GA In NEwly Diagnosed Diffuse Large B Cell Lymphoma

Study Overview
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Brief Summary
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This study is designed to investigate: the interest of a new monoclonal antibody (GA101)versus rituximab the interest of PET to identify early responders Patients will receive either rituximab (standard treatment), either GA101 (study treatment), according to the randomization arm. The monoclonal antibody will be associated to a chemotherapy: CHOP or ACVBP according to site's choice.A PET scan will be done before inclusion, after 2 chemotherapy cycles, and after 4 chemotherapy cycles, to identify early patients responders, for who consolidation with ASCT is not required.

Official Title
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Randomized Phase III Study Using a Pet-driven Strategy and Comparing GA101 OR Rituximab Associated to a Chemotherapy Delivered Every 14 Days (ACVBP or CHOP) in DLBCL CD20+ Lymphoma Untreated Patients From 18 to 60 Presenting With 1 or More Adverse Prognostic Factors of the Age-adjusted IPI

Conditions
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Diffuse Large B Cell Lymphoma CD20 Positive

Intervention / Treatment
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* Drug: GA101
* Drug: Rituximab
* Drug: Doxorubicin
* Drug: Cyclophosphamide
* Drug: Prednisone
* Drug: Bleomycin
* Drug: Vindesin
* Drug: Vincristine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven CD20+ diffuse large B cell lymphoma (WHO Classification) Baseline PET scan available with at least one hypermetabolic lesion Aged ≥ 18 years and ≤ 60 years Eligible for autologous stem cell transplant Patient not previously treated Age adjusted International Prognostic Index (aa-IPI) equal to 1, 2 or 3 Life expectancy ≥ 3 months Negative HIV, HBV (anti-HBc negativity) and HCV serologies before inclusion Having signed a written informed consent Having ability and willingness to comply with study protocol procedures Men must agree to use a barrier method of contraception during the treatment period and until 3 months after the last dose of GA101 or rituximab, or ACVBP14 or CHOP14 chemotherapy, whichever is longer Women of childbearing potential must agree to use an adequate method of contraception, such as oral contraceptives, intrauterine device, or barrier method of contraception during the treatment period and until 12 months after the last dose of GA101, Rituximab, ACVBP14, or CHOP14 chemotherapy, whichever is longer Exclusion Criteria: Any other histological type of lymphoma Any history of treated or non-treated indolent lymphoma. However, patients not previously diagnosed and having a diffuse large B-cell lymphoma with some small cell infiltration in bone marrow or lymph node may be included Central nervous system or meningeal involvement by lymphoma Contra-indication to any drug contained in the chemotherapy regimens Poor cardiac function (LVEF < 50%) on echocardiogram or MUGA scan Poor renal function (creatinine level > 150*mol/l or clearance < 30ml/min), poor hepatic function (total bilirubin level > 30µmol/l, transaminases > 2.5 X 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 Pregnant or lactating women Adult patient under tutelage Prior history of Progressive Multifocal Leukoencephalopathy (PML)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GA101<br>GA101 - Chemotherapy (ACVBP or CHOP) | Drug: GA101<br>* in GA-ACBVP or in GA-CHOP 1000 mg on D1 and D8 (D8 in cycle 1 and 2)<br>* Other names: Gazivaro;Drug: Doxorubicin<br>* in ACBVP : 75 mg/m² on D1 in CHOP : 50 mg/m² on D1<br>Drug: Cyclophosphamide<br>* in ACBVP : 1200 mg/m² on D1 in CHOP : 750 mg/m² on D1<br>Drug: Prednisone<br>* in ACBVP : 60 mg/m² from D1 to D5 in CHOP : 40 mg/m² from D1 to D5<br>Drug: Bleomycin<br>* in ACBVP 10 mg from D1 to D5<br>Drug: Vindesin<br>* in ACBVP 2 mg/m² from D1 to D5<br>Drug: Vincristine<br>* in CHOP 1,4 mg/m² on D1<br>|
| Active Comparator: Rituximab<br>Rituximab - Chemotherapy (ACVBP or CHOP) | Drug: Rituximab<br>* in R-ACBVP or in R-CHOP 375 mg/m² on D1<br>* Other names: Mabthera;Drug: Doxorubicin<br>* in ACBVP : 75 mg/m² on D1 in CHOP : 50 mg/m² on D1<br>Drug: Cyclophosphamide<br>* in ACBVP : 1200 mg/m² on D1 in CHOP : 750 mg/m² on D1<br>Drug: Prednisone<br>* in ACBVP : 60 mg/m² from D1 to D5 in CHOP : 40 mg/m² from D1 to D5<br>Drug: Bleomycin<br>* in ACBVP 10 mg from D1 to D5<br>Drug: Vindesin<br>* in ACBVP 2 mg/m² from D1 to D5<br>Drug: Vincristine<br>* in CHOP 1,4 mg/m² on D1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-year Event Free Survival | EFS is defined as PET positivity according to ΔSUVmax criteria after 2 or 4 induction cycles as defined by RAC (based on central PET review), progression or relapse according to Cheson 2007, modification of planned treatment out of progression or death of any cause. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| • Overall Response rate and Best overall response after 4 cycles and end of treatment according to Cheson 2007 criteria | Response will be assessed after 4 cycles and again at the end of treatment, based on RAC assessment for PET 4 and investigator assessment for EoT PET. Assessment of response will be based on the International Workshop to Standardize Response criteria for NHL Criteria for evaluation of response in Non-Hodgkin's lymphoma (Cheson, 2007). Overall (CR//PR) response rates and Best Response Rate will be presented. Patient without response assessment (due to whatever reason) will be considered as non-responder. | Up to 3.5years | 
| • Overall Response Rate and Best overall response after 4 cycles and end of treatment according to Cheson 1999 criteria | Response will be assessed after 4 cycles and at the end of treatment, based on investigator assessment. Assessment of response will be based on the International Workshop to Standardize Response criteria for NHL Criteria for evaluation of response in Non-Hodgkin's lymphoma (Cheson, 1999). Overall (CR/CRu/PR) response rates and Best Overall Response Rate will be presented. Patient without response assessment (due to whatever reason) will be considered as non-responder. | Up to 3.5 years | 
| • Duration of response (DoR) | Duration of response is defined as the period from the time of attainment a CR or PR to the date of progression, relapse or death from any cause. Duration or response would be assessed as survival in the whole population, in the two inductive arms (R-Chemo14 vs GA101-Chemo14) For patients achieving a response but who have not progressed or relapsed or died at the time of analysis, DOR will be censored on the date of last disease assessment | Up to 6.5 years | 
| • Progression-Free Survival (PFS) | Progression-Free Survival is defined as the period from the date of randomization to the date of first documented disease progression, relapse, or death from any cause. For patients who have not progressed, relapsed, or died at the time of analysis, PFS will be censored on the date of last disease assessment. If no tumor assessments were performed after the baseline visit, PFS will be censored at the time of randomization | Up to 6.5 years | 
| • Overall survival (OS) | Overall survival is defined as the period from the date of randomization to the date of death from any cause. Alive patients at the time of the analysis will be censored at their last contact date | Up to 6.5 years | 
| • Blood samples and on tumor tissue biopsy | Analysis on blood samples and tumor tissue biopsy will be driven, in order to explore prognosis factors of the patients and their tumors that influence treatment response based on PET assessment and prognosis | Up to 6.5 years | 
| • Focus on subpopulation | Duration of response, PFS and OS will be performed according to treatment arms (R-Chemo14 vs GA101-Chemo14) on different analysis populations. The subpopulations are based on the outcome during the induction phase and a statistical bias could be introduced as subpopulations have not been defined at baseline. Population with a Δ SUVmaxPET0-2≤66% (slow and intermediate responders), Population with a Δ SUVmaxPET0-2>66% (fast responders), Patients submitted to autologous stem cell transplant (PFS and OS only) | Up to 6.5 years | 
| Number of stem cell collected after GA101 treatment | Number of stem cell collected after GA101 administration Number of required collects to achieve 3Mcells/kg. | Up to 3.5 years | 
| • Early metabolic response according to PET after 2 and 4 cycles | Based on results of central PET review | Up to 3.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DLBCL, aa-IPI > or equal to 1, Diagnosis, 18 to 60 years, Lymphoma