GA In NEwly Diagnosed Diffuse Large B Cell Lymphoma (GAINED)

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

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.

Study Overview

• Status: Terminated
• Conditions: Diffuse Large B Cell Lymphoma CD20 Positive
• Intervention / Treatment: Drug: GA101; Drug: Doxorubicin; Drug: Cyclophosphamide; Drug: Prednisone; Drug: Bleomycin; Drug: Vindesin; Drug: Vincristine; Drug: Rituximab

• Study Type: Interventional
• Enrollment (Actual): 671
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Antwerpen, Belgium, 2060
    • ZNA Stuivenberg
  • Arlon, Belgium, 6700
    • Hopital Saint Joseph
  • Baudour, Belgium, 7331
    • RHMS Baudour
  • Brugge, Belgium, 8000
    • AZ ST JAn Brugge Oostende AV
  • Bruxelles, Belgium, 1000
    • Institut Jules Bordet
  • Bruxelles, Belgium, 1070
    • Hopital Erasme
  • Bruxelles, Belgium, 1020
    • CHU Brugmann
  • Bruxelles, Belgium, 1200
    • Clinique Universitaire Saint Luc
  • Charleroi, Belgium, 6000
    • Grand Hopital de Charleroi
  • Charleroi, Belgium, 6000
    • CHU de Charleroi
  • Gent, Belgium, 900
    • Universitair Ziekenhuis Gent
  • Haine Saint Paul, Belgium, 7100
    • CH Jolimont
  • Kortrijk, Belgium, 8500
    • AZ GROENINGE - Oncology Centre - Campus Maria's Voorzienigheid
  • Liège, Belgium, 4000
    • CHR de la Citadelle
  • Liège, Belgium, 4000
    • CHU de Liège - Clinique Saint Joseph
  • Liège, Belgium, 4000
    • CHU de Liège -Domaine Sart Tilman
  • Mons, Belgium, 7000
    • CHU Ambroise Pare
  • Mons, Belgium, 7000
    • Clinique Saint Joseph -Hôpital de Warquignies
  • Namur, Belgium, 5000
    • Clinique Sainte Elisabeth
  • Ottignies, Belgium, 1340
    • Clinique Saint Pierre
  • Roeselare, Belgium, 8800
    • Heilig Hart Ziekenhuis
  • Tournai, Belgium, 7500
    • Centre Hospitalier de Wallonie Picarde - CHwapi
  • Verviers, Belgium, 4800
    • CH de la Tourelle-Peltzer
  • Yvoir, Belgium, 5530
    • Université Catholique de Louvain Mont Godinne
• France
  • Abbeville, France, 80142
    • CH d'Abbeville
  • Amiens, France, 80054
    • Chu D'Amiens - Hopital Sud
  • Angers, France, 49033
    • CHU d'Angers
  • Argenteuil, France, 95100
    • CH Victor Dupouy
  • Arras, France, 62022
    • CH d'Arras
  • Avignon, France, 84902
    • CH d'Avignon
  • Bayonne, France, 64109
    • Hôpital de Bayonne - CHU de la Côte Basque
  • Beauvais, France, 60000
    • CH de Beauvais
  • Besançon, France, 25030
    • CHU de Besançon - Hôpital Jean Minjoz
  • Blois, France, 41016
    • CH de Blois
  • Bobigny, France, 93000
    • APHP - Hôpital Avicenne
  • Bordeaux, France, 33076
    • Institut Bergonié
  • Bordeaux, France, 33077
    • Polyclinique Bordeaux Nord Aquitaine
  • Boulogne sur Mer, France, 62321
    • CH Dr Duchenne
  • Bourg en Bresse, France, 01012
    • Ch Fleyriat
  • Brest, France, 29609
    • CHU de Brest - Hôpital de Morvan
  • Brive la Gaillarde, France, 19100
    • CH Brive la Gaillarde
  • Caen, France, 14076
    • Centre Francois Baclesse
  • Caen, France, 14033
    • CHU de Caen
  • Cannes, France, 06400
    • CH de Cannes
  • Castelnau Le Lez, France, 34170
    • Clinique du parc
  • Chambéry, France, 73011
    • CH de Chambery
  • Châlon sur Saône, France, 71100
    • CHU de Châlon sur Sâone
  • Clamart, France, 92141
    • Hôpital d'Instruction des Armées PERCY
  • Clamart, France, 92140
    • APHP - Hôpital Antoine Béclère
  • Clermont Ferrand, France, 63003
    • Chu D'Estaing
  • Clermont Ferrand, France, 63050
    • Pôle Santé Publique
  • Compiègne, France, 60200
    • CH de Compiègne
  • Corbeil Essonnes, France, 91100
    • CH SUd Francilien
  • Créteil, France, 94010
    • APHP - Hopital Henri Mondor
  • Dijon, France, 21000
    • CHU de Dijon
  • Dunkerque, France, 59385
    • CH de Dunkerque
  • Grenoble, France, 38043
    • CHU de Grenoble
  • Grenoble, France, 38000
    • Institut Daniel Hollard
  • La Roche Sur Yon, France, 85925
    • CHD Vendee
  • La Rochelle, France, 17019
    • CH La Rochelle
  • Le Kremlin Bicêtre, France, 94275
    • APHP - Hôpital Bicêtre
  • Le Mans, France, 72000
    • CH du Mans
  • Le Mans, France, 72000
    • Clinique Victor Hugo
  • Lens, France, 62307
    • CH de Lens
  • Lille, France, 59037
    • CHRU LILLE - Hôpital Claude Huriez
  • Lille, France, 59000
    • CH Saint Vincent de Paul
  • Limoges, France, 87042
    • CHU Dupruytren - Limoges
  • Lorient, France, 56100
    • CH Bretagne Sud
  • Lyon, France, 69008
    • Centre Leon Berard
  • Mantes La Jolie, France, 78201
    • CH Mantes La Jolie
  • Marseille, France, 13009
    • Institut Paoli Calmettes
  • Marseille, France, 13005
    • Hôpital de la Conception
  • Meaux, France, 77100
    • CH de Meaux
  • Melun, France, 77011
    • CH Marc Jacquet
  • Metz, France, 57038
    • Hôpital Notre Dame Bon Secours
  • Meulan en Yvelines, France, 78250
    • CHI de Meulan
  • Montpellier, France, 34295
    • CHU de Montpellier - Saint Eloi
  • Montpellier, France, 34298
    • Centre Val d'Aurélie - Paul Lamarque
  • Mougins, France, 06250
    • Centre Auréen de Cancérologie
  • Mulhouse Cedex, France, 68070
    • CH de Mulhouse - Hôpital Emile Muller
  • Nantes, France, 44093
    • CHU de Nantes - Hotel Dieu
  • Nantes, France, 44200
    • Centre Catherine de Sienne
  • Nice, France, 06202
    • CHU de Nice
  • Nice Cedex 2, France, 06189
    • Centre Antoine Lacassagne
  • Nîmes, France, 30029
    • CHU de NIMES
  • Nîmes, France, 30900
    • Clinique Valdegour
  • Orléans, France, 45067
    • CHR d'Orléans
  • Paris, France, 75014
    • Hopital Cochin
  • Paris, France, 75005
    • Institut Curie
  • Paris, France, 75015
    • APHP - Hopital Necker
  • Paris, France, 75013
    • APHP - Hopital de la Pitie Salpetriere
  • Paris Cedex 10, France, 75475
    • Aphp - Hopital Saint Louis
  • Paris Cedex 12, France, 75571
    • APHP - Hopital Saint Antoine
  • Perpignan, France, 66000
    • CH Saint Jean
  • Pessac, France, 33604
    • CHU de Haut Leveque
  • Pierre Bénite, France, 69495
    • Hospices Civils de Lyon - CHU Lyon Sud
  • Poitiers, France, 86000
    • CHU De Poitiers
  • Pontoise, France, 95300
    • CH René Dubos
  • Pringy, France, 74370
    • CH d'Annecy
  • Reims, France, 51100
    • CHU Robert Debré
  • Reims, France, 51100
    • Institut du Cancer de Courlancy
  • Rennes, France, 35033
    • CHU de Rennes
  • Roubaix, France, 59100
    • CH de Roubaix
  • Rouen, France, 76000
    • Centre Henri Becquerel
  • Rouen, France, 76000
    • Clinique Mathilde
  • Saint Brieuc, France, 22000
    • CH Yves Le Foll - St Brieuc
  • Saint Cloud, France, 92210
    • Centre René Huguenin
  • Saint Malo, France, 35400
    • CHU de Saint Malo
  • Saint Quentin, France, 21000
    • CH de Saint Quentin
  • Saint germain en laye, France, 78105
    • CHI de Poissy St Germain
  • St Priest en Jarez, France, 42270
    • Institut de Cancérologie
  • Strasbourg, France, 67000
    • Strasbourg Oncologie Libérale
  • Strasbourg, France, 67098
    • CHU de Strasbourg
  • Toulon, France, 83100
    • Hopital Saint Husse
  • Toulouse, France, 31059
    • Institut Universitaire du Cancer - Oncopole Toulouse (IUCT-O)
  • Tours, France, 37000
    • CHU de Tours
  • Valence, France, 26953
    • CHU de Valence
  • Valenciennes, France, 59322
    • CH de Valenciennes
  • Vandœuvre-lès-Nancy, France, 54511
    • CHU de Brabois
  • Vannes, France, 56017
    • CH Bretagne Atlantique
  • Versailles, France, 78750
    • CH de Versailles
  • Villejuif, France, 84085
    • Institut Gustave Roussy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 58 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: The Lymphoma Academic Research Organisation
• Collaborators: Hoffmann-La Roche
• Investigators: Study Chair: Olivier Casasnovas, MD, Lymphoma Study Association; Study Chair: Steven Le Gouill, MD, Lymphoma Study Association

Publications and helpful links

General Publications

• Jullien M, Tessoulin B, Ghesquieres H, Oberic L, Morschhauser F, Tilly H, Ribrag V, Lamy T, Thieblemont C, Villemagne B, Gressin R, Bouabdallah K, Haioun C, Damaj G, Fornecker LM, Schiano De Colella JM, Feugier P, Hermine O, Cartron G, Bonnet C, Andre M, Bailly C, Casasnovas RO, Le Gouill S. Deep-Learning Assessed Muscular Hypodensity Independently Predicts Mortality in DLBCL Patients Younger Than 60 Years. Cancers (Basel). 2021 Sep 7;13(18):4503. doi: 10.3390/cancers13184503.
• Le Gouill S, Ghesquieres H, Oberic L, Morschhauser F, Tilly H, Ribrag V, Lamy T, Thieblemont C, Maisonneuve H, Gressin R, Bouhabdallah K, Haioun C, Damaj G, Fornecker L, Bouhabdallah R, Feugier P, Sibon D, Cartron G, Bonnet C, Andre M, Chartier L, Ruminy P, Kraeber-Bodere F, Bodet-Milin C, Berriolo-Riedinger A, Briere J, Jais JP, Molina TJ, Itti E, Casasnovas RO. Obinutuzumab vs rituximab for advanced DLBCL: a PET-guided and randomized phase 3 study by LYSA. Blood. 2021 Apr 29;137(17):2307-2320. doi: 10.1182/blood.2020008750.
• Blanc-Durand P, Jegou S, Kanoun S, Berriolo-Riedinger A, Bodet-Milin C, Kraeber-Bodere F, Carlier T, Le Gouill S, Casasnovas RO, Meignan M, Itti E. Fully automatic segmentation of diffuse large B cell lymphoma lesions on 3D FDG-PET/CT for total metabolic tumour volume prediction using a convolutional neural network. Eur J Nucl Med Mol Imaging. 2021 May;48(5):1362-1370. doi: 10.1007/s00259-020-05080-7. Epub 2020 Oct 24.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2012
• Primary Completion (Actual): August 1, 2016
• Study Completion (Actual): December 31, 2017

Study Registration Dates

• First Submitted: July 4, 2012
• First Submitted That Met QC Criteria: August 2, 2012
• First Posted (Estimate): August 7, 2012

Study Record Updates

• Last Update Posted (Actual): March 7, 2018
• Last Update Submitted That Met QC Criteria: March 6, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: DLBCL; Lymphoma; Diagnosis; aa-IPI > or equal to 1; 18 to 60 years
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Cyclophosphamide; Rituximab; Prednisone; Doxorubicin; Vincristine; Obinutuzumab; Bleomycin
• Other Study ID Numbers: GAINED