Tolerability and Clinical Activity of Novel First-in-Class Oral Agent, Inobrodib (CCS1477), in Combination with Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma

Background

Inobrodib (CCS1477) is a first-in-class potent, selective, and orally bioavailable inhibitor of the conserved bromodomains of p300 and CBP, two closely related histone acetyl transferases with oncogenic roles in hematological malignancies. Inobrodib exhibits potent anti-tumor cell activity in a range of hematological cell lines including multiple myeloma, and demonstrates synergistic activity with pomalidomide.

Aims:

We report an update on safety (primary objective) and efficacy (secondary) data for inobrodib in combination with pomalidomide (pom) and dexamethasone (dex) from relapsed/refractory multiple myeloma (RRMM) patients treated in the Phase I/IIa trial (NCT04068597).

Methods:

Eligible patients (pts) had confirmed RRMM and had exhausted available or suitable standard of care treatment options. Three dose escalation combination cohorts were completed; inobrodib 25mg, or 35mg, bid on a 4 days on/3 days off intermittent schedule with 4mg pom; or inobrodib 25mg bid 4 days on/3 days off with 3mg pom. All regimens were 28-day cycles and included a standard dose of dex, 20-40mg depending on age. Each cohort was further expanded to include up to 10 patients. Adverse events were graded by CTCAE v5.0. Responses were investigator assessed per IMWG. Pharmacodynamic (PD) profiling of paired bone marrow samples and serial PBMC samples, using CyTOF for IRF4, MYC, and other markers is ongoing.

Results:

Dose escalation cohorts have enrolled 48 RRMM pts to date with a median age of 68 yrs (range 41-82). Median prior lines of therapy was 6 (range 2-10), all were triple-class exposed, 39 pts (81%) were triple class refractory, and 16 pts (33%) received prior BCMA therapy. In addition, 31 pts (65%) were pomalidomide-refractory.

Median duration of treatment for 36 evaluable patients to date was 177 days (range 35-601), with a median of 6 cycles (range 1-21). Over 1/3^rd of the patients continue on treatment. Almost 1/3^rd of patients have died in the survival follow-up, mainly due to disease progression, but a number of patients remain in follow-up for overall survival.

At the data cut-off (4^th June 2024), Grade (gr) 3/4 treatment-emergent adverse events (TEAEs) were reported in 35 of 48 (73%) pts. The most frequent gr 3/4 events were hematological (56%); neutropenia (27%: 19% gr 3, 8% gr 4), thrombocytopenia (27%: 21% gr 3, 6% gr 4) and anemia (13%, all gr 3). Frequency of gr 3/4 infections was 29%. This is in line with the anticipated profile of pom/dex only. The main potential for overlapping toxicity is thrombocytopenia however no significant increase in frequency or severity has been seen with the triplet. Inobrodib as monotherapy has not been shown to cause neutropenia. One patient died due to an unrelated cardiac event at the end of cycle 2. Five pts (10%) discontinued due to TEAEs. The pattern of TEAEs considered related to study treatments is consistent with the known safety profile of the individual agents, with the majority of events gr 1/2 and the most common gr 3/4 events being hematological toxicities.

Objective responses were seen across all dose levels tested with best ORR (6/8 evaluable patients, 75%) in the highest dose cohort. In general responses start rapidly after initiation of treatment and deepen with time on treatment.

Among pom-refractory pts, 7 had progressed on a pom-containing regimen as the last prior therapy and 5 of these achieved OR, providing clinical proof of concept on published non-clinical data regarding the exquisite synergy of this combination (Welsh et al. 2024). Responses were also seen in patients exposed to anti-BCMA and/or TCE therapies; further recruitment is ongoing in this population.

In the initial sample of pom-naïve pts (12), there is a trend for deeper response with 2 patients achieving CRs (17%) and 2 patients having MRD negativity 10^-5 .

Summary:

The first in class agent inobrodib in combination with pom-dex (all oral combination) shows promising early efficacy in heavily pre-treated, including pom-refractory, RRMM patients. The combination is tolerable, with no overt overlapping toxicity, based on the anticipated safety profile of inobrodib and pom/dex doublet. Preliminary PD data, safety and efficacy will be used to support dose expansion and dose optimisation decisions in the current study, before a pivotal trial is initiated.