Phase I dose-escalation study of F50067, a humanized anti-CXCR4 monoclonal antibody alone and in combination with lenalidomide and low-dose dexamethasone, in relapsed or refractory multiple myeloma

Abstract

PurposeMultiple myeloma (MM) remains an incurable disease as tumor cells ultimately resist to all available drugs. Homing of tumor cells to the bone marrow microenvironment, involving especially the CXCR4/SDF-1 axis, allows them to survive, proliferate and resist to therapy. F50067, a humanized anti-CXCR4 IgG1 antibody, has promising preclinical activity in MM.We present a phase I multicenter escalation study in relapsed/refractory MM (RRMM) to determine the maximum tolerated dose (MTD) for F50067 alone and in combination with lenalidomide and low dose dexamethasone (Len-Dex).Experimental design14 end-stage RRMM patients received F50067 single agent (n = 10) or in combination with Len-Dex (n = 4).ResultsOne dose-limiting toxicity was observed, a grade 4 neutropenia lasting more than 7 days in combination arm. MTD could not be established. Thrombocytopenia was observed in 100% and neutropenia in 92.9% of patients with no cases of febrile neutropenia and no severe bleeding or hematoma. Non-hematological adverse events were of mild to moderate severity.Nine patients (6 in single arm and 3 in combination arm) were evaluable for response, with 66.7% overall response rate (≥PR) in combination arm, and 33.3% of disease control (≥SD) in single agent arm. At the time of study termination, 55.6% had progressed.ConclusionThis study suggests that egression of tumor cells to the blood stream can represent a novel therapeutic strategy for MM. However, because of significant hematological toxicity, this study had to be discontinued. Further studies are needed to validate the feasibility of this approach in clinical practice.

Investigational Monoclonal Antibodies in the Treatment of Multiple Myeloma: A Systematic Review of Agents under Clinical Development

“…Fouquet et al studied 14 RRMM patients as F50067 monotherapy and combination of F50067 + Rd (low-dose dexamethasone) with 66.7% ORR (≥PR) in combination cohort and OR of 33.3% (≥SD). Investigators discontinued the study due to hematological toxicities [48].…”

Role and Therapeutic Targeting of SDF-1α/CXCR4 Axis in Multiple Myeloma

“…F50067 is a humanized monoclonal IgG1 anti-CXCR4 antibody and exerts antitumor effects via reducing the interaction of MM cells with the BM microenvironment and inducing antibody-dependent cellular cytotoxicity and compliment-dependent cytotoxicity. Fouquet et al reported a phase I dose escalation study of F50067 alone and in combination with lenalidomide and low-dose dexamethasone (Len-dex) in RRMM [104]. Moreover, 14 patients with RRMM were enrolled in the study.…”

A review of antibody-based therapeutics targeting G protein-coupled receptors: an update

“…The analysis excludes targets that would require CNS penetration for efficacy unless the program harnesses BBB transcytosis technology, where binding to the transferrin receptor (TfR) is used for delivery into the brain and can be engineered as a bispecific antibody or into the Fc domain of the molecule. Anti-GPCR antibodies are also under investigation as combination therapies, for example, with checkpoint inhibitor antibodies [51] or lenalidomide and dexamethasone [52] or in combination with cell therapy [53]. What is also apparent is the significant interest and sustained activity in directing mAbs to this important drug class as evidenced by the total number of programs in the R&D pipeline and the success of more mAbs attaining advanced clinical development over the past decade (Figure 3).…”