GLSG/OSHO Study Group. Supported by Deutsche Krebshilfe

Transcription

1 GLSG/OSHO Study Group Supported by Deutsche Krebshilfe founded in 1985

2 Comparison of Two Consecutive Study Generations of the GLSG Overall Survival

3 Follicular Lymphomas Questions for the Next Steps of Therapy Best Chemotherapy to be combined with Rituximab Value of Radio-Immuno Therapy Value of Stem Cell Transplantation after R Chemo Improvement of Rituximab Application Improvement of Rituximab Maintenance New Antibodies New Agents

4 Antibody Therapy for B - Cell Lymphomas CD22 CD25 CD20 slg HLA-DR CD37 Targeting agent Monoclonal antibody Engineered antibody Recombinant toxin CD19 B-CellB CD52 Modifications None Conjugation Radioisotopes Drugs Toxins Adapted from Press. Cancer J Sci Am. 1998;4(suppl 2):S19. @med.uni-muenchen.de

5 GA101 Type II anti-cd20 mab 1 Glycoengineered Fc region 2 Increased Direct Cell Death 2 Increased antibody-dependent cellular cytotoxicity (ADCC) 2 1. Niederfellner G, et al. Blood 2011; 118: Mössner E, et al. Blood 2010; 115:

6 GALLIUM Phase III - Study Design Previously untreated indolent NHL (n=1400) GA mg x 6-8 cycles + CHOP/CVP/Bendamustine x 6-8 cycles Rituximab 375 mg/m 2 x 6-8 cycles + CHOP/CVP/Bendamustine x 6-8 cycles CR/PR CR/PR Maintenance GA101 q2m 2 years Maintenance rituximab q2m 2 years Experimental arm GA mg d1, d8, d15 cycle 1; d1 cycles 2 6/8 + CHOP q 21d / CVP q 21 d / Bendamustine 90 mg/m 2 d1, d2 q28d Control arm Rituximab 375 mg/m 2 d1 cycles 1-6/8 + CHOP q 21d / CVP q 21 d / Bendamustine 90 mg/m 2 d1, d2 q28d Patient population Primary endpoint Maintenance treatment 1200 fnhl and 200 MZL PFS of 1200 fnhl patients Patients achieving CR or PR continue therapy every 2 months for up to 2 years Source:

7 GALLIUM Recruitment

8 8 GALLIUM Country Recruitment

9 GALLIUM: Patient Distribution

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13 Current Strategy/Studies: Strategy of GLSG/OSHO in Follicular Lymphomas Stage I/II: Radio- Immunotherapy (MASAI) Stage III/IV asymptomatic: Watch and Wait Recommendation, No Study Stage III/IV symptomatic: medically fit pts. GALLIUM, RELEVANCE medically non-fit pts. G vs. GB @med.uni-muenchen.de

14 Follicular Lymphomas Questions for the Next Steps of Therapy Best Chemotherapy to be combined with Rituximab Value of Radio-Immuno therapy Value of Stem Cell Transplantation after R Chemo Improvement of Rituximab Application Improvement of Rituximab Maintenance New Antibodies New Agents

15 Bachy E, and Salles G Clin Cancer Res 2014;20:

16 Lenalidomide Mechanism of Action

17 RELEVANCE : Phase 3 Study Design (Rituximab and LEnalidomide Versus ANy ChEmotherapy, FL-001) International, multi-centre, randomised study CR, CRu, PR 1st line FL n = 1000 R R 2 R-Chemo R 2 Maintenance 2 Years Rituximab Maintenance CR, CRu, PR R 2 Induction Lenalidomide 20 mg d 2-22 for 6 Cycles Ritux 4xCycle 1, 1x Cycles 2-6 R-Chemo R-CHOP (6x), R-CVP (8x), R-B (6x) R 2 maintenance 2 Years of Rituximab Maintenance 1 Year of Lenalidomide Maintenance

18 PRIMA RELEVANCE 3 Yrs. PFS: 74,9% G. Salles, Lancet Yrs. PFS: 89% N. Fowler, Lancet Oncology 2014

19 Follicular Lymphomas Questions for the Next Steps of Therapy Best Chemotherapy to be combined with Rituximab Value of Radio-Immuno therapy Value of Stem Cell Transplantation after R Chemo Improvement of Rituximab Application Improvement of Rituximab Maintenance New Antibodies New Agents

20 R. M. Young & L. M. Staudt, Nature Reviews Drug Discovery 12, )

21 R. M. Young & L. M. Staudt, Nature Reviews Drug Discovery 12, )

22 R. M. Young & L. M. Staudt, Nature Reviews Drug Discovery 12, )

23 Ibrutinib: First-in-class Inhibitor of Bruton s Tyrosine Kinase (BTK) Co-development by Janssen and Pharmacyclics Oral, small-molecule inhibitor of BTK with once daily dosing; previously PCYC Forms a specific and covalent bond that causes highly potent BTK inhibition Naming origins of ibrutinib (eye-broo-ti-nib): I: to indicate a modern breakthrough, ie: iphone, ipad, etc. Brut: this is a Bruton Tyrosine Kinase (BTK) inhibitor tinib: all tyrosine kinase inhibitors end with the tinib suffix >1400 patients treated to date with ibrutinib across multiple B-cell malignancies 3/26/

24 Initial Phase 1 Study (PCYC-04753) N CR PR SD ORR % CLL/SLL % FL % MCL % DLBCL % MZL/MLT % WM % TOTAL % Advani et al. ASCO /26/

25 Durable BTK inhibition following an oral dose 70 Plasma Concentration of PCI vs. BTK Occupancy Patients dosed at 2.5 mg/kg/day 100% Plasma Concentration (ng/ml) Plasma Conc 0% Time Postdose (h) Occupancy indicates irreversible inhibition of BTK Plasma concentration profile reflects inhibition profile of reversibly inhibited off targets 90% 80% 70% 60% 50% 40% 30% 20% 10% BTK Active-Site Occupancy 3/26/

26 BTK Occupancy Comparison of the Degree of BTK Occupancy by Ibrutinib at Each Dose-Level Cohort in the Study *** P< /26/

27 Efficacy in FL Patients Percent of patients (%) 54.5% 55.6% Median DOR: Median PFS: 10.3 months 13.4 months 12.3 months 19.6 months 3/26/

28 SELENE Study Design Population: relapsed/refractory inhl (FL or MZL) Stratification factors: 1. Background chemoimmunotherapy: BR or R-CHOP 2. Refractory vs relapsed disease 3. inhl histology: FL vs. MZL 4. Prior lines of therapy (1 vs >1) Primary endpoint: PFS Secondary endpoints: OS CR ORR (CR+PR) rate DOR PRO Safety N 400 subjects R A N D O M I Z E 1:1 BR or R-CHOP x 6 cycles + Placebo* BR or R-CHOP x 6 cycles + 560mg Ibrutinib* * continued until disease progression or unacceptable toxicity Janssen Research & Development 28

29 R. M. Young & L. M. Staudt, Nature Reviews Drug Discovery 12, ) Janssen Research & Development

30 Study : Phase 2 Monotherapy in Refractory inhl Accrual Completed October 2012 Single-Arm Study (N=125) Idelalisib 150 mg BID continuously Therapy maintained until progression Long Term follow-up Tumor assessments: Weeks 0, 8, 16, 24, 36, 48 Every 12 weeks thereafter Evaluated by Independent Review Committee 2 radiologists with adjudication if needed clinical review Primary endpoint: Overall Response Rate (ORR) Secondary endpoints: Duration of Response (DOR) Progression Free Survival (PFS) Safety Quality of life Salles G. et al., ICML 2013 Slide 30

31 Study : Prior Therapy Refractoriness Characteristic Rituximab Alkylating agent R-CHOP B-R R-CVP 125/125 (100%) 124/125 (99%) 46/60 (77%) 39/54 (72%) 27/36 (75%) Bendamustine 45/81 (56%) Refractory to 2 regimens Refractory to last regimen 99 (79%) 93 (74%) Slide 31

32 Study : ORR Characteristic N=125 Overall Response Rate, n (%) Complete Response Partial Response Stable Disease Progressive Disease Not Evaluated 70 (56) 12 (10) 58 (46) 43 (34) 10 (8) 2 (2) Time to response, months (N=67) Median (Q1, Q3) 1.9 (1.8, 3.7) A.K. Gopal ASH 2014 Slide 32

33 Study : PFS A.K. Gopal ASH 2014

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35 Follicular Lymphoma First Line ALTERNATIVE Studies 6 x GA Idelalisib GA 101/ Idela. Maintenance 6 x GA Ibrut GA 101/ Ibrut. Maintenance

36 Concept Antibody Partner: GA 101 Study Design: 6 Cycles Ibrutinib/Idelalisib plus GA 101 followed by 2 years maintenance of Ibrutinib/Idelalisib plus GA 101 MRD Monitoring Accompanying Research: MRD Molecular Risikfactors NGS

37 Concept Endpoint: PFS at 1 Year (MRD Negativity) Patient Number: 98 Study Duration: 1 Year Recrutment ½ Year Induction 2 Years Maintenance 3 Years Follow-up

38 Follicular Lymphoma First Line ALTERNATIVE Studies 6 x GA CHOP /B GA 101 Maintenance R 6 x GA New Drugs New Drug Maint.

39 Key Steps in Improving Treatment for Follicular Lymphoma Prolongation of Life since mid 1990ies Cure? Chronic Disease? Today New Antibodies New Drugs Palliation of Symptomes until mid 1990ies Antibodies ASCT Cytostatic Drugs Radiation