A Phase 1/2, First-in-Human, Multicenter, Open-Label, Dose Escalation and Dose-Expansion Study of Single-Agent ISB 1442 in Patients with Relapsed/Refractory Multiple Myeloma

Background

Multiple myeloma (MM) is a hematologic malignancy caused by the proliferation of plasma cells in the bone marrow and extramedullary sites. The addition of anti-CD38 monoclonal antibodies such as daratumumab into the standard of care has improved disease outcomes; however, MM remains an incurable disease and resistance mechanisms are emerging. These include reduced CD38 expression and suppressed antibody-dependent cell cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC) activities. Of note, overexpression of CD47 on MM cells activates the CD47-SIRPα “do not eat me” signal and blunts ADCP. Hence, an enhanced CD38 targeted therapy that unleashes the innate immune cell mediated tumor killing potential and overcomes daratumumab resistance mechanisms may present a unique opportunity to treat MM. ISB 1442 is a 2+1 biparatopic bispecific antibody with CD38 and CD47 targeting domains as well as an engineered Fc domain to enhance ADCP, CDC, and ADCC. Notably, ISB 1442 binds to a different CD38 epitope than daratumumab, and therefore the two compounds do not functionally compete. Preclinically, ISB 1442 has demonstrated higher killing potency of both CD38 high and low expressing tumors compared to daratumumab (Figure 1). Through the Fc domain engineering, ISB 1442 also induced more potent tumor killing by CDC, ADCP, and ADCC (Figure 1). Due to low-affinity binding to CD47, ISB 1442 engages CD47 efficiently only upon CD38 binding (avidity-induced binding), thereby reducing the potential for on-target, off-tumor effects, and it does not cause any detectable RBC depletion in vitro compared to magrolimab (Figure 2).

Study design and methods

This open-label, first-in-human, multicenter Phase 1/2 study is assessing the safety, tolerability, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of ISB 1442 in relapsed refractory multiple myeloma (RRMM) patients. Criteria for enrollment in this study include patients with RRMM with measurable disease who have been treated with a CD38 antibody, IMiDs, PIs, and who must not be candidates for regimens known to provide clinical benefit; in the United States patients must have failed 3 or more prior lines of therapies. ISB 1442 is being administered subcutaneously weekly at the starting dose derived using a pharmacological active dose (PAD) approach, and the study will follow a rapid titration single patient dose escalation design until reaching the safety threshold, after which it will be converted to a conventional 3+3 approach. The primary outcome measure is the number of DLTs, defined as the number of predefined treatment-related adverse events within the first 28 days of study treatment. Once RP2D has been identified, the Phase 2 expansion will start with enrollment in two arms: 1) patients who have been treated with at least three prior lines of therapies including a CD38 antibody, IMiD, and PI; 2) RRMM patients who have been treated with T cell redirected therapies. The primary endpoint of Phase 2 is the overall response rate. Secondary endpoints include PFS, OS, DoR, PK, immunogenicity, etc. Exploratory endpoints include CD38 and CD47 expression, cytokine level changes, immunophenotyping, and MRD negative rate. Approximately 46 patients will be enrolled in Phase 1 in sites in Australia and the United States. A total of approximately 75 evaluable patients will be enrolled in Phase 2 at the RP2D for the two cohorts. The study is currently open for enrollment. Clinicaltrials.gov identifier: NCT05427812.