A Phase I, Open-Label Study to Evaluate the Safety, Pharmacokinetic, Pharmacodynamic, and Clinical Activity of PF-06863135, a B-Cell Maturation Antigen/CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Advanced Multiple Myeloma

Background: Despite a number of recent advances in the treatment of multiple myeloma (MM), the majority of patients are likely to relapse or become resistant to current treatment options. PF-06863135 (PF-3135) is a humanized immunoglobulin G (IgG) CD3 bispecific monoclonal antibody that utilizes anti-B-cell maturation antigen (BCMA) and anti-CD3 targeting arms paired through hinge-mutation technology within an IgG2a backbone. The molecule binds to BCMA-expressing myeloma cell lines and to T cells with affinities of 20 pM and ~40 nM, respectively (Panowski et al. Blood 2016). PF-3135 has a half-life of ~4-6 days in cynomolgus monkeys, which is predicted to be similar in humans (Panowski et al. Blood 2016).

This is an ongoing open-label, multidose, multicenter, dose-escalation phase I study to assess the safety, pharmacokinetics (PK), and pharmacodynamics of PF-3135 in adult patients with advanced MM who have relapsed from, or are refractory to, standard therapy (ClinicalTrials.gov, identifier: NCT03269136).

Methods: Patients aged ≥18 years with relapsed or refractory MM and measurable disease (as per International Myeloma Working Group updated criteria 2014), who have received prior therapy that included a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody, either in combination or as a single agent, received escalating doses of PF-3135 intravenously. The primary objectives include assessment of safety and tolerability at increasing dose levels of PF-3135 to estimate the maximum tolerated dose and select the recommended phase 2 dose (RP2D). Secondary objectives include evaluation of the overall safety profile, anti-myeloma activity, PK, and immunogenicity of PF-3135. A modified toxicity probability interval method, which targets a dose-limiting toxicity rate of 25% with an acceptable equivalence interval (± 5%), is utilized for dose escalation.

Results: Five patients have received PF-3135 in the dose-escalation portion of the study. No dose-limiting toxicities or cytokine-release syndrome events have been reported. One patient experienced a grade 1 fever (not related to PF-3135) that was reported as a serious adverse event (AE) because the patient was hospitalized for observation. The majority of reported treatment-emergent AEs (all-causality) have been grade ≤2. One patient experienced acute grade 3 alanine aminotransferase/aspartate aminotransferase elevation (<5 days' duration) following Cycle 1 Day 1 dosing, which was considered related to study drug. To date, all reported AEs are as expected for the patient population.

Conclusion: PF-3135 has been well tolerated at the dose levels studied in the ongoing phase I study to date. This encouraging safety profile supports the continued study of higher dose levels to select the RP2D. Updated clinical trial data will be presented in the poster.