary involved organ. If
the diagnosis of Hodgkin´s Disease is histologically proven and the patient accepts
inclusion in the study, verification by one of the study´s reference pathologists is
obligatory.
5.1.1. Pathology review procedure
The primary pathologist must send the slides of material to the review pathologist
mentioned, immediately after submission of the patient to the study.
Within three weeks the panel will check the material and verify the diagnosis of
Hodgkin´s Disease. The result is submitted to the treating hematologist/oncologist,
the primary pathologist and the study coordination office.
A detailed description of the review procedure will be sent to the responsible
hematologist/oncologist,
together
with
confirmation
of
randomization
and
documentation forms, and should be forwarded to the local primary pathologist. This
document can also be used as application form for pathological review.
Diagnostically difficult and scientific interesting cases will be examined and
diagnosed in regular pathology panel meetings by all of the panel members.
For questions concerning the pathology review procedure please contact:
Klinik I für Innere Medizin der Universität zu Köln
Klinisches Studienzentrum Hämatologie
Kerpener Str. 62, Ebene 4
50937 Köln/Germany
Fax: +49/221/478-3531
Tel: +49/221/478-6128 or –3777 or –6628
E-mail: [email protected]
Study centre will be able to supply you with a complete list of reference centers of the
German Hodgkin`s study group.
22
5.2.
Registration
5.2.1. Registration procedure
After completion of diagnostic examinations and patient briefing, registration can be
performed by telephone or fax. Please contact the coordination office in Cologne
(Tel. +49-221-478-6128 or -3777 or –6628; Fax. Tel. +49-221-478-3531). If the
patient qualifies for the study, he / she will be enrolled into the trial.
If the patient wants anonymity they can be registered by code. Informed consent is
documented by signing the informed consent form.
5.2.2. Entry criteria for enrolment
1. Staging according to protocol
2. Documented informed consent
3. Histologically proven HD (Excluded: Lymphocyte Predominant, Nodular type
Hodgkin’s Lymphoma).
4. Clinical stage (CS) IA, IB, IIA, IIB with riskfactors bulky mediastinal mass (> 1/3 of
the maximal transverse thoracic diameter) extranodal involvement, high ESR,
and/or ≥ 3 involved lymphnode areas; CS III and IV.
5. Age 60 to 75.
6. Previously untreated patients.
7. WHO performance status grades 0, 1, or 2
8. Written informed consent or confirmed informed consent according to ICH/EU
Good Clinical Practice, and national/local regulations.
9. Leukocytes > 2.5 x109/L and platelets >100 000 x109/L.
10. Normal Pulmonary function
5.2.3. Exclusion criteria:
1. Incomplete staging examinations
2. Concurrent or previous diseases, which would prohibit a therapy according to
protocol.
−
Severe pulmonary, neurological or metabolic disease, interfering with normal
life- expectancy or normal application of treatment.
−
Severe cardiac disease affecting the normal ejection fraction.(include
myocardial infarction < 6 months prior, or NYHA class 3 or 4 failure)
−
Any psychological, familial, sociological or geographical condition potentially
hampering compliance with the study protocol and follow-up schedule.
23
−
Known HIV positivity.
−
Inadequate liver (bilirubin > 2.5 x normal) or renal (creatinine >150 mmol/L)
function, unless due to HD.
History of HBV infection defined as presence of HBs antigen, or in absence
−
of HBs antigen the presence of HBc antibody without HBs antibody.
3. Malignant disease in anamnesis
4. Diagnosis of M. Hodgkin as part of a composite lymphoma
5. Prior chemo- or radiation therapy
6. Long-time application of steroids or cytostatic drugs
7. Simultaneous participation on other trials within the last 30 days
5.3.
Staging (AN and ST form; see appendix)
5.3.1. Diagnosis of clinical stage
All staging examinations should be completed within 14 days from diagnosis. For this
reason it is advisable to do the bone-marrow biopsy immediately after diagnosis.
5.3.1.1
Case history and Laboratory
Anamnesis should include all clinical aspects, especially B-symptoms, severe
previous and concurrent diseases (including all hematological malignancies in the
patient or in family members) and/or history of infectious mononucleosis. Physical
status is documented according the WHO activity index.
Laboratory (obligatory):
-
ESR
AP
Differential blood count
Albumin
Total protein
HIV1/2 antibody
Hepatitis A, B, C
5.3.1.2
Physical examination
Physical examination must be done, especially lymph nodes, liver, spleen and
abdomen. Please document all clinical findings even if not histologically verified.
24
5.3.1.3
Obligatory image-based examinations
For exact staging the following examinations must be done:
-
Chest x-ray (p.a. and lateral)
-
Contrast enhanced CT scan (neck, chest and abdomen)
-
Ultrasonogram of the abdomen
-
Bone marrow biopsy
Jamshidi-needle punction from spina iliaca with 1,5 cm minimum length of
bone cast. Diagnosis only by an experienced hematopathologist
-
Liver biopsy:
Obligatory in patients with the following clinical constellation:
-
Only infradiaphragmatic disease and/or
-
Alkaline phosphatase > 25% over the upper range and/or
-
Age > 40 years and NO mediastinal mass
Moreover, all clinically suspect extranodal or organ involvement should be checked
using adequate methods. If possible, suspicious involved sites should verified by
biopsy.
Other image-based examinations may be used for staging but are not obligatory: (If
in doubt, please discuss the particular case with the study cooperation office)
-
Laparotomy and/or bilateral lower extremity lymphangiography
(in case of suspected abdominal involvement with therapeutic consequences and
no further clarification to be obtained by a regular diagnostic approach.
-
Nuclear resonance scanning
-
Gallium radionuclide imaging / positron-emission tomography (PET)
5.3.1.4
Obligatory organ specific examinations prior to therapy
In order to evaluate the toxicity profile of the regimen, the following examinations
must be done before the beginning of treatment:
-
ECG
-
Lung function test: Hb, PaO2, PaCO2, DCO, vital capacity
-
Thyroid function: TSH
25
5.3.2. Definition of lymph node areas
N.B. LYMPH NODE REGION IS NOT THE SAME AS LYMPH NODE AREA !!!
The definition of lymph node areas does not correspond to the Ann Arbor definition of
lymph node regions. This distinction is important for the definition of risk factor
d (3 or more lymph node areas).
Lymph node areas are defined as follows:
a) right cervical + right infra-/ supraclavicular/ nuchal lymph nodes
b) left cervical + left infra-/ supraclavicular/ nuchal lymph nodes
c) right/left hilar + mediastinal lymph nodes
d) right axillary lymph nodes
e) left axillary lymph nodes
f) lymph nodes of the upper abdomen (spleen hilum, liver hilum, coeliacal)
g) lymph nodes of the lower abdomen ( paraaortal and mesenterial)
h) right iliac lymph nodes
i) left iliac lymph nodes
k) right inguinal + femoral lymph nodes
l) left inguinal + femoral lymph nodes
LYMPH NODE AREAS
LYMPH NODE REGIONS
26
5.3.3. Staging classification of Hodgkin´s Disease (modified Ann Arbor)
Stage is determined by the examination results as follows.
The classification corresponds in general to the Ann Arbor classification apart from a
few points (stage IV, extranodal involvement).
CS: clinical stage
PS: pathological stage (including splenectomy)
stage I:
Involvement of a single lymph node region (I,N) or a single
extranodal focus (I, E)
stage II:
Involvement of 2 or more lymph node regions or extranodal
structures on the same side of the diaphragm
(II,N or II,N,E or II,E)
stage III:
Involvement of lymph node regions on both sides of the
diaphragm (II,N) or extranodal involvement with or without nodal
involvement
stage IV:
Disseminated involvement of one or more extralymphatic organs
with or without nodal involvement
The lymphatic tissue contains:
Lymph nodes, spleen, thymus gland, Waldeyer´s tonsillar ring
Organ symbols:
N = lymph nodes
H = liver
S = spleen
L = lung
M = bone marrow
O = bone
D =skin
P = pleura
General symptoms:
All patients are classified as A or B according to the absence or presence,
respectively, of one or more of the following B-symptoms:
−
fever (not otherwise explainable)
−
drenching night sweats (not otherwise explainable)
−
weight loss of ≥10% of body weight within last 6 months (not otherwise
explainable)
5.3.3.1
Definition:
Extranodal involvement (E-involvement)
27
Localized involvement of an extralymphatic tissue (by continuous growth from an
involved lymph node or in close anatomic proximity) that is treatable by irradiation. 2
or more E-involvements might be found in stage II or III.
5.3.3.2
Bulky Disease (measured by CT-scan)
Bulky disease is defined as:
- A single lymph node involvement or a conglomerate mass of > 5 cm max. diameter
- Mediastinal bulk of > 5 cm max. diameter (do not include hili or pericard!)
5.3.3.3
Mediastinal mass
Definition: > 1/3 of the max. thoracic diameter (in the chest x-ray p.a.!)
5.3.3.4
Mediastinal involvement
When determining fields to be irradiated, involvement exclusively above the tracheal
bifurcation must be differentiated from involvement below the bifurcation. For
involvement at bifurcation height, the whole mediastinum is to be defined as involved.
5.4.
Patients consent and termination
At completion of staging, the patient will be informed whether he qualifies for the
PVAG trial. The patient will be informed about the trial objectives, treatment, side
effects, use of personal data and samples and freedom to make decisions. Consent
to participate in the trial should be given in writing in the presence of a witness. The
patient can decide freely at any point in time whether to continue participation.
Refusal to continue permits free choice of further treatment. Termination of protocol
therapy can occur at the patient's wish, after unacceptable toxicity, progression,
serious intercurrent disease or pregnancy.
5.5.
Recruitment
After a patient has given his/her written informed consent to participate in the study
he/she is enrolled by telephone or fax at the study coordination office in Cologne.
Clinical data relevant to randomization are recorded. A supply of blank
documentation forms are sent to the clinician. It is important to return the
documentation forms as soon as possible by fax (Registration- and Anamnesisforms) to the study coordination office (Cologne).
28
Recruitment
Tel: +49-221-478-6128,-3777, -6628
Fax: +49-221-478-3531
6.
6.1.
PVAG regimen
Chemotherapy
6.1.1. Administration of chemotherapy
Chemotherapy is given in an outpatient setting. Therapy can be started directly after
recruitment. The treatment will be continued at full dosage in accordance with the
time schedule if at the day of the planned treatment continuation the leukocyte count
exceeds > 2000/mm3 and platelets > 75.000/mm3 with a rising trend (having passed
the nadir). In case of lower blood counts, treatment is modified according to the
strategy for therapy delay and dose reduction (see below).
6.1.2. PVAG scheme
PVAG scheme
Prednisone
40 mg/m2
p.o.
day 1-5
Vinblastine
6 mg/m2
i.v.
day 1
2
i.v.
day 1
1000 mg/m2
i.v.
day 1
Doxorubicine
Gemcitabine
50 mg/m
Recycle day 22
6.1.3. Duration
The first treatment evaluation takes place after four cycles (see 4.2.1: Interim
staging). Dependent on the grade of remission after 4 cycles, patients receive
additional 2 (in case of CR) or 4 cycles (in case of PR) PVAG. The definitive
29
restaging is held after completion of chemotherapy (6 or 8 cycles); in the case of less
than CR, additional radiotherapy is planned to sites of tumor rest.
Without treatment delay, the chemotherapy will take 18 (six cycles) or 24 (eight
cycles) weeks.
6.1.4. Laboratory controls during chemotherapy
The following parameters are checked during therapy:
-
Two times a week following each cycle: leukocytes, platelets, hemoglobin
-
Daily: body temperature
-
Prior to each cycle: leukocytes, platelets, hemoglobin, creatinine, uric acid,
bilirubin, AST, ALT, GGT
Note:
Pulmonary function is measured at the initial staging, at the end of therapy, 6
months after the end of therapy and at any time in case of a sign of pulmonary
symptoms during treatment or in the follow-up period, that can’t be explained by
verified infection. The lung function tests include measuring of vital capacity, DLCO,
PaCO2 and PaO2. In case of clinical symptoms or pathological findings in the lung
function test a HR-CT scan of the lung is performed together with bronchial lavage
and simultaneous transbronchial biopsy (if necessary).
6.1.5. Therapy postponement and dose reduction
a) Hematological toxicity
Therapy is continued in time with full dosage if leukocyte count exceed > 2000/mm3
and platelets > 75.000/mm3 (no grade 3 or 4 toxicity).
If the required values are not reached at the day of planned therapy continuation,
blood parameters are checked again on day 3, 7, 10, and 14 after first control. If
parameters have not been reached within two weeks doses have to be reduced as
detailed below (Therapy is to be continued when the required values are reached;
maximum delay: 21 days). In addition, doses have to be reduced in case of
leucopenia WHO grade 4 (<1000/m³) for more than 4 days.
If blood parameters do not reach the required values within two weeks in subsequent
cycles (reduced dose-level) or if a patient experiences leucopenia WHO grade 4 for
30
more than 4 days on the reduced dose-level the patient should be withdrawn from
the trial.
b) Non-hematological toxicity
In case of WHO grade 4 non-hematological toxicity doses have to be reduced as
detailed below (Exceptions: alopecia, nausea and vomiting if controlled by supportive
measures). Treatment should be postponed until recovery to grade 2 (maximum
delay: 21 days).
If a patient experiences WHO grade 4 non-hematological toxicity on subsequent
cycles (reduced dose-level) the patient should be withdrawn.
c) Dose reduction scheme
In case of both hematological and non-hematological toxicity the highest dosereduction schedule will be used. Patients will be treated on the reduced dose-level in
subsequent cycles.
The reduced dose-level is as follows:
Prednisone
40 mg/m²
p.o.
day 1-5
Vinblastine
5 mg/m²
i.v.
day 1
Doxorubicine
40 mg/m²
i.v.
day 1
Gemcitabine
800 mg/m²
i.v.
day 1
Growth factor G-CSF:
Not foreseen in this trial.
If clinically indicated:
300 µg/d if body weight <75 kg
480 µg/d if body weight >75 kg
Stop G-CSF administration if granulocytes rise over 1000/mm3.
At least 2 days rest between end of G-CSF administration and continuation of
chemotherapy
Pulmonary toxicity:
Any sign of pulmonary impairment during chemotherapy must initiate diagnostic
procedures described above. If the symptoms disappear after a duration of more
than two weeks, therapy is continued according to the non-hematological dosereduction schedule. If the analysis concludes the lung-injury as drug induced, the
31
patient has to be excluded from therapy continuation. Please contact study
coordination center immediately.
6.1.6. Documentation of side-effects
An accurate documentation of side-effects of chemotherapy and radiotherapy
according to WHO-recommendations is necessary
(WHO Handbook for Reporting Results of Cancer Treatment, Geneva 1979). These
are documented for each chemotherapy cycle on the appropriate chemotherapy-form
(C-form).
Moreover, days of hospitalization, blood transfusions and the use of growth factors
must be recorded.
6.2.
Restaging
6.2.1. Interim Restaging
A clinical interim restaging is carried out after 4 cycles of chemotherapy. The aim is to
identify possible progressive disease during chemotherapy; in case of no change,
minor response or progressive disease, the patient is excluded from the study.
Time:
between day 14 – 20 of cycle No. 4
Examinations:
- laboratory:
-
ESR
-
LDH
-
AP
-
Differential blood count
-
Albumin
- Clinical examination (including resolution of B-symptoms)
- Chest x-ray
- CT scan of all initially involved regions
32
6.2.2. Definitive Restaging
A definitive restaging is carried out 4-6 weeks after the last cycles of chemotherapy
or after completion of irradiation.
The success of the combined modality therapy is to be documented for every initially
involved region using appropriate methods (CT-scan, ultrasonography).
If in doubt a histological examination (biopsy) is recommended.
Examinations:
- laboratory:
-
ESR
-
LDH
-
AP
-
Differential blood count
-
Albumin
- Clinical examination
- Chest x-ray
- CT-scan check-up of all initially involved regions
- ultrasonography of the abdomen
- Lung function test: Hb, PaO2, PaCO2, DCO, vital capacity
(- bone marrow biopsy: only in case of initial bone marrow
involvement)
Note: Pulmonary function is at any time to be investigated in case of pulmonary
symptoms during treatment or in the follow-up period, that can’t be explained by a
verified infection. In case of clinical symptoms or pathological findings in the lung
function test a HR-CT scan of the lung is performed together with bronchial lavage
and simultaneous transbronchial biopsy (if necessary).
6.3.
Relapse diagnostics and second line treatment
If relapse occurs, a complete staging and renewed histological investigation should
be undertaken. All relapses will be reviewed by the pathology review committee, and
the radiology review committee will examine the diagnostic images. Therefore, X-ray,
CT and NMR images together with the relevant follow-up form (F) should be sent to
trial coordination center.
33
If progression or relapse occurs, further treatment should be discussed with the trial
centre in Cologne. At present we generally recommend:
(a) Early progression or relapse within one year of end of treatment:
If the intention is curative, high dose chemotherapy with autologous stem cell
support.
(b) Late relapse (> 1 year after end of primary therapy) the possibility of conventional
chemotherapy with a first-line protocol could be considered. Use of high-dose
chemotherapy with ASCT should be considered according to the individual case.
In certain cases, the possibility of irradiation alone should be considered, especially
with peripheral nodal relapse suitable for extended irradiation (e.g., inguinal or iliakal
relapse after primary supradiaphragmatic involvement. Please discuss treatment with
the radiotherapy review centre.
Current German Hodgkin Lymphoma Study Group protocols are also available for
patients with multiple relapse – please contact the trial centre in Cologne.
6.4.
Follow-up
After treatment has been completed, the patient should be requested to attend
regular follow-up examinations, whose results should be recorded on the F-form. If
no unfavorable events have occurred, then a copy of a current medical record will
suffice.
Follow-up examinations are to be performed and documented every 6 months for the
first 2 years and once a year in years 3, 4 and 5.
Examinations:
- laboratory:
-
ESR
-
LDH
-
AP
-
Differential blood count
-
Albumin
- Clinical examination (including resolution of B-symptoms)
34
- Chest x-ray
6.5.
Serious unfavorable events (SAE forms; see appendix)
All serious adverse events during the study must be reported immediately to the
study center on the appropriate form.
Progressive disease, relapse, and second malignancy should be reported
immediately to the study center.
The events must also be recorded on the appropriate documentation form.
6.6.
Death (Final report)
If the patient dies, the final report form should be completed and the cause of death
classified as:
•
Hodgkin's disease
•
acute therapy related (e.g., infection during chemotherapy, ileus under
laparotomy)
•
accident
•
second malignancy
•
suicide
•
other disease
7.
Radiotherapy
In the PVAG-pilot, patients with tumor rest following chemotherapy are to be
irradiated to 30 Gy. A central radiology review committee may produce the
radiotherapy plan after studying the diagnostic images from staging and restaging
examinations (optional, please contact the coordination center). Residual tumor is
defined, for the purposes of this trial, by the following criteria for the computed
tomography image:
•
tumor has a diameter larger than 2.5 cm after end of chemotherapy
•
no sign of a progressive disease (no B symptoms or abnormal ESR (≥ 50 mm/h)
at restaging) detectable
35
•
initial bulky disease (> 5 cm in largest diameter), that has not shrunk by more than
50%, is a tumor rest by definition
The restaging examination to determine remission status should be performed 2-3
weeks after the end of the last chemotherapy course. CT images (from initial-, and
defintive restaging) may be sent to the radiotherapy review in Cologne (optional,
please contact the coordination center). Within one week the review committee will
evaluate the remission and return the images. Irradiation, if required, should begin
within 6 weeks of completing chemotherapy.
7.1.
Radiation dose and volume
Radiation dose: 30 Gy. A single dose between 1.8 and 2.0 Gy should be
administered on at least 4 days per week.
The volume has to be limited to the anatomical region with residual lymphoma.
7.2.
Blood tests and documentation of side-effects
Blood parameters should be monitored at least once per week during irradiation and
any side effects documented on the RX form.
7.3.
Restaging
Final restaging examinations are to be performed after radiotherapy if received. All
initially involved lymph nodes and organs should be included. The following methods
are obligatory:
Examinations:
- laboratory:
-
ESR
-
LDH
-
AP
-
Differential blood count
-
Albumin
- Clinical examination (including resolution of B-symptoms)
36
- Chest x-ray
- CT-scan check-up of all initially involved regions
- ultrasonography of the abdomen
- Lung function test: Hb, PaO2, PaCO2, DCO, vital capacity
7.4.
Technical requirements
Radiotherapy should employ megavoltage photons up to 10 MeV. Fast electrons of
appropriate energies may be used for superficial lymph nodes.
Dose calculations must conform to the ICRU report 50/62, specifying reference
points and the total reference dose. The single dose should be not more than 1,8 2Gy daily with a minimum of four weekly fractions. The start of radiotherapy on Friday
should be avoided. Each treatment field should be simulated and verified by x-ray
imaging at the simulator and accelerator. Photographs should be prepared for all
electron beam fields.
8.
Criteria for remission
The following criteria for remission are used for the definite restaging after the end of
chemotherapy and will be applied analogously for the interim restaging (if appropriate).
Complete Remission (CR):
Disappearance of all symptoms (clinical and radiological).
Residual radiological abnormalities (especially concerning the mediastinum) are
compatible with a CR in the definitive restaging, if there are no other signs of lymphoma
activity. Such a result should be monitored but not treated. It has to be compatible with
former treatment procedures (e.g. radiation fibrosis). In case of persistence for more
than 3 months, the result will be classified as "CR with residual tissue" (CRr). If the
patient is defined CR or CRr, no further therapeutic intervention is necessary.
Partial Remission (PR):
Continuing presence of lymphoma with:
-
significant reduction of all lesions and
-
reduction of the majority (at least 50%) of large lymph nodes or localized
measurable organ lesions (larger than 3 cm in diameter) by more than 50% in the
largest diameter (If none is larger than 3 cm each of the 2 largest lesions must
exhibit a reduction at least 50% in their largest diameter) and
37
-
reduction of a large mediastinal tumor by at least 25% in the maximum thoracic
diameter.
Notes:
1) Definition of PR implies the curability of the disease. In general, CR corresponds to a
tumor cell kill of several orders of magnitude. The definition of PR in our studies
demands a cell kill of approximately one order of magnitude. (Reduction of the tumor
diameter of 50% means reduction of the total tumor volume down to 12,5%). This
requirement exceeds the usual definition of PR for solid tumors where only a reduction
of 50% total tumor volume is required.
2) In this definition it is assumed that the kinetics of small or diffuse lesions parallels that
of prominent lesions. (Therefore measurement of all single lesions is not necessary.)
No Change (NC):
Active lymph node tissue is still present.
Criteria for PR not satisfied (i.e., not all nodes significantly reduced or less than 50%
reduction in majority of large nodes) and
No node enlarged by more than 25% in largest diameter
Progress (PRO):
Occurrence of new lesions or increase of at least one already known lesion by more
than 25% during or within 3 months after therapy.
Note: PR, NC and PRO require therapeutic intervention!!!
Patients in PR after end of chemotherapy receive radiotherapy (see 7. ff).
Patients with NC or PRO after end of therapy will be treated according to current
treatment protocols; please contact study coordination center.
Relapse:
A relapse is defined as an appearance of new or reappearance of initial tumor or Bsymptoms after a remission period (CR) of at least 3 months. In the case of a shorter
interval it will be judged as progressive disease (PRO). In case of relapse a new
histological evaluation should be performed.
38
9.
Documentation
For an acurate and punctual data monitoring, the protocol provides case report forms
(CRFs, see appendices) as follows:
9.1.
•
Anamnesis
AN
•
Staging
S
•
Chemotherapy cycle 1-4
C
•
Chemotherapy cycle 5-8
C
•
Restaging
RE
•
Follow Up
F
•
Final report
FR
•
Dose limiting toxicities
DLT
•
Severe adverse events
SAE
Documentation of dose reductions
The occurence of one (or more) of toxicities requiring dose reductions and/or dose
reductions have to be reported immediately to the trial coordination center. This
information is mandatory to ensure the safety of the trial participants. Subsequent
cycles of the therapy must not be applied unless this basic information has been
send to the trial coordination center. (Telephone call is accepted)
9.2.
Documentation of adverse events
The documentation of all adverse events happening in the course of therapy in an
exact and careful way are absolutely mandatory. For this reason, the WHO
Handbook for Reporting Results of Cancer Treatment (Geneva, 1979) is
recommended. An adverse event is characterized as any clinical impairment of a
patient during the course of therapy; dependend or not from the schedule applied in
terms of causality. Everx single therapy cycle is analysed for such an event and
documented in the CRFs. Moreover, the number of hospitalizations, the substitution
of erythrocytes or thrombocytes or the use of growth factors (G-CSF, Erythropoietin)
has to be noted.
39
9.2.1. Severe adverse events (SAE)
The following severe adverse events are characterized to be reported to the trial
coordination center within 24 hrs.
These events are
•
causing the patients death
•
lifethreatening
•
causing the patients hospitalisation or are reasonable for the lenghtening of a
prior hospitalisation
•
causing permanent or significant impairment
•
resulting in a secundary neoplasia
This urgent report within 24 hrs can be done by using of the DLT form as a short
message. A detailed analysis has to be send to the trial organisation center within 15
days after occurence by using the SAE forms.
40
10.
Publication of study results
The results of the study will be published in accordance to the Declaration of Helsinki
(12.5.). All publications have to be discussed beforehand with the trial coordination
center.
41
11.
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Blood 1972; 40: 317-32.
31.
Sleijfer S. Bleomycin-induced pneumonitis. Chest 2001; 120: 617-24.
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Aisenberg AC. Problems in Hodgkin's disease management. Blood. 1999; 93:
761-79.
33.
Breuer K, Engelbertz V, Schiller P et al. Pulmonary sequelae in the treatment
of Hodgkin's disease. Ann.Oncol. 2002; 13: 64 (abstract 213).
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Abbruzzese JL, Grunewald R, Weeks EA et al. A phase I clinical, plasma, and
cellular pharmacology study of gemcitabine. J.Clin.Oncol. 1991; 9: 491-8.
35.
Grunewald R, Abbruzzese JL, Tarassoff P, Plunkett W. Saturation of 2',2'difluorodeoxycytidine 5'-triphosphate accumulation by mononuclear cells during a
phase I trial of gemcitabine. Cancer Chemother.Pharmacol. 1991; 27: 258-62.
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Plunkett W, Huang P, Xu YZ, Heinemann V, Grunewald R, Gandhi V.
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Plunkett W, Huang P, Searcy CE, Gandhi V. Gemcitabine: preclinical
pharmacology and mechanisms of action. Semin.Oncol. 1996; 23: 3-15.
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Santoro A, Devizzi L, Bonfante V et al. Phase II study with gemcitabine in
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2000; 85: 926-9.
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45
12.
Appendices
12.1
Patient Information
12.2
Patient Consent Form
12.3
Patientenaufklärung (deutsche Fassung)
12.4
Einverständniserklärung (deutsche Fassung)
12.5
Datenschutz
12.6
Declaration of Helsinki
12.7
Performance Status Scale
12.8
WHO Toxicity
12.9
Assessment of each Cycle
12.10
Course of Assessment
12.11
PVAG-Flowsheet
12.12
Certificate of insurance
12.13
Approval from the ethics committee of the University of Cologne
12.14
Approval from the ethics committee of the University of Cologne
(amendment #1)
12.15
Approval from the ethics committee of the University of Cologne
(amendment #2)
12.16
Changes made by amendment # 1
12.17
Changes made by amendment # 2
12.18
CRFs
46
12.1 Patient information (english version)
Therapy study
PVAG – a phase I/II dose finding trial in elderly patients (> 60 years) with
intermediate and advanced stages Hodgkin’s disease.
Patient name
Date of birth:
Dear patient,
We would like to inform you of a clinical study on the treatment of patients with
Hodgkin’s disease.
Background of the study
Patients above the age of 60 years often receive inadequate chemotherapy
compared to younger patients, because elderly people appears to have a poor
tolerability of standard chemotherapy. In the elderly patients, the standard of care in
Hodgkin’s disease patients is the regimen ABVD (A: adriamycin, B: bleomycin, V:
vinblastine and D: dacarbazine).
In order to improve the tolerability of chemotherapy in the treatment of the disease
we introduce a new regimen PVAG. It is considered to be less toxic than ABVD and
at least as effective as ABVD. This is achieved by substituting B (bleomycin) and D
(dacarbazine) in ABVD with P (prednisone) and G (gemcitabine) thereby establishing
PVAG.
Prednisolone is a cortisone preparation with a known efficicay on the disease.
Gemcitabine is a well known drug in the treatment in a variety of malignant diseases.
It has a low frequency of side effects and they are generally very mild. Recent studies
have shown gemcitabine as a single agent to be a very effective drug in patients with
relapsed Hodgkin’s disease after standard chemotherapy and/or radiotherapy or
bone marrow transplantation.
The study
The study is divided into two parts. In the first part the toxicity profile of gemcitabine is
defined (the doses of prednisone, adriamycin and vinblastine are well-defined). For
this purpose 26 patients will be recruited in the first part. You will be treated with 1000
mg of gemcitabine per square meter body-surface and at each day of treatment the
side effects are registered and reported to the study coordination center. Doses will
be reduced or treatment delayed if you experience any relevant side-effects. Based
on the continous collection of information on side effects, the toxicity profile of PVAG
47
is defined. If the rate of serious side-effects does not exceed the pre-defined
threshold the second part of the trial will start.
In the second part of the trial the feasibility and activity of the PVAG regimen will be
evaluated.
The treatment with PVAG
The treatment with PVAG is given with a three weekly interval. On the first day of
each treatment (or cycle) you start on tablets of prednisone for 5 days and the
cytotoxic drugs vinblastine, adriamycin and gemcitabine are infused.
You will receive from 6 to 8 cycles of PVAG. It is the interim analysis after four cycles
of treatment that decides the final number of chemotherapy cycles in your case.
In case there is residual tissue (scar tissue) left at the end of treatment you are going
to receive radiation therapy at this tissue.
Examinations prior to and during the treatment courses
During this study several examinations will be performed with the goal to assess the
patients condition before, during and after treatment. The examinations do not
exceed extent and frequency of treatment outside the study except for the number of
blood examinations. During the treatment period blood examinations are carried out
weekly.
Examinations prior to therapy
Before therapy the medical history will be reviewed and your treating physician will
perform a physical examination. Please inform your doctor of any medication you are
taking. Laboratory diagnostics (blood samples) and testing for possible viral
infections such as hepatitis and HIV (Human Immunodeficiency Virus) will be
performed. Without your consent to these examinations you will not be included in
the study.
To assess the extent of disease a bone marrow biopsy will be performed. In case of
suspicion of hepatic involvement of the liver, a liver biopsy may be performed.
Furthermore the following examinations are going to be done: ECG
(electrocardiogram), lung function test, chest X-ray, CT scan (computer tomography)
of the neck, chest and abdomen and ultrasound of the abdomen.
Examinations during treatment
During the treatment blood samples will be taken regularly. After 4 cycles of therapy
the following examinations are repeated: physical examination, chest x-ray, CT scan
(computer tomography) of the neck, chest and abdomen.
Examinations at the end of therapy
Physical examination, blood testing, chest x-ray and CT scan (computer tomography)
of the neck, chest and abdomen will be performed again.
The follow-up examinations are beeing performed up to 3 years after end of
therapy. Estimating a total time for recruitment of 18 months, an individual
therapy duration of 6 months, and, additionally, a calculated therapy delay
which can not be specified exactly, the time for the trial is defined with a total
of six years after activation.
48
Potential side effects of chemotherapy
Chemotherapy is always associated with side effects. The substances not only attack
the tumor cells but also normal cells. The following and most frequent side effects
may occur:
Hair loss (after therapy, the hair will grow out again), nausea and vomiting especially
on the day of therapy, fever, gastric discomfort and loss of appetite. Furthermore long
term organ dysfunction of lung and heart may occur.
You are prone to infections during treatment and in case of fever, dyspnoea or
discomfort in general you should contact your doctor.
Further information
The ethical committee has approved the study protocol.
Your participation in this study is voluntary and you have the right to withdraw at any
time during the study period without a reason and without experiencing any
disadvantages.
If you decide not to participate in the study you are going to be treated according to
the standard of care at your department.
Patients insurance
Insurance conditions are available at the GHSG office in Cologne.
Study organisation
This study is performed by the GHSG (German Hodgkin Study Group, Cologne) in
collaboration with EORTC centers (European Organisation of research and
Treatment of Cancer, Brussels). Eli-Lilly producing Gemcitabine supports the study.
Data protection
During this clinical trial medical data will be recorded and passed on to the GHSG
datacenter for evaluation and analysis. Results of any examination before, during
and after treatment will be recorded in the datacenter in Cologne.
The lymph node biopsy is going to be reviewed by an expert panel of pathologist in
Germany. The CT scans are also going to be reviewed by an expert panel in
Germany.
By signing the consent you agree that medical data are passed on the datacenter of
the GHSG. By signing the consent you also agree that the lymph node biopsy and
the CT scans are passed on the review panels of the GHSG. Authorized persons and
authorities may inspect these data. All persons are bound to confidentiality and the
data protection by law.
49
12.2. Patient Consent Form
Clinical Study: PVAG pilot trial in elderly patients with intermediate and advanced stage
Hodgkin´s disease
Patient’s Surname:………….............. First Name:…………...….Date of Birth: ……….....….
I have received detailed information from my doctor regarding my disorder and the prospects
of success of the various forms of treatment currently available. The discussion with my
doctor covered all the points mentioned in the patient information sheet, which I have also
signed. I have been given full information regarding the method, aims and risks of this
treatment. I understand all aspects of the study as explained to me. I have had sufficient
opportunity to discuss details of the treatment, including its aims and risks, with my doctors.
I agree to undergo additional scientific examinations which are necessary to monitor and
evaluate the treatment. I agree that the samples taken from me for scientific purposes
become the property of the clinic. I also agree to the evaluation of my medical data in
depersonalised form. Participation in this study is voluntary and I may withdraw at any time
without having to give reasons.
I agree, that my medical data will be recorded and might be passed on to the
competent authority. I agree that the lymph node biopsy and the CT scans are mailed
to the review panels for examination. I also give my consent that authorized persons
and relevant responsible authorities may inspect these data (for example to ensure
quality of the study).
I agree to be tested for possible viral infections such as Hepatitis B and HIV (Human
Immunodeficiency Virus).
I have no further questions and agree to undergo the treatment explained to me as well as
any other measures which may become necessary during the course of treatment.
The patient information has been given to the patient.
____________________
Place, date
____________________
Patient’s signature
________________________
Signature of treating physician
50
12.3. Patienten Information (deutsche Fassung, Version Köln deutsch 2-2005)
Therapiestudie:
PVAG – eine Phase I/II – Dosisfindungsstudie in älteren Patienten (> 60 Jahren)
in intermediären und fortgeschrittenen Stadien eines Morbus Hodgkin
Name:
Geburtsdatum:
Sehr geehrte Patientin, sehr geehrter Patient,
wir möchten Sie um Ihr Einverständnis zur Teilnahme an einer klinischen Studie
bitten. Die folgenden Seiten sollen Sie eingehend über die geplante Studie
informieren und Ihnen helfen, die Entscheidung über Ihre Teilnahme zu treffen.
Ihr behandelnder Arzt hat Sie darüber aufgeklärt, dass Sie an einem HodgkinLymphom erkrankt sind, einer Krebserkrankung des lymphatischen Systems. Das
Hodgkin Lymphom ist eine der am besten behandelbaren Krebserkrankungen des
Erwachsenen und in den meisten Fällen heilbar.
Da aber noch nicht alle Patienten mit dieser Erkrankung geheilt werden können, wird
zur Zeit versucht, die Therapie hinsichtlich ihrer Wirkung weiter zu verbessern und
die Nebenwirkungen zu reduzieren.
Hintergrund der Studie:
Im Vergleich mit jüngeren Patienten erhalten Patienten mit Morbus Hodgkin im Alter
über 60 Jahren häufig eine unzureichende Therapie. Dies liegt an einer bei älteren
Patienten größeren Nebenwirkungsrate der Behandlungen, was am ehesten auf
bestehende Nebenerkrankungen, Wechselwirkungen mit Begleitmedikamenten und
eine geringere Erholungsfähigkeit im Vergleich mit jüngeren Patienten zurückgeführt
werden kann.
Um die Verträglichkeit einer notwendigen Chemotherapie zu verbessern, haben wir
ein neues Behandlungsschema entwickelt: die internationale Standardbehandlung
ABVD (A: Adriamycin, B: Bleomycin, V: Vinblastin, D: Dacarbazin) wurde mit dem
Ziel verändert, eine Therapie von vergleichbarer Wirksamkeit bei verminderter
Nebenwirkungsrate zu ermöglichen. Hierzu wurden Bleomycin und Dacarbazin aus
dem ABVD-Schema entfernt und durch die Substanzen Gemcitabin und Prednison
ersetzt. Von dem resultierenden PVAG-Schema wird angenommen, das es bei
vergleichbarer Wirksamkeit weniger nebenwirkungsreich ist als ABVD.
Prednison ist ein bekanntes Kortison-Präparat mit erwiesener Wirksamkeit bei der
Hodgkin´schen Erkrankung. Gemcitabin hat seine Wirksamkeit in einer Reihe
verschiedener Tumorerkrankungen und auch beim Morbus Hodgkin gezeigt. Art und
Ausprägung der beobachteten Nebenwirkungen wurden allgemein als mild
bezeichnet. In jüngeren Studien bei Patienten mit einem Rezidiv (einem Rückfall)
51
eines M. Hodgkin nach einer ersten oder zweiten Therapie konnte für die Substanz
eine gute Wirksamkeit beschrieben werden.
Die Studie:
Die Studie besteht aus zwei Teilen. Im ersten Teil der Studie wird die Verträglichkeit
des Prüfmedikamentes Gemcitabin herausgefunden. (Die Verträglichkeit von
Adriamycin, Vinblastin und Prednison sind gut geprüft und bekannt.) Hierfür werden
zu Beginn 26 Patienten mit 1000 mg pro Quadratmeter Körperoberfläche behandelt
und das Auftreten von Nebenwirkungen sehr engmaschig überprüft. Um dies sicher
zu stellen, wird der Verlauf jedes einzelnen Behandlungstages von jedem Patienten
an die Studienzentrale in Köln übermittelt. Sollten bei Ihnen starke Nebenwirkungen
auftreten, wird die Dosis der einzelnen Mediakmente angepasst oder die Gabe der
Therapie um einige Tage verschoben. Mit den vorliegenden Daten wird dann die
Verträglichkeit berechnet. Liegt diese unter einem vorher definierten Grenzwert, wird
der zweite Teil der Studie begonnen. Durch diese ständige Überwachung der
Nebenwirkungen ist eine größtmögliche Sicherheit für die Patienten gewährleistet.
Im zweiten Teil wird die Durchführbarkeit und Wirkung der Behandlung getestet.
Hierzu wir geprüft, ob das Behandlungsschema zeitgerecht und in der beabsichtigten
Dosierung verabreicht werden kann. Zu diesem Zweck wird die sorgfältige
Beobachtung der während der Behandlung Patienten fortgesetzt. Für die
Bestimmung der Wirkung, wird das Ansprechen des Tumors auf die behandlung mit
Hilfe von verschiedenen Untersuchungen im Lauf und nach der Behandlung
bestimmt (z.B. mit Computertomographien). Diese Untersuchungen unterscheiden
sich nicht von den ohnehin notwendigen Untersuchungen im Rahmen der Therapie
außerhalb der Studie.
Die Behandlung mit PVAG
Das PVAG-Schema wird in dreiwöchigen Abständen verabreicht. An Tag 1 jeder
Behandlungsrunde (auch Zyklus genannt) werden die Chemotherapeutika Vinblastin,
Adriamycin (auch Doxorubicin) und Gemcitabin als Infusion verabreicht. Prednison
wird in Tablettenform von Tag 1 bis Tag 5 verabreicht. Je nach Ansprechen der
Tumorerkrankung, werden 6 oder 8 Zyklen der Therapie gegeben. Um dies
herauszufinden, wird nach 4 Zyklen die Wirkung der Behandlung überprüft. Liegt
bereits ein maximaler Rückgang der Lymphome nach 4 Zyklen vor, werden nur noch
2 weitere Zyklen verabreicht. Ist nach 4 Zyklen noch Tumorgewebe zu entdecken,
wird die volle Zahl von insgesamt 8 Zyklen PVAG verabreicht. Sollte nach Gabe von
8 Zyklen noch ein Tumorrest auffällig sein, wird zusätzlich eine
Bestrahlungsbehandlung auf die entsprechenden Gebiete angeschlossen.
Untersuchungen vor und während der Behandlung
Um die Verfassung der Patienten vor, während und nach der Behandlung genau zu
beschreiben, werden einige Untersuchungen notwendigerweise durchgeführt. Anzahl
und Art dieser Untersuchungen überschreiten jedoch nicht das auch außerhalb von
Studien übliche Ausmaß.
Untersuchungen vor Beginn der Studie:
Vor der Behandlung erfolgt die Erhebung der Krankengeschichte sowie die
körperliche Untersuchung durch den behandelnden Arzt. Sollten Sie regelmäßig
Medikamente einnehmen, teilen Sie dieses Ihrem Arzt bitte mit. Eine umfangreiche
Labordiagnostik (d.h. Blutentnahme) sowie eine Testung auf mögliche
Viruserkrankungen wie Hepatitis B, C und HIV (Humanes Immundefizienz-Virus) wird
52
vorgenommen. Im Falle eines positiven Hepatitis-B- und C-Tests erfolgt eine
gesetzlich
vorgeschriebene
namentliche
Meldung
an
die
zuständige
Gesundheitsbehörde. Die Besonderheit einer HIV-Infektion besteht darin, daß viele
Infizierte von Ihrer Infektion nichts wissen, weil sie jahrelang keine Krankheitszeichen
verspüren. Dennoch kann eine Infektion mit HIV bereits bestehen. Die Mitteilung, daß
eine HIV-Infektion vorliegt, belastet den betroffenen schwer. Dennoch gibt es gute
Gründe, einen solchen Test zu machen, denn das Vorliegen einer HIV-Infektion hat
erhebliche Auswirkungen auf die Therapie Ihrer Grunderkrankung. Die Durchführung
des HIV-Tests unterliegt der strengen ärztlichen Schweigepflicht, so daß keiner
außer dem Patienten von dem Ergebnis erfährt. Im Falle eines positiven HIV-Tests
erfolgt eine anonyme Meldung an das Robert-Koch-Institut in Berlin. (über den HIVTest werden Sie von Ihrem behandelnden Arzt noch einmal gesondert aufgeklärt).
Ohne Ihr Einverständnis zu diesen Untersuchungen kann keine Behandlung
innerhalb dieser Studie erfolgen. Nach der Lymphknotenentnahme ist zur
Abschätzung des Krankheitsausmaßes auch eine Knochenmarkbiopsie (d.h. eine
Punktion von Knochengewebe) und in bestimmten Fällen auch eine Leberbiopsie
(d.h. eine Punktion der Leber) nötig. Die Knochenmarkbiopsie erfolgt mit lokaler
Betäubung in der Regel am Hüftknochen
(über die Durchführung dieser
Untersuchungen werden Sie noch einmal gesondert von Ihrem behandelndem Arzt
aufgeklärt). Ferner ist die Überprüfung einiger weiterer Organfunktionen vor Beginn
der Therapie erforderlich. Aufgrund dieser Voruntersuchungen können mögliche
Nebenwirkungen der Therapie gezielter festgestellt werden. Zu diesen
Untersuchungen
gehören:
EKG
(Elektrokardiogramm),
Echokardiogramm
(Ultraschalluntersuchung des Herzens), Lungenfunktionsprüfung und die Ermittlung
der Schilddrüsenfunktion mittels Blutabnahme.
Zur exakten Beschreibung der Krankheitsausdehnung werden verschiedene
bildgebende
Untersuchungsverfahren
eingesetzt:
Röntgenaufnahmen
des
Brustraumes (von vorne und von der Seite), Ultraschalluntersuchungen des
Bauchraumes sowie Computertomographien von Hals, Brustbereich und
Bauchregion. In Einzelfällen kann auch eine Kernspintomographie nötig sein.
Weiterhin ist eine Darstellung des Knochensystems, eine Skelettszintigraphie
erforderlich.
Nach Abschluss der vollständigen diagnostischen Untersuchungen, die etwa zwei
Wochen beanspruchen, kann zügig mit der Therapie begonnen werden.
Untersuchungen während der Therapie:
Die Behandlung wird von regelmäßigen Blutuntersuchungen begleitet, damit
auftretende Nebenwirkungen möglichst frühzeitig erkannt werden. Zur Vorbeugung
möglicher Nebenwirkungen werden neben den Chemotherapeutika
weitere
Substanzen verabreicht. Dies können Antibiotika, Mittel gegen Übelkeit und
Erbrechen auch Blut und Blutprodukte sein.
Die Therapie erfordert einen engen Kontakt zwischen Arzt und Patient. Beschwerden
jeglicher Art sollen deshalb unbedingt mit dem behandelnden Arzt besprochen
werden.
Überprüfung des Behandlungserfolges (Restaging):
Ein Restaging wird immer nach Beendigung der Chemotherapie bzw. nach Abschluß
der Strahlentherapie durchgeführt. In der PVAG-Studie erfolgt zusätzlich ein
Restaging (Zwischenstaging) zwischen dem vierten und fünften Zyklus der
Chemotherapie. Bei diesen Kontrollen werden erneut eine körperliche Untersuchung,
53
Blutuntersuchungen,
Röntgenuntersuchungen
und
Computer-tomographien
durchgeführt.
Über diese Untersuchungen hinaus werden alle diagnostischen Untersuchungen
wiederholt, die vor Therapiebeginn einen krankhaften Befund gezeigt haben. War
z.B. zu Beginn eine Skelettuntersuchung positiv, d.h. Nachweis eines Befalls im
Sinne der Hodgkin-Erkrankung, so muß diese Untersuchung nun noch einmal
wiederholt werden.
Untersuchungen nach der Therapie (Nachsorge):
Bei jeder Krebsbehandlung ist eine regelmässig durchgeführte Tumornachsorge
unentbehrlich. Diese Nachsorge hat zur Aufgabe, ein Wiederauftreten der Krankheit
(Rezidiv) rechtzeitig zu erkennen, Begleit- und Folgeerkrankungen festzustellen und
zu behandeln sowie den Patienten bei seinen körperlichen, gefühlsmässigen und
sozialen Befindlichkeiten (Lebensqualität) zu stützen.
Nach Beendigung der Chemo- und/oder Strahlentherapie sollen regelmäßige
Nachsorgeuntersuchungen erfolgen. In anfänglich vierteljährlichen, später halb- und
dann in jährlichen Abständen werden Kontrolluntersuchungen vorgenommen, die
eine körperliche Untersuchung, Blutbildkontrolle, Röntgen- und gegebenenfalls
Computertomographie sowie Ultraschall-untersuchungen (Sonographie) umfassen.
Hierdurch sollen rechtzeitig Rezidive (Wiedererkrankungen) sowie Zweittumore
erkannt werden.
Die Nachsorge innerhalb der Studie ist auf einen Zeitraum von 3 Jahren nach Ende
der Therapie begrenzt. Bei einer angenommenen Rekrutierungsdauer von 18
Monaten, einer individuellen Therapiedauer von 6 Monaten plus nicht
auszuschließender Therapieverzögerungen besteht die entsprechende Studiendauer
insgesamt in einem Zeitraum von 6 Jahren nach Aktivierung.
Nebenwirkungen/Risiken
Sowohl Chemotherapie als auch Strahlentherapie sind mit Nebenwirkungen behaftet.
Da die verabreichten Substanzen außer den Tumorzellen auch gesundes
Körpergewebe angreifen, können unter der Behandlung folgende Nebenwirkungen
auftreten:
Häufig ist ein Verlust des Kopfhaares zu beobachten. Nach Ende der Therapie
wachsen die Haare wieder nach. Insbesondere an den Therapietagen kann es zu
Übelkeit und Erbrechen kommen. Diesem kann in den allermeisten Fällen
medikamentös gut entgegengewirkt werden. Ebenfalls können Appetitlosigkeit,
Schlafstörungen,
Fieber,
grippeähnliche
Symptome,
Hautausschlag,
Schleimhautentzündungen im Mund-, Rachen-, Speiseröhrenbereich und allergische
Reaktionen auftreten. Darüber hinaus kann es zu zeitweiligen, aber auch
dauerhaften Organstörungen z.B. an Lunge, Niere, Rückenmark, peripheren Nerven,
Leber (in Form eines toxischen Leberschadens), Herz sowie am Knochenmark
kommen. Diese Schäden sind jedoch sehr selten.
Bestimmte Medikamente können zu Kribbeln und Pelzigkeitsgefühl meist in den
Händen und Füßen führen. Auch der Verdauungstrakt kann in Form von
Durchfällen/Verstopfung in Mitleidenschaft gezogen werden. Während der gesamten
Dauer der Chemotherapie sind Sie verstärkt durch Infektionen gefährdet. Während
der gesamten Behandlungszeit sollten Sie daher auf eine gründliche Hygiene,
insbesondere Mundhygiene achten. Auch sollten Sie kleine Schleimhautverletzungen
vermeiden, indem Sie eine weiche Zahnbürste benutzen. Die Erniedrigung roter
54
Blutkörperchen kann zu Belastungsatemnot und allgemeiner Müdigkeit führen. In
Einzelfällen können Bluttransfusionen notwendig werden.
Fieber entwickeln, suchen Sie bitte immer Kontakt zu Ihren Arzt.
Viele Patienten, die am Hodgkin Lymphom erkranken, können heute geheilt werden.
Die dafür erforderlichen Behandlungsschritte führen zu den zuvor beschriebenen
Nebenwirkungen. Darüber hinaus aber ist die Behandlung mit dem Risiko von
Spätfolgen belastet. Durch die eingesetzte Chemo- und Strahlentherapie ist das
Risiko von sogenannten Sekundärneoplasien (Zweittumoren) wie Leukämien und
soliden Tumoren erhöht. Außerdem können langfristige Spätfolgen noch Monate bis
Jahre nach dem Abklingen von akuten Nebenwirkungen an Herz, Lunge und
anderen Organen auftreten.
Andere Behandlungsmöglichkeiten
Falls Sie sich entscheiden, nicht an dieser Studie teilzunehmen, wird Ihr Arzt Ihnen
erklären, welche anderen Behandlungsmöglichkeiten zur Verfügung stehen. Dies
könnte zum Beispiel eine Behandlung mit anderen Chemotherapeutika beinhalten.
Weitere Informationen
Dieses Studienprotokoll wurde der Ethikkommission vorgelegt und von dieser positiv
bewertet.
Die Teilnahme an dieser klinischen Studie ist selbstverständlich freiwillig. Ihr Arzt
wird Sie bitten, eine Einverständniserklärung zu unterzeichnen und damit auch zu
bestätigen, dass Sie vollständig über die Studie informiert wurden und deren
Zielsetzung verstehen.
Sie haben jedoch das Recht, Ihre Einwilligung zur Teilnahme an der Studie jederzeit
und ohne Angabe von Gründen zu widerrufen, ohne dass das Vertrauensverhältnis
zu Ihrem behandelnden Arzt darunter leidet. Aus Sicherheitsgründen sollten jedoch
bei
vorzeitigem
Studienabbruch
abschließende
Untersuchungen
sowie
Nachsorgeuntersuchungen stattfinden. Bei vorzeitigem Abbruch werden Sie
außerhalb dieser Studie nach bestem medizinischen Wissen weiter behandelt
werden.
Sie werden selbstverständlich auch über alle neuen Informationen, die für die
Teilnahme an der Studie relevant sein könnten, umgehend informiert. Sollte Ihr
behandelnder Arzt der Meinung sein, dass eine weitere Teilnahme an dieser Studie
für Sie von Nachteil ist, so kann er Ihre Behandlung im Rahmen dieser Studie auch
ohne Ihre Zustimmung beenden. In diesem Fall würden Sie außerhalb dieser Studie
nach bestem medizinischen Wissen weiter behandelt.
Der Nutzen Ihrer Teilnahme besteht in der Möglichkeit, durch eine neue Therapie
erfolgreicher behandelt zu werden. Mit den Ergebnissen dieser Studie lassen sich
möglicherweise wertvolle Erkenntnisse für die zukünftige Behandlung Ihrer
Erkrankung erzielen. Es kann Ihnen jedoch nicht garantiert werden, daß Sie durch
eine Teilnahme an dieser Studie einen Vorteil haben werden. Bei einer Teilnahme
entstehen Ihnen keine zusätzlichen Kosten.
Patientenversicherung
Gemäß den Vorschriften des §40 Abs. 1 Nr. 8 und Abs. 3 des deutschen
Arzneimittelgesetzes (AMG) besteht für Sie eine sogenannte Probandenversicherung
(Vers. Nr. 70-5621716-3) bei der GERLING Industrie Deutschland GmbH, NL West
(Ansprechpartner Herr B. Hoppe).
55
Der Versicherungsschutz umfasst Gesundheitsschäden, die im zeitlichen und
ursächlichen Zusammenhang mit dieser klinischen Prüfung aufgetreten sind. Die
maximale Deckungssumme pro versicherte Person beträgt 500.000 €. Die
Höchstleistung für alle Versicherungsfälle innerhalb dieser Studie beträgt 5.000.000
€.
Der Versicherungsschutz ist insbesondere an folgende Bedingungen geknüpft:
1.
Während der Dauer der klinischen Prüfung dürfen Sie sich einer anderen
medizinischen Behandlung nur nach Rücksprache mit Ihrem behandelnden
Arzt unterziehen. Dies gilt nicht in einem medizinischem Notfall; Ihr
behandelnder Arzt ist jedoch von der Notfallbehandlung unverzüglich zu
unterrichten.
2.
Eine Gesundheitsschädigung, die als Folge der klinischen Prüfung eingetreten
sein könnte, ist dem Versicherer unverzüglich zu melden.
3.
Im möglichen Schadensfall sind von Ihnen alle zweckmäßigen Maßnahmen zu
treffen, die der Aufklärung der Ursache und des Umfangs des eingetretenen
Schadens und der Minderung dieses Schadens dienen.
4.
Auf Verlangen des Versicherers ist der behandelnde Arzt – als solcher gilt
auch ein Konsiliararzt oder ein gutachterlich tätiger Arzt – zu veranlassen,
einen Bericht über die Gesundheitsschädigung und, nach Abschluss der
ärztlichen Behandlung, einen Schlussbericht zu erstatten, außerdem ist Sorge
zu tragen, dass alle etwa weiter noch von dem Versicherer geforderten
Berichte des behandelnden Arztes geliefert werden. Alternativ können Sie
Ihren behandelnden Arzt von der ärztlichen Schweigepflicht entbinden, damit
der Versicherer die vorab genannten Berichte direkt beim Arzt anfordern kann.
5.
Die behandelnden Ärzte - auch diejenigen, von denen Sie aus anderen
Anlässen behandelt oder untersucht worden sind – und die
Sozialversicherungsträger sowie andere Versicherer – wenn dort die
Gesundheitsschädigung gemeldet ist - sind zu ermächtigen, dem Versicherer
auf Verlangen Auskunft zu erteilen.
6.
Hat der Versicherungsfall den Tod zur Folge, so ist dies unverzüglich
anzuzeigen, und zwar auch dann, wenn eine Meldung nach Abs. 2 bereits
erfolgt ist. Dem Versicherer ist das Recht zu verschaffen, eine Obduktion
durch einen von ihm beauftragten Arzt vornehmen zu lassen.
Die Meldungen sind unter Angabe der Versicherungsnummer 70-5621716-3 bei der
Niederlassung der GERLING Industrie Deutschland GmbH in Düsseldorf
einzureichen.
Die Adresse lautet:
GERLING Industrie Deutschland GmbH
NL West
Prinzenallee 21
40549 Düsseldorf
Tel. 0211/4956-183
Fax. 0211/4956-487
Bitte beachten Sie, dass Ihr Versicherungsschutz bei Nichtbeachten der
Versicherungsbedingungen gefährdet ist.
Eine
Kopie
der
Versicherungsbestätigung
sowie
der
allgemeinen
Versicherungsbedingungen können Sie über Ihren behandelnden Arzt oder die
Studienzentrale erhalten. Die Adresse lautet:
56
Medizinische
Klinik
I
der
Universität
zu
Köln,
Studiensekretariat
Hämatologie/Onkologie, Joseph-Stelzmann-Str. 9, 50924 Köln, Tel.: 0221-478-6628
(-6128), Fax: 0221-478-3531.
Über etwaige Versicherungsleistungen hinausgehende Schadenersatzansprüche
sind ausgeschlossen.
Datenschutz:
Im Rahmen dieser Studie werden personenbezogene Behandlungsdaten von Ihnen
erhoben, an die Studienzentrale in Köln weitergeleitet. Ebenso werden CT-Bilder und
Lymphknotenpräparate an Expertengremien versandt. Alle Personen, die Einblick in
die gespeicherten Daten haben, sind zur Wahrung des Datenschutzes verpflichtet.
Ihr Name wird zu keiner Zeit öffentlich gemacht.
Im Rahmen der Überwachung von klinischen Studien können unabhängige Personen
(z.B.
Monitore)
oder
Vertreter
der
Überwachungsbehörden
(z.B.
Regierungspräsidium, Bundesoberbehörde) Einsicht in Ihre Krankenakten nehmen,
um sicherzustellen, daß die Daten in dieser Studie korrekt erhoben wurden. Diese
Personen sind jedoch von Amts wegen zur Verschwiegenheit verpflichtet. Mit dem
Unterzeichnen der Einverständniserklärung geben Sie Ihre Einwilligung zur
Erhebung und Weitergabe ihrer Daten sowie zur Einsichtnahme durch autorisierte
Dritte.
Falls die Studienzentrale über einen längeren Zeitraum keine Informationen von
Ihnen erhalten hat, wird sie sich schriftlich (falls sie uns hierzu die Genehmigung
erteilt haben) mit der Bitte an Sie wenden, sich zu einer Nachsorgeuntersuchung zu
einem Arzt Ihrer Wahl zu begeben bzw. uns die Adresse Ihres behandelnden Arztes
mitzuteilen.
Weitere Fragen:
Sollten Sie weitere Fragen bezüglich dieser Studie oder Ihren Rechten und Pflichten
als Teilnehmer haben, so wenden Sie sich bitte jederzeit an Ihren behandelnden
Arzt/Ärztin:
Name: .....................................
Tel..........................................................
oder an das Studiensekretariat Hämatologie/Onkologie (Tel. 0221/478-6128; -3777).
Sollten Sie sich für eine Teilnahme an dieser Studie entschließen, möchten wir Ihnen
schon jetzt herzlich für Ihre Unterstützung danken.
57
12.4. Einverständniserklärung
Therapiestudie:
PVAG – eine Phase I/II – Dosisfindungsstudie in älteren Patienten (> 60 Jahren)
in intermediären und fortgeschrittenen Stadien eines Morbus Hodgkin
Name:
Vorname:
Geburtsdatum:
Ich bin von meinem behandelnden Arzt ausführlich und verständlich über die Art
meiner Erkrankung, die durchzuführende Behandlung, Wirkungen und
Nebenwirkungen, mögliche Spätfolgen und Risiken sowie über Ziele, Bedeutung und
Tragweite der oben genannten Studie informiert worden. Auf andere
Behandlungsmethoden außerhalb dieser Studie wurde ich hingewiesen.
Ich bin damit einverstanden, daß vor Beginn der Behandlung ein HIV-Test
durchgeführt wird.
Ich wurde darüber aufgeklärt, daß regelmäßige Nachsorgeuntersuchungen in
meinem Interesse über viele Jahre hinweg durchgeführt werden sollen. Hierdurch
sollen rechtzeitig Rezidive (Wiedererkrankungen) und Zweittumore erkannt werden.
Ich wurde über die bestehende Patientenversicherung aufgeklärt sowie über die sich
für mich daraus ergebenden Anforderungen. Über die mündliche Aufklärung hinaus
habe ich den Text der Patienteninformation und dieser Einwilligungserklärung
gelesen und verstanden. Aufgetretene Fragen wurden mir vom behandelnden Arzt
verständlich und ausreichend beantwortet. Ein Ansprechpartner für weitere
zukünftige Fragen wurde mir genannt.
Folgende Themen wurden zusätzlich im mündlichen Aufklärungsgespräch behandelt:
........................................................................................................................................
........................................................................................................................................
Ich bin damit einverstanden, daß die mir entnommenen Gewebeproben einem
besonders qualifizierten Pathologen (Referenzpathologen) zur Überprüfung der
Diagnose zugeschickt werden. Ich bin weiterhin damit einverstanden, daß Teile der
zu diagnostischen Zwecken entnommenen Blut-, Knochenmark- und Gewebeproben
zu wissenschaftlichen, nicht-kommerziellen Untersuchungen verwendet werden und
übertrage hiermit der Studienleitung das Verfügungsrecht an diesem Material.
Untersuchungen am Probematerial dürfen nur im Rahmen der in der Studie
untersuchten Fragestellung durchgeführt werden. Das Eigentumsrecht an den von
mir entnommenen Gewebeproben verbleibt bei mir. Keinesfalls werden zusätzliche
Gewebe- oder Blutuntersuchungen über das aus medizinischer Sicht notwendige
Maß hinaus entnommen.
58
Ich bin mit der im Rahmen dieser klinischen Studie erfolgenden Aufzeichnung
von Krankheits-/Studiendaten und ihrer anonymisierten Weitergabe zur
Überprüfung an die Studienzentrale, die zuständige Überwachungsbehörde
oder Bundesoberbehörde einverstanden. Darüber hinaus bin ich damit
einverstanden, dass zum Zwecke der Dokumentation Einsicht in meine
Krankenakte genommen wird von zur Verschwiegenheit verpflichteten
Beauftragten der Studienzentrale oder den Behörden. Ich habe Anspruch auf
Information über Ziel, Zweck und Verbleib dieser Datensammlung. Alle
Personen, die Zugang zu den Daten haben, sind zur Wahrung des
Datengeheimnisses verpflichtet. Veröffentlichungen erfolgen nur anonymisiert.
Ich bestätige durch meine Unterschrift, daß ich bereit bin an der obengenannten
Studie zur Primärtherapie des Hodgkin Lymphoms teilzunehmen. Ich erkläre mich mit
der Behandlung gemäß der jeweiligen Studie einschließlich der dafür notwendigen
wissenschaftlichen und ärztlichen Untersuchungen einverstanden. Ich bin darüber
informiert, daß ich meine heute gegebene Einwilligung jederzeit und ohne Angabe
von Gründen widerrufen kann, ohne daß mir daraus Nachteile entstehen.
Eine
Kopie
dieser
Einwilligungserklärung
und
der
dazugehörigen
Patienteninformation habe ich erhalten.
Unterschriften:
1. Aufklärender Arzt
Name: ......................................
Unterschrift: .........................
Datum: ................
Unterschrift: .........................
Datum: ................
2. Zeuge (falls erforderlich)
Name: ......................................
3. Patient
Name: ......................................
Vorname: .........................
Geburtsdatum: .........
Adresse des Patienten:
Straße ....................................................................
PLZ/Ort ..................................................................
Ort/Datum: ...............................
Unterschrift: ...........................................................
Ich erkläre mich damit einverstanden, daß ich von der Studienzentrale persönlich
angeschrieben werden kann, falls diese über einen längeren Zeitraum keine
59
Informationen von mir erhalten hat. In diesem Fall wird sich die Studienzentrale mit
der Bitte an mich wenden, mich bezüglich meiner Nachsorgeuntersuchungen zu
einem Arzt meiner Wahl zu begeben bzw. ihr die Adresse meines behandelnden
Arztes mitzuteilen.
Ort/Datum:..........................................
Unterschrift:................................................................................
60
12.5. Datenschutz
61
12.6. Declaration of Helsinki
World Medical Association Declaration of Helsinki
Ethical Principles for
Medical Research Involving Human Subjects
Adopted by the 18th World Medical Assembly
Helsinki, Finland, June 1964
and amended by the
29th World Medical Assembly, Tokyo, Japan, October 1975
35th World Medical Assembly, Venice, Italy, October 1983
41st World Medical Assembly, Hong Kong, September 1989
48th General Assembly, Somerset West, Republic of South Africa, October 1996
and the
nd
52 WMA General Assembly, Edinburgh, Scotland, October 2000
A.
INTRODUCTION
1.
The World Medical Association has developed the Declaration of Helsinki as
a statement of ethical principles to provide guidance to physicians and other
participants in medical research involving human subjects. Medical research
involving human subjects includes research on identifiable human material or
identifiable data.
2.
It is the duty of the physician to promote and safeguard the health of the
people. The physician’s knowledge and conscience are dedicated to the
fulfillment of this duty.
3.
The Declaration of Geneva of the World Medical Association 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 only in the patient's interest when providing medical care
which might have the effect of weakening the physical and mental condition
of the patient."
4.
Medical progress is based on research which ultimately must rest in part on
experimentation involving human subjects.
5.
In medical research on human subjects, considerations related to the wellbeing of the human subject should take precedence over the interests of
science and society.
6.
The primary purpose of medical research involving human subjects is to
improve prophylactic, diagnostic and therapeutic procedures and the
understanding of the aetiology and pathogenesis of disease. Even the best
proven prophylactic, diagnostic, and therapeutic methods must continuously
be challenged through research for their effectiveness, efficiency,
accessibility and quality.
7.
In current medical practice and in medical research, most prophylactic,
diagnostic and therapeutic procedures involve risks and burdens.
8.
Medical research is subject to ethical standards that promote respect for all
human beings and protect their health and rights. Some research populations
are vulnerable and need special protection. The particular needs of the
62
economically and medically disadvantaged must be recognized. Special
attention is also required for those who cannot give or refuse consent for
themselves, for those who may be subject to giving consent under duress, for
those who will not benefit personally from the research and for those for
whom the research is combined with care.
9.
B.
Research Investigators should be aware of the ethical, legal and regulatory
requirements for research on human subjects in their own countries as well
as applicable international requirements. No national ethical, legal or
regulatory requirement should be allowed to reduce or eliminate any of the
protections for human subjects set forth in this Declaration.
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH
10. It is the duty of the physician in medical research to protect the life, health,
privacy, and dignity of the human subject.
11. 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 on adequate
laboratory and, where appropriate, animal experimentation.
12. Appropriate caution must be exercised in the conduct of research which may
affect the environment, and the welfare of animals used for research must be
respected.
13. The design and performance of each experimental procedure involving
human subjects should be clearly formulated in an experimental protocol.
This protocol should be submitted for consideration, comment, guidance, and
where appropriate, approval to a specially appointed ethical review
committee, which must be independent of the investigator, the sponsor or
any other kind of undue influence. This independent committee should be in
conformity with the laws and regulations of the country in which the research
experiment is performed. The committee has the right to monitor ongoing
trials. The researcher has the obligation to provide monitoring information to
the committee, especially any serious adverse events. The researcher should
also submit to the committee, for review, information regarding funding,
sponsors, institutional affiliations, other potential conflicts of interest and
incentives for subjects.
14. The research protocol should always contain a statement of the ethical
considerations involved and should indicate that there is compliance with the
principles enunciated in this Declaration.
15. Medical research involving human subjects should be conducted only by
scientifically qualified persons and under the supervision of a clinically
competent medical person. The responsibility for the human subject must
always rest with a medically qualified person and never rest on the subject of
the research, even though the subject has given consent.
16. Every medical research project involving human subjects should be preceded
by careful assessment of predictable risks and burdens in comparison with
foreseeable benefits to the subject or to others. This does not preclude the
participation of healthy volunteers in medical research. The design of all
studies should be publicly available.
63
17. Physicians should abstain from engaging in research projects involving
human subjects unless they are confident that the risks involved have been
adequately assessed and can be satisfactorily managed. Physicians should
cease any investigation if the risks are found to outweigh the potential
benefits or if there is conclusive proof of positive and beneficial results.
18. Medical research involving human subjects should only be conducted if the
importance of the objective outweighs the inherent risks and burdens to the
subject. This is especially important when the human subjects are healthy
volunteers.
19. Medical research is only justified if there is a reasonable likelihood that the
populations in which the research is carried out stand to benefit from the
results of the research.
20. The subjects must be volunteers and informed participants in the research
project.
21. The right of research subjects to safeguard their integrity must always be
respected. Every precaution should be taken to respect the privacy of the
subject, the confidentiality of the patient’s information and to minimize the
impact of the study on the subject's physical and mental integrity and on the
personality of the subject.
22. In any research on human beings, 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. The subject
should be informed of the right to abstain from participation in the study or to
withdraw consent to participate at any time without reprisal. After ensuring
that the subject has understood the information, the physician should then
obtain the subject's freely-given informed consent, preferably in writing. If the
consent cannot be obtained in writing, the non-written consent must be
formally documented and witnessed.
23. When obtaining informed consent for the research project the physician
should be particularly cautious if the subject is in a dependent relationship
with the physician or may consent under duress. In that case the informed
consent should be obtained by a well-informed physician who is not engaged
in the investigation and who is completely independent of this relationship.
24. For a research subject who is legally incompetent, physically or mentally
incapable of giving consent or is a legally incompetent minor, the investigator
must obtain informed consent from the legally authorized representative in
accordance with applicable law. These groups should not be included in
research unless the research is necessary to promote the health of the
population represented and this research cannot instead be performed on
legally competent persons.
25. When a subject deemed legally incompetent, such as a minor child, is able to
give assent to decisions about participation in research, the investigator must
obtain that assent in addition to the consent of the legally authorized
representative.
26. Research on individuals from whom it is not possible to obtain consent,
including proxy or advance consent, should be done only if the
64
physical/mental condition that prevents obtaining informed consent is a
necessary characteristic of the research population. The specific reasons for
involving research subjects with a condition that renders them unable to give
informed consent should be stated in the experimental protocol for
consideration and approval of the review committee. The protocol should
state that consent to remain in the research should be obtained as soon as
possible from the individual or a legally authorized surrogate.
27. Both authors and publishers have ethical obligations. In publication of the
results of research, the investigators are obliged to preserve the accuracy of
the results. Negative as well as positive results should be published or
otherwise publicly available. Sources of funding, institutional affiliations and
any possible conflicts of interest should be declared in the publication.
Reports of experimentation not in accordance with the principles laid down in
this Declaration should not be accepted for publication.
C.
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH
MEDICAL CARE
28. The physician may combine medical research with medical care, only to the
extent that the research is justified by its potential prophylactic, diagnostic or
therapeutic value. When medical research is combined with medical care,
additional standards apply to protect the patients who are research subjects.
29. The benefits, risks, burdens and effectiveness of a new method should be
tested against those of the best current prophylactic, diagnostic, and
therapeutic methods. This does not exclude the use of placebo, or no
treatment, in studies where no proven prophylactic, diagnostic or therapeutic
method exists.
30. At the conclusion of the study, every patient entered into the study should be
assured of access to the best proven prophylactic, diagnostic and therapeutic
methods identified by the study.
31. The physician should fully inform the patient which aspects of the care are
related to the research. The refusal of a patient to participate in a study must
never interfere with the patient-physician relationship.
32. In the treatment of a patient, where proven prophylactic, diagnostic and
therapeutic methods do not exist or have been ineffective, the physician, with
informed consent from the patient, must be free to use unproven or new
prophylactic, diagnostic and therapeutic measures, if in the physician’s
judgement it offers hope of saving life, re-establishing health or alleviating
suffering. Where possible, these measures should be made the object of
research, designed to evaluate their safety and efficacy. In all cases, new
information should be recorded and, where appropriate, published. The other
relevant guidelines of this Declaration should be followed.
65
12.7. Performance Status Scales
Status
Karnofsky
ECOG
Status
Normal, no complaints.
100
0
Nomal activity
Able to carry on normal activities.
Minor signs or symptoms of
disease.
90
1
Symptoms but nearly
ambulatory
Normal activity with effort.
80
Care for self. Unable to carry on
normal activity or to do active
work.
70
2
Some bed time, but to be in
bed less than 50% of normal
daytime
Requires occasional assistance
and frequent medical care.
60
Requires considerable
assistance.
50
3
Needs to be in bed more than
50% of nomal daytime
Disabled. Requires special care
and assistance and frequent
medical care.
40
Severely disabled. Hospitalization
indicated though death nonimminent.
30
4
Unable to get out of bed
Very sick. Hospitalization
necessary. Active supportive
treatment necessary.
20
Moribund.
10
Dead.
0
66
12.8. WHO Toxicity
Toxicity
Grade 0
Grad 1
Grade 2
Grade 3
Grade 4
Hemoglobin (g/dl)
≥ 11.0
9.5-10
8.0-9.4
6.5-7.9
< 6.5
Leucocytes (1,000/mm3)
≥ 4.0
3.0-3.9
2.0-2.9
1.0-1.9
< 1.0
HEMATOLOGICAL
Platelets (1,000/mm3)
≥ 100
75-99
50-74
25-49
< 25
Hemorrhage
none
petechiae
mild blood loss
gross blood loss
debilitating blood
loss
Bilirubin
≤ 1.25xN
1.26-2.5xN
2.5-5xN
5.1-10xN
> 10 xN
Transaminases (OT/PT)
≤ 1.25xN
1.26-2.5xN
2.5-5xN
5.1-10xN
> 10 xN
AP
≤ 1.25xN
1.26-2.5xN
2.5-5xN
5.1-10xN
> 10 xN
ORAL
no change
soreness/
erythema
erythema, ulcers, Ulcers, required Aliment.
can eat solids
liquid diet
not possible
DIARRHOE
none
transsient
< 2 days
tolerable
> 2 days
NAUSEA AND VOMITING
none
nausea
transient vomiting vomiting
requiring therapy
GASTROINTESTINAL
intolerable
requiring therapy
hemorrhagic
dehydratin
intractable
vomoting
RENAL
Blood urea or creatinine
≤ 1.25xN
1.26-2.5xN
2.5-5xN
5.1-10xN
> 10 xN
Proteinuria (g/L)
no change
<3
3-10
>10
nephrotic
syndome
Hematuria
no change
microscopic
gross
gross + clots
obstructive
uropathy
PULMONARY
no change
mild symptoms
exertional
dyspnea
dyspnea
at rest
complete
rest
FEVER WITH DRUGS
none
< 38 °C
38-40°C
> 40°C
fever
with hypotension
ALLERGIC
no change
edema
bronchospasm,
bronchospasm,
no
parenteral parenteral
therapy
therapy rquired
anaphylaxis
CUTANEUS
no change
erythema
dry
desquamation,
vesiculation,
pruritus
moist
desquamanation,
ulceration
exfoliative
dermatitis
HAIR
no change
minimal hair loss
moderate
alopecia
complte alopecia, non-reversible
reversible
alopecia
INFECTION
none
minor infection
moderate
infection
major infection
major infection
with hypotension
Rhythm
no change
sinus tachycardia unifocal PVC
>110 bpm at rest atrial arrythmia
multifocal PVC
ventricular
tachycardia
Function
no change
asymptomatic,
but normal
symptomatic
no tap required
sympt.
dysfunction
response to tap
non-responsive
to therapy
Pericarditis
no change
asympt. effusion
sympt. no
tap required
tamponade
tap required
tamponade,
surgery required
State of consciousness
none
trans. lethargy
somn. <50% of somn. >50% of coma
waking hours
waking hours
Peripheral
none
mild paresthesia
sev. paresthesia
intolerable
Constipation
none
mild
moderate
abd. distension
dist.+vomiting
PAIN
none
mild
moderate
severe
intractable
bed
CARDIAC
NEUROTOXCITY
paralysis
67
12.9. Assessment of each cycle
Assessments and
Laboratory Tests
Cycle 1
Day #
1
Weight
X
Temperature
X
Diff. Bc
X
CBC a
X
Comedikation
X
d
2
3
4
5
6
7
8
9
10
11
12
13
14 15
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
16
17
18
19
20
21
X
X
X
X
X
X
Until next
cycle
X
If leukocytes < 2.5 x109/L and platelets < 80 x 109/L, CBC should be taken at least 3 times a week until leukocyte and platelet recovery.
68
12.10. Course of Assessments
Assessment/ Laboratory Tests
Screening
1
2
3
4
Cycle-No.
Interim
Staging
5
6
7
8
Restaging
Informed consent
X
Anamnesis
X
Physical Examination
X
Performance-Status
X
X
X
Staging
X
X
X
Body Weight
X
X
X
X
X
X
X
X
Temperature
X
X
X
X
X
X
X
X
CBC
X
X
X
X
X
X
X
X
X
X
X
Differential Blood Count
X
X
X
X
X
X
X
X
X
X
X
Comedication
X
X
X
X
X
X
X
X
X
X
SAEs
X
X
X
X
X
X
X
X
69
12.11. Flow-chart
Intermediate and advanced stages HL in patients > 60
CRF
years
Registration by fax:
Studiensekretariat
Hämatologie/Onkologie
+49 (0)221 478 3531
DOSE
REG
AN
ST
4 cycles PVAG
C
Interim Staging
RE
CR
< CR
2 cycles PVAG
4 cycles PVAG
Restaging
C
RE
PR
RX 30 Gy
Definitive Restaging
Follow-up
RX
RE
F
70
12.12. Certificate of insurance
71
12.13. Approval from the ethics committee of the University of Cologne
72
12.14. Approval from the ethics committee of the University of Cologne
(amendment #1)
73
74
12.15. Approval from the ethics committee of the University of Cologne
(amendment #2)
75
76
12.16. Changes by amendment # 1
Since recruitment is slower than expected the protocol committee decided to amend
the protocol (final version; October 28, 2003) based on the available data. In detail
the following changes have been made:
Old version (title page)
PVAG Study Coordination:
Klinik I für Innere Medizin der Universität zu Köln
Studiensekretariat Hämatologie/Onkologie
Joseph-Stelzmann-Str. 9
D-50924 Köln (Cologne)
Tel:
+49 221 478 - 6128 or - 3777 or - 6628
Fax:
+49 221 478 - 3531
E-mail:
[email protected]
New version (title page)
PVAG Study Coordination:
Klinik I für Innere Medizin der Universität zu Köln
Klinisches Studienzentrum Hämatologie
Kerpener Str. 62, Bettenhaus Ebene 4
D-50937 Köln (Cologne)
Tel:
+49 221 478 - 6128 or - 3777 or - 6628
Fax:
+49 221 478 - 3531
E-mail:
[email protected]
Old version (Synopsis)
Objective
The study is designed to
1) determine the maximum tolerated dose (MTD) of
gemcitabine in this combination and setting
2) test the toxicity, feasibility and short-term efficacy of
PVAG using the MTD for gemcitabine
Regimen
P
V
A
G
Prednisone
Vinblastine
Doxorubicin
Gemcitabine
p.o
i.v.
i.v.
i.v.
40 mg/m2
d1-5
2
6 mg/m
d1
50 mg/m2
d1
2
800 mg/m * d1
77
Recycle on day 22
* the starting dosage will be subsequently increased:
1000 mg/m², 1250 mg/m², 1500 mg/m²
Study Design
This is an oligocenter, non-randomized, single-arm
trial, run by a collaboration of the GHSG and selected
members of the EORTC. A phase I-part is to define the
maximum tolerated dose (MTD) of gemcitabine, which
is applied in the following phase II.
…
Primary Endpoints
Phase I: occurrence of dose limiting toxicities (DLT) as
defined in section 9.1
…
…
Sample Size
Estimated 20 (15-25) patients are required for the
phase I-part. Subsequently, 40-50 patients will be
included for the phase II-part.
New version (Synopsis)
Objective
The study is designed to test the toxicity, feasibility and
short-term efficacy of PVAG
Regimen
P
V
A
G
Prednisone
Vinblastine
Doxorubicin
Gemcitabine
p.o
i.v.
i.v.
i.v.
40 mg/m2
d1-5
6 mg/m2
d1
50 mg/m2
d1
1000 mg/m2 d1
Recycle on day 22 (platelets have to be > 75.000/mm³
and leukocytes > 2000/mm³ otherwise treatment has to
be delayed for a maximum of 21 days; if platelets or
leukocytes recover between day 14 and 21, dose
reduction as detailed in section 6.1.5 have to be
employed; patients not reaching the specified values
within 21 days have to be withdrawn from the study)
A specific dose reduction scheme will be applied
(section 6.1.5) to patients experiencing grade 4
leukopenia for more than four days or grade 4 nonhematological toxicities.
Study Design
This is an oligocenter, non-randomized, single-arm
trial, run by a collaboration of the GHSG and selected
members of the EORTC. A phase I-part is to evaluate
the safety of the regimen with reasonable certainty.
Subsequently a phase II will determine the short term
efficacy and safety.
78
…
Primary Endpoints
Phase I: occurrence of dose-limiting toxicities (DLT)
and dose reductions as defined in section 6.1.5.
…
…
Sample Size
26 patients are required for the phase I-part.
Subsequently, 14 patients will be included for the
phase II-part resulting in an overall sample size of 40
patients.
Old version (page 14)
Drug
Doxorubicin
Bleomycin
Vinblastine
Dacarbazine
Prednisone
Gemcitabine
PVAG (d1) mg/m2
50
6
40 (d1-5)
800-1500, dose to be
defined
ABVD (d1, d15) mg/m2
25
10
6
375
-
PVAG (d1) mg/m2
50
6
40 (d1-5)
1000
ABVD (d1, d15) mg/m2
25
10
6
375
-
New version (page 14)
Drug
Doxorubicin
Bleomycin
Vinblastine
Dacarbazine
Prednisone
Gemcitabine
Old version (page 15)
The table below shows the dose intensity (mg/m2/week) and the total cumulated
dose (mg/m2) for each regimen, eight cycles. For calculation purposes the dose of
gemcitabine is 1000 mg/m2 and indicated in brackets:
…
New version (page 13)
The table below shows the dose intensity (mg/m2/week) and the total cumulated
dose (mg/m2) for each regimen, eight cycles. For calculation purposes the dose of
gemcitabine is 1000 mg/m2 and indicated in brackets:
Old version (page 15)
79
… The toxicity is expected to fall due to elimination of the most toxic drugs.
The dose-finding (phase I) will be analyzed in two age groups (60-65 and 66-75
years), because tolerability of therapy in patients aged >65 may be lower than in
patients < 65 years.
No consolidating irradiation in either arm is planned to patients in complete remission
after chemotherapy…
New version (page 14)
… The toxicity is expected to fall due to elimination of the most toxic drugs.
The dose-finding (phase I) will be analyzed in two age groups (60-65 and 66-75
years), because tolerability of therapy in patients aged >65 may be lower than in
patients < 65 years.
No consolidating irradiation in either arm is planned to patients in complete remission
after chemotherapy…
Old version (page 16)
… In order to ensure the MTD safety is unaffected by an increased intolerance in the
oldest patients, the inclusion is limited to patients aged 60-75 years. The final
analysis will evaluate the results with respect to two different age groups (60 – 65
years and 66 – 75 years). In case the MTD differs between the groups, the phase III
trial stratifies the treatment according to age and the age-specific MTD.
New version (page 15)
In order to ensure the MTD safety is unaffected by an increased intolerance in the
oldest patients, the inclusion is limited to patients aged 60-75 years. The final
analysis will evaluate the results with respect to two different age groups (60 – 65
years and 66 – 75 years). In case the MTD differs between the groups, the phase III
trial stratifies the treatment according to age and the age-specific MTD.
Old version (page 16)
P
Prednisone
p.o
40 mg/m2
d1-5
V
Vinblastine
i.v.
6 mg/m2
d1
A
Doxorubicine
i.v.
50 mg/m2
d1
G
Gemcitabine
i.v.
800 mg/m2*
d1
Recycle on day 22
* the starting dosage will be subsequently increased to define the maximum tolerable
dose (MTD); 1000 mg/m2; 1250 mg/m2; 1500 mg/m2 are planned to administer.
In case the MTD is not reached a two-weekly PVAG schedule will be considered.
80
New version (page 15)
P
Prednisone
p.o
40 mg/m2
2
d1-5
d1
V
Vinblastine
i.v.
6 mg/m
A
Doxorubicine
i.v.
50 mg/m2
d1
G
Gemcitabine
i.v.
1000 mg/m2
d1
Recycle on day 22
* the starting dosage will be subsequently increased to define the maximum tolerable
dose (MTD); 1000 mg/m2; 1250 mg/m2; 1500 mg/m2 are planned to administer.
In case the MTD is not reached a two-weekly PVAG schedule will be considered.
Old version (page 17/18)
Phase I : PVAG dose finding
The phase I part of the study will evaluate the maximum tolerable dose (MTD) of
gemcitabine of PVAG. For this reason gemcitabine will be increased from an initial
dosage of 800 mg/m2, 1000 mg/m2 and 1250 mg/m2 until an expected maximum of
1500 mg/m2, each dose given on day 1 only of each cycle.
The chosen dose-finding strategy is based upon the continous reassessment method
[63]. In this method, the currently available toxicity data for patients already treated is
continuously reassessed during the study. At each assessment, the data are
modelled in order to estimate the expected level of the MTD. The next patient is then
treated at this estimated dose level. In this way, the given doses converge rapidly
towards the MTD, which is beneficial for the patients involved and the estimation of
the MTD. An estimated number of 20 patients will evolve the MTD. For providing the
clinical data a close contact to the participating centres is mandatory.
The patient cohort will be stratified into two age groups a) 60 – 65 years and b) 66 –
75 years with respect to differences in the incidences of the expected toxicities,
especially hematotoxicities
New version (page 16)
Phase I : Safety
The phase I part of the study will evaluate the safety profile of 1000 mg/m²
gemcitabine in combination with prednisone, vinblastine and doxorubicin. 26 patients
will be recruited on this dose level to establish the safety with reasonable certainty.
Recruitment will not be stopped during this interim analysis..
The chosen dose-finding strategy is based upon the continous reassessment method
[63]. In this method, the currently available toxicity data for patients already treated is
continuously reassessed during the study. At each assessment, the data are
modelled in order to estimate the expected level of the MTD. The next patient is then
81
treated at this estimated dose level. In this way, the given doses converge rapidly
towards the MTD, which is beneficial for the patients involved and the estimation of
the MTD. An estimated number of 20 patients will evolve the MTD. For providing the
clinical data a close contact to the participating centres is mandatory.
The patient cohort will be stratified into two age groups a) 60 – 65 years and b) 66 –
75 years with respect to differences in the incidences of the expected toxicities,
especially hematotoxicities.
Old version (page 18)
After defining the MTD an additional cohort of 40-50 patients will be treated with the
evaluated MTD to characterize the feasibility and efficacy of the regimen. This
sample size will allow the proportion of complete responders (CR) and the proportion
of patients experiencing toxic events to be determined within +/- 12%.
New version (page 16)
After phase I an additional cohort of 14-50 patients will be treated with the evaluated
MTD to better characterize the feasibility and efficacy of the regimen. The total
sample size of 40 patients will allow the proportion of complete responders (CR) and
the proportion of patients experiencing toxic events to be determined within +/- 14%.
Old version (page 18)
This study is designed to test
1)
the toxicity, feasibility and short-term efficacy of PVAG and
2)to determine the maximum tolerable dose (MTD) of gemcitabine in this drug
combination and setting
New version (page 17)
This study is designed to test
1)
the toxicity, feasibility and short-term efficacy of PVAG and
2)to determine the maximum tolerable dose (MTD) of gemcitabine in this drug
combination and setting
Old version (page 19)
1)
For the phase I-part (determination of the MTD) the endpoint is the occurrence
of dose-limiting toxicities (DLT) as defined in section 8.1.ff.
New version (page 17)
1)
For the phase I-part (safety) the endpoint is the occurrence of dose-limiting
toxicities (DLT) and dose reductions as defined in section 6.1.5.
82
Old version (page 19-21)
3.1.
Dose-finding strategy
The aim of the dose-finding phase is to identify that dose of Gemcitabine for which
the probability of incurring one or more dose-limiting toxicity/ies (DLT) in a given
cycle of PVAG is on average 33%. This dose is termed the maximum tolerable dose
(MTD). DLTs are defined in section 8.1.
Remarks:
1.The probability of 33% is related to each cycle – the probability that a given patient
will incur a DLT at some time during the 8-cycle treatment is greater than 33%.
2.Patients differ in their susceptibility to toxicity. Under administration of PVAG with
Gemcitabin at the MTD level, certain patients (e.g., females) will have a probability of
more than 33% of suffering a DLT, while others (e.g., males) will have a probability
lower than 33%.
3.It is to be expected that the severity of toxicity will increase from the first to the
eighth cycle. The probability of 33% applies to an average over all cycles.
The dose-finding strategy for this study will be an adapted version of the likelihoodbased continual reassessment method (CRML; O'Quigley and Shen 1996). This
method is more efficient and more reliable than the standard method (O'Quigley and
Chevret 1991, Ahn 1998), which was developed mainly for single cycles of single
drugs for pretreated patients. The CRML can be tailored to meet the special
requirements of this study, as described below.
The CRML is based upon a logistic regression model for the relationship between
Gemcitabine dose and the probability of a DLT. The model probability tends towards
zero for low doses and towards unity for high doses, while for a certain intermediate
dose a probability of 33% is predicted – this is the estimated MTD. The probabilitydose relationship is allowed to depend upon the cycle number (between 1 and 8), the
patient's sex and the patient's age, as soon as sufficient data is available to take
account of these factors.
The first patient is treated at the lowest dose level (800 mg/m2). In order to
accumulate sufficient data to begin fitting the logistic regression model, the standard
dose-finding method (up-and-down method, design D in Störer 1989) will be
employed until the first DLT has been observed and toxicity results from at least 12
cycles have been received. With the standard method, 3 patients receive the current
dose; if 0/3 DLTs are observed then the next 3 patients are treated at a level one
step up, if 1/3 DLT is observed then the next 3 receive the same level again, and if at
least 2/3 DLTs are reported then the next 3 are treated at a level one step down; and
so on.
83
Thereafter, the CRML will be employed. Whenever a new toxicity result for a patient's
cycle is reported, the logistic model is fitted to all toxicity data received so far. The
estimated MTD and a confidence interval therefore will be calculated. The next
patient will be treated at the level closest to the current predicted MTD, with the
restriction than the dose can be increased by at most one step at a time.
Dose-finding terminates when the 95% confidence interval for the MTD includes only
one of the predefined dose levels, or failing this when 30 patients have been treated
with at least one PVAG cycle. Additionally, the complete regimen of 8 PVAG cycles
must have been administered to at least 5 patients. Thereafter, further patients will
be treated at this dose level (the 'estimated optimal level') in order to assess the
toxicity profile at each cycle, the feasibility (postponement, dose reduction, dose
intensity) and the approximate efficacy (complete remission rate) of PVAG at the
optimal level of Gemcitabine.
3.2.
Sample size and duration of recruitment
Objectives: when recruitment ends, the optimal dose level must have been estimated
to the required precision (see above) and a sufficient number of patients must have
been treated at the optimal Gemcitabine level.
A recruitment rate of approximately 2-3 patients per month is expected. Therefore,
the minimum requirement of 30 patients with at least 1 complete cycle should be
achieved within about 12+1=13 months. Normally, a sample size of about 25 should
be adequate for estimation of the MTD as specified above. The minimum
requirement of at least 5 patients with 8 complete cycles should be satisfied within
about 2+8=10 months; in this time a total recruitment of about 25 patients would be
expected.
… Therefore, overall we aim to recruit approximately 25+50=7550 patients during the
entire study (phases I and II). This should be achieved within circa 30 months. After
30 months at the latest, recruitment will terminate.
New version (page 18)
3.1.
Phase I
Phase I of the study is a pragmatic approach to establish the safety of the PVAG
regimen in this selected patient cohort of elderly with Hodgkin lymphoma based on
data about gemcitabine published so far and available data from patients already
entered into the trial (recriuted until December 31, 2004; final version of this protocol,
October 28, 2003).
The aim of phase I is to demonstrate that the rate of dose-limiting toxicities is below a
predefined maximum tolerable rate (MTD). Sample size calculations are based on
the following considerations:
−
Maximum tolerable rate of dose-limiting toxicities: 0,33
−
True rate of dose-limiting toxicities: 0,20
84
−
Probability to consider PVAG by mistake too toxic (rate of DLT > 0,33) although
the true rate of DLTs is acceptable (rate of DLT = 0,20): ≤ 0,2 (β = 0,2
corresponding to a power of 80%)
−
Probability to consider PVAG by mistake promising (rate of DLT ≤ 0,33)
although the true rate of DLTs is unacceptable high (rate of DLT > 0,33): 0,05 (α
= 0,05)
According to these considerations and data from a previous trial (BAGCOPP trial of
the GHSG) 26 patients will be entered in phase I.
3.2.
Phase II
Based on the results of 68 advanced stage patients aged 66-75 years treated with 8
cycles COPP/ABVD or BEACOPP (baseline dose) +/- localised radiotherapy in the
GHSG trial HD9 (1993-98), we expect PVAG to achieve a complete remission rate of
70-80%. The requirement that the width of the 90% confidence interval for the
complete remission rate does not exceed 28% is satisfied with a sample size of 40
patients (method: interval width calculated as 1.96 x SE, where SE = SQRT (p (1-p) /
n) is the standard error of a proportion, p is the true value, n is the sample size).
Therefore, overall we aim to recruit approximately 25+50=7540 patients during the
entire study (phases I and II). This should be achieved within circa 30 months. After
30 months at the latest, recruitment will terminate.
Recruitment will be stopped if 40 evaluable patients have been entered or on 31th of
December 2006 whichever comes first.
Old version (page 22)
Firstly, a preliminary description of acute toxicity and its relationship to dose will be
reported at the end of the dose-finding phase:
(1) Estimation of the MTD and the probabilities of DLT at the estimated optimal level
of Gemcitabine, according to cycle number, age and sex if appropriate.
(2) Description of the toxicity profile of PVAG at the estimated optimal level.
New version (page 19)
Firstly, a preliminary description of acute toxicity and its relationship to dose dose
reductions will be reported at the end of phase I the dose-finding phase:
(1) Description of the toxicity profile of PVAG.
Old version (page 23)
For questions concerning the pathology review procedure please contact:
Klinik I für Innere Medizin der Universität zu Köln
85
Studiensekretariat Hämatologie/Onkologie
Jospeh-Stelzmann-Str. 9
50924 Köln/Germany
New version (page 20)
For questions concerning the pathology review procedure please contact:
Klinik I für Innere Medizin der Universität zu Köln
Klinisches Studienzentrum Hämatologie
Kerpener Str. 62, Ebene 4
50937 Köln/Germany
Old version (page 31)
... The treatment will be continued at full dosage in accordance with the time
schedule if at the day of the planned treatment continuation the leukocyte count
exceeds > 2500/mm3 and platelets > 80.000/mm3 with a rising trend (having passed
the nadir). ...
New version (page 27)
... The treatment will be continued at full dosage in accordance with the time
schedule if at the day of the planned treatment continuation the leukocyte count
exceeds > 2000/mm3 and platelets > 75.000/mm3 with a rising trend (having passed
the nadir). ...
Old version (page 31)
6.6.1. PVAG scheme
PVAG scheme
Prednisone
40 mg/m2
p.o.
day 1-5
Vinblastine
6 mg/m2
i.v.
day 1
Doxorubicine
50 mg/m
2
i.v.
day 1
Gemcitabine
800 mg/m2*
i.v.
day 1
Recycle day 22
* starting dosage
New version (page 27)
6.6.1. PVAG scheme
86
PVAG scheme
Prednisone
40 mg/m2
p.o.
day 1-5
Vinblastine
6 mg/m2
i.v.
day 1
50 mg/m2
i.v.
day 1
1000 mg/m2
i.v.
day 1
Doxorubicine
Gemcitabine
Recycle day 22
Old version (page 32)
6.1.5. Therapy postponement and dose reduction
a) Hematological toxicity
Therapy is continued in time with full dosage if leukocyte count exceed > 2500/mm³
and platelets > 75.000/mm³.
If the required values are not reached at the day of planned therapy continuation,
blood parameters are checked again on day 3, 7, 10, and 14 after first control.
Therapy is to be continued when the required values are reached.
New version (page 28)
6.1.5. Therapy postponement and dose reduction
a) Hematological toxicity
Therapy is continued in time with full dosage if leukocyte count exceed > 2000/mm³
and platelets > 75.000/mm³ (no grade 3 or 4 toxicity).
If the required values are not reached at the day of planned therapy continuation,
blood parameters are checked again on day 3, 7, 10, and 14 after first control. If
parameters have not been reached within two weeks doses have to be reduced as
detailed below (Therapy is to be continued when the required values are reached;
maximum delay: 21 days). In addition, doses have to be reduced in case of
leucopenia WHO grade 4 (<1000/m³) for more than 4 days.
If blood parameters do not reach the required values within two weeks in subsequent
cycles (reduced dose-level) or if a patient experiences leucopenia WHO grade 4 for
more than 4 days on the reduced dose-level the patient should be withdrawn from
the trial.
Delay up to two weeks:
no dose reduction
Delay > two weeks:
dose reduction of PVAG to:
Prednisone
0%
87
Vinblastine
75%
Doxorubicin
75%
Gemcitabine
75%
These are the doses used in the subsequent cycle. In case the WBC and
thrombocyte count is lower than described above, the treatment is postponed
following the same scheme.
Old version (page 32)
b) Non-hematological toxicity
In case of a WHO grade 4 non-hematological toxicity that delays the therapy for up to
two weeks, consideration of dose reduction will be made at the discretion of the
treating physician (taking into account the type of toxicity). In case of further protocol
treatment, the future dose must be discussed with the study investigator.
In case of both hematological and non-hematological toxicity the highest dosereduction schedule will be used. Once the dose has been reduced, it must remain
reuced.
In case of more than 14 days of delay for any reason, the patient is excluded from
the trial.
New version (page 28/29)
b) Non-hematological toxicity
In case of WHO grade 4 non-hematological toxicity doses have to be reduced as
detailed below (Exceptions: alopecia, nausea and vomiting if controlled by supportive
measures). Treatment should be postponed until recovery to grade 2 (maximum
delay: 21 days).
If a patient experiences WHO grade 4 non-hematological toxicity on subsequent
cycles (reduced dose-level) the patient should be withdrawn.
c) Dose reduction scheme
In case of both hematological and non-hematological toxicity the highest dosereduction schedule will be used. Patients will be treated on the reduced dose-level in
subsequent cycles.
The reduced dose-level is as follows:
Prednisone 40 mg/m²
p.o.
day 1-5
Vinblastine 5 mg/m²
i.v.
day 1
Doxorubicine40 mg/m²
i.v.
day 1
Gemcitabine 800 mg/m²
i.v.
day 1
88
Old version (page 43)
9.1.
Documentation of dose limiting toxicities
The following toxicities are defined as dose limiting:
–
Leucopenia WHO grade 4 for more than 4 days (< 1000/m3)
–
Thrombopenia WHO grade 4 on at least 1 day (< 25000 /m3)
–
Infectious diseases WHO grade 4
–
Any toxicity WHO grade 4
–
Therapy delay of > 2 weeks due to unsufficient blood stemcell recovery (as
defined in 6.1.5.)
The occurence of one (or more) of these toxicities has to be reported immediately
after the detecting or – at least – at the very end of every single cycle (meaning: DLT
yes or no). This information is mandatory to define the current dosage of a following
patient and is absolutely necessery for the dose finding part of the trial (see 3.ff).
Subsequent cycles of the therapy must not be applied unless this basic information
has been send to the trial coordination center. (Telephone call is accepted)
New version (page 37)
9.1.
Documentation of dose reductions
The occurence of one (or more) of these toxicities requiring dose reductions and/or
dose reductions has to be reported immediately after the detecting or – at least – at
the very end of every single cycle (meaning: DLT yes or no)to the trial coordination
center. This information is mandatory to define the current dosage of a following
patient and is absolutely necessery for the dose finding part of the trial (see
3.ff)ensure the safety of the trial participants. Subsequent cycles of the therapy must
not be applied unless this basic information has been send to the trial coordination
center. (Telephone call is accepted)
89
Old version (page 50)
The study
The study is divided into two parts. In the first part the maximal dose of gemcitabine
is defined and in the following second part the feasibility of the regimen is tested.
The doses of prednisone, adriamycin and vinblastine are well-defined.
The optimal dose of gemcitabine has to be defined in first part of the study. Four
dose levels are tested starting with the lowest dose known to be active in the
disease. At each day of treatment the side effects are registered and reported to the
study coordination center. Based on the continous collectection of information on
side effects, the dose for each patient is defined. This will result in the definition of
the maximal dose of gemcitabine.
When the maximal dose of gemcitabine has been defined the feasibility of the PVAG
regimen needs to be demonstrated. This is done in the second part of the study.
New version (page 45-46)
The study
The study is divided into two parts. In the first part the toxicity profile of gemcitabine is
defined (the doses of prednisone, adriamycin and vinblastine are well-defined). For
this purpose 26 patients will be recruited in the first part. You will be treated with
1000 mg of gemcitabine per square meter body-surface and at each day of treatment
the side effects are registered and reported to the study coordination center. Doses
will be reduced or treatment delayed if you experience any relevant side-effects.
Based on the continous collection of information on side effects, the toxicity profile of
PVAG is defined. If the rate of serious side-effects does not exceed the pre-defined
threshold the second part of the trial will start.
In the second part of the trial the feasibility and activity of the PVAG regimen will be
evaluated.
Old version (page 53)
12.3 Patienten Information (deutsche Fassung)
New version (page 53)
12.3 Patienten Information (deutsche Fassung, Version Köln deutsch 1-2005)
Old version (page 54)
Die Studie:
Die Studie besteht aus zwei Teilen. Im ersten Teil der Studie wird die maximale
Dosierung des Prüfmedikamentes Gemcitabin herausgefunden. (Die Dosierungen
90
von Adriamycin, Vinblastin und Prednison sind gut geprüft und bekannt.) Um die
optimale Dosierung von Gemcitabin zu ermitteln, werden verschiedene
Dosierungsstufen getestet. Begonnen wird natürlich mit der niedrigsten wirksamen
Gemcitabin-Dosierung, eine Steigerung wird nur dann vorgenommen, wenn keinerlei
Hinweise auf Nebenwirkungen der Behandlungen bestehen. Um dies sicher zu
stellen, wird der Verlauf jedes einzelnen Behandlungstages von jedem Patienten an
die Studienzentrale in Köln übermittelt. Mit allen vorliegenden Daten wird dann die
nächste Dosisstufe berechnet. Die Studienzentrale informiert wiederum alle
Teilnehmer der Studie informiert. Mit dieser Absicherung soll die maximal mögliche
Dosierung von Gemcitabin herausgefunden werden. Durch diese ständige
Überwachung der Nebenwirkungen ist eine größtmögliche Sicherheit für die
Patienten gewährleistet, und es wird gleichzeitig vermieden, daß Patienten eine zu
geringe Dosierung erhalten.
Im zweiten Teil wird die Durchführbarkeit der Behandlung getestet. Hierzu wir
geprüft, ob das Behandlungsschema zeitgerecht und in der beabsichtigten
Dosierung, die im ersten Teil der Studie ermittelt wurde, verabreicht werden kann. Zu
diesem Zweck wird die sorgfältige Beobachtung der während der Behandlung
Patienten fortgesetzt.
Die Behandlung mit PVAG
Das PVAG-Schema wird in dreiwöchigen Abständen verabreicht. An Tag 1 jeder
Behandlungsrunde (auch Zyklus genannt) werden die Chemotherapeutika, Vinblastin
und Gemcitabin als Infusion verabreicht. ...
New version (page 50)
Die Studie:
Die Studie besteht aus zwei Teilen. Im ersten Teil der Studie wird die maximale
Dosierung Verträglichkeit des Prüfmedikamentes Gemcitabin herausgefunden. (Die
Dosierungen Verträglichkeit von Adriamycin, Vinblastin und Prednison sind gut
geprüft und bekannt.) Um die optimale Dosierung von Gemcitabin zu ermitteln,
werden verschiedene Dosierungsstufen getestet. Begonnen wird natürlich mit der
niedrigsten wirksamen Gemcitabin-Dosierung, eine Steigerung wird nur dann
vorgenommen, wenn keinerlei Hinweise auf Nebenwirkungen der Behandlungen
bestehen. Hierfür werden zu Beginn 26 Patienten mit 1000 mg pro Quadratmeter
Körperoberfläche behandelt und das Auftreten von Nebenwirkungen sehr
engmaschig überprüft. Um dies sicher zu stellen, wird der Verlauf jedes einzelnen
Behandlungstages von jedem Patienten an die Studienzentrale in Köln übermittelt.
Sollten bei Ihnen starke Nebenwirkungen auftreten, wird die Dosis der einzelnen
Mediakmente angepasst oder die Gabe der Therapie um einige Tage verschoben.
Mit allen den vorliegenden Daten wird dann die nächste Dosisstufe Verträglichkeit
berechnet. Die Studienzentrale informiert wiederum alle Teilnehmer der Studie
informiert. Mit dieser Absicherung soll die maximal mögliche Dosierung von
Gemcitabin herausgefunden werden. Liegt diese unter einem vorher definierten
91
Grenzwert, wird der zweite Teil der Studie begonnen. Durch diese ständige
Überwachung der Nebenwirkungen ist eine größtmögliche Sicherheit für die
Patienten gewährleistet, und es wird gleichzeitig vermieden, daß Patienten eine zu
geringe Dosierung erhalten.
Im zweiten Teil wird die Durchführbarkeit und Wirkung der Behandlung getestet.
Hierzu wird geprüft, ob das Behandlungsschema zeitgerecht und in der
beabsichtigten Dosierung, die im ersten Teil der Studie ermittelt wurde, verabreicht
werden kann. Zu diesem Zweck wird die sorgfältige Beobachtung der während der
Behandlung Patienten fortgesetzt. Für die Bestimmung der Wirkung, wird das
Ansprechen des Tumors auf die behandlung mit Hilfe von verschiedenen
Untersuchungen im Lauf und nach der Behandlung bestimmt (z.B. mit
Computertomographien). Diese Untersuchungen unterscheiden sich nicht von den
ohnehin notwendigen Untersuchungen im Rahmen der Therapie außerhalb der
Studie.
Die Behandlung mit PVAG
Das PVAG-Schema wird in dreiwöchigen Abständen verabreicht. An Tag 1 jeder
Behandlungsrunde (auch Zyklus genannt) werden die Chemotherapeutika Vinblastin,
Adriamycin (auch Doxorubicin) und Gemcitabin als Infusion verabreicht. ...
Old version (page 54)
... sowie eine Testung auf mögliche Viruserkrankungen wie Hepatitis B, C und HIV
(Humanes Immundefizienz-Virus) wird vorgenommen. Die Besonderheit einer HIVInfektion besteht darin, ...
New version (page 50-51)
... sowie eine Testung auf mögliche Viruserkrankungen wie Hepatitis B, C und HIV
(Humanes Immundefizienz-Virus) wird vorgenommen. Im Falle eines positiven
Hepatitis-B- und C-Tests erfolgt eine gesetzlich vorgeschriebene namentliche
Meldung an die zuständige Gesundheitsbehörde. Die Besonderheit einer HIVInfektion besteht darin, ... Im Falle eines positiven HIV-Tests erfolgt eine anonyme
Meldung an das Robert-Koch-Institut in Berlin. ...
Old version (page 57)
Weitere Informationen
Dieses Studienprotokoll wurde der Ethikkommission zur Begutachtung vorgelegt und
positiv begutachtet.
...
New version (page 53)
92
Weitere Informationen
Dieses Studienprotokoll wurde der Ethikkommission zur Begutachtung vorgelegt und
von dieser positiv begutachtet bewertet.
...
Old version (page 60)
...
Auf
alternative
Behandlungsmethoden
Therapieoptimierungsstudien wurde ich hingewiesen.
außerhalb
dieser
...
New version (page 56)
...
Auf
alternative
andere
Behandlungsmethoden
Therapieoptimierungsstudien Studie wurde ich hingewiesen.
außerhalb
dieser
...
Old version (page 61)
...
Ich bestätige durch meine Unterschrift, daß ich bereit bin an der obengenannten
Therapieoptimierungsstudie zur Primärtherapie des Hodgkin Lymphoms
teilzunehmen. ...
New version (page 57)
...
Ich bestätige durch meine Unterschrift, daß ich bereit bin an der obengenannten
Therapieoptimierungsstudie Studie zur Primärtherapie des Hodgkin Lymphoms
teilzunehmen. ...
93
12.17. Changes by amendment # 2
Old version (Title)
PVAG – phase I/II dose finding trial in elderly patients (> 60 yrs) with advanced
stages Hodgkin's lymphoma
New version (Title)
PVAG – phase I/II dose finding trial in elderly patients (> 60 yrs) with intermediate
and advanced stages Hodgkin's lymphoma
Old version (Synopsis)
Title
PVAG – a phase I/II dose finding trial in elderly patients
(> 60 years) with advanced* stages Hodgkin´s
lymphoma
* CS (PS) IIB + risk factors, CS (PS) III and IV
...
Eligibility Criteria
…
(d) Clinical stage (CS) IIB (with riskfactors bulky
mediastinal mass and/or extranodal involvement),
CS III and IV.
…
New version (Synopsis)
Title
PVAG – a phase I/II dose finding trial in elderly patients
(> 60 years) with intermediate* and advanced** stages
Hodgkin´s lymphoma
* CS (PS) IA, IB, IIA, and IIB + risk factors
** CS (PS) IIB + risk factors, CS (PS) III and IV
...
Eligibility Criteria
…
(d) Intermediate stage: clinical stage (CS) IA, IB, or IIA
(with risk factors riskfactors bulky mediastinal mass,
extranodal involvement, high ESR, and/or ≥ 3
involved lymphnode areas), IIB (with risk factors
94
high ESR and/or ≥ 3 involved lymphnode areas) or
Advanced stage: CS IIB (with riskfactors bulky
mediastinal mass and/or extranodal involvement),
CS III and IV.
…
Old version (p. 15)
2.1. Entry criteria
CS(PS) IIB with one or both of the risk factors:
a)
bulky mediastinal mass (> 1/3 of maximum transverse thorax diameter)
b)
extranodal involvement
...
New version (p. 15)
CS(PS) IA, IB, IIA, IIB with one or more of the risk factors:
a)
bulky mediastinal mass (> 1/3 of maximum transverse thorax diameter)
b)
extranodal involvement
c)
high ESR (≥ 50 mm in IA and IIA; ≥ 30 mm in IB)
d)
≥ 3 involved lymphnode areas
...
Old version (p. 18)
...
According to these considerations and data from a previous trial (BAGCOPP trial of
the GHSG) 26 patients will be entered in phase I.
...
New version (p. 18)
...
According to these considerations and data from a previous trial (BAGCOPP trial of
the GHSG) 26 patients will be entered in phase I. Analysis will be performed
separately for patients with intermediate and advanced stage disease resulting in 26
+ 26 patients overall.
…
95
Old version (p. 18-19)
… Therefore, overall we aim to recruit 40 patients during the entire study (phases I
and II).
Recruitment for advanced stage patients will be stopped if 40 evaluable patients with
advanced stage disease have been entered or on 31th of December 2006 whichever
comes first.
3.3.
Data Analysis
The data will be analysed in the German Hodgkin Lymphoma Study Group biometry
unit in Cologne. Results will be reported at two points in time, as follows.
…
New version (p. 18-19)
... Therefore, overall we aim to recruit 40 patients during the entire study (phases I
and II). Analysis will be performed separately for patients with intermediate and
advanced stage disease resulting in 40 + 40 patients overall.
Recruitment for advanced stage patients will be stopped if 40 evaluable patients with
advanced stage disease have been entered or on 31th of December 2006 whichever
comes first. Recruitment for intermediate stage patients will be stopped if 40
evaluable patients with intermediate stage disease have been entered or on 30th of
July 2007 whichever comes first.
3.3.
Data Analysis
The data will be analysed in the German Hodgkin Lymphoma Study Group biometry
unit in Cologne. Results will be reported at two points in time separately for patients
with intermediate and advanced stage disease, as follows.
...
Old version (p. 21)
5.2.2. Entry criteria for enrolment
1.
Staging according to protocol
2.
Documented informed consent
3.
Histologically proven HD (Excluded: Lymphocyte Predominant, Nodular type
Hodgkin’s Lymphoma).
4.
Clinical stage (CS) IA, IB, IIA, IIB with riskfactors a) bulky mediastinal mass (>
1/3 of the maximal transverse thoracic diameter) and/or b) extranodal
involvement; CS III and IV.
...
New version (p. 21)
96
5.2.2. Entry criteria for enrolment
1.
Staging according to protocol
2.
Documented informed consent
3.
Histologically proven HD (Excluded: Lymphocyte Predominant, Nodular type
Hodgkin’s Lymphoma).
4.
Clinical stage (CS) IA, IB, IIA, IIB with riskfactors bulky mediastinal mass (> 1/3
of the maximal transverse thoracic diameter), extranodal involvement, high
ESR, and/or ≥ 3 involved lymphnode areas; CS III and IV.
...
Old version (p. 46)
12.1 Patient information (english version)
Therapy study
PVAG – a phase I/II dose finding trial in elderly patients (> 60 years) with advanced
stages Hodgkin’s disease.
...
New version (p. 46)
12.1 Patient information (english version)
Therapy study
PVAG – a phase I/II dose finding trial in elderly patients (> 60 years) with
intermediate and advanced stages Hodgkin’s disease.
...
Old version (p. 48)
12.2. Patient Consent Form
Clinical Study: PVAG pilot trial in elderly patients with advanced stage Hodgkin´s
disease
...
New version (p. 48)
12.2. Patient Consent Form
Clinical Study: PVAG pilot trial in elderly patients with intermediate and advanced
stage Hodgkin´s disease
...
97
Old version (p. 49)
12.3. Patienten Information (deutsche Fassung, Version Köln deutsch 1-2005)
Therapiestudie:
PVAG – eine Phase I/II – Dosisfindungsstudie in älteren Patienten (> 60 Jahren) in
fortgeschrittenen Stadien eines Morbus Hodgkin
...
New version (p. 50)
12.3. Patienten Information (deutsche Fassung, Version Köln deutsch 2-2005)
Therapiestudie:
PVAG – eine Phase I/II – Dosisfindungsstudie in älteren Patienten (> 60 Jahren) in
intermediären und fortgeschrittenen Stadien eines Morbus Hodgkin
...
Old version (p. 56)
12.4. Einverständniserklärung
Therapiestudie:
PVAG – eine Phase I/II – Dosisfindungsstudie in älteren Patienten (> 60 Jahren) in
fortgeschrittenen Stadien eines Morbus Hodgkin
...
New version (p. 57)
12.4. Einverständniserklärung
Therapiestudie:
PVAG – eine Phase I/II – Dosisfindungsstudie in älteren Patienten (> 60 Jahren) in
intermediären und fortgeschrittenen Stadien eines Morbus Hodgkin
...
98
12.18. Clinical Report Formulars (CRFs)
Registration Form ....................................................................... REG
Anamnesis Form .......................................................................... AN
Staging Form ................................................................................. ST
Chemotherapy Form ................................................................ C 1 - 4
................................................................................................. C 5 - 6
Restaging Form ............................................................................ RE
Radiotherapy Form ....................................................................... RX
Follow Up For .................................................................................. F
Final Report ................................................................................... FR
Dose Limiting Toxicity Severe Adverse Event .................... DLT/SAE