Safety, Clinical Activity, Pharmacokinetics, and Pharmacodynamics from a Phase I Study of PF-06863135, a B-Cell Maturation Antigen (BCMA)-CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)
Authors: Raje Noopur S. , Jakubowiak Andrzej , Gasparetto Cristina , Cornell Robert F. , Krupka Heike I. , Navarro Daniel , Forgie Alison J. , Udata Chandrasekhar , Basu Cynthia , Chou Jeffrey , Leung Abraham , Lesokhin Alexander M. 
Published: November 2019

Introduction: PF-06863135 (PF-3135) is a bispecific, humanized, monoclonal antibody (mAb) consisting of BCMA- and CD3-targeting arms paired on an IgG2a backbone by hinge-mutation technology. PF-3135 binds BCMA+ myeloma cells and CD3+ T cells with affinities of 20 pM and ~40 nM, respectively (Panowski et al. Blood 2016). We report here findings from the dose-escalation portion of an ongoing, multi-center, open-label, phase I study (NCT03269136) of PF-3135 in patients with RRMM.
Methods: Adult patients (≥18 years of age) with RRMM, previously treated with a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 mAb, received escalating, intravenous (IV) doses of PF-3135, once weekly. Prior BCMA-targeted bispecific T-cell engager or chimeric antigen receptor T-cell (CART) treatment was allowed by protocol. Patients had measurable disease per the International Myeloma Working Group (IMWG) updated criteria 2014. A modified toxicity probability interval method (mTPI), targeting a dose-limiting toxicity (DLT) rate of 25% (equivalence interval ± 5%) was used for dose escalation. The primary study objectives are to assess PF-3135 safety and tolerability, to determine the maximum tolerated dose (MTD) and select the recommended phase II dose (RP2D). Secondary objectives include evaluation of anti-myeloma activity, pharmacokinetics (PK), and immunogenicity of PF-3135.
Results: As of April 9, 2019, 17 patients had received once weekly, non-continuous, IV infusion of PF-3135 in 6 dose-escalation groups. The majority were men (71%). The median age was 61 yrs (range, 47-82 yrs) and median disease duration since onset was 7 yrs (range, 1.1-13.3 yrs). Ten (59%) patients had ≥1 chromosomal abnormality and 5 (29%) had a normal karyotype (status not known for 2 [12%] patients). The median number of prior anti-myeloma therapies was 11; 5 (29%) patients had received prior BCMA-targeted therapy. Eight (47%) patients had relapsed MM and 8 (47%) had refractory disease (recurrence type not known for 1 [6%] patient). Ten (59%) patients experienced treatment-related (TR) AEs of any grade. Most TRAEs were grade 1-2, including cytokine release syndrome (CRS, 24%), thrombocytopenia (24%), anemia (18%), and pyrexia (18%). Three (18%) patients had grade 3 TRAEs (increased alanine aminotransferase/aspartate aminotransferase, leukocytopenia, neutropenia, and lymphopenia). One patient treated at the highest dose level, who had received prior BCMA CART therapy, developed treatment-related febrile neutropenia, a DLT, which may have been related to CRS and borderline/low neutrophil count at baseline. None of the patients had grade 4-5 TRAEs or discontinued treatment due to a TRAE. The median duration of treatment was 4 (range, 2-12) actual dosing days. Sixteen of the 17 patients were evaluable for response. At the time of data cut-off, one (6%) patient had a minimal response and 6 (35%) patients had stable disease (SD) across dose levels, as best response by investigator IMWG assessment; 9 (53%) patients experienced disease progression. The clinical benefit rate (defined as best response ≥SD) was 41% (95% CI: 18.4%, 67.1%).
Conclusions: Treatment with IV PF-3135 was well tolerated at the dose levels evaluated. The observed CRS events were moderate and dose-dependent. Additional dose cohorts are accruing. The latest clinical, biomarker, and PK data will be presented for this ongoing study.

Disclosures
Raje: Medscape: Honoraria; Research to Practice: Honoraria; Takeda: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AstraZeneca: Research Funding. Jakubowiak:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyLineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; KaryoPharm Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Gasparetto:Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Cornell:KaryoPharm: Consultancy; Takeda: Consultancy. Krupka:Pfizer: Employment, Equity Ownership. Navarro:Pfizer: Employment, Equity Ownership. Forgie:Pfizer: Employment, Equity Ownership. Udata:Pfizer: Employment, Equity Ownership. Basu:Pfizer: Employment, Equity Ownership. Chou:Pfizer: Employment, Equity Ownership. Leung:Pfizer: Employment, Equity Ownership. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Serametrix Inc.: Patents & Royalties; Takeda: Consultancy, Honoraria; Genentech: Research Funding; Juno: Consultancy, Honoraria; GenMab: Consultancy, Honoraria; Janssen: Research Funding.

OffLabel Disclosure:
PF-06863135, investigational agent