Evaluating inobrodib (CCS1477) in combination with teclistamab or elranatamab in patients with Relapsed/Refractory multiple myeloma; Specific cohorts within a Phase I/IIa study evaluating inobrodib in patients with advanced hematological malignancies

Abstract

Abstract Inobrodib (Ino, CCS1477) is a first in class potent, selective, and orally bioavailable inhibitor of the bromodomains of p300 and CBP, two closely related histone acetyl transferases with oncogenic roles in hematological malignancies. Preclinical studies revealed combination with IMiDs, including pomalidomide, showed impressive synergy, and this is associated with enhanced targeting of IRF4, a well-established oncogenic driver in MM. This Phase I/II study (Study CCS1477-02) of Ino with pomalidomide and dexamethasone (InoPd) showed high response rates (75% ORR) with a manageable safety profile in heavily pre-treated relapsed/refractory multiple myeloma (RRMM), all of which were refractory to their last line of therapy. In particular, patients that were previously refractory to pomalidomide and novel immunotherapies such as T cell engagers (TCE) responded to InoPd (Searle et al., ASH 2024). Preclinical investigation of additional combinations revealed that Ino synergistically combined with a B cell maturity antigen (BCMA)-targeted TCE in a syngeneic mouse model of RRMM. These data warrant clinical investigation of this combination. Study Design and Methods This study aims to characterize the safety, tolerability, and preliminary clinical activity of Ino in combination with the approved BCMA-targeted TCEs elranatamab and teclistamab for the treatment of RRMM. Study CCS1477-02 (NCT04068597) is an adaptive multi-arm/multi-stage study allowing exploration of Ino as monotherapy or in combination with different agents across multiple indications including AML/higher risk MDS, RRMM, and NHL. The current focus is in evaluating novel Ino combination regimens in RRMM, with a particular emphasis on elranatamab and teclistamab. An initial single-patient cohort design, followed by a rolling 6 design, will be used to ensure tolerability with the possibility to further expand cohorts of interest. The study is not powered to support comparisons between the two TCEs. Key inclusion criteria include patients with confirmed relapsed or refractory disease, with patients having received standard therapy (typically at least two prior lines of therapy). Responses are assessed via IMWG criteria. Serial blood and bone marrow samples are being collected for exploratory biomarker analysis to understand mechanisms of response to treatment or disease progression. These cohorts will be opened in approximately 8 sites in the UK and US.