LNH 03B PROGRAM    FIFTH MULTICENTRIC GELA PROGRAM FOR AGGRESSIVE LYMPHOMAS                                            Spo...
Program writing committee :For the GELA       André Bosly, Reda Bouabdallah, Josette Brière, Olivier Casasnovas, Bertrand ...
GELA                                                                                    LNH03B Program                    ...
GELA                                                                                                  LNH03B Program      ...
GELA                                                                                 LNH03B Program                       ...
GELA                                                                                       LNH03B Program                 ...
GELA                                                                              LNH03B Program- arm B (R-CHOP)          ...
GELA                                                                                   LNH03B Program                     ...
GELA                                                                                                             LNH03B Pr...
GELA                                                                               LNH03B Program                         ...
GELA                                                                                LNH03B Program                        ...
GELA                                                                                   LNH03B Program- arms A(A1 or A2)   ...
GELA                                                                                                                      ...
GELA                                                                                                                      ...
GELA                                                                                                                      ...
GELA                                                                                                                      ...
GELA                                                                                                                      ...
GELA                                                                                                                      ...
GELA                                                                                    LNH03B Programm1 RESPONSABILITIES ...
GELA                                                                            LNH03B Programm• Chairmen LNH 03-1B :Dr Ni...
GELA                                                                             LNH03B Programm        1.3 InvestigatorsA...
GELA                                                                                           LNH03-1B3 LNH 03 - 1B STUDY...
GELA                                                                                            LNH03-1B     complete resp...
GELA                                                                                             LNH03-1B"    Ann Arbor st...
GELA                                                                                      LNH03-1B    • Biochemical tests:...
GELA                                                                                                                      ...
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
011   fith multicentric gela program for agressive lymphomas
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011 fith multicentric gela program for agressive lymphomas

  1. 1. 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 : 06/11/2003Edition date: 07/11/2003
  2. 2. 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, PhilippeGaulard, Corinne Haioun, Nicolas Ketterer, Pierre Lederlin, Eric Lepage, Thierry Molina, PierreMorel, 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 andLaboratoires 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 LNH03-6BEdition date: 07/11/2003
  3. 3. GELA LNH03B Program SYNOPSIS – LNH 03-1B STUDYTitle 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’AdulteCoordinator Investigators Hervé TILLY and Corinne HAIOUNChairmen Nicolas KETTERER and Félix REYESInvestigators GELA (Groupe d’Etude des Lymphomes de l’Adulte) centres in France, Belgium and SwitzerlandObjective 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 studyNumber of subjects 400 patients over 4 yearsStudy 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-
  4. 4. 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 Cyclophosphamide 1200 mg/m2 X 2 Vindesine 2 mg/m 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: 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 daysEthic Committee Approved by Ethic Committee Haute-Normandie on 18/09/2003ApprovalPlanned start/end of 2003 / 2007recruitment Edition date: 06/11/2003 -2-
  5. 5. GELA LNH03B Program SYNOPSIS – LNH 03-2B STUDY LNH 03-2B study : RANDOMIZED STUDY OF ACVBP PLUS RITUXIMAB VERSUSTitle 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.Sponsor GELA : Groupe d’Etude des Lymphomes de l’AdulteCoordinator Investigators Hervé TILLY and Corinne HAIOUNChairmen Christian RECHER and Hervé TILLYInvestigators GELA (Groupe d’Etude des Lymphomes de l’Adulte) centres in France, Belgium and SwitzerlandObjective 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 design Phase III, multicentric, open-label, randomized studyNumber of subjects 380 patients over 4 yearsStudy 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. - 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). - 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. - Any serious active disease (according to the investigator’s decision). - Poor renal function (creatinin level>150µmol/l), poor hepatic functionEdition date: 06/11/2003 -3-
  6. 6. 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. - Any history of cancer during the last 5 years, with the exception of non- melanoma skin tumors or stage 0 (in situ) cervical carcinoma. - 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.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 Rituximab 375 mg/m X 2 Doxorubicin 75 mg/m X 2 Cyclophosphamide 1200 mg/m X 2 Vindesine 2 mg/m X X Bleomycine 10 mg (total dose) X X 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-
  7. 7. GELA LNH03B Program- arm B (R-CHOP) ! Induction. : 4 cycles of R-CHOP, 3 weeks interval. Chemotherapy regimen Dose D1 D2 D3 D4 D5 Prednisone 40 mg/m2 X X X X X Rituximab 375 mg/m2 X Doxorubicin 50 mg/m2 X Cyclophosphamide 750 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 Chemotherapy regimen Dose D1 D2 D3 D4 D5 Prednisone 40 mg/m2 X X X X X Rituximab 375 mg/m2 X Doxorubicin 50 mg/m2 X Cyclophosphamide 750 mg/m2 X Vincristine 1.4 mg/m2 XEthic Committee Approval Approved by Ethic Committee Haute-Normandie on 18/09/2003.Planned start/end of 2003 / 2007recruitmentEdition date: 06/11/2003 -5-
  8. 8. GELA LNH03B Program SYNOPSIS – LNH 03-3B STUDYTitle 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)Sponsor GELA : Groupe d’Etude des Lymphomes de l’AdulteCoordinator Investigators Hervé TILLY and Corinne HAIOUNChairmen Olivier FITOUSSI and Christian GISSELBRECHTInvestigators GELA (Groupe d’Etude des Lymphomes de l’Adulte) centres in France, Belgium and SwitzerlandObjective 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 patients and their tumours that influence treatment response and prognosis.Study design Phase II, multicentric, open-label, non-randomized studyNumber of subjects 120 patients over 2 yearsStudy 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. - Patient not previously treated. - Age adjusted International Prognostic Index equal to 2 or 3. - With a minimum life expectancy of 3 months. - 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 Edition date: 06/11/2003 -6-
  9. 9. 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. - 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.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 Prednisone 60 mg/m2 X X X X X 2 Rituximab 375 mg/m X Doxorubicin 75 mg/m2 X 2 Cyclophosphamide 1200 mg/m X 2 Vindesine 2 mg/m X X Bleomycine 10 mg (total dose) X X 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 XEthic Committee Approved by Ethic Committee Haute-Normandie on 06/11/2003.ApprovalPlanned start/end of 2003 / 2005recruitment Edition date: 06/11/2003 -7-
  10. 10. GELA LNH03B Program SYNOPSIS – LNH 03-6B STUDYTitle 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.Sponsor GELA : Groupe d’Etude des Lymphomes de l’AdulteCoordinator Investigators Hervé TILLY and Corinne HAIOUNChairmen Richard DELARUE and André BOSLYInvestigators GELA (Groupe d’Etude des Lymphomes de l’Adulte) centres in France, Belgium and SwitzerlandObjectives 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 patients and their tumours that influence treatment response and prognosis.Study design Phase III, multicentric, open-label, randomized studyNumber 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 - Aged from 66 to 80 years. - Patient not previously treated. Edition date: 06/11/2003 -8-
  11. 11. GELA LNH03B Program - Ann Arbor stage II, III or IV - Age-adjusted IPI 1,2 or 3 - ECOG performance status 0 to 2. - With a minimum life expectancy of 3 months. - 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. - 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. - Treatment with any investigational drug within 30 days before planned first cycle of chemotherapy and during the study. - Adult patient under tutelage.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-
  12. 12. GELA LNH03B Program- arms A(A1 or A2) 8 cycles of R-CHOP (with IT Methotrexate for the first 4 cycles), 2 weeksR-CHOP-14 interval. Chemotherapy regimen Dose D1 D2 D3 D4 D5 Prednisone 40 mg/m2 X X X X X Rituximab 375 mg/m2 X Doxorubicin 50 mg/m2 X Cyclophosphamide 750 mg/m2 X Vincristine 1.4 mg/m2 X Methotrexate (IT) First 4th cycles only 15 mg 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. • 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 weeksR-CHOP-21 interval. Chemotherapy regimen Dose D1 D2 D3 D4 D5 Prednisone 40 mg/m2 X X X X X Rituximab 375 mg/m2 X Doxorubicin 50 mg/m2 X Cyclophosphamide 750 mg/m2 X Vincristine 1.4 mg/m2 X Methotrexate (IT) First 4th cycles only 15 mg 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. • 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 -
  13. 13. GELA LNH03B Program TABLE OF CONTENTSSYNOPSIS – LNH 03-1B STUDY...............................................................................................................................1SYNOPSIS – LNH 03-2B STUDY...............................................................................................................................3SYNOPSIS – LNH 03-3B STUDY...............................................................................................................................6SYNOPSIS – LNH 03-6B STUDY...............................................................................................................................81 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 ......................................................................................................................................192 RATIONALE ......................................................................................................................................................193 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 ....................................................................................................................................25Edition date: 06/11/2003 - 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  14. 14. 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 ......................................................................................................................................274 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 4.4.1 Inclusion criteria ..................................................................................................................................29 4.4.2 Exclusion criteria..................................................................................................................................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 4.5.3 Evaluation during each induction cycle ...............................................................................................30 4.5.4 Evaluation 3 weeks after the 4th cycle of induction...............................................................................30 4.5.5 Evaluation during each consolidation cycle.........................................................................................30 4.5.6 Evaluation 1 month after the last cycle of treatment ............................................................................31 4.5.7 Evaluation during the first 2 years .......................................................................................................31 4.5.8 Evaluation during next following 2 years.............................................................................................31 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 4.6.4 Investigational products .......................................................................................................................33 4.6.5 Supplies – Drug accountability ............................................................................................................33 4.6.6 Dose adjustment....................................................................................................................................34 4.7 STATISTICAL ANALYSIS ................................................................................................................................34 4.7.1 Judgement criteria ................................................................................................................................34Edition date: 06/11/2003 - 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  15. 15. GELA LNH03B Program 4.7.2 Sample size calculation.........................................................................................................................34 4.7.3 Demographic analysis ..........................................................................................................................35 4.7.4 Efficacy analysis ...................................................................................................................................35 4.7.5 Safety analysis ......................................................................................................................................355 LNH 03-3B STUDY ............................................................................................................................................36 5.1 RATIONALE ...................................................................................................................................................36 5.2 STUDY OBJECTIVES ......................................................................................................................................36 5.2.1 Primary Endpoint .................................................................................................................................36 5.2.2 Secondary Endpoints ............................................................................................................................36 5.3 STUDY DESIGN..............................................................................................................................................37 5.4 STUDY POPULATION .....................................................................................................................................37 5.4.1 Inclusion criteria ..................................................................................................................................37 5.4.2 Exclusion criteria..................................................................................................................................37 5.5 STUDY FLOW CHART AND SCHEDULE OF ASSESSMENTS ..............................................................................38 5.5.1 Study flow chart ....................................................................................................................................38 5.5.2 Screening examination..........................................................................................................................38 5.5.3 Evaluation during each induction cycle ...............................................................................................39 5.5.4 Evaluation 3 weeks after the 4th cycle of induction...............................................................................39 5.5.5 Evaluation during each consolidation cycle.........................................................................................39 5.5.6 Evaluation before ASCT .......................................................................................................................39 5.5.7 Evaluation 3 months after ASCT ..........................................................................................................39 5.5.8 Evaluation during the first 2 years .......................................................................................................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 5.6.3 Investigational products .......................................................................................................................41 5.6.4 Supplies.................................................................................................................................................42 5.6.5 Dose adjustment....................................................................................................................................42 5.7 STATISTICAL ANALYSIS ................................................................................................................................42 5.7.1 Judgment criteria..................................................................................................................................42 5.7.2 Sample size calculation.........................................................................................................................42 5.7.3 Demographic analysis ..........................................................................................................................43 5.7.4 Efficacy analysis ...................................................................................................................................43 5.7.5 Safety analysis ......................................................................................................................................43Edition date: 06/11/2003 - 13 -
  16. 16. GELA LNH03B Program6 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 STUDY OBJECTIVES ......................................................................................................................................45 6.2.1 Primary endpoint ..................................................................................................................................45 6.2.2 Secondary endpoints.............................................................................................................................45 6.3 STUDY DESIGN..............................................................................................................................................46 6.4 STUDY POPULATION .....................................................................................................................................46 6.4.1 Inclusion criteria ..................................................................................................................................46 6.4.2 Exclusion criteria..................................................................................................................................46 6.5 STUDY FLOW CHART AND SCHEDULE OF ASSESSMENTS ..............................................................................47 6.5.1 Study flow chart ....................................................................................................................................47 6.5.2 Screening examination and selection procedures ................................................................................47 6.5.3 Evaluation during each induction cycle ...............................................................................................48 6.5.4 Evaluation before the 5th cycle of treatment .........................................................................................48 6.5.5 Evaluation during each consolidation cycle.........................................................................................48 6.5.6 Evaluation 1 month after the last cycle of treatment ............................................................................48 6.5.7 Evaluation during the first 2 years .......................................................................................................48 6.5.8 Evaluation during next following 2 years.............................................................................................49 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 6.6.3 Investigational products .......................................................................................................................51 6.6.4 Supplies.................................................................................................................................................51 6.6.5 Responsibilities .....................................................................................................................................51 6.6.6 Dose adjustment....................................................................................................................................51 6.7 STATISTICAL ANALYSIS ................................................................................................................................52 6.7.1 Judgement criteria ................................................................................................................................52 6.7.2 Sample size calculation.........................................................................................................................52 6.7.3 Demographic analysis ..........................................................................................................................52 6.7.4 Efficacy analysis ...................................................................................................................................52 6.7.5 Safety analysis ......................................................................................................................................53Edition date: 06/11/2003 - 14 -
  17. 17. GELA LNH03B Program7 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 .................................................................................................558 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.................................................................................................................579 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...................................................................................................5810 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 ....................................................................................................................................................6011 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) ........................................................................6112 ETHICAL AND REGULATORY STANDARDS .......................................................................................61 12.1 ETHICAL PRINCIPLES .....................................................................................................................................61 12.2 LAWS AND REGULATIONS .............................................................................................................................61Edition date: 06/11/2003 - 15 -
  18. 18. GELA LNH03B Program 12.3 INFORMED CONSENT .....................................................................................................................................62 12.4 ETHICS REVIEW COMMITTEE (ERC) ............................................................................................................6213 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 ...................................................................................................................................6414 REFERENCES ...............................................................................................................................................6415 APPENDICES.................................................................................................................................................67 15.1 APPENDIX 1: LNH 03 - 1B STUDY FLOW CHART .........................................................................................67 15.2 APPENDIX 2 : LNH 03 – 2B STUDY FLOW CHART ........................................................................................68 15.3 APPENDIX 3 : LNH 03 – 3B STUDY FLOW CHART ........................................................................................69 15.4 APPENDIX 4 : LNH 03 – 6B STUDY FLOW CHART ........................................................................................70 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) ..........................................................................................................77Edition date: 06/11/2003 - 16 -
  19. 19. GELA LNH03B Programm1 RESPONSABILITIES 1.1 Title of the trialLNH 03B PROGRAM : Fifth multicentric GELA program for aggressive lymphomas. 1.2 Sponsor and program coordination center 1.2.1 SponsorGroupe 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 InvestigatorsPr Hervé TILLY Pr Corinne HAIOUNService d’Hématologie Service d’HématologieCentre Henri Becquerel – F76038 ROUEN Centre Henri Mondor - F94010 CRETEIL$ : +33 (0) 2 32 08 22 23 $ : +33 (0) 1 49 81 20 51Fax : +33 (0) 2 32 08 22 83 Fax : +33 (0) 1 49 81 20 67herve.tilly@rouen.fnclcc.fr corinne.haioun@hmn.ap-hop-paris.fr• Pathological CoordinatorsPr Philippe GAULARD Pr Josette BRIERE Pr Thierry MOLINAService d’Anatomie Pathologique Service d’Anatomie Pathologique Service d’Anatomie PathologiqueCentre 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 82Fax : +33 (0) 1 49 81 27 33 Fax : +33 (0) 1 42 49 49 22 Fax : +33 (0) 1 42 34 86 41philippe.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 LEPAGEDépartement de biostatistique et d’informatique Département de biostatistique et d’informatiquehospitalière hospitalièreCentre Henri Mondor - F94010 CRETEIL Centre Henri Mondor - F94010 CRETEIL$: +33 (0) 1 49 81 23 82 $: +33 (0) 1 49 81 23 82Fax : +33 (0) 1 49 81 29 32 Fax : +33 (0) 1 49 81 29 32nicolas.mounier@sls.ap-hop-paris.fr eric.lepage@hmn.ap-hop-paris.frEdition date: 06/11/2003 - 17 -
  20. 20. GELA LNH03B Programm• Chairmen LNH 03-1B :Dr Nicolas KETTERER Pr Félix REYESService d’Hématologie Service d’HématologieCHU Vaudois – CH 1011 LAUSANNE Suisse Centre Henri Mondor – F94010 CRETEIL$ : +41 21 314 01 66 $ : +33 (0) 1 49 81 20 51Fax : +41 21 314 07 37 Fax : +33 (0) 1 49 81 20 67Nicolas.Ketterer@chuv.hospvd.ch felix.reyes@hmn.ap-hop-paris.fr• Chairmen LNH 03-2B :Dr Christian RECHER Pr Hervé TILLYService d’Hématologie Service d’HématologieCHU Purpan – F31059 TOULOUSE Centre Henri Becquerel – F76038 ROUEN$ : +33 (0) 5 61 77 20 78 $ : +33 (0) 2 32 08 22 23Fax : +33 (0) 5 61 77 75 41 Fax : +33 (0) 2 32 08 22 83RECHER.C@chu-toulouse.fr herve.tilly@rouen.fnclcc.fr• Chairmen LNH 03-3B:Dr Olivier FITOUSSI Pr Christian GISSELBRECHTService de Radiothérapie Service d’HématologiePolyclinique Bordeaux Nord – F33300 BORDEAUX Hôpital Saint Louis – F PARIS$ : +33 (0) 5 56 43 73 54 $ : +33 (0) 1 42 49 92 96Fax : +33 (0) 5 56 43 70 32 Fax : +33 (0) 1 42 49 96 41o.fitoussi@bordeauxnord.com christian.gisselbrecht@sls.ap-hop-paris.fr• Chairmen LNH 03-6B : Dr Richard DELARUE Pr André BOSLYService d’Hématologie Adultes Service d’HématologieHôpital Necker – F75743 PARIS Cedex 15 UCL Mont Godinne – B5530 YVOIR Belgique$ : +33 (0) 1 44 49 54 62 $ : +32 81 42 38 31Fax : +33 (0) 1 44 49 52 80 Fax : +32 81 42 38 32richard.delarue@nck.ap-hop-paris.fr andre.bosly@sang.ucl.ac.be 1.2.2 Program coordination centerGroupe 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 33Fax : +33 (0) 4 72 66 93 71Edition date: 06/11/2003 - 18 -
  21. 21. GELA LNH03B Programm 1.3 InvestigatorsAll 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 andgovernment according to each country procedures and have had the initiation visit. To be declared as aparticipating center, the principal investigator must have sent to the GELARC his curriculum vitae with thelocal number affiliation to the Conseil de l’Ordre des Médecins for french centers. 1.4 Laboratory sitesLaboratory (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 RATIONALEThe LNH 03-B is the fifth multicentric program designed by the GELA for aggressive lymphomas and assuch 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 lymphomastratified according to age and number of age-adjusted prognostic factors [1]: 03-1B, 03-2B and 03-3Bstudies in adult patients under 60 or 65 year old; 03-6B in patients 65-80 year old. In addition, the 03-Bprogram will incorporate the 01-5B study of patients 60-65 year old activated since 2001. Finally, a 03-7Bstudy 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 pointsdeserve 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 -
  22. 22. GELA LNH03-1B3 LNH 03 - 1B STUDY 3.1 RationaleApproximately 30 to 40% of the totality of diffuse large B cell lymphoma are localized at diagnosis (stageI-II). Until the seventies, radiotherapy was used as the single modality to treat these localized stages butno more than half of the patients were cured [9,10]. From the eighties, anthracycline-based regimenscombined or not with radiotherapy gave superior results in term of relapse free survival compared withradiotherapy alone [11]. Later on Miller et al. published a randomized study showing that 3 cycles ofCHOP combined with radiotherapy gave superior results in term of overall survival compared with 8cycles of CHOP [12]. However, one of the problem was that this trial did not consider the InternationalPrognostic 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 differencebetween 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’tgive any benefit to elderly patients treated for a low risk localized diffuse large cell lymphoma, and thatACVBP regimen is superior to 3 CHOP + radiotherapy in patients <60 years, and has to be considered asthe treatment of reference in these patients.Two other GELA trials contributed recently to improve the treatments of diffuse large B-cell lymphoma andhave 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 sameEdition date: 06/11/2003 - 20 -
  23. 23. 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-celllymphoma (age-adjusted IPI = 0), and to extend the upper age limit from 60 to 65 years. 3.2 Study Objectives 3.2.1 Primary EndpointsTo evaluate the efficacy of R-ACVBP in comparison with ACVBP in previously untreated patients agedfrom 18 to 65 years with low risk localized (age-adjusted IPI = 0) CD20+ diffuse large B-cell lymphomameasured by the event-free survival (EFS), events defined as death from any cause, relapse for completeresponders (CR) and undocumented complete responders (uCR), progression during and after treatmentand changes of therapy. 3.2.2 Secondary Endpoints- Efficacy and safety measured by response rate at the end of the treatment, disease-free survival forcomplete 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 tumoursthat influence treatment response and prognosis. 3.3 Study designThis study is a multicentric, phase III open-label, randomized trial evaluating the efficacy of R-ACVBPcompared with ACVBP in previously untreated patients aged from 18 to 65 years with low risk localizedCD20+ 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 approximately26 weeks. 3.4 Study populationAdult 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 performancestatus (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 -
  24. 24. 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 chartSee on Appendix 1. 3.5.2 Screening examinationThe subject’s eligibility has to be evaluated during the baseline period (BL) prior to administration of thefirst cycle of chemotherapy. The laboratory assessments are to be conducted within 1 week beforeadministration 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, CRPEdition date: 06/11/2003 - 22 -
  25. 25. 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 • Clinical examination • Thoracic and abdominal CT scan • PET scan will be performed whenever possible (optional) • Blood cell counts • LDH • Bone marrow biopsy if initially involved • Adverse events (cf. Chapter 8) 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 • Adverse events (cf. Chapter 8) 3.5.6 Evaluation 1 month after the last cycle of treatment • Clinical examination • Thoracic and abdominal CT scan • Blood cell counts • LDHEdition date: 06/11/2003 - 23 -
  26. 26. GELA LNH03-1B • Bone marrow biopsy if initially involved • Adverse events (cf. Chapter 8) 3.5.7 Evaluation during the first 2 years ! Every 3 months • Clinical examination • Blood cell counts • LDH ! After 6, 12, 18 and 24 months • Thoracic and abdominal CT scan 3.5.8 Evaluation during next following 2 years ! Every 6 months • Clinical examination • Blood cell counts • LDH ! Annually • Thoracic and abdominal CT scan 3.5.9 Evaluation after 4 years • Clinical examination • Blood cell counts • 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 monthsArm A C1 C2 C3 C4 C5 FU0 C6 C7 C8 C9 C10 C11 FU1 FU n R RESPONSE RESPONSEArm B C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 FU 0 FU1 FUn12 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 -

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