Tolerability and Clinical Activity of Novel First in Class Oral Agent, Inobrodib (CCS1477), in Combination with Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma
Authors: Searle Emma , Cavet James , Campbell Victoria , Knapper Steve , Bygrave Ceri , El-Sharkawi Dima , Pawlyn Charlotte , Creignou Maria , Walter Harriet , Valcárcel David , Hidalgo Soto Marta , O'Nions Jenny , Sridhar Amrutha , Knurowski Tomasz , Clegg Karen , Pegg Neil , West Will Henry , Haynes Debbie , Frese Kris , Somervaille Tim 
Published: December 2023

Background
Inobrodib (CCS1477) is a first in class potent, selective, and orally bioavailable inhibitor of the bromodomains of p300 and CBP, two closely related histone acetyltransferases 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 additive/synergistic activity with pomalidomide.
Aims:
We report preliminary 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. Two dose escalation combination cohorts were completed; pts received inobrodib at doses of 25 mg or 35 mg bidaily on a 4 days on/3 days off intermittent schedule, as well as standard dosing of pom and dex in 28-day cycles. Adverse events were graded by CTCAE v5.0. Responses were investigator assessed per IMWG.
Results:
Initial dose escalation cohorts enrolled 15 RRMM pts with a median age of 71 yrs (range 41-80). Median prior lines of therapy was 5 (range 3-9). Median follow-up was 56 days (range 13-189), with a median number of 3 cycles received (range 1-7). Almost all patients were pomalidomide-refractory (13/15, 87%), 13/13 (100%, 2 pts data missing) were triple class refractory and 3 pts (20%) received prior BCMA therapy.
At the data cut-off (5 th June 2023), Grade (gr) 3 /4 treatment-emergent adverse events (TEAEs) were reported in 11 of 15 (73%) pts. Over half of the patients remain on treatment and all but three remain in follow-up for survival analysis. Of these three patients, two died due to disease progression and one due to an unrelated cardiac event at the end of cycle 2. The most frequent gr 3/4 events were infections (41.1%). The majority of the other gr 3/4 TEAE were hematological and seen in 5 of 13 (38.5%) pts; neutropenia (23.5%) thrombocytopenia (5.9%, all gr 3) and anemia (11.8%, all gr 3). Seven of 15 (47%) pts experienced TEAEs considered related to inobrodib; all events were gr 1/2 apart from a single patient with gr 3 electrolyte abnormalities. No DLTs were noted; two pts (13%) discontinued due to related events.
The majority of patients 13/15 (87%) showed signs of activity with disease markers decreasing over time. At the point of data cut off, 7/15 (47%) heavily pre-treated patients achieved confirmed responses (MR or better) per IMWG criteria; 2 VGPR, 3 PR and 2 MR. Of note, two further patients, who initially received inobrodib monotherapy but progressed were transferred into the pom-dex combination cohort and subsequently achieved objective responses (VGPR and PR).
Summary:
The first in class agent inobrodib in combination with pom-dex shows promising early efficacy in heavily pre-treated, including pom-refractory, RRMM patients. The combination is tolerable, with the most common events being infections, as expected in this patient population. Dose optimisation continues as part of this study with expansion arms in an earlier setting planned.