011 fith multicentric gela program for agressive lymphomas

LNH 03B PROGRAM

FIFTH MULTICENTRIC GELA PROGRAM FOR AGGRESSIVE LYMPHOMAS

Sponsor
Groupe d’Etude des Lymphomes de l’Adulte (GELA)

RANDOMISATION / INCLUSION
GELA - Fax : + 33 (0) 1 42 49 99 72

COORDINATOR INVESTIGATORS : Hervé TILLY, Corinne HAIOUN

LNH 03-1B STUDY CHAIRMEN: Nicolas KETTERER, Félix REYES

LNH 03-2B STUDY CHAIRMEN: Christian RECHER, Hervé TILLY

LNH 03-3B STUDY CHAIRMEN: Olivier FITOUSSI, Christian GISSELBRECHT

LNH 03-6B STUDY CHAIRMEN: Richard DELARUE, André BOSLY

PATHOLOGICAL COORDINATORS : Thierry MOLINA, Josette BRIERE, Philippe GAULARD

STATISTICAL COORDINATORS : Nicolas MOUNIER, Eric LEPAGE

PROGRAM COORDINATION CENTER : GELA - Recherche Clinique (GELARC)

Protocol Final Version : 18/09/2003
Amended (#1) Protocol : 06/11/2003

Edition date: 07/11/2003

Program writing committee :

For the GELA
André Bosly, Reda Bouabdallah, Josette Brière, Olivier Casasnovas, Bertrand Coiffier,
Richard Delarue, Alain Delmer, Olivier Fitoussi, Christian Gisselbrecht, Olivier Hermine, Philippe
Gaulard, Corinne Haioun, Nicolas Ketterer, Pierre Lederlin, Eric Lepage, Thierry Molina, Pierre
Morel, Franck Morschhauser, Nicolas Mounier, Christian Recher, Felix Reyes, Gilles Salles,
Anne Sonet, Hervé Tilly, Achiel Van Hoof.

For the GELARC
Stéphanie Baulu, Delphine Germain.

The present program 2003 of the GELA is supported by grants from Amgen France and
Laboratoires Produits Roche.

General scheme of the LNH03-B program

aa-IPI
0 1 2 3
age

<60 LNH03-2B LNH03-3B
LNH03-1B
60-65 LNH01-5B (on going since july 2001)

66-80 LNH03-6B

Edition date: 07/11/2003

GELA LNH03B Program

SYNOPSIS – LNH 03-1B STUDY
Title LNH 03-1B study : RANDOMIZED STUDY OF ACVBP VERSUS ACVBP PLUS
RITUXIMAB IN PREVIOUSLY UNTREATED PATIENTS AGED FROM 18 TO 65 YEARS WITH
LOW RISK LOCALIZED CD20+ DIFFUSE LARGE B-CELL LYMPHOMA (AGE-ADJUSTED
IPI = 0)
Sponsor GELA : Groupe d’Etude des Lymphomes de l’Adulte
Coordinator Investigators Hervé TILLY and Corinne HAIOUN
Chairmen Nicolas KETTERER and Félix REYES
Investigators GELA (Groupe d’Etude des Lymphomes de l’Adulte) centres in France, Belgium
and Switzerland
Objective Evaluation of the efficacy and the safety of ACVBP plus rituximab (R-ACVBP) in
comparison with ACVBP in previously untreated patients aged from 18 to 65
years with low risk localized (age-adjusted IPI=0) CD20+ diffuse large B-cell
lymphoma.
- Primary endpoint - Efficacy measured by event free survival (EFS), events being death from any
cause, relapse for complete responders and undocumented complete
responders, progression during and after treatment and changes of therapy.
- Secondary endpoints - Efficacy and safety measured by response rate at the end of the treatment,
disease-free survival for complete responders, overall survival and additional
toxicities with R-ACVBP.
- Analysis on blood samples and on tumor biopsy of biological factors of the
patients and their tumours that influence treatment response and prognosis.
Study design Phase III, multicentric, open-label, randomized study
Number of subjects 400 patients over 4 years
Study Population - Patient with histologically proven CD20+ diffuse large B cell lymphoma (WHO
- Inclusion criteria Classification). DLBCL with some small cell infiltration in bone marrow or lymph
node may be included.
- Aged from 18 to 65 years.
- Patient non previously treated.
- Ann Arbor stage I and II
- ECOG performance status < 2.
- Normal LDH
- Negative HIV, HBV and HCV serologies ≤ 4 weeks (except after vaccination).
- Having previously signed a written informed consent.
- Exclusion criteria - Any other histological type of lymphoma.
- Any history of treated or non-treated indolent lymphoma.
- Central nervous system or meningeal involvement by lymphoma.
- Contra-indication to any drug contained in the chemotherapy regimens.
- Poor renal function (creatinin level>150µmol/l), poor hepatic function (total
bilirubin level>30mmol/l, transaminases>2.5 maximum normal level) unless
these abnormalities are related to the lymphoma.
- Poor bone marrow reserve as defined by neutrophils < 1.5 G/l or platelets <
100 G/l, unless related to bone marrow infiltration.
- Any history of cancer during the last 5 years, with the exception of non-
melanoma skin tumors or stage 0 (in situ) cervical carcinoma.
- Any serious active disease (according to the investigator’s decision).
- Treatment with any investigational drug within 30 days before planned first
cycle of chemotherapy and during the study.
- Pregnant or lactating women or women of childbearing potential not currently

Edition date: 06/11/2003 -1-

GELA LNH03B Program
practicing an adequate method of contraception.
- Adult patient under tutelage.
Statistical analysis Comparison of event-free survival, using the log-rank test. A Kaplan-Meier plot
! Primary endpoint of time to first event for each treatment group will also produce. A 10%
improvement of 5y-EFS is expected.
! Secondary endpoints Progression, overall survival and duration of response will be analyzed using
the log rank test. Complete response rate will be analyzed using chi-square
test.
Treatment Treatment is allocated according to a central randomization procedure between
arm A (ACVBP) and arm B (ACVBP + rituximab). Treatment allocation will be
stratified according to tumor bulk (≥10 cm).

- arm A (ACVBP) ! Induction: 3 cycles of ACVBP at 2 weeks interval.
Chemotherapy
Doses D1 D2 D3 D4 D5
regimen
2
Prednisone 60 mg/m X X X X X
2
Doxorubicin 75 mg/m X
Cyclophosphamide 1200 mg/m2 X
Vindesine 2 mg/m2 X X
Bleomycine 10 mg (total dose) X X
G-CSF support is not planned in this group. In case of severe neutropenia sub-
cutaneous G-CSF (Filgrastim) is recommended from day 6 to day 13 or until
neutrophils ≥ 1.0 G/l.
! Consolidation (in case of >50% tumour response [PR, uCR, CR] following
induction) - 8 cycles spaced out 14 days, beginning 4 weeks after day 1 of
the 3rd cycle of induction:
" 2 cycles high-dose Methotrexate with folinic acid rescue: 3g/m2
" 4 cycles Ifosfamide-Etoposide (1,5 g/m2 and 300 mg/m2 respectively, at day 1)
" 2 cycles Cytarabine : 100mg/m2/d sub-cutaneous, during 4 days
- arm B (R-ACVBP) ! Induction: 3 cycles of R-ACVBP at 2 weeks interval.
Chemotherapy Doses D1 D2 D3 D4 D5
regimen
2
Prednisone 60 mg/m X X X X X
2
Rituximab 375 mg/m X
Doxorubicin 75 mg/m2 X
2
Vindesine 2 mg/m X X
G-CSF support is not planned in this group. In case of severe neutropenia sub-
cutaneous G-CSF (Filgrastim) is recommended from day 6 to day 13 or until
neutrophils ≥ 1.0 G/l.
! Consolidation (in case of >50% tumour response [PR, uCR, CR] following
induction). 8 cycles spaced out 14 days, beginning 4 weeks after day 1 of
the 3rd cycle of induction:
" 2 cycles high-dose Methotrexate with folinic acid rescue: 3 g/m2
" 4 cycles Ifosfamide-Etoposide (1,5 g/m2 and 300 mg/m2 respectively, at day
1). No rituximab at this phase.
" 2 cycles Cytarabine : 100mg/m2/d sub-cutaneous, during 4 days
Ethic Committee Approved by Ethic Committee Haute-Normandie on 18/09/2003
Approval
Planned start/end of 2003 / 2007
recruitment

Edition date: 06/11/2003 -2-

GELA LNH03B Program

LNH 03-2B study : RANDOMIZED STUDY OF ACVBP PLUS RITUXIMAB VERSUS
Title
CHOP PLUS RITUXIMAB IN NON PREVIOUSLY TREATED PATIENTS AGED FROM
18 TO 59 YEARS WITH CD20+ DIFFUSE LARGE B-CELL LYMPHOMA AND AN
AGE-AJUSTED IPI OF 1.



Chairmen Christian RECHER and Hervé TILLY
Investigators GELA (Groupe d’Etude des Lymphomes de l’Adulte) centres in France,
Belgium and Switzerland
Objective Evaluation of the efficacy and the safety of ACVBP plus rituximab (R-
ACVBP) in comparison with CHOP plus rituximab (R-CHOP) in patients
aged from 18 to 59 years with non previously treated CD20+ large B-cell
lymphoma with an age-adjusted IPI of 1, as measured by the event free
survival (EFS).
- Primary endpoint - Efficacy measured by event free survival (EFS), events being death from
any cause, relapse for complete responders, progression and changes of
therapy.
- Efficacy and safety measured as complete response rate, progression
- Secondary endpoints
rate, relapse rate, disease-free survival for complete responders, overall
survival, neuro-meningeal relapse rate and additional toxicities.
- Analysis on blood samples and on tumor biopsy of biological factors of
the patients and their tumours that influence treatment response and
prognosis.
Study Population
- Inclusion criteria - Patient with histologically proven CD20+ diffuse large B cell lymphoma
(WHO Classification). DLBCL with some small cell infiltration in bone
marrow or lymph node may be included.
- Age adjusted International Prognostic Index equal to 1
- Patient not previously treated.
- With a minimum life expectancy of 3 months.
- Negative HIV, HBV and HCV serologies ≤ 4 weeks (except after
vaccination).
- Poor renal function (creatinin level>150µmol/l), poor hepatic function

Edition date: 06/11/2003 -3-

GELA LNH03B Program
(total bilirubin level>30mmol/l, transaminases>2.5 maximum normal level)
unless these abnormalities are related to the lymphoma.
- Poor bone marrow reserve as defined by neutrophils<1.5G/l or
platelets<100G/l, unless related to bone marrow infiltration.
- Treatment with any investigational drug within 30 days before planned
first cycle of chemotherapy and during the study.
- Pregnant or lactating women or women of childbearing potential not
currently practicing an adequate method of contraception.
Statistical analysis
! Primary endpoint Comparison of event-free survival, using the log-rank test. A Kaplan-Meier
plot of time to first event for each treatment group will also produce. A 10%
improvement of 2y-EFS is expected.
! Secondary endpoints Progression, overall survival and duration of response will be analyzed
using the log rank test. Complete response rate will be analyzed using chi-
square test.
Treatment Treatments are allocated according to a central randomization procedure
between ACVBP + rituximab and CHOP + rituximab.

- arm A (R-ACVBP) ! Induction. : 4 cycles of R-ACVBP, 2 weeks interval.

Chemotherapy D6 to
Dose D1 D2 D3 D4 D5
regimen D13
Prednisone 60 mg/m2 X X X X X
2
2
Doxorubicin 75 mg/m X
2
Cyclophosphamide 1200 mg/m X
2
Methotrexate (IT) 15 mg (total dose) X
G-CSF (SC) 5 µg/kg/day X

! Consolidation :
" High-dose methotrexate with folinic acid rescue: 3g/m2; 2 cycles
spaced out 14 days.
" Rituximab-Ifosfamide-Etoposide : 4 cycles spaced out 14 days.
Dose D1
Rituximab 375 mg/m² X
Ifosfamide 1,5 mg/m² X
Etoposide 300 mg/m² X
" Cytarabine : 100mg/m2 sub-cutaneous, during 4 days; 2 cycles
spaced out 14 days.

Edition date: 06/11/2003 -4-

GELA LNH03B Program

- arm B (R-CHOP) ! Induction. : 4 cycles of R-CHOP, 3 weeks interval.
Chemotherapy regimen Dose D1 D2 D3 D4 D5
Rituximab 375 mg/m2 X
Vincristine 1.4 mg/m2 X
Methotrexate (IT) 15 mg (total dose) X
G-CSF support is not planned in this group. In case of severe neutropenia
sub-cutaneous G-CSF (Filgrastim) is recommended from day 6 to day 13
or until neutrophils ≥ 1.0 G/l.

! Consolidation : 4 cycles of R-CHOP, 3-weeks interval

Ethic Committee Approval Approved by Ethic Committee Haute-Normandie on 18/09/2003.

recruitment

Edition date: 06/11/2003 -5-

GELA LNH03B Program

Title LNH 03-3B study : STUDY OF ACVBP PLUS RITUXIMAB IN PREVIOUSLY
UNTREATED PATIENTS AGED FROM 18 TO 59 YEARS WITH HIGH RISK CD20+
DIFFUSE LARGE B-CELL LYMPHOMA (AGE-ADJUSTED IPI = 2-3)
Chairmen Olivier FITOUSSI and Christian GISSELBRECHT
Objective Evaluation of the efficacy and the safety of ACVBP plus rituximab (R-ACVBP)
followed by autologous transplant in previously untreated patients aged from
18 to 59 years with high risk (aa-IPI=2-3) CD20+ diffuse large B-cell
lymphoma.
- Primary endpoint To evaluate the complete remission rate (CR + uCR) after 4 cycles of R-
ACVBP.
- Secondary endpoints To evaluate the overall response rate and safety after 4 cycles R-ACVBP.
To compare the complete response rate after 4 cycles of R-ACVBP of patients
with aa-IPI score 2 or 3
To evaluate the overall response rate at the end of treatment and safety of
autologous transplant.
To evaluate the event-free survival and overall survival of patients submitted to
autologous transplant and of the entire population.
To evaluate PBSC harvest after R-ACVBP as measured by the number of
CD34 positive cells.
To evaluate the number of patients who are eligible for autologous transplant
and who receive it
Analysis on blood samples and on tumour biopsy of biological factors of the
Study design Phase II, multicentric, open-label, non-randomized study
Study Population
- Inclusion criteria - Patient with histologically proven CD20+ diffuse large B cell lymphoma
(WHO Classification). DLBCL with some small cell infiltration in bone marrow
or lymph node may be included.
- Aged from 18 to 59 years, eligible for transplant.
- Age adjusted International Prognostic Index equal to 2 or 3.
vaccination).
- Poor renal function (creatinin level>150µmol/l), poor hepatic function (total
bilirubin level>30mmol/l, transaminases>2.5 maximum normal level) unless

Edition date: 06/11/2003 -6-

GELA LNH03B Program
these abnormalities are related to the lymphoma.
- Poor bone marrow reserve as defined by neutrophils < 1.5 G/l or platelets <
100 G/l, unless related to bone marrow infiltration.
- Pregnant or lactating women or women of childbearing potential not
currently practicing an adequate method of contraception.
Statistical analysis The primary endpoint is complete response rate (CR + UCR). A complete
remission rate of 75% is expected. Event free survival and overall survival will
be analyzed using a Kaplan-Meier plot of time.

Treatment ! Induction: 4 cycles of R-ACVBP at 2 weeks interval.
Chemotherapy D6 to
Doses D1 D2 D3 D4 D5
regimen D13
2
2
Cyclophosphamide 1200 mg/m X
2
Methotrexate (IT) 15 mg X
G-CSF (SC) 5 µg/kg/day X

After the 3rd cycle, collection of peripheral blood stem cell progenitors will be
organized at the time of hematological recovery under support with G-CSF. If
necessary, a second attempt will be realized after the fourth cycle.
The target dose of collected CD34+ cells is 2x106 cells/kg.
! Consolidation (in case of CR, uCR, PR > 50%)
" 2 cycles high-dose Methotrexate with folinic acid rescue: 3g/m2
" High dose with BEAM conditioning regimen followed by autologous
transplant

Chemotherapy regimen Dose D-6 D-5 D-4 D-3 D-2 D-1 D0

BCNU 300 mg/m2 X
G
Etoposide (1hour infusion) 100 mg/m x 2 2
X X X X R
2
A
200 mg/m / F
Aracytine (2 hours infusion) XX XX XX XX
12 hours
T
Melphalan 140 mg/m² X

Ethic Committee Approved by Ethic Committee Haute-Normandie on 06/11/2003.
Approval
recruitment

Edition date: 06/11/2003 -7-

GELA LNH03B Program

Title LNH 03-6B study : Randomized study of intensified CHOP plus
rituximab (R-CHOP given every 14 days : R-CHOP 14) versus CHOP
plus rituximab given every 21 days (R-CHOP 21) and randomized study
of frontline/prophylactic Darbepoetin alfa treatment versus usual
symptomatic treatment of anemia in non previously treated patients
aged from 66 to 80 years, with CD20+ diffuse large B-cell lymphoma.



Chairmen Richard DELARUE and André BOSLY


Objectives Evaluation of the efficacy and the safety of intensified R-CHOP
(R-CHOP 14) versus R-CHOP 21 and evaluation of the efficacy of
frontline/prophylactic Darbepoetin alfa treatment versus treatment of
symptomatic anemia.
! Primary endpoint Efficacy of R-CHOP 14 versus R-CHOP 21 measured by event free survival
(EFS), events being death from any cause, relapse for complete or
undocumented complete responders, progression during and after treatment
and changes of therapy.
! Secondary endpoints Efficacy of treatment with Darbepoetin alfa (ARANESP) to improve EFS.
Efficacy and safety measured as response rate at the end of the treatment,
progression rate, relapse rate, disease-free survival for complete
responders, overall survival and additional toxicities with R-CHOP 14.
Efficacy and safety measured as response rate, overall survival, disease-
free survival for complete responders and predictive factors of
haematological response with frontline/prophylactic Darbepoetin alfa
(ARANESP) compared to treatment of symptomatic anemia (transfusion or
Darbepoetin alfa).

- Analysis on blood samples and on tumor biopsy of biological factors of the


Number of subjects 600 patients over 4 years.

Study Population

! Inclusion criteria - Patient with histologically proven CD20+ diffuse large B cell lymphoma
(WHO Classification). DLBCL with some small cell infiltration in bone
marrow or lymph node may be included

Edition date: 06/11/2003 -8-

GELA LNH03B Program
- Ann Arbor stage II, III or IV
- Age-adjusted IPI 1,2 or 3
- ECOG performance status 0 to 2.
vaccination).

! Exclusion criteria - Any other histological type of lymphoma.
- Any serious co-morbid active disease (according to the investigator’s
decision).
- Poor renal function (creatinin level > 150 µmol/l), poor hepatic function
(total bilirubin level > 30 mmol/l, transaminases > 2.5 maximum normal
level) unless these abnormalities are related to the lymphoma.
- Poor bone marrow reserve as defined by neutrophils < 1.5 G/l or platelets
< 100 G/l, unless related to bone marrow infiltration.
- Any history of cancer during the last 5 years, with the exception of
non-melanoma skin tumours or stage 0 (in situ) cervical carcinoma.
- Uncontrolled hypertension.
- Known hypersensibility to erythropoietin.
- Myocardial infarction during last 3 months or unstable coronary disease or
uncontrolled cardiac insufficiency.
- Venous thrombosis or pulmonary embolism during last 3 months.

Statistical analysis
! Primary endpoint Comparison (R-CHOP-14 vs R-CHOP-21) of event-free survival, using the
log-rank test. A Kaplan-Meier plot of time to first event of each treatment
group will also produce. An improvement of 10 % in EFS at 3 years is
expected by R-CHOP14.

! Secondary endpoints Comparison (frontline/prophylactic Darbepoetin alfa versus usual supportive
care, stratified according to R-CHOP-14 or R-CHOP-21) of event-free
survival, using the log-rank test. A Kaplan-Meier plot of time to first event for
each treatment group will also produce. For the two randomizations,
progression, overall survival and duration of response will be analysed using
the log rank test and complete response rate will be analysed using chi-
square test.

Treatment Treatments are allocated according to a central randomization procedure
between A arm (R-CHOP 14) and B arm (R-CHOP 21).
In each group of treatment, patients were allocated by central randomization
to receive frontline/prophylactic Darbepoetin alfa (ARANESP) or no
prophylactic treatment.

Edition date: 06/11/2003 -9-

GELA LNH03B Program

- arms A(A1 or A2) 8 cycles of R-CHOP (with IT Methotrexate for the first 4 cycles), 2 weeks
R-CHOP-14 interval.
Methotrexate (IT) First 4th cycles only 15 mg X

sub-cutaneous G-CSF (Filgrastim) is recommended from day 6 to day 13 or
until neutrophils ≥ 1.0 G/l.
• A1 arm Darbepoetin alfa (ARANESP) 2.25 µg/kg once a week subcutaneously to
maintain Hb level above 13 g/dl. If Hb level is below 13 g/dl at C3, dose will
be increased to 4.5 µg/kg once a week. If Hb level is above 14 g/dl, dose will
be decreased to 1.5 µg/kg once a week. If Hb level is above 15 g/dl,
treatment will be suspended until Hb level falls below 14 g/dl and dose will
be decreased to 1.5 µg/kg once a week. Treatment will be pursued until 4
weeks after completion of chemotherapy.

• A2 arm Patients with symptomatic anemia will be treated according to local practice
including blood transfusions or erythropoietin (Darbepoetin alfa) but
erythropoietin should be started only if Hb is inferior to 9 g/dl.

- arms B (B1 or B2) 8 cycles of R-CHOP (with IT Methotrexate for the first 4 cycles), 3 weeks
R-CHOP-21 interval.
Methotrexate (IT) First 4th cycles only 15 mg X

sub-cutaneous G-CSF (Filgrastim) is recommended from day 6 to day 13 or
until neutrophils ≥ 1.0 G/l.

• B1 arm Darbepoetin alfa (ARANESP) 2.25 µg/kg once a week subcutaneously to
maintain Hb level above 13 g/dl. If Hb level is below 13 g/dl at C3, dose will
be increased to 4.5 µg/kg once a week. If Hb level is above 14 g/dl, dose will
be decreased to 1.5 µg/kg once a week. If Hb level is above 15 g/dl,
treatment will be suspended until Hb level falls below 14 g/dl and dose will
be decreased to 1.5 µg/kg once a week. Treatment will be pursued until 4
weeks after completion of chemotherapy.

• B2 arm Patients with symptomatic anemia will be treated according to local practice
including blood transfusions or erythropoietin (Darbepoetin alfa) but
erythropoietin should be started only if Hb is inferior to 9 g/dl.

Ethic Committee Approval Approved by Ethic Committee Haute-Normandie on 18/09/2003.

Planned start/end of
2003 / 2007.
recruitment

Edition date: 06/11/2003 - 10 -

GELA LNH03B Program

TABLE OF CONTENTS
SYNOPSIS – LNH 03-1B STUDY...............................................................................................................................1




1 RESPONSABILITIES .......................................................................................................................................17

1.1 TITLE OF THE TRIAL ......................................................................................................................................17
1.2 SPONSOR AND PROGRAM COORDINATION CENTER .......................................................................................17
1.2.1 Sponsor .................................................................................................................................................17
1.2.2 Program coordination center ...............................................................................................................18
1.3 INVESTIGATORS ............................................................................................................................................19
1.4 LABORATORY SITES ......................................................................................................................................19

2 RATIONALE ......................................................................................................................................................19

3 LNH 03 - 1B STUDY .........................................................................................................................................20

3.1 RATIONALE ...................................................................................................................................................20
3.2 STUDY OBJECTIVES ......................................................................................................................................21
3.2.1 Primary Endpoints................................................................................................................................21
3.2.2 Secondary Endpoints ............................................................................................................................21
3.3 STUDY DESIGN ..............................................................................................................................................21
3.4 STUDY POPULATION......................................................................................................................................21
3.4.1 Inclusion criteria ..................................................................................................................................21
3.4.2 Exclusion criteria..................................................................................................................................22
3.5 STUDY FLOW CHART AND SCHEDULE OF ASSESSMENTS ..............................................................................22
3.5.1 Study flow chart ....................................................................................................................................22
3.5.2 Screening examination..........................................................................................................................22
3.5.3 Evaluation during each induction cycle ...............................................................................................23
3.5.4 Evaluation 3 weeks after the 3rd cycle of induction ..............................................................................23
3.5.5 Evaluation during each consolidation cycle.........................................................................................23
3.5.6 Evaluation 1 month after the last cycle of treatment ............................................................................23
3.5.7 Evaluation during the first 2 years .......................................................................................................24
3.5.8 Evaluation during next following 2 years.............................................................................................24
3.5.9 Evaluation after 4 years........................................................................................................................24
3.6 TREATMENTS ................................................................................................................................................24
3.6.1 Dosage regimen ....................................................................................................................................25

Edition date: 06/11/2003 - 11 -

GELA LNH03B Program

3.6.2 Arm A: ACVBP .....................................................................................................................................25
3.6.3 Arm B: ACVBP + rituximab (R-ACVBP) .............................................................................................25
3.6.4 Investigational products .......................................................................................................................26
3.6.5 Supplies.................................................................................................................................................26
3.6.6 Dose adjustment....................................................................................................................................26
3.7 STATISTICAL ANALYSIS ................................................................................................................................26
3.7.1 Judgment criteria..................................................................................................................................26
3.7.2 Sample size calculation.........................................................................................................................27
3.7.3 Demographic analysis ..........................................................................................................................27
3.7.4 Efficacy analysis ...................................................................................................................................27
3.7.5 Safety analysis ......................................................................................................................................27

4 LNH 03 - 2B STUDY ..........................................................................................................................................28

4.1 RATIONALE ...................................................................................................................................................28
4.2 STUDY OBJECTIVES .......................................................................................................................................28
4.2.1 Primary endpoints ................................................................................................................................28
4.2.2 Secondary endpoints.............................................................................................................................28
4.3 STUDY DESIGN ..............................................................................................................................................28
4.4 STUDY POPULATION......................................................................................................................................29
4.5 STUDY FLOW CHART AND ASSESSMENTS ......................................................................................................30
4.5.1 Study flow chart ....................................................................................................................................30
4.5.2 Screening examination and selection procedures ................................................................................30
4.5.4 Evaluation 3 weeks after the 4th cycle of induction...............................................................................30
4.6 TREATMENT ..................................................................................................................................................31
4.6.1 Dosage regimen ....................................................................................................................................32
4.6.2 Arm A: ACVBP + rituximab .................................................................................................................32
4.6.3 Arm B: CHOP plus rituximab...............................................................................................................32
4.6.5 Supplies – Drug accountability ............................................................................................................33
4.6.6 Dose adjustment....................................................................................................................................34
4.7.1 Judgement criteria ................................................................................................................................34

Edition date: 06/11/2003 - 12 -

GELA LNH03B Program

4.7.5 Safety analysis ......................................................................................................................................35

5 LNH 03-3B STUDY ............................................................................................................................................36

5.1 RATIONALE ...................................................................................................................................................36
5.2.1 Primary Endpoint .................................................................................................................................36
5.2.2 Secondary Endpoints ............................................................................................................................36
5.3 STUDY DESIGN..............................................................................................................................................37
5.4 STUDY POPULATION .....................................................................................................................................37
5.5.1 Study flow chart ....................................................................................................................................38
5.5.2 Screening examination..........................................................................................................................38
5.5.4 Evaluation 3 weeks after the 4th cycle of induction...............................................................................39
5.5.6 Evaluation before ASCT .......................................................................................................................39
5.5.7 Evaluation 3 months after ASCT ..........................................................................................................39
5.5.9 Evaluations during next following 2 years ...........................................................................................40
5.5.10 Evaluation after 4 years........................................................................................................................40
5.6 TREATMENTS ................................................................................................................................................40
5.6.1 Induction treatment...............................................................................................................................40
5.6.2 Consolidation treatment .......................................................................................................................41
5.6.4 Supplies.................................................................................................................................................42
5.6.5 Dose adjustment....................................................................................................................................42
5.7.1 Judgment criteria..................................................................................................................................42
5.7.5 Safety analysis ......................................................................................................................................43

Edition date: 06/11/2003 - 13 -

GELA LNH03B Program

6 LNH 03 - 6B STUDY ..........................................................................................................................................44

6.1 RATIONALE ...................................................................................................................................................44
6.1.1 Rationale for the use of R-CHOP 14 ....................................................................................................44
6.1.2 Rationale of the use of Darbepoetin alfa ..............................................................................................44
6.2.1 Primary endpoint ..................................................................................................................................45
6.2.2 Secondary endpoints.............................................................................................................................45
6.3 STUDY DESIGN..............................................................................................................................................46
6.4 STUDY POPULATION .....................................................................................................................................46
6.5.1 Study flow chart ....................................................................................................................................47
6.5.2 Screening examination and selection procedures ................................................................................47
6.5.4 Evaluation before the 5th cycle of treatment .........................................................................................48
6.6 TREATMENTS ................................................................................................................................................49
6.6.1 Dosage regimen : Arm A R-CHOP 14 vs arm B R-CHOP 21 ..............................................................49
! Arm A - R-CHOP 14 .....................................................................................................................................50
! Arm B – R-CHOP 21 ....................................................................................................................................50
6.6.2 Dosage of Darbepoetin.........................................................................................................................50
! Arm 1 – Darbepoetin alfa (ARANESP).......................................................................................................50
! Arm 2 : usual management of anemia ..........................................................................................................51
6.6.4 Supplies.................................................................................................................................................51
6.6.5 Responsibilities .....................................................................................................................................51
6.6.6 Dose adjustment....................................................................................................................................51
6.7.1 Judgement criteria ................................................................................................................................52
6.7.5 Safety analysis ......................................................................................................................................53

Edition date: 06/11/2003 - 14 -

GELA LNH03B Program

7 GLOBAL REGISTRATION PROCEDURES.................................................................................................53

7.1 INFORMED CONSENT .....................................................................................................................................53
7.2 RANDOMIZATION/INCLUSION PROCEDURE ...................................................................................................53
7.3 PATHOLOGICAL REVIEW ...............................................................................................................................54
7.3.1 Practical aspects...................................................................................................................................54
7.3.2 Emergency advice on difficult cases for diagnosis ...............................................................................55
7.4 SUBJECT COMPLIANCE MONITORING ............................................................................................................55
7.5 CONCOMITANT TREATMENT RESTRICTIONS .................................................................................................55

8 ADVERSE EVENTS ..........................................................................................................................................55

8.1 GENERALITIES ..............................................................................................................................................55
8.2 SERIOUS ADVERSE EVENTS (SAE) ................................................................................................................56
8.2.1 Definition ..............................................................................................................................................56
8.2.2 Actions to be taken................................................................................................................................57
8.3 FOLLOW-UP OF ADVERSE EVENTS.................................................................................................................57

9 CRITERIA FOR PREMATURE DISCONTINUATION OF THE STUDY ................................................57

9.1 PREMATURE WITHDRAWAL OF A PATIENT ....................................................................................................57
9.2 PREMATURE DISCONTINUATION OF THE STUDY ...........................................................................................58
9.3 DATA MONITORING / SAFETY COMMITTEE...................................................................................................58

10 ANALYSIS OF STUDY DATA : JUDGEMENT CRITERIA ...................................................................58

10.1 EVENT-FREE SURVIVAL ................................................................................................................................58
10.2 OTHER ENDPOINTS ........................................................................................................................................59
10.2.1 Progression rates..................................................................................................................................59
10.2.2 Disease-free survival (DFS) for CR/uCR patients................................................................................59
10.2.3 Overall survival ....................................................................................................................................59
10.2.4 Response rate at the end of treatment...................................................................................................59
10.2.5 Central nervous system (CNS) progression or relapse rate .................................................................60
10.2.6 Safety ....................................................................................................................................................60

11 STUDY MONITORING ................................................................................................................................60

11.1 RESPONSABILITIES OF INVESTIGATORS ........................................................................................................60
11.2 RESPONSABILITIES OF THE SPONSOR ............................................................................................................61
11.3 SOURCE DOCUMENT REQUIREMENTS............................................................................................................61
11.4 USE AND COMPLETION OF THE CASE REPORT FORMS (CRF) ........................................................................61

12 ETHICAL AND REGULATORY STANDARDS .......................................................................................61

12.1 ETHICAL PRINCIPLES .....................................................................................................................................61
12.2 LAWS AND REGULATIONS .............................................................................................................................61

Edition date: 06/11/2003 - 15 -

GELA LNH03B Program

12.3 INFORMED CONSENT .....................................................................................................................................62
12.4 ETHICS REVIEW COMMITTEE (ERC) ............................................................................................................62

13 ADMINISTRATIVE PROCEDURES..........................................................................................................62

13.1 CURRICULUM VITAE .....................................................................................................................................62
13.2 SECRECY AGREEMENT ..................................................................................................................................62
13.3 RECORD RETENTION IN INVESTIGATING CENTER(S) .....................................................................................63
13.4 OWNERSHIP OF DATA AND USE OF THE STUDY RESULTS ..............................................................................63
13.5 PUBLICATION ................................................................................................................................................63
13.6 INSURANCE COMPENSATION .........................................................................................................................63
13.7 COMPANY AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ..............................................................63
13.8 CLINICAL STUDY REPORT .............................................................................................................................64
13.9 STUDY AMENDMENTS ...................................................................................................................................64

14 REFERENCES ...............................................................................................................................................64

15 APPENDICES.................................................................................................................................................67

15.1 APPENDIX 1: LNH 03 - 1B STUDY FLOW CHART .........................................................................................67
15.2 APPENDIX 2 : LNH 03 – 2B STUDY FLOW CHART ........................................................................................68
15.5 APPENDIX 5 : ANN ARBOR STAGING .............................................................................................................71
15.6 APPENDIX 6 : WHO PERFORMANCE STATUS ................................................................................................71
15.7 APPENDIX 7 : AGE-ADJUSTED INTERNATIONAL PROGNOSTIC INDEX (AA-IPI) ............................................72
15.8 APPENDIX 8 : BIOLOGICAL SAMPLES ............................................................................................................72
15.8.1 Tumor sample .......................................................................................................................................72
15.8.2 Serum sample........................................................................................................................................72
15.8.3 Samples for DNA genomic analysis of polymorphisms ........................................................................72
15.9 APPENDIX 9 : STUDY DRUGS .........................................................................................................................73
15.9.1 Study Drugs Administration .................................................................................................................73
15.9.2 Study Drugs Information (Vidal) ..........................................................................................................77

Edition date: 06/11/2003 - 16 -

GELA LNH03B Programm

1 RESPONSABILITIES
1.1 Title of the trial

LNH 03B PROGRAM : Fifth multicentric GELA program for aggressive lymphomas.

1.2 Sponsor and program coordination center

1.2.1 Sponsor

Groupe d’Etude des Lymphomes de l’Adulte (GELA)
# : CHU Saint Louis – Centre Hayem - 75475 Paris cedex 10
$ : +33 (0) 1 42 49 98 11 Fax : +33 (0) 1 42 49 99 72

• Coordinator Investigators
Pr Hervé TILLY Pr Corinne HAIOUN
Service d’Hématologie Service d’Hématologie
Centre Henri Becquerel – F76038 ROUEN Centre Henri Mondor - F94010 CRETEIL
$ : +33 (0) 2 32 08 22 23 $ : +33 (0) 1 49 81 20 51
Fax : +33 (0) 2 32 08 22 83 Fax : +33 (0) 1 49 81 20 67
herve.tilly@rouen.fnclcc.fr corinne.haioun@hmn.ap-hop-paris.fr

• Pathological Coordinators
Pr Philippe GAULARD Pr Josette BRIERE Pr Thierry MOLINA
Service d’Anatomie Pathologique Service d’Anatomie Pathologique Service d’Anatomie Pathologique
Centre Henri Mondor - F94010 CRETEIL Hôpital St Louis – F75475 PARIS Hôpital Hôtel Dieu – F75181 PARIS
$ : +33 (0) 1 49 81 27 43 $ : +33 (0) 1 42 49 99 32 $ : +33 (0) 1 42 34 82 82
Fax : +33 (0) 1 49 81 27 33 Fax : +33 (0) 1 42 49 49 22 Fax : +33 (0) 1 42 34 86 41
philippe.gaulard@hmn.ap-hop-paris.fr josette.briere@sls.ap-hop-paris.fr thierry.molina@htd.ap-hop-paris.fr

• Data analysis, Statistical center:
Dr Nicolas MOUNIER Pr Eric LEPAGE
Département de biostatistique et d’informatique Département de biostatistique et d’informatique
hospitalière hospitalière
Centre Henri Mondor - F94010 CRETEIL Centre Henri Mondor - F94010 CRETEIL
$: +33 (0) 1 49 81 23 82 $: +33 (0) 1 49 81 23 82
Fax : +33 (0) 1 49 81 29 32 Fax : +33 (0) 1 49 81 29 32
nicolas.mounier@sls.ap-hop-paris.fr eric.lepage@hmn.ap-hop-paris.fr

Edition date: 06/11/2003 - 17 -

• Chairmen LNH 03-1B :
Dr Nicolas KETTERER Pr Félix REYES
CHU Vaudois – CH 1011 LAUSANNE Suisse Centre Henri Mondor – F94010 CRETEIL
$ : +41 21 314 01 66 $ : +33 (0) 1 49 81 20 51
Fax : +41 21 314 07 37 Fax : +33 (0) 1 49 81 20 67
Nicolas.Ketterer@chuv.hospvd.ch felix.reyes@hmn.ap-hop-paris.fr

Dr Christian RECHER Pr Hervé TILLY
CHU Purpan – F31059 TOULOUSE Centre Henri Becquerel – F76038 ROUEN
$ : +33 (0) 5 61 77 20 78 $ : +33 (0) 2 32 08 22 23
Fax : +33 (0) 5 61 77 75 41 Fax : +33 (0) 2 32 08 22 83
RECHER.C@chu-toulouse.fr herve.tilly@rouen.fnclcc.fr

• Chairmen LNH 03-3B:

Dr Olivier FITOUSSI Pr Christian GISSELBRECHT
Service de Radiothérapie Service d’Hématologie
Polyclinique Bordeaux Nord – F33300 BORDEAUX Hôpital Saint Louis – F PARIS
$ : +33 (0) 5 56 43 73 54 $ : +33 (0) 1 42 49 92 96
Fax : +33 (0) 5 56 43 70 32 Fax : +33 (0) 1 42 49 96 41
o.fitoussi@bordeauxnord.com christian.gisselbrecht@sls.ap-hop-paris.fr

Dr Richard DELARUE Pr André BOSLY
Service d’Hématologie Adultes Service d’Hématologie
Hôpital Necker – F75743 PARIS Cedex 15 UCL Mont Godinne – B5530 YVOIR Belgique
$ : +33 (0) 1 44 49 54 62 $ : +32 81 42 38 31
Fax : +33 (0) 1 44 49 52 80 Fax : +32 81 42 38 32
richard.delarue@nck.ap-hop-paris.fr andre.bosly@sang.ucl.ac.be

1.2.2 Program coordination center

Groupe d’Etude des Lymphomes de l’Adulte – Recherche Clinique (GELARC)

#: Centre Hospitalier Lyon Sud
Secteur Sainte Eugénie – Bâtiment 4 I
Chemin du Grand Revoyet - 69310 Pierre Bénite
$: +33 (0) 4 72 66 93 33
Fax : +33 (0) 4 72 66 93 71

Edition date: 06/11/2003 - 18 -


1.3 Investigators
All participating GELA centers from France, Belgium and Switzerland may include patients in this study.
Before any inclusion, each center must have been declared to the CCPPRB / Ethical Committee and
government according to each country procedures and have had the initiation visit. To be declared as a
participating center, the principal investigator must have sent to the GELARC his curriculum vitae with the
local number affiliation to the Conseil de l’Ordre des Médecins for french centers.

1.4 Laboratory sites
Laboratory (ies) used by the individual study center for hematological and biochemical tests and assays.
All the laboratories must provide their normal values and an updated accreditation for quality control.

2 RATIONALE
The LNH 03-B is the fifth multicentric program designed by the GELA for aggressive lymphomas and as
such integrates therapeutic strategies derived from previous GELA studies (LNH 84, 87, 93, 98).

The LNH 03-B program comprises several new studies of patients with aggressive B-cell lymphoma
stratified according to age and number of age-adjusted prognostic factors [1]: 03-1B, 03-2B and 03-3B
studies in adult patients under 60 or 65 year old; 03-6B in patients 65-80 year old. In addition, the 03-B
program will incorporate the 01-5B study of patients 60-65 year old activated since 2001. Finally, a 03-7B
study of patients older than 80 years will be added before the end of this year.

Although the specific rationale of each study of the 03-B program is detailed below, the following points
deserve to be emphasized:

• localized low-risk forms in the 03-1B study will not receive radiotherapy but will be treated by
chemotherapy alone, as a result of the previous 93-1 and 93-4 studies [2, 3].

• in 03-1B, 03-2B and 03-3B studies of patients under 60 or 65 year old, ACVBP will be the
reference chemotherapy regimen as a result of the previous 93-5 study which demonstrated its
superiority over standard CHOP [ 4].

• considering the results of the previous 98-5 study which demonstrated the superiority of R-CHOP
[5], rituximab will be combined to chemotherapy in both ACVBP and CHOP arms of all 03-B
studies (except in the reference treatment arm of 03-1B).

• in the 03-3B study of patients under 60 year old and presenting with 2-3 factors of the age-
adjusted IPI, a full inductive phase will be followed by consolidative high-dose therapy rescued by
autologous stem cell infusion, in accordance with the GELA policy based on the results of previous
87-2 and 93-3 studies [6, 7].

• in the 03-6B study, patients aged 65-80 years in which ACVBP was found to be too toxic by the
previous 93-5 study [4] will be allocated to either R-CHOP 21 or 14, following the results of the
German High Grade non Hodgkin Lymphoma Study Group [8]; the study will also explore the
benefit of prophylactic erythropoietin (darbepoietin) treatment.

The LNH 03-B program gives the opportunity of developing large scale tissue collections with the
objective to explore biological parameters possibly affecting outcome of patients treated with a
combination of rituximab and chemotherapy. Gene profiling studies, phenotyping of tumoral tissue and
determination of genetic polymorphisms are major ancillary objectives of the present 03-B program.

Edition date: 06/11/2003 - 19 -

GELA LNH03-1B

3 LNH 03 - 1B STUDY
3.1 Rationale
Approximately 30 to 40% of the totality of diffuse large B cell lymphoma are localized at diagnosis (stage
I-II). Until the seventies, radiotherapy was used as the single modality to treat these localized stages but
no more than half of the patients were cured [9,10]. From the eighties, anthracycline-based regimens
combined or not with radiotherapy gave superior results in term of relapse free survival compared with
radiotherapy alone [11]. Later on Miller et al. published a randomized study showing that 3 cycles of
CHOP combined with radiotherapy gave superior results in term of overall survival compared with 8
cycles of CHOP [12]. However, one of the problem was that this trial did not consider the International
Prognostic Index [1], 20% of the patients included having elevated LDH, and 50% being older than 60.
This study was recently updated with a follow up of more than 8 years and shows no more difference
between the two arms, due to an excess of late mortality after the combined treatment.

Recently, two trials were conduced by the GELA to compare chemotherapy alone to a combined chemo-
radiotherapy approach in patients with low risk localized diffuse large cell lymphoma (age-adjusted IPI =
0). Patients were stratified in these studies according to the tumor bulk (≥ 10cm):

• The objective of the LNH 93-1 study was to compare in patients aged from 18 to 60 years 3 cycles of
CHOP followed by radiotherapy with chemotherapy alone consisting in 3 cycles of ACVBP [3]. The
ACVBP regimen includes a more intensive induction followed by a sequential consolidation with
different drugs from those used during the induction phase. It is the reference regimen for the GELA
since more than 15 years [13]. About 600 patients have been included, and with a median follow up of
55 months, the results have shown a superiority of the ACVBP arm for both the 5 year event free
(83±5% vs. 74±5%, p = 0.004) and overall survival (89±4% vs. 80±5%, p = 0.02). The difference was
also statistically significant for the large tumor masses (≥ 10cm).

• The LNH 93-4 study compared in patients >60 years the association of 4 cycles of CHOP +
radiotherapy to the same regimen without irradiation [3]. This study fails to demonstrate any benefit of
the combined chemo-radiotherapy in term of survival, but indicates that chemotherapy alone is
probably less toxic in patients older than 69 years.

Considering these two trials, we may first conclude that radiotherapy given after chemotherapy doesn’t
give any benefit to elderly patients treated for a low risk localized diffuse large cell lymphoma, and that
ACVBP regimen is superior to 3 CHOP + radiotherapy in patients <60 years, and has to be considered as
the treatment of reference in these patients.

Two other GELA trials contributed recently to improve the treatments of diffuse large B-cell lymphoma and
have to be considered for the elaboration of future studies:

• The objective of the LNH 98-5 study was to compare the association of CHOP + rituximab (R-CHOP)
to the CHOP regimen alone in elderly patients with previously untreated large B-cell lymphoma [5].
The analysis shows with a median follow up of 2 years a significant superiority of the association
CHOP + rituximab in terms of complete response rate (p = 0.005), event-free survival (p < 0.001) and
overall survival (p = 0.007). There was no significant difference between the two arms in terms of
toxicity.

• The LNH 93-5 study compared the ACVBP regimen to the CHOP in patients aged from 61 to 69 years
with aggressive lymphoma and at least one adverse prognostic factor according to the International
Prognostic Index [4]. Out of 703 patients included in this study, the results have shown the same

Edition date: 06/11/2003 - 20 -

GELA LNH03-1B
complete response rate in the two arms, but a significantly better 3-year event free survival and overall
survival in the ACVBP arm than in the CHOP arm (39% versus 29%, p=0.005 and 46% vs. 38%, p =
0.036 respectively). However, the benefit seems to be greater in patients <66 years, due to higher
toxicity with the ACVBP regimen in elderly patients..

All the above-mentioned results led us to propose a randomized trial comparing ACVBP to ACVBP +
rituximab (R-ACVBP) in previously untreated patients with low risk localized CD20+ diffuse large B-cell
lymphoma (age-adjusted IPI = 0), and to extend the upper age limit from 60 to 65 years.

3.2 Study Objectives
3.2.1 Primary Endpoints
To evaluate the efficacy of R-ACVBP in comparison with ACVBP in previously untreated patients aged
from 18 to 65 years with low risk localized (age-adjusted IPI = 0) CD20+ diffuse large B-cell lymphoma
measured by the event-free survival (EFS), events defined as death from any cause, relapse for complete
responders (CR) and undocumented complete responders (uCR), progression during and after treatment
and changes of therapy.

3.2.2 Secondary Endpoints
- Efficacy and safety measured by response rate at the end of the treatment, disease-free survival for
complete responders, overall survival and additional toxicities with R-ACVBP.
- Analysis on blood samples and on tumour biopsy of biological factors of the patients and their tumours
that influence treatment response and prognosis.

3.3 Study design
This study is a multicentric, phase III open-label, randomized trial evaluating the efficacy of R-ACVBP
compared with ACVBP in previously untreated patients aged from 18 to 65 years with low risk localized
CD20+ diffuse large B-cell lymphoma (age-adjusted IPI =0).

The anticipated study dates (start / end) are: 2003 – 2007.

The study will evaluate a cohort of 400 patients (200 in each arm).

Patients will be recruited over 4 years and followed until death.

The duration of the treatment period for ACVBP (A arm) and ACVBP + rituximab (B arm) is approximately
26 weeks.

3.4 Study population
Adult previously untreated patients aged from 18 to 65 years with low risk localized (age-adjusted IPI = 0)
CD20+ diffuse large B-cell lymphoma, with Ann Arbor stage I or II, normal LDH level, a good performance
status (ECOG PS < 2) and no contra-indication to any drug included in chemotherapy regimens.

3.4.1 Inclusion criteria
" Patient with histologically proven CD20+ diffuse large B-cell lymphoma (WHO classification). DLBCL
with some small cell infiltration in bone marrow or lymph node may be included.

" Aged from 18 to 65 years.

" Patient not previously treated.
Edition date: 06/11/2003 - 21 -

GELA LNH03-1B
" Ann Arbor stage I or II.

" ECOG performance status < 2.

" Normal LDH.
" Negative HIV, HBV and HCV serologies ≤ 4 weeks (except after vaccination).
" Having previously signed a written informed consent.

3.4.2 Exclusion criteria
" Any other histological type of lymphoma.
" Any history of treated or non-treated indolent lymphoma.
" Central nervous system or meningeal involvement by lymphoma.
" Contra-indication to any drug contained in the chemotherapy regimens.
" Poor renal function (creatinin level >150 µmol/l), poor hepatic function (total bilirubin level >30 mmol/l,
transaminases >2.5 maximum normal level) unless these abnormalities are related to the lymphoma.
" Poor bone marrow reserve as defined by neutrophils < 1.5 G/l or platelets < 100 G/l, unless related to
bone marrow infiltration.
" Any history of cancer during the last 5 years with the exception of non-melanoma skin tumors or stage
0 (in situ) cervical carcinoma.
" Any serious active disease (according to the investigator’s decision).
" Treatment with any investigational drug within 30 days before planned first cycle of chemotherapy and
during the study.
" Pregnant or lactating women or women of childbearing potential not currently practicing an adequate
method of contraception.
" Adult patient under tutelage.

3.5 Study flow chart and Schedule of assessments

3.5.1 Study flow chart

See on Appendix 1.

3.5.2 Screening examination
The subject’s eligibility has to be evaluated during the baseline period (BL) prior to administration of the
first cycle of chemotherapy. The laboratory assessments are to be conducted within 1 week before
administration of the study drug and within 1 month for the other following assessments:

• Age, gender, weight, height
• Relevant medical history
• History of the NHL
• Clinical examination
• Complete blood cell count, CRP

Edition date: 06/11/2003 - 22 -

GELA LNH03-1B
• Biochemical tests: blood ionogram, serum creatinin, ASAT, ALAT, total bilirubin and alkaline
phosphatases
• Lactate deshydrogenase (LDH) and β2 microglobulin levels
• Serum electrophoresis
• HIV, HBV and HCV serologies
• Thoracic and abdominal CT scan
• PET scan will be performed whenever possible (optional)
• Bone marrow biopsy
• Exploratory lumbar puncture
• Samples for genetic analyses (cf. Appendix 8)
• ECG
• Echocardiography or isotopic method to determine resting ejection fraction
• Cerebral CT scan if clinically indicated
• Cryopreservation of sperm should be offered

3.5.3 Evaluation during each induction cycle
• Clinical examination prior administration of the cycle
• Blood cell counts prior treatment administration and on days 7 and 10 of the cycle
• Adverse events (cf. Chapter 8)

3.5.4 Evaluation 3 weeks after the 3rd cycle of induction
• PET scan will be performed whenever possible (optional)
• Blood cell counts
• LDH
• Bone marrow biopsy if initially involved

3.5.5 Evaluation during each consolidation cycle
• Clinical examination prior administration of the cycle
• Blood cell counts prior administration
• Blood methotrexate sample, 24 hours after each methotrexate’s infusion

3.5.6 Evaluation 1 month after the last cycle of treatment
• LDH

Edition date: 06/11/2003 - 23 -

GELA LNH03-1B
• Bone marrow biopsy if initially involved

3.5.7 Evaluation during the first 2 years

! Every 3 months
• LDH

! After 6, 12, 18 and 24 months

3.5.8 Evaluation during next following 2 years

! Every 6 months
• LDH

! Annually

3.5.9 Evaluation after 4 years
• LDH

3.6 Treatments
INDUCTION PHASE CONSOLIDATION PHASE
8 weeks 18 weeks

ACVBP
MTX IV Ifosfamide + etoposide Cytarabine

2 weeks 2w 3 w 1w 2w 2w 2w 2w 2w 2w 2w 4w 3 months
Arm A C1 C2 C3 C4 C5 FU0
C6 C7 C8 C9 C10 C11
FU1 FU n

R RESPONSE RESPONSE

Arm B C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 FU 0 FU1 FUn
12 2 weeks 2w 2 w 1w 1w 2w 2w 2w 2w 2w 2w 2w 4w 3 months

Rituximab + Ifosfamide + etoposide Cytarabine
MTX IV
ACVBP
4TH RITUXIMAB

Edition date: 06/11/2003 - 24 -

011 fith multicentric gela program for agressive lymphomas

011 fith multicentric gela program for agressive lymphomas

Recommandé

Recommandé

Contenu connexe

Tendances

Tendances (20)

Similaire à 011 fith multicentric gela program for agressive lymphomas

Similaire à 011 fith multicentric gela program for agressive lymphomas (20)

Dernier

Dernier (7)

011 fith multicentric gela program for agressive lymphomas