Clin Cancer Res: Activity and safety of the BET protein inhibitor Molibresib in hematologic malignancies

Bromodomains (BRD) are conserved modules located in chromatin-associated proteins that regulate the chromatin templating process
by recognizing acetylated histones as epigenetic readings.
BRD-containing proteins regulate the transcription
of many genes that control growth, cell cycle progression, and differentiation.
BRD and BET family proteins have attracted widespread interest
as potential therapeutic targets for various cancers.

Molibresib is a selective small molecule inhibitor
of the BET protein family.
An open-label, two-part Phase I/II study evaluated the efficacy and safety
of Molibresib monotherapy in the treatment of hematologic malignancies.

The first part of the study (dose escalation) aimed to determine the recommended Phase 2 dose (RP2D)
of Molibresib for acute myeloid leukemia (AML), non-Hodgkin lymphoma (NHL), or multiple lymphoma.
The second part of the study (dose expansion) evaluated the efficacy and safety
of Molibresib at the recommended Phase 2 dose of Molibresib for the treatment of recurrent/refractory myelodysplastic syndrome (MDS) or cutaneous T-cell lymphoma (CTCL).
The primary endpoints for Part I are safety and objective response rate (ORR)
for Part II.

Occurrence of some adverse reactions

A total of 111 patients (87 in Part I and 24 in Part II)
were enrolled.
The recommended Phase 2 dose for MDS is 75 mg (1 time/day) and the recommended Phase 2 dose for CTCL is 60 mg (CTCL).

The most common grade 3+ adverse reactions (AEs) were thrombocytopenia (37%), anemia (15%), and febrile neutropenia (15%)
.

Clinical remission of the test patient

Six patients achieved complete remission (three in Part I [2 AML, 1 NHL], three in Part II [MDS]), and seven patients achieved partial response (6 in Part I [4 AML, 2 NHL], and 1 in Part II [MDS]
).
The objective response rates for patients in Part I, Part II, and the total study population were 10%, 25%, and 13%,
respectively.

Overall, although the antitumor activity of Molibresib has been observed in patients with hematologic malignancies, its application is limited
by gastrointestinal and thrombocytopenic toxicity.

Original source:

Mark A.
Dawson, Gautam Borthakur, Brian Huntly, et al.
A phase I/II open-label study of molibresib for the treatment of relapsed/refractory hematologic malignancies.
Clin Cancer Res 2022; https://doi.
org/10.
1158/1078-0432.
CCR-22-1284