Overview of Lymphoma Clinical Trials

Transcription

1 Overview of Lymphoma Clinical Trials Dr Pam McKay Beatson West of Scotland Cancer Centre Lymphoma Action Patient Conference September 2018

2 Clinical trials medical research involving human participants treatment related new treatment does it work? how does it work? is it better than standard treatment? existing treatments comparing one treatment with another comparing different ways of using treatment eg doses, scheduling

3 Clinical trials pathology eg molecular subtypes MAPLE study radiology eg use of PET/CT scans to guide treatment patient pathway eg Horizons study late effects eg fertility RATHL ovarian substudy

4 Clinical Trials phase 1 small trials; often aim to find best dose or test safety phase 2 aim to find out more about the safety and effectiveness of the treatment phase 3 larger trials; test a new treatment or a new way of using a treatment against the standard treatment phase 4 after a drug has been licensed, to find out more about it

5 Potential Advantages access to latest treatments access to information access to expert staff careful follow up longer follow up helping others in future

6 Potential Disadvantages uncertainty about outcome might be in group with worse outcome unexpected side effects greatest in phase 1 trials (usually for patients with no other treatment options) extra hospital visits reassuring or stressful? extra tests

7 Diffuse Large B Cell Lymphoma

8 Diffuse Large B cell lymphoma (DLBCL) commonest subtype of lymphoma aggressive but curable 1994: 7-8 drug regimens no better than CHOP but significantly greater toxicity 2002: addition of rituximab to CHOP (R-CHOP) improvement in response rates, progression free survival and overall survival by ~15% RCHOP21 =standard of care

9 R-CHOP vs CHOP 1. Coiffier et al. Blood, 2010.

10 How can we improve on R-CHOP21? chemotherapy scheduling different monoclonal Ab ofatumumab, obinotuzumab additional agents bortezomib, ibrutinib addition of radiotherapy

11 Chemotherapy scheduling established that 8 cycles R-CHOP no better than 6 cycles PFS 14 day cycle no better than 21 days OS

12 Different monoclonal antibody Goya study Obinutuzumab anti CD20 antibody, more potent than R CHOP + Obinutuzumab (G-CHOP) vs CHOP + Rituximab 1418 patients No difference in response rate, PFS or OS More significant toxicity with G-CHOP. PFS OS

13 Additional agents ABC DLBCL poorer prognosis focus of attention Some novel agents appear to have preferential activity in ABC type Bortezomib, ibrutinib, lenalidomide in combination with R- CHOP

14 Additional agents REMODEL-B study Large phase III study, multicentre, UK 1132 patients from 109 sites First line treatment of DLBCL R-CHOP vs R-CHOP + Bortezomib No difference in outcome Phoenix study Large phase III study R-CHOP vs R-CHOP + Ibrutinib Ibrutinib - BTK inhibitor Preferential activity in ABC type DLBCL follow up ongoing

15 Addition of Radiotherapy German RICOVER-60 trial Patients aged >60 yrs 6xR-CHOP14 + 2xR Value of adding radiotherapy to sites of initial bulk (>7.5cm) or extranodal disease

16 Management of patients with poor cardiac function/multiple co-morbidities INCA study Multicentre, randomised, phase II trial 1 st line DLBCL Not suitable for anthracycline cardiac or other co-morbidities IO-R-CVP v Gem-R-CVP IO= inotuzumab ozogamacin anti CD22 conjugated to calicheamicin (potent anti tumour antibiotic) 6 cycles, 3 weekly intervals 1y end point - PFS

17 Molecular Profiling Studies - MaPLe DLBCL or grade 3B FL newly diagnosed Samples molecular diagnostic lab, Barts, London Molecular profiling Basic clinical data collected In event of progression, patient screened for targeted treatment EZH2 mutation present Epizyme study

18 Primary Mediastinal B cell IELSG 37 study Ph III, multicentre 1 st line treatment lymphoma standard of care is R chemotherapy followed by radiotherapy (RT) can we use PET scan to determine need for RT? If PET negative randomize between RT or no further treatment

19 Secondary CNS Lymphoma MARIETTA study systemic B-cell lymphoma with CNS involvement at diagnosis or at relapse outlook very poor sequential MATRIX and R-ICE, followed by high-dose chemotherapy + ASCT

20 Relapsed DLBCL Epizyme study Phase II study, multicentre Tazemetostat (EZH2 histone methyl transferase inhibitor) Single agent, oral therapy > 2 previous lines of therapy well tolerated ARGO study phase II study, multicentre patients who have relapsed post ASCT or unsuitable for transplant max 2 previous therapies R + gemcitabine + oxaloplatin (RGO) vs RGO + Atezolizumab (check point inhibitor)

21 Follicular Lymphoma

22 Follicular lymphoma (FL) commonest low grade lymphoma, incurable treatment not always required at diagnosis watch and wait watch & wait vs rituximab study rituximab delay in time to require definitive treatment compared to observation alone potential toxicity from infection

23 FL addition of rituximab to chemotherapy improved outcomes rituximab maintenance (2 monthly for 2 years) improves PFS but not OS (PRIMA study) PRIMA study

24 FL Standard of care: Rituximab + chemotherapy eg CVP, CHOP, bendamustine Maintenance Rituximab for 2 years Current Q s can other CD20 antibodies eg Obinotuzumab result in better outcome? (GALLIUM study) can PET/CT scans be used to determine those patients who will not benefit from maintenance rituximab? (PETREA study)

25 GALLIUM study Large phase III study, ASH 2016 Comparison of obinutuzumab (O) + chemo versus rituximab (R) + chemo chemo - CHOP or CVP or bendamustine maintenance O or R for 2 years 34% reduction in risk of PFS event in the obinutuzumab arm. Non-lymphoma related mortality higher in bendamustine treated patients (5%) vs CHOP and CVP (<2%) Mainly infection marked reduction in CD4 helper cells persists up to 18 months 17. R Marcus et al, ASH 2016

26 GALLIUM study reduction in risk of PFS event

27 PETREA study R-chemotherapy (CVP, CHOP or bendamustine) PET/CT scan at diagnosis and post chemotherapy If PET/CT negative after R-chemo, randomize between maintenance R (MR) and observation If PET/CT positive after R-chemo, randomize between MR and MR + lenolidamide

28 Relapsed FL - GADOLIN Study ph 3 study, ~ 400 pts with indolent NHL (80% FL) rituximab refractory

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30 GADOLIN update Additional 10mths FU median PFS 25.8 (G-B) v 14.1 mths median OS not reached (G-B) v 53.9 mths 43% reduction in risk of PD or death with G-B no new safety signals severe neutropenia & infusion related reactions more common with G-B

31 Other FL relapse studies REBEL study rituximab and lenolidamide +/- bendamustine Epizyme study tazemetostat multiple relapsed FL very encouraging results especially if have EZH2 mutation (~70% RR)

32 T cell Lymphomas

33 Chemo T study CHOP versus GEM-P in previously untreated patients with peripheral T-cell lymphoma phase 2, multicentre Complete response rates 1y end point Looking for 20% superior response for GEM-P Closed early as GEM-P no better than CHOP but more toxic 62% CR/CRu for CHOP vs 46% for GEM-P Lancet Haematol 2018, Gleeson M et al

34 ECHELON 2 CD30 + mature T cell lymphomas double-blinded CHOP vs CHP + Brentuximab Brentuximab antibody to CD30 conjugated to MMAE HDT + ASCT at clinicians discretion

35 Mantle cell lymphoma ENRICH 1 st line > 60 years, unsuitable for ASCT R-chemo (R-CHOP or R-bendamustine) vs R- ibrutinib maintenance R for 2 years (both arms) continuous ibrutinib (R-I arm only)

36 Hodgkin Lymphoma

37 Hodgkin s Lymphoma ABVD standard treatment for many years 70-80% cure rates Evens et al - importance of delivering full doses on time early stage disease ABVD 2-4 cycles + radiotherapy advanced stage disease ABVD x 6

38 Early stage disease RAPID study randomization between no further treatment and radiotherapy in patients who are PET negative after 3 cycles of ABVD OS PFS

39 RAPID study 3-year progression-free survival rate was 97.1% in the radiotherapy group and 90.8% in the group with no further therapy Modest improvement in the 3-year PFS rate (6.3%) can be obtained with the addition of radiotherapy Avoidance of RT may reduce incidence of second cancers and cardiac disease

40 Advanced stage disease RATHL study using PET scan after 2 cycles to determine treatment is it safe to omit bleomycin in those that are PET negative? does escalation of therapy to BEACOPP improve outcome in those who are PET +ve? NEJM, 2016, Johnson P et al

41 RATHL 1200 advanced HL PET 1 2 cycles ABVD PET positive PET 2 PET negative 4 cycles BEACOPP-14 or 3 cycles escbeacopp PET positive PET 3 PET negative Randomize 4 cycles ABVD 4 cycles AVD no bleomycin RT or salvage 2 cycles BEACOPP-14 or 1 cycle escbeacopp No RT Endpoint : PFS No further treatment No RT

42 RATHL study 1203 patients UK, Europe, Australia, NZ 83.7% of patients had a negative PET2 3 yr PFS 85.7% (ABVD) vs 84.4% (AVD) 3 yr OS 97.2% vs 97.6% Conclusion: bleomycin can be omitted from C3-6 with no loss of efficacy respiratory events reduced

43 Primary Endpoint: PFS for PET-negative randomized, eligible patients (Median follow up 41 months) Intention to treat analysis: Per protocol analysis: ABVD-AVD = 1.6% ( ) ABVD-AVD = 1.3% ( ) HR: 1.13 ( ), p = 0.48 HR: 1.10 ( ), p = Year PFS, ABVD: 85.7% (95% CI: ) 3 Year PFS, ABVD: 85.3% (95% CI: Year PFS, AVD: 84.4% (95% CI: ) 3 Year PFS, AVD: 84.6% (95% CI:

44 Overall survival: PET-2 negative 3 year OS % ABVD: 97.2 ( ) AVD: 97.6 ( ) patients HR 0.90 ( ), p =0.76

45 phase III, commercial study untreated HL, stage III-IV Echelon I study: ABVD v A-AVD ABVD v A(brentuximab)+AVD x 6 2 year modified PFS: 77.2% vs 82.1% A+AVD superior efficacy (4.9% improvement in modified PFS) Peripheral neuropathy more common with A+AVD (67% vs 43%) Serious pulmonary toxicity more common with ABVD (3% vs 1%) NEJM, 2018, Connors. J et al

46 Probability of modified PFS 1.0 Modified PFS per independent review Number of events No. of patients at risk: A+AVD ABVD HR 0.77 (95% CI: ) Log-rank test p-value: Time from randomization (months) A+AVD ABVD Category Time 2- year A+AVD (95% CI) 82.1 ( ) Median follow-up (range): 24.9 months ( ) A+AVD N=117 ABVD (95% CI) 77.2 ( ) ABVD N=146 Progression Death Modified progression Chemotherapy Radiotherapy Connors, J. et al: Abstract no 0006

47 Patients (%) Patients (%) 80% 60% 40% 20% 0% Peripheral neuropathy and pulmonary events Treatment-emergent PN* 67% A+AVD 43% Drug discontinuations due to PN: A+AVD 7% ABVD 2% ABVD Grade 3-4 Grade 2 Grade % A+AVD Interstitial lung disease 7% ABVD <1% 3% Category 1Category 2Category 3Category 4 All A+AVD ABVD Grade 3 *Includes the preferred terms peripheral sensory neuropathy, PN, hypoesthesia, polyneuropathy, paraesthesia, muscular weakness, peripheral motor neuropathy, peroneal nerve palsy, muscle atrophy, hypotonia, autonomic neuropathy, neuralgia, burning sensation, dysesthesia, gait disturbance, toxic neuropathy, neurotoxicity, and sensory disturbance; PN, peripheral neuropathy Includes the preferred terms lung infiltration, pneumonitis, interstitial lung disease, acute respiratory distress syndrome, organizing pneumonia, pulmonary fibrosis, and pulmonary toxicity Connors, J. et al: Abstract no 0006

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49 Early interim PET within the German HD18 study R-eBEACOPP x4/6 Advanced stage Hodgkin lymphoma ebeacopp x2 PET2 +ve (DS3-5) PET2 ve (DS1-2) R R ebeacopp x4/6 ebeacopp x4/6 ebeacopp x2 HD15 Lancet May 12;379(9828): Lancet Dec 23;390(10114): Borchmann P. et al: Abstract no 0737

50 Results of German HD18 PET2 negative (DS1-2) 5 year PFS 6/8 cycles of ebeacopp versus 4 cycles % vs 92.2% (ns) PET2 positive (DS3-5) 5 year PFS ebeacopp vs R-eBEACOPP 89.7% vs 88.1% (ns) Early progression/relapse 1.6% in DS1-3 - they will treat DS3 as low risk in future studies Conclusions: 4 cycles ebeacopp is standard of care if PET negative after 2 cycles Rituximab is of no additional benefit

51 Elderly HL - PFS with multi-agent chemotherapy Age >70 Cannot perform ADLs Andrew M. Evens et al. Blood 2012;119: by American Society of Hematology

52 BREVITY study untreated HL not for standard treatment due to age, frailty, co-morbities single agent brentuximab, 3 weekly 4 cycles then evaluate by PET/CT if CR further 8 if PR further 4 then if CR, further 8 total of cycles

53 BREVITY study ORR 84% (CMR or PMR at PET 4) (N=26/31) CMR rate at PET4 was 26% (N=8/31) Median PFS 7.4 months PFS for 8 patients in CMR 11.9 months

54 Progression-Free Survival

55 Brevity study Tolerable therapy but high incidence of lowgrade toxicity and dose reductions in this difficult-to-treat population Peripheral neuropathy an issue High overall response rates but mainly partial response CMR and PFS unsatisfactory

56 Conclusion Clinical trials are important in improving medical care for ALL patients They may improve outcome for the individual patient They may provide treatment opportunities when standard treatment has been exhausted