Successful practice changing development plans: Rituximab in Burkitt lymphoma

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1 Successful practice changing development plans: Rituximab in Burkitt lymphoma Véronique Minard-Colin, MD, PhD Pediatric and Adolescent Oncology Gustave Roussy, Villejuif, France

2 No disclosure

3 CD20 immunotherapy question in childhood B-NHL High survival rates ~ 90% Rituximab may have unexpected/severe toxicity in children Two rituximab phase 2 trials in children BFM single There agent was a upfront necessity window to demonstrate study COG effectiveness pilot study of LMB rituximab chemo in + childhood rituximab B-NHL No randomized trial in Burkitt except one in adults in France LeBien, Tedder Blood 2008; Meinhardt, JCO 2010; Goldman, Leukemia 2013 and BJH 2014; Barth, BJH 2014

4 k Trial design: Historical comparison? Fluctuations over time NHL-BFM 95 MTX 4h : 77% R MTX 24h : 92% MTX Standard 24h non during R : 71% RCT : 71% MTX Standard 24h after R: RCT 86% : 86% At risk Years Group C - CNS negative - EFS LMB89 LMB96 standard LMB96 reduced LMB Years logrank : p = 0.03 Need for controled/randomised studies

5 Who are the high risk patients who may benefit for rituximab? St III high LDH, st IV and B-AL At risk BFM R3, R4, trt std, LMB SFOP St III LDH>2N, group C BFM 95&04 : 85% SFOP 96&01 : 87% Years Randomized Phase 3 trial EFS 84% 92% 301 pts/arm 5

6 To make a long story short Dec2008 PHRC JAN2009 Budapest 2009 APR2009 BFM/GPOH proposal R-combo With LMB or BFM A common LMB-based protocol JAN 2010 IGR approval for sponsorship NOV2009 Wroclaw A comprehensive Burkitt Programm With 7 risk groups APR2010 BFM/GPOH Stepped down MAY2010 Amsterdam NCI will support the Ritux study only A Phase III In high-risk A phase II In PLMLB MAR2011 COG approval AUG2011 NCI/CTEP approval NOV2011 Paris Investigator meeting A Phase III In high-risk A phase II In PLMLB Nov28th 1st center opening

7 Inter-B-NHL Ritux 2010 ACADEMIC STUDY with an EXPERIMENTAL DRUG and a Pediatric Investigation Plan required by EMA (EMEA PIP01-08-M02) Sponsors Partner INTERGROUP COLLABORATION 12 countries 292 sites USA Canada Australia

8 Inter-B-NHL Ritux 2010: Model of academic study with industry partnership Opportunity to develop a trial with efficacy and safety data Intergroup Collaboration (12 countries 292 sites) 3 continents New countries on board (Poland, HK) Common backbone chemotherapy: LMB High quality of care and analysis Two separate databases (GR and COG) fused in GR for analysis All events reviewed by an international SC An active Independent Data Monitoring Committee

9 To make a long story short First patient Dec 2011 (France) May 2012 (USA) July 2014 (UK) Nov 2016 (Poland)

10 Results of the randomized intergroup trial Inter-B-NHL ritux 2010 for children and adolescents with high risk B-cell non Hodgkin s lymphoma and mature acute leukemia: Evaluation of rituximab efficacy in addition to standard LMB chemotherapy regimen. Minard-Colin V, Aupérin A, Pillon M, Burke A, Anderson J, Barkauskas D, Wheatley K, Delgado RF, Alexander S, Uyttebroeck A, Bollard C, Zsíros J, Csoka M, Goma G, Tulard A, Patte C, and Gross T Sponsors: Gustave Roussy and COG N EudraCT: ClinicalTrials.gov Identifier: NCT

11 July 2015: 1 st Interim analysis At risk Event Free Survival With Rituximab Without Rituximab Months since randomization Minard-Colin ASCO year EFS (95%CI) 94.2% (88.5%-97.2%) 81.5% (73.0%-87.8%) HR=0.33

12 First Interim Analysis - Decisions - Following IDMC recommendation, sponsors decided to halt the randomization in Nov 2015 and continue follow-up to have mature data for all randomized patients Final analysis in progress, 49/332 pts follow-up < 1 year - March 2016: Study re-open with a single-arm rituximab for 120 additional patients To answer to the secondary objectives: Safety/Immunity status/ancillary studies March,1, 2017: 92/120 patients included

13 Future of childhood B-NHL treatment? High Risk: Backbone chemotherapy + Rituximab Inter-B-NHL results will change our clinical practice Standard Risk (40-45% pts; Stages I/II/III LDH<2N)* Current EFS 97-98% - Survival 99% Acute toxicity of CT but no expected long term side effects The use of rituximab is questionable? Patte C, SIOP 2010 *n=291 pts from LMB96 (SFOP) and LMB2001

14 Refractory/relapsed B NHL Rare (< 5 patients / year in France) Clonal heterogeneity and resistance to CD20 mab International Phase 1/2 in progress: Backbone chemotherapy + rituximab +/-ibrutinib New drugs: CAR CD19 - anti PD1/PDL1 (DLBCL) BiTE - anti CD79 - EZH2 (DLBCL)- PI3K/Akt/mTOR How to develop new drugs? Need international and adult collaborations

15 Conclusion InterB NHL 2010: -Initiated by Academic: Medical need in childhood -Conducted on 3 different continents -A success of Academic/Pharma collaboration and PIP development > 95% of children with B NHL are now cured A few challenges remain ahead: new drugs development in rare refractory/relapse disease and cure of Burkitt in less privileged countries

16 Inter-B-NHL Ritux 2010: a Successfull Academic study with International and Transatlantic collaboration and Pharma support Steering Committee: Anne Aupérin, Amos Burke, Angelo Rosolen, Marta Pillon, Jim Anderson, Don Barkauskas, Keith Wheatley, Tom Gross and Catherine Patte Independent Data Monitoring Committee: Richard Sposto, François Pein, Robert Marcus, and Ross Pinkerton Sponsors: Gilles Vassal and Peter Adamson Roche Team Acknowledgement and Funding Treating Physicians, Nurses, Pharmacists and Research Staff F. Hoffmann-La Roche Programme Hospitalier de Recherche Clinique (PHRC, INCa France) U10CA and U10 CA98548 (NCI, USA) Cancer Research UK Patients and their Families