Preliminary Results from a Phase 1b Study of TAK-079, an Investigational Anti-CD38 Monoclonal Antibody (mAb) in Patients with Relapsed/ Refractory Multiple Myeloma (RRMM)
Authors: Krishnan Amrita Y. , Patel Krina K. , Hari Parameswaran , Jagannath Sundar , Niesvizky Ruben , Silbermann Rebecca W. , Berg Deborah , Lin Jianchang , Fedyk Eric Robert , Palumbo Antonio , Stockerl-Goldstein Keith E. 
Published: February 2020

Background: TAK-079 is a subcutaneously (SC) administered, mAb which exhibits more selective binding to human CD38 protein expressed by myeloma cells and less cross reactivity with the CD38 antigen present on red blood cells and platelets. It depletes myeloma cells via apoptosis antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP). TAK-079 was safe and well-tolerated in a first in human study in healthy subjects with potent pharmacodynamic activity when administered as a SC injection (Fedyk et al ASH 2018; abstract 3249).
Methods: A multicenter phase 1 study (NCT03439280) evaluating safety, pharmacokinetic (PK), pharmacodynamics, and efficacy of TAK-079 in patients with heavily pretreated RRMM was initiated. Pt with RRMM were eligible after at least 3 lines of therapy and previous exposure to immunomodulatory drug (IMiD), proteasome inhibitor (PI), alkylating agent, and corticosteroid with or without an anti-CD38 or SLAMF7 antibody. Patients were refractory or intolerant to at least 1 PI and 1 IMiD. Ph 1 dose escalation proceeded using a 3+3 design. The TAK-079 dose was given as a SC injection weekly for 8 doses, every other week for 8 doses, then monthly until disease progression (PD) or unacceptable toxicity.
Results: 31 patients have been enrolled across 4 dose cohorts (TAK-079 45-135-300-600 mg fixed dose SC); data is available on 28 patients as of the 14 June 2019 data cutoff. Median age was 65 (53-81) years. ISS stage at study entry was I/II/III/missing in 42%, 32%, 19%, 6% of patients respectively, 94% of patients were refractory to either a PI or IMiD and 61% were refractory to both, 23% of patients were previously exposed to at least 1 anti-CD38 monoclonal antibody; 84% had a prior stem cell transplant. The maximum volume of a SC injection was 2 mL, resulting in an administration duration of ≤ 1 minute. No ≥ Grade 1 early or late systemic infusion reactions have been reported. One (&lt;1 %) Grade 1 (pruritus) injection site reaction has been described in the more than 500 injections administered. No dose limiting toxicities have occurred and no MTD has been identified. Drug related adverse events (AEs), any grade, occurring in at least 3 patients were: fatigue (14%) and anemia (11%). No drug-related ≥ Grade 1 lymphopenia or thrombocytopenia. One (4%) drug-related infection (Grade 2 upper respiratory tract infection) was observed. Drug related grade 3 AEs were reported in 2 (7%) patients (decreased neutrophil count and anemia; 1 each). No drug-related grade 4 AEs, drug-related serious AEs, AEs leading to study discontinuation, or on-study deaths have been reported. In this dose escalation study, discontinuation occurred in 14 (45%) patients due to PD and 1 (3%) patient withdrew consent. Clinical activity occurred early and was observed across dose levels. In the 14 patients receiving at least 4 cycles of therapy by the time of the data cutoff, the objective response rate (ORR; partial response or better) was 43%, 1 patient's response deepened over time to VGPR, the clinical benefit rate (minimal response or better) was 57%. Within this group, in patients never exposed to anti-CD38 therapy, the ORR was 46%. Pharmacodynamic analyses demonstrated dose-dependent saturation of CD38 and depletion of bone marrow myeloma cells, which was maximal at 300mg.
Conclusion: Emerging data show that across the 4 dose levels tested, SC TAK-079 induced ORR in 43% of these heavily pretreated patients with no infusion reaction, no drug-related lymphopenia or thrombocytopenia, 4% rate of drug-related infections, and 11% drug-related anemia. TAK-079 SC has a low treatment burden with the low volume (2 mL) subcutaneous injections performed in ≤ 1-minute signifying the potential for home-based self-administration. The high potency of TAK-079 may result from selective binding to myeloma cells (ie less binding to RBC and platelets). Updated safety, efficacy, pharmacodynamics, and PK data for this heavily pre-treated RRMM population will be available for presentation at the meeting.

Disclosures
Krishnan: Celgene, Janssen, Sanofi, BMS: Consultancy; Sutro BioPharma, zPredicta: Consultancy; Celgene, Z Predicta: Other: Stock Ownership; Amgen, Takeda: Speakers Bureau; Takeda: Research Funding. Patel:Poseida Therapeutics, Cellectis, Abbvie: Research Funding; Oncopeptides, Nektar, Precision Biosciences, BMS: Consultancy; Takeda, Celgene, Janssen: Consultancy, Research Funding. Hari:AbbVie: Consultancy, Honoraria; Amgen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Cell Vault: Equity Ownership; Sanofi: Honoraria, Research Funding; Spectrum: Consultancy, Research Funding. Jagannath:Multiple Myeloma Research Foundation: Speakers Bureau; Celgene: Consultancy; Novartis: Consultancy; Merck: Consultancy; Medicom: Speakers Bureau; BMS: Consultancy. Niesvizky:Takeda, Amgen, BMS, Janssen, Celgene: Consultancy, Research Funding. Silbermann:Janssen, Sanofi: Other: Consultant/Advisor. Berg:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd: Employment, Patents & Royalties. Lin:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Fedyk:Millennium, a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd: Employment, Patents & Royalties. Palumbo:Millennium, a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd: Employment, Patents & Royalties. Stockerl-Goldstein:Abbott: Equity Ownership; AbbVie: Equity Ownership.

OffLabel Disclosure:
Investigation of TAK-079 for the treatment of relapsed and/ or refractory multiple myeloma