STUDY DESIGN. VMP 6-week cycles, total of 9 cycles. Figure 2. Alcyone study design. Countries housing study sites are shaded in gold.

Transcription

1 TPS8608 A Randomized Open-label Study of Bortezomib, Melphalan, And Prednisone (VMP) Versus Daratumumab () Plus VMP in Patients With Previously Untreated Multiple Myeloma (MM) Who Are Ineligible for High-dose Therapy: MMY3007 (Alcyone) Maria Victoria Mateos, 1 Michele Cavo, 2 Andrzej Jakubowiak, 3, * Robin Carson, 4 Ming Qi, 4 Rajesh Bandekar, 4 Wendy Crist, 4 Tahamtan Ahmadi, 4 Jesus San Miguel 5 1University Hospital of Salamanca/IBSAL, Salamanca, Spain; 2 Seràgnoli Institute of Hematology, Bologna University School of Medicine, Bologna, Italy; 3 University of Chicago Medicine, Chicago, IL, USA; 4Janssen Research & Development, LLC, Spring House, PA, USA; 5 Clinica Universidad de Navarra, Navarra, Spain. *Presenting author. INTRODUCTION Despite the availability of immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs), multiple myeloma (MM) remains an incurable disease, and therapies that target novel pathways are urgently needed CD38 is expressed at relatively low levels in normal myeloid, lymphoid, and nonhematopoietic cells, 1 but is highly and ubiquitously expressed on the surface of myeloma cells, 2,3 which makes it a promising target for MM therapy Daratumumab () is a human anti-cd38 immunoglobulin G1 (IgG1) monoclonal antibody, with anticancer activity mediated through multiple pathways that include complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, apoptosis, and direct enzymatic inhibition 4,5 (Figure 1) Apoptotic s Apoptosis Cross-linking ADCC NK cell ADCP CD38 Macrophage Effector cells C1q MAC C1qR CR3 CR1 CDC OBJECTIVES Primary Compare progression free survival (PFS) in patients receiving plus VMP versus VMP alone Secondary Compare clinical outcomes of the 2 treatment groups, which include time to disease progression, overall response rate, complete response (CR) rate, stringent CR (scr) rate, proportion of patients with very good partial response, overall survival, and duration of response Assess the minimal residual disease (MRD) negative rate Evaluate the efficacy of plus VMP in high-risk patient subgroups Assess patient-reported outcomes and health resource utilization Assess pharmacokinetics and immunogenicity of Assess safety and tolerability of when combined with VMP Exploratory Explore biomarkers predictive of response to STUDY DESIGN Phase 3, randomized, open-label, controlled, multicenter study (Figure 2) A total of approximately 700 patients are expected to be enrolled in approximately 200 sites in 25 countries (Figure 3) Patients will be randomized 1:1 to treatment with plus VMP or VMP alone (Figure 4) Treatment phase Arm A VMP Screening phase ( 21 days) Randomization First dose within 72 hours of randomization Arm B Dara + VMP Post-VMP Q4W until PD, unacceptable toxicity, or study end phase Prior to PD: disease evaluations per protocol schedule After PD: PFS2, anticancer therapy, second primary malignancies, and survival Q16W Study end 330 deaths or 5 years after the last patient was randomized VMP, bortezomib-melphalan-prednisone;, daratumumab; Q4W, every 4 weeks; PD, progressive disease; PFS2, time from randomization to progression on the next line of therapy or death, whichever comes first; Q16W, every 16 weeks. Figure 2. Alcyone study design. Table 1. Evaluation Schedule STUDY ENDPOINTS AND EVALUATIONS Efficacy The primary efficacy endpoint is PFS Safety Timing Method Disease Year 1: Q3W M-protein levels evaluation* Year 2: Q4W and/or serum-free Thereafter: Q8W light chain levels, calcium, albumin, and radiology, if indicated scr Patients with CR Serum-free light chain assay MRD 14, 20, and 26 months Blood sample and after first dose in patients with CR or scr bone marrow biopsy and/or aspirate Patient-reported Year 1: Q3M EORTC-QLQ-30 outcomes Thereafter until PD: Q6M and EQ-5D-5L Post-PD: Weeks 8 and 16 after PD Post PD: Q16W Subsequent anticancer treatment, PFS2, and survival Q3W, every 3 weeks; Q4W, every 4 weeks; Q8W, every 8 weeks; scr, stringent complete response; CR, complete response; MRD, minimal residual disease; Q3M, every 3 months; PD, progressive disease; Q6M, every 6 months; Q16W, every 16 weeks; PFS2, time from randomization to progression on the next line of therapy or death, whichever comes first. *Disease progression will be validated by 1 assessment (within 1-3 weeks of first assessment). Two interim analyses will be performed to evaluate safety and efficacy, with stopping boundaries defined for superiority and futility NAD cadpr NAADP Bone marrow stromal cell Adapted from Laubach JP, et al. Expert Opin Investig Drugs. 2014;23(4): Figure 1. mechanism of action. lysis, daratumumab; MM, multiple myeloma; ADCC, antibody-dependent cell-mediated toxicity; ADCP, antibody-dependent cell-mediated phagocytosis; NK, natural killer; CDC, complement-dependent cytotoxicity; MAC, membrane attack complex; NAD, nicotinamide adenine dinucleotide; cadpr, cyclic ADP-ribose; NAADP, nicotinic acid adenine dinucleotide phosphate. has demonstrated encouraging tolerability and efficacy in combination with other MM backbone therapies, including lenalidomide plus dexamethasone or pomalidomide plus dexamethasone in relapsed or relapsed and refractory patients, 6,7 and with bortezomib (Velcade ) plus dexamethasone, bortezomib-thalidomide-dexamethasone, or bortezomib-melphalan-prednisone (VMP) in newly diagnosed, transplant-ineligible patients 7 In patients with newly-diagnosed, transplantineligible disease, 6 of 6 patients had a response after receiving plus VMP (5 partial responses [PR] and 1 very good PR [VGPR]) 7 here, the efficacy of plus VMP is evaluated in a randomized, open-label, controlled, phase 3 study in patients with newly diagnosed MM who are considered ineligible for high-dose chemotherapy with stem cell transplant (SCT) KEY ELIGIBILITY CRITERIA Age 18 years Documented MM satisfying International Myeloma Working Group diagnostic criteria and with measurable secretory disease Newly diagnosed and ineligible for high-dose chemotherapy with SCT due to the following: Age 65 years Age <65 years with a comorbid condition that is likely to have a negative impact on the tolerability of high-dose chemotherapy with SCT ECOG performance status score of 2 No primary amyloidosis, monoclonal gammopathy, smoldering MM, Waldenström's disease, or meningeal involvement of MM No prior systemic anti-mm therapy Countries housing study sites are shaded in gold. Figure 3. Alcyone clinical sites. 16 mg/kg IV (Arm B Only) Bortezomib 1.3 mg/m 2 SC Melphalan 9 mg/m 2 PO Prednisone 60 mg/m 2 PO D1 D8 D15 D22 D29 D36 D1 D22 D1 D1 D8 D22 D29 D4 D11 D25 D32 D1 D8 D22 D29 Cycles 10+ (4-week cycles), daratumumab; IV, intravenous; SC, subcutaneous; PO, orally; D, day. Figure 4. Alcyone treatment schedule. CONCLUSIONS Alcyone is a phase 3, randomized, open-label, controlled, multicenter trial evaluating the efficacy and safety of combining with VMP therapy in patients with newly diagnosed MM who are over 65 years of age or have a comorbid condition that makes them ineligible for high-dose chemotherapy and SCT The study is actively enrolling patients REFERENCES 1. Deaglio S, et al. Leuk Res. 2001;25(1): Lin P, et al. Am J Clin Pathol. 2004;121(4): Santonocito AM, et al. Leuk Res. 2004;28(5): de Weers M, et al. J Immunol. 2011;186(3): Overdijk MB, et al. MAbs. 2015;7(2): Plesner T, et al. Blood. 2014;124(21). Abstract Moreau P, et al. Blood. 2014;124(21). Abstract 176. ACKNOWLEDGMENTS The authors would like to acknowledge the patients participating in this study and their families, as well as the global network of investigators, research nurses, study coordinators, and operations staff. This study (ClinicalTrials.gov Identifier: NCT ) is sponsored by Janssen Research & Development, LLC. Editorial and medical writing support was provided by Erica S. Chevalier-Larsen, PhD, of MedErgy, and was funded by Janssen Global Services. An electronic version of the poster can be viewed by scanning the QR code. The QR code is intended to provide scientific information for individual reference. The PDF should not be altered or reproduced in any way. Copies of this poster obtained through Quick Response (QR) Code are for personal use only and may not be reproduced without permission from ASCO and the author of this poster. POSTER PRESENTED AT ThE ANNuAL MEETING OF ThE AMERICAN SOCIET Y FOR CLINICAL ONCOLOGY (ASCO); M AY 29-JuNE 2, 2015; ChICAGO, ILLINOIS.

2 INTRODUCTION Despite the availability of immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs), multiple myeloma (MM) remains an incurable disease, and therapies that target novel pathways are urgently needed CD38 is expressed at relatively low levels in normal myeloid, lymphoid, and nonhematopoietic cells, 1 but is highly and ubiquitously expressed on the surface of myeloma cells, 2,3 which makes it a promising target for MM therapy Daratumumab () is a human anti-cd38 immunoglobulin G1 (IgG1) monoclonal antibody, with anticancer activity mediated through multiple pathways that include complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, apoptosis, and direct enzymatic inhibition 4,5 (Figure 1) Macrophage Apoptotic s ADCC ADCP C1qR Apoptosis NK cell Effector cells CR1 Cross-linking CD38 CR3 C1q MAC CDC NAD cadpr NAADP Bone marrow stromal cell lysis Adapted from Laubach JP, et al. Expert Opin Investig Drugs. 2014;23(4): , daratumumab; MM, multiple myeloma; ADCC, antibody-dependent cell-mediated toxicity; ADCP, antibody-dependent cell-mediated phagocytosis; NK, natural killer; CDC, complement-dependent cytotoxicity; MAC, membrane attack complex; NAD, nicotinamide adenine dinucleotide; cadpr, cyclic ADP-ribose; NAADP, nicotinic acid adenine dinucleotide phosphate. Figure 1. mechanism of action. has demonstrated encouraging tolerability and efficacy in combination with other MM backbone therapies, including lenalidomide plus dexamethasone or pomalidomide plus dexamethasone in relapsed or relapsed and refractory patients, 6,7 and with bortezomib (Velcade ) plus dexamethasone, bortezomib-thalidomide-dexamethasone, or bortezomib-melphalan-prednisone (VMP) in newly diagnosed, transplant-ineligible patients 7 In patients with newly-diagnosed, transplantineligible disease, 6 of 6 patients had a response after receiving plus VMP (5 partial responses [PR] and 1 very good PR [VGPR]) 7 here, the efficacy of plus VMP is evaluated in a randomized, open-label, controlled, phase 3 study in patients with newly diagnosed MM who are considered ineligible for high-dose chemotherapy with stem cell transplant (SCT)

3 OBJECTIVES Primary Compare progression free survival (PFS) in patients receiving plus VMP versus VMP alone Secondary Compare clinical outcomes of the 2 treatment groups, which include time to disease progression, overall response rate, complete response (CR) rate, stringent CR (scr) rate, proportion of patients with very good partial response, overall survival, and duration of response Assess the minimal residual disease (MRD) negative rate Evaluate the efficacy of plus VMP in high-risk patient subgroups Assess patient-reported outcomes and health resource utilization Assess pharmacokinetics and immunogenicity of Assess safety and tolerability of when combined with VMP Exploratory Explore biomarkers predictive of response to KEY ELIGIBILITY CRITERIA Age 18 years Documented MM satisfying International Myeloma Working Group diagnostic criteria and with measurable secretory disease Newly diagnosed and ineligible for high-dose chemotherapy with SCT due to the following: Age 65 years Age <65 years with a comorbid condition that is likely to have a negative impact on the tolerability of high-dose chemotherapy with SCT ECOG performance status score of 2 No primary amyloidosis, monoclonal gammopathy, smoldering MM, Waldenström's disease, or meningeal involvement of MM No prior systemic anti-mm therapy

4 STUDY DESIGN Phase 3, randomized, open-label, controlled, multicenter study (Figure 2) A total of approximately 700 patients are expected to be enrolled in approximately 200 sites in 25 countries (Figure 3) Patients will be randomized 1:1 to treatment with plus VMP or VMP alone (Figure 4) Screening phase ( 21 days) Randomization First dose within 72 hours of randomization Treatment phase Arm A VMP Arm B Dara + VMP Post-VMP Q4W until PD, unacceptable toxicity, or study end phase Prior to PD: disease evaluations per protocol schedule After PD: PFS2, anticancer therapy, second primary malignancies, and survival Q16W Study end 330 deaths or 5 years after the last patient was randomized VMP, bortezomib-melphalan-prednisone;, daratumumab; Q4W, every 4 weeks; PD, progressive disease; PFS2, time from randomization to progression on the next line of therapy or death, whichever comes first; Q16W, every 16 weeks. Figure 2. Alcyone study design. Countries housing study sites are shaded in gold. Figure 3. Alcyone clinical sites. 16 mg/kg IV (Arm B Only) D1 D8 D15 D22 D29 D36 D1 D22 D1 Cycles 10+ (4-week cycles) D1 D8 D22 D29 D4 D11 D25 D32 D1 D8 D22 D29 Bortezomib 1.3 mg/m 2 SC Melphalan 9 mg/m 2 PO Prednisone 60 mg/m 2 PO, daratumumab; IV, intravenous; SC, subcutaneous; PO, orally; D, day. Figure 4. Alcyone treatment schedule.

5 Table 1. Evaluation Schedule Timing Method Disease Year 1: Q3W M-protein levels evaluation* Year 2: Q4W and/or serum-free Thereafter: Q8W light chain levels, calcium, albumin, and radiology, if indicated scr Patients with CR Serum-free light chain assay MRD 14, 20, and 26 months Blood sample and after first dose in patients with CR or scr bone marrow biopsy and/or aspirate Patient-reported Year 1: Q3M EORTC-QLQ-30 outcomes Thereafter until PD: Q6M and EQ-5D-5L Post-PD: Weeks 8 and 16 after PD Post PD: Q16W Subsequent anticancer treatment, PFS2, and survival Q3W, every 3 weeks; Q4W, every 4 weeks; Q8W, every 8 weeks; scr, stringent complete response; CR, complete response; MRD, minimal residual disease; Q3M, every 3 months; PD, progressive disease; Q6M, every 6 months; Q16W, every 16 weeks; PFS2, time from randomization to progression on the next line of therapy or death, whichever comes first. *Disease progression will be validated by 1 assessment (within 1-3 weeks of first assessment). STUDY ENDPOINTS AND EVALUATIONS Efficacy The primary efficacy endpoint is PFS Safety Two interim analyses will be performed to evaluate safety and efficacy, with stopping boundaries defined for superiority and futility CONCLUSIONS Alcyone is a phase 3, randomized, open-label, controlled, multicenter trial evaluating the efficacy and safety of combining with VMP therapy in patients with newly diagnosed MM who are over 65 years of age or have a comorbid condition that makes them ineligible for high-dose chemotherapy and SCT The study is actively enrolling patients REFERENCES 1. Deaglio S, et al. Leuk Res. 2001;25(1): Lin P, et al. Am J Clin Pathol. 2004;121(4): Santonocito AM, et al. Leuk Res. 2004;28(5): de Weers M, et al. J Immunol. 2011;186(3): Overdijk MB, et al. MAbs. 2015;7(2): Plesner T, et al. Blood. 2014;124(21). Abstract Moreau P, et al. Blood. 2014;124(21). Abstract 176. ACKNOWLEDGMENTS The authors would like to acknowledge the patients participating in this study and their families, as well as the global network of investigators, research nurses, study coordinators, and operations staff. This study (ClinicalTrials.gov Identifier: NCT ) is sponsored by Janssen Research & Development, LLC. Editorial and medical writing support was provided by Erica S. Chevalier-Larsen, PhD, of MedErgy, and was funded by Janssen Global Services. An electronic version of the poster can be viewed by scanning the QR code. The QR code is intended to provide scientific information for individual reference. The PDF should not be altered or reproduced in any way. Copies of this poster obtained through Quick Response (QR) Code are for personal use only and may not be reproduced without permission from ASCO and the author of this poster.