Disclosures WOJCIECH JURCZAK

Transcription

1 Disclosures WOJCIECH JURCZAK ABBVIE (RESEARCH FUNDING), CELGENE (RESEARCH FUNDING); EISAI (RESEARCH FUNDING); GILEAD (RESEARCH FUNDING); JANSEN (RESEARCH FUNDING); MORPHOSYS (RESEARCH FUNDING), MUNDIPHARMA (SCIENTIFIC ADVISORY BOARD); PHARMACYCLICS (RESEARCH FUNDING); PFIZER (RESEARCH FUNDING); ROCHE (RESEARCH FUNDING); SANDOZ NOVARTIS (RESEARCH FUNDING, SCIENTIFIC ADVISORY BOARD); SPECTRUM (RESEARCH FUNDING, SCIENTIFIC ADVISORY BOARD); TAKEDA (RESEARCH FUNDING, SCIENTIFIC ADVISORY BOARD); TEVA (RESEARCH FUNDING, SCIENTIFIC ADVISORY BOARD).

2 Phase IIa study of single-agent MOR208 in patients with relapsed or refractory B-cell non-hodgkin s lymphoma (NHL) W. Jurczak,* P. L. Zinzani, A. Goy, M. Provencio, Z. Nagy, T. Robak, K. Maddocks, C. Buske, R. Korolkiewicz, M. Winderlich, K. A. Blum *Jagiellonian University, Kraków, Poland

3 Background CD19, a B-lymphocyte lineage specific surface antigen, is the earliest and most broadly expressed of the selective B-cell markers, and is highly expressed in most B-cell NHLs Consequently, a CD19 antibody may have clinical utility as a new therapeutic approach to NHL treatment MOR208 is an Fc-engineered humanized monoclonal antibody that targets CD19 Phase I study has shown MOR208 to be generally safe and well-tolerated, with encouraging single-agent activity in patients with CLL (Woyach et al, 2014) Recommended intravenous dose of 12 mg/kg, administered weekly Woyach JA, et al. Blood 2014;124: CLL, chronic lymphocytic leukemia

4 MOR208: Mode of Action Significantly enhanced in vitro ADCC, ADCP through Fc engineering; direct cytotoxic effects (apoptosis) on tumor cells ADCC, antigen-dependent cell-mediated cytotoxicity ADCP, antigen-dependent cell-mediated phagocytosis

5 Objectives Primary: Assess antitumor activity (objective response rate) of single-agent MOR208 in adult patients with relapsed or refractory NHL who had received at least one prior therapy containing the CD20 antibody, rituximab Key Secondary: Evaluate duration of response Establish safety and tolerability of MOR208 Assess potential immunogenicity of MOR208 Evaluate the pharmacokinetics and pharmacodynamics of MOR208

6 Study Design R-R NHL cohorts (DLBCL, MCL, FL, other inhl) MOR mg/kg iv Days 1, 8, 15, day cycles MOR mg/kg iv Every 14 or 28 days* Cycle 1 Cycle 2 SD Cycle 3 PR Maintenance Non-randomized, phase IIa, open-label, multicenter study (NCT ) 2-stage design Stage 1: 10 patients were enrolled into each of 4 NHL subtype cohorts; DLBCL, MCL, FL, other inhl Stage 2: cohorts with 2 responses (complete or partial) expanded by at least 20 additional patient *Until disease progression or unacceptable toxicity DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; inhl, indolent non-hodgkin s lymphoma; iv, intravenous infusion; MCL, mantle cell lymphoma; PR, partial response; R-R relapsed or refractory; SD, stable disease

7 Eligibility Criteria Inclusion: Aged 18 years Histologically-confirmed diagnosis of DLBCL, FL, other inhl or MCL NHL progressed after at least one prior rituximab-containing therapy ECOG PS 2 Measurable disease; 1.5 x 1.5 cm Life expectancy >3 months Adequate bone marrow, renal and liver function Exclusion: Previous treatment with CD19 antibody or fragments Previous allogenic stem cell transplant Major surgery or radiotherapy within 4 weeks before first study drug administration ECOG PS, Eastern Cooperative Oncology Group performance status

8 Baseline Characteristics Characteristic DLBCL n=35 FL n=34 Other inhl n=11 MCL n=12 Age, years: median Total n= (54) 15 (44) 9 (82) 6 (50) 49 (53) Sex: Male 24 (69) 16 (47) 5 (45) 11 (92) 56 (61) Ann Arbor stage: I II 4 (11) 5 (15) 0 1 (8) 10 (11) III IV 30 (86) 28 (82) 11 (100) 11 (92) 80 (87) Unknown 1 (3) 1 (3) (2) ECOG PS, %: 0, 1, 2 57, 34, 9 71, 26, 3 82, 18, 0 58, 33, 8 65, 29, 5 Prior lines therapy: 1 15 (43) 14 (41) 3 (27) 3 (25) 35 (38) 2 8 (23) 5 (15) 2 (18) 1 (8) 16 (17) 3 12 (34) 15 (44) 6 (55) 8 (67) 41 (45) Last rituximab dose <6 months ago 14 (40) 5 (15) 1 (9) 1 (8) 21 (23) Prior stem-cell transplant 2 (6) 5 (15) 2 (18) 1 (8) 10 (11) Data are n (%) unless otherwise stated

9 Treatment Exposure (until cycle 3): DLBCL and FL Cohorts % 60 Patients (%) % 6% 17% 6% 34% 15% 37% 0 <1 cycle 1 cycle 2 cycles 3 cycles Treatment cycles completed in expanded cohorts DLBCL (n=35) FL (n=34)

10 Objective Response Best overall response,* n (%) DLBCL n=35 FL n=34 Other inhl n=11 MCL n=12 Total n=92 Complete response 2 (6) 2 (6) 2 (18) 0 6 (7) Partial response 7 (20) 7 (21) 1 (9) 0 15 (16) Stable disease 5 (14) 17 (50) 4 (36) 6 (50) 32 (35) Progressive disease 11 (31) 4 (12) 3 (27) 5 (42) 23 (25) Not evaluable 10 (29) 4 (12) 1 (9) 1 (8) 16 (17) *Investigator assessed inhl cohort not expanded due to heterogeneity Post-baseline response assessment not performed/data unavailable CR, complete response; ORR, objective response rate

11 Tumor Shrinkage 200 Tumor shrinkage data represent mean values of measurements performed by two independent central radiologists Percentage change in indicator lesion from baseline to nadir Data available for 60 patients DLBCL (n=19) FL (n=25) Other inhl (n=7) MCL (n=9) -100

12 Duration of Response Patients with CR or PR Duration of response DLBCL (n=9) FL (n=9) Other inhl (n=3) Time to response (n=21) Ongoing response (n=16) Weeks

13 DLBCL Case Study Atypical large cells dispersed in a background of small lymphocytes and histiocytes. H&E. Obj. magn. x20. Scattered atypical neoplastic lymphocytes with CD20 expression. Immunohistochemical staining, CD20. Obj. magn. x60.

14 DLBCL Case Study First-line R-CHOP x 8 DecpoCyte x 4 Second-line R-ESHAP x 3 DexaBEAM Z- BEAM ASCT Third-line MOR208 Staging (CT) First relapse (PET-CT) Second relapse (PET-CT) PR (CT) CR (PET-CT) PR (PET-CT) CR (PET-CT) PR (PET-CT) CR (PET-CT) CR (PET-CT) Months Patient has remained responsive to MOR208 for over 16 months BEAM-ASCT, autologous stem-cell transplant conditioned by DexaBEAM (dexamethasone, carmustine, etoposide, cytarabine and melphalan; CT, computed tomography; DepoCyte, liposomal cytarabine; PET, positron emission tomography; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone; R-ESHAP, rituximab etoposide, methylprednisolone, cytarabine, cisplatin.

15 DLBCL Case Study Cervical nodal mass 1 Cycle 1 Follow-up 2 Follow-up 4

16 Safety: Adverse Events Grade 3 Grade 3,* n (%) Hematologic adverse events in 2 patients DLBCL n=35 FL n=34 Other inhl n=11 Any 10 (29) 3 (9) 0 1 (8) 14 (15) MCL n=12 Neutropenia 5 (14) 2 (6) (8) Anemia 4 (11) (4) Thrombocytopenia 2 (6) 1 (3) 0 1 (8) 4 (4) Non-hematologic adverse events in 2 patients Any 10 (29) 8 (24) 4 (36) 2 (17) 24 (26) Dyspnea 2 (6) 1 (3) 0 1 (8) 4 (4) Hypokalemia 1 (3) 1 (3) (2) Total n=92 Infusion-related reactions reported in only 9 (10%) of 92 patients (grade 1/2 in 8 patients; grade 4 dyspnea in 1 patient) *Treatment emergent adverse events reported in two or more patients overall at grade 3 according MedDRA preferred terms

17 Conclusions The Fc-engineered CD19 antibody, MOR208, has shown encouraging preliminary single-agent activity in patients with R-R NHL ORRs of 26% in the DLBCL and FL cohorts and 27% in the inhl cohort were observed 2 CRs were seen in each of these cohorts Longest response duration to date reaches up to 67 weeks for FL and 62 weeks for DLBCL MOR208 is well tolerated Infusion-related reactions were reported in 10% of patients and were typically grade 1/2 Protocols are being developed for trials which combine MOR208 with other antilymphoma therapies

18 Acknowledgments The authors would like to thank Patients who took part in the study and their families Colleagues at participating centers MorphoSys AG, the study sponsor