An Open-label, Multicenter, Phase 1b Study of Daratumumab in Combination with Backbone Regimens in Patients with Multiple Myeloma

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1 An Open-label, Multicenter, Phase 1b Study of Daratumumab in Combination with Backbone Regimens in Patients with Multiple Myeloma Philippe Moreau, MD; Maria-Victoria Mateos, MD, PhD; Joan Bladé,MD; Lotfi Benboubker, MD; Javier de la Rubia, MD, PhD; Thierry Facon, MD; Raymond Comenzo, MD; Joseph Fay, MD; Xiang Qin, MS; Tara Masterson, MS; Jordan Schecter, MD; Tahamtan Ahmadi, MD, PhD; Jesus San-Miguel, MD, PhD 1 University Hospital of Nantes, Nantes, France; 2 University Hospital of Salamanca/IBSAL, Salamanca, Spain; 3 IDIBAPS, Hospital Clinic de Barcelona, Barcelona, Spain; 4 CHU Tours Hopital Bretonneau, Tours, France; 5 Hospital La Fe and Universidad Católica San Vicente Mártir, Valencia, Spain; 6 Centre Hospitalier Régional Universitaire de Lille, Lille, France; 7 Division of Hematology-Oncology, Tufts Medical Center, Boston, MA, USA; 8 Baylor Institute for Immunology Research, Dallas, TX, USA; 9 Janssen Pharmaceutical Research & Development, Spring House, PA, USA; 10 Janssen Pharmaceutical Research & Development, Raritan, NJ, USA; 11 Clinica Universidad de Navarra, Spain

2 CD38, cell surface receptor and an ectoenzyme, is a rational therapeutic target for treatment of myeloma CD38 has several intracellular functions 1. Regulates signaling, homing and adhesion in close contact with BCR complex and CXCR4 2. Regulates activation and proliferation of human T lymphocytes 3. As an ectoenzyme, CD38 interacts with NAD+ and NADP+, which are converted to cad, AD, and NAADP in intracellular Ca2+-mobilization Type II transmembrane protein (m.w. 45 kda) Highly and uniformly expressed on myeloma cells CD38 present on CD4, CD8, NK cells and B lymphocytes at a relatively low level Also some CD38 expression on tissues of non-hematopoietic origin Malavasi F, et al. Blood 2011;118:

3 Daratumumab Human IgG1K mab in clinical development for the treatment of MM Binds to CD38 and elicits signaling cascade and immune effector function engagement, leading to 1,2 Complement-dependent cytotoxicity (CDC) Antibody-dependent cell-mediated cytotoxicity (ADCC) Antibody-dependent cell-mediated phagocytosis (ADCP) Induction of apoptosis Modulation of cellular enzymatic activities associated with calcium mobilization and signaling Combination of these activities leads to elimination of plasma cells from bone marrow in MM patients IMiD Laubach et al., Expert Opin. Investig. Drugs (2014) 23(4): De Weers M, et al. J Immunol. 2011;186(3): Lammerts van Bueren J, et al. 56th ASH Annual Meeting and Exposition; December 6-9, 2014; San Francisco, CA Abstract

4 GEN501: Daratumumab monotherapy in patients with relapsed or relapsed, refractory MM Response rate (%) n = 29 RR = 10% VG n = 20 RR = 35% n = 4 (20%) n= 1 (5%) n = 3 (10%) CR n = 2 (10%) 8 mg/kg 16 mg/kg Daratumumab was well tolerated, with no severe infusionrelated reactions RR, response rate; CR, complete response; VG, very good partial response;, partial response; Lokhorst H, et al. Oral presentation at: 50th Annual Meeting of the American Society of Clinical Oncology (ASCO); May 30-June 3, 2014; Chicago, IL, USA. 4

5 GEN503: Daratumumab with lenalidomide and dexamethasone in relapsed or relapsed and refractory MM Maximum percentage change in M protein from baseline Part 1 Dose Escalation Study 2-, 4-, 8- & 16 mg/kg dose n = 13 Part 2 Expansion Cohort Study 16 mg/kg dose n = 30 0 S S S S U U S S S S S S U 0 SFSSSUSSFSSSSSSUSSSSSSUSSSSSUS Relative change in M protein from baseline (%) Relative change in M protein from baseline (%) Patient number Patient number 2 mg/kg 4 mg/kg 8 mg/kg 16 mg/kg 16 mg/kg Majority had >50% reduction of M protein Plesner, T. et al. Presented at 56th ASH Annual Meeting & Exposition, San Francisco, CA, 6-9 Dec Abstract 84. 5

6 MMY1001: Objective The aim of this ongoing open-label, 4-arm, multicenter, phase 1b study was to Evaluate the safety and tolerability of daratumumab, at a starting dose of 16 mg/kg, in combination with other MM backbone treatments, including Bortezomib (sc)-dexamethasone (VD) Bortezomib (sc)-thalidomide-dexamethasone (VTD) Bortezomib (sc)-melphalan-prednisone (VMP) Pomalidomide-dexamethasone (POM-D) sc, subcutaneous. 12/7/2014 6

7 MMY1001 (NCT ): Phase Ib study of daratumumab + backbone treatments VD: bortezomib (1.3 mg/m 2 twice weekly x 4 cycles, then once weekly x 14 cycles)/dexamethasone (20 mg) a Newly diagnosed; n = 6 VMP: bortezomib (1.3 mg/m 2 twice weekly x 1 cycle, then once weekly x 8 cycles)/melphalan (9 mg/m 2 )/prednisone (60 mg/m 2 ) b Newly diagnosed, transplant ineligible; n = 12 VTD: bortezomib (1.3 mg/m 2 twice weekly x 4 cycles, then once weekly x 14 cycles )/thalidomide (100 mg daily x 21 days)/dexamethasone (20 mg) a Newly diagnosed; n = 12 POM-D: pomalidomide (4 mg once daily)/dexamethasone (40 mg) c Relapsed/refractory, 2 lines of therapy, including 2 consecutive cycles of lenalidomide and bortezomib; n = 50 subjects maximum a Daratumumab once weekly x 2 cycles, then once every 3 weeks x 16 cycles or until transplantation. b Daratumumab once weekly x 1 cycle, then every 3 weeks x 8 cycles. c Daratumumab once weekly x 2 cycles, then once every 2 weeks x 4 cycles, then once every 4 weeks x 7 cycles or until disease progression; dexamethasone 20 mg if age >75 y. ClinicalTrials.gov Identifier: NCT Available at: Accessed 10/27/14. 7

8 MMY1001 (NCT ): Phase Ib study of daratumumab + backbone treatments (cont d) Treat 6 subjects in a given treatment regimen IDSMB review after Cycles 1, 2, and 3 1 of 6 subjects with DLT Enroll 6 more subjects VTD + DARA VMP + DARA Enroll 6 more subjects POM-D + DARA Up to 38 subjects expansion POM-D + DARA ClinicalTrials.gov Identifier: NCT Available at: Accessed 10/27/14. 8

9 MMY1001: Demographics, exposure, and disposition Median age (range), y Sex Male Female Median # daratumumab infusions (range) Median # cycles Disposition VD + DARA (n = 6) VMP + DARA (n = 6) VTD + DARA (n = 6) POM-D + DARA (n = 7 a ) 72.5 (50-82) 72 (67-75) 57 (40-61) 62 (45-85) (8-11) 12.5 (10-14) 8 (7-11) 11 (1-17) subject electively taken off study for ASCT after cycle 4 No discontinuations subjects electively taken off study for ASCT after cycle subjects discontinued study (1 due to physician decision after 1st dose; 2 due to PD) V, bortezomib; D, dexamethasone; DARA, daratumumab; M, melphalan; P, prednisone; T, thalidomide; POM, pomalidomide; ASCT, autologous stem cell transplant; PD, progressive disease. a 2 refractory to PI; 1 refractory to IMID; 3 refractory to both PI/IMID; 1 subject relapsed but not refractory; 4 refractory to the last line of prior therapy. All patients treated with DARA 16 mg/kg. 9

10 MMY1001: Safety Serious AEs Grade 3 AEs (all Gr. 3 except for Gr. 4 neutropenia in POM-D) Infusion related reactions VD + DARA (n = 6) Pneumonia a,b Soft tissue infection a,b Dehydration a,b Positive indirect Coombs assay c VMP + DARA (n = 6) Neutropenia b,c Neutropenia Anemia b,d (n = 2) a Thrombocytopenia c VTD + DARA (n = 6) POM-D+ DARA (n = 7) None None Infectious pneumonia c Neutropenia b,c Anemia b,d All Grade 1 or 2 Neutropenia (n = 5) Anemia (n = 2) Thrombocytopenia Leukopenia 1 episode each of diarrhea, flank pain, peripheral sensory neuropathy, hypokalemia, pneumonia, hip fracture, rash, eye hemorrhage, and decreased lymphocyte count V, bortezomib; D, dexamethasone; DARA, daratumumab; M, melphalan; P, prednisone; T, thalidomide; POM, pomalidomide; AE, adverse events; Gr, grade. a Not related to daratumumab, b same subject, c possibly or probably related to daratumumab, d reported pre-dose. Each AE occurred in 1 subject unless otherwise noted. All patients treated with DARA 16 mg/kg. 10

11 MMY1001: Efficacy 7 6 Number of patients PD MR VG scr 0 ORR: VD + DARA (n = 6) VMP + DARA (n = 6) 100% in newly diagnosed group 50% in the relapsed group VTD + DARA (n = 6) POM-D + DARA (n = 6) V, bortezomib; D, dexamethasone; DARA, daratumumab; M, melphalan; P, prednisone; T, thalidomide; POM, pomalidomide. scr, stringent complete response; VG, very good partial response;, partial response; MR, minimal response; PD, progressive disease. a 1 VG confirmed, 1 VG repeat assessment pending. 11 All patients treated with DARA 16 mg/kg. a

12 MMY1001: Maximal percentage change in paraprotein from baseline Relative change in paraprotein from baseline (%) U S S S S S S S S S S S S S S S S S S S S S S S S Patient number VD + DARA (16 mg/kg) VTD + DARA (16 mg/kg) VMP + DARA (16 mg/kg) POM-D + DARA (16 mg/kg) V, bortezomib; D, dexamethasone; DARA, daratumumab; M, melphalan; P, prednisone; T, thalidomide; POM, pomalidomide. 12

13 MMY1001: Median time to first response VD + DARA (n = 6) VMP + DARA (n = 6) VTD + DARA (n = 6) POM-D + DARA (n = 3) Median time to first response (range), days V, bortezomib; D, dexamethasone; DARA, daratumumab; M, melphalan; P, prednisone; T; thalidomide; POM, pomalidomide. All patients treated with DARA 16 mg/kg. 13

14 MMY1001: Best response ( or better) and duration of follow up X VG VG VG VG VG VG scr VG Time from first dosing date (weeks) VD + DARA VTD + DARA VMP + DARA POM-D + DARA scr, stringent complete response; VG, very good partial response;, partial response. V, bortezomib; D, dexamethasone; DARA, daratumumab; M, melphalan; P, prednisone; T, thalidomide; POM, pomalidomide. All patients treated with DARA 16 mg/kg. 14

15 MMY1001 case study: scr in patient who received daratumumab + POM-D 64 yo woman, first diagnosed with MM in February 2013 Treated with lenalidomide, bortezomib, dexamethasone ASCT September 2013 Lenalidomide maintenance 10 mg daily until progression Developed PD in April 2014 Staging bone marrow showed 80% plasma cell burden FISH showed del 13 More than 10 lytic lesions on skeletal survey No extramedullary plasmacytomas scr, stringent complete response; POM, pomalidomide; D, dexamethasone; ASCT, autologous stem cell transplant; PD, progressive disease; FISH, fluorescence in situ hybridization. 15

16 MMY1001 case study: scr in patient who received daratumumab + POM-D (cont d) Baseline SPEP showed 1.7 g/dl of IgG Lambda Cycle 2: 0.5 g/dl Cycle 3: 0.2 g/dl Cycle 4: 0.4 g/dl Cycle 5: 0 g/dl (IFE positive) Cycle 6: 0 g/dl (IFE positive) Cycle 7: 0 g/dl (IFE negative) Repeat bone marrow shows <5% plasma cells Negative IHC for clonal plasma cells Normalization of Free Light Chain Ratio scr, stringent complete response; POM, pomalidomide; D, dexamethasone; SPEP, serum protein electrophoresis; IFE, immunofixation electrophoresis; IHC, immunohistochemistry. 16

17 MMY1001: Mobilization regimen and stem cell yield of transplant patients Treatment Mobilization regimen Days of collection Total stem cell yield (x 10 6 /kg body weight) VD Cyclophosphamide VTD G-CSF and Plerixafor VTD G-CSF VTD Cyclophosphamide VTD Cyclophosphamide VTD G-CSF G-CSF, Granulocyte colony stimulating factor. 17

18 MMY1001: Summary Addition of 16 mg/kg daratumumab to the various backbones was well tolerated in all evaluable patients and did not result in significant additional toxicity Daratumumab was associated with promising response rates in combination with VD, VMP, VTD and POM-D Daratumumab does not appear to have a negative impact on stem cell mobilization Phase 3 studies are either ongoing or will be initiated shortly VD (relapsed, MMY3004-CASTOR) VMP (non-transplant eligible, MMY3007-ALCYONE) VTD (induction, MMY3006/IFM-HOVON-CASSIOPEIA) V, bortezomib; D, dexamethasone; M, melphalan; P, prednisone; T, thalidomide; POM, pomalidomide. 18

19 Backup Most patients were in prior to ASCT These patients tended to have fewer cycles (typically 4) before ASCT 19

20 Cytogenetics: VD + DARA Cohort Subject number Cytogenetics/FISH Normal t (14;16) Unknown Normal Normal Unknown 20

21 Cytogenetics: VMP + DARA cohort Subject number Cytogenetics/FISH FISH del 17, AMP 1q FISH AMP 1q IgH translocation, otherwise normal Normal FISH Translocation 14:16; AMP 1q FISH AMP 1q 21

22 Cytogenetics: VTD + DARA Cohort Subject number Cytogenetics/FISH Unknown No high risk features Normal t4:14; AMP Normal No high risk features 22

23 Pom/Dex refractory status (n=7) Refractor to PI/IMiD Number (%) None 1 (14.3%) PI only 2 (28.6%) IMiD only 1 (14.3%) Both PI and IMiD 3 (42.9% Refractory to last line of prior therapy 4 (57.1%) 23

24 Disclosures Philippe Moreau, MD: Honoraria (Janssen); membership on an entity s Board of Directors or advisory committees (Janssen) Maria-Victoria Mateos, MD PhD: Honoraria (Janssen); membership on an entity s Board of Directors or advisory committees (Janssen) Joan Bladé,MD: Honoraria (Janssen and Celgene); research funding (Janssen and Celgene) Lotfi Benboubker, MD: None Javier de la Rubia, MD, PhD: None Thierry Facon, MD: Membership on an entity s Board of Directors or advisory committees (Janssen) Raymond Comenzo, MD: Consultancy (Takeda Millenium and Prothena); membership on an entity s Board of Directors or advisory committees (Takeda Millenium and Janssen); research funding (Takeda Millenium, Prothena, Janssen, and Teva) Joseph Fay, MD: Honoraria (BMS) Xiang Qin, MS: Employment (Janssen) Tara Masterson, MS: Employment (Janssen) Jordan Schecter, MD: Employment (Janssen) Tahamtan Ahmadi, MD: Employment (Janssen) Jesus San-Miguel, MD PhD: Membership on an entity s Board of Directors or advisory committees (Millenium, Celgene, Novartis, Onyx, Janssen, BMS, MSD) 24