TY - JOUR
T1 - A Phase I/II Open-Label Study of Molibresib for the Treatment of Relapsed/Refractory Hematologic Malignancies
AU - Dawson, Mark A.
AU - Borthakur, Gautam
AU - Huntly, Brian J.P.
AU - Karadimitris, Anastasios
AU - Alegre, Adrian
AU - Chaidos, Aristeidis
AU - Vogl, Dan T.
AU - Pollyea, Daniel A.
AU - Davies, Faith E.
AU - Morgan, Gareth J.
AU - Glass, Jacob L.
AU - Kamdar, Manali
AU - Mateos, Maria Victoria
AU - Tovar, Natalia
AU - Yeh, Paul
AU - Delgado, Regina García
AU - Basheer, Faisal
AU - Marando, Ludovica
AU - Gallipoli, Paolo
AU - Wyce, Anastasia
AU - Krishnatry, Anu Shilpa
AU - Barbash, Olena
AU - Bakirtzi, Evi
AU - Ferron-Brady, Geraldine
AU - Karpinich, Natalie O.
AU - McCabe, Michael T.
AU - Foley, Shawn W.
AU - Horner, Thierry
AU - Dhar, Arindam
AU - Kremer, Brandon E.
AU - Dickinson, Michael
N1 - Funding Information:
The funder (GSK) provided support in the form of salaries for authors and provided general feedback on study design. The authors were solely responsible for data collection and analysis and preparation of the article. It is current GSK policy that all clinical studies be published. The specific roles of these authors are articulated in the “author contributions” section (116183; NCT01943851). Editorial support was provided by Anna Polyakova, PhD, at Fishawack Indicia Ltd. of Fishawack Health, UK, and Moamen Hammad of Scion, London, UK, and was funded by GSK.
Publisher Copyright:
© 2022 TheAuthors.
PY - 2023/2/1
Y1 - 2023/2/1
N2 - Purpose: Molibresib is a selective, small molecule inhibitor of the bromodomain and extra-terminal (BET) protein family. This was an open-label, two-part, Phase I/II study investigating molibresib monotherapy for the treatment of hematological malignancies (NCT01943851). Patients and Methods: Part 1 (dose escalation) determined the recommended Phase 2 dose (RP2D) of molibresib in patients with acute myeloid leukemia (AML), Non-Hodgkin lymphoma (NHL), or multiple myeloma. Part 2 (dose expansion) investigated the safety and efficacy of molibresib at the RP2D in patients with relapsed/refractory myelodysplastic syndrome (MDS; as well as AML evolved from antecedent MDS) or cutaneous T-cell lymphoma (CTCL). The primary endpoint in Part 1 was safety and the primary endpoint in Part 2 was objective response rate (ORR). Results: There were 111 patients enrolled (87 in Part 1, 24 in Part 2). Molibresib RP2Ds of 75 mg daily (for MDS) and 60 mg daily (for CTCL) were selected. Most common Grade 3+ adverse events included thrombocytopenia (37%), anemia (15%), and febrile neutropenia (15%). Six patients achieved complete responses [3 in Part 1 (2 AML, 1 NHL), 3 in Part 2 (MDS)], and 7 patients achieved partial responses [6 in Part 1 (4 AML, 2 NHL), 1 in Part 2 (MDS)]. The ORRs for Part 1, Part 2, and the total study population were 10% [95% confidence interval (CI), 4.8-18.7], 25% (95% CI, 7.3-52.4), and 13% (95% CI, 6.9-20.6), respectively. Conclusions: While antitumor activity was observed with molibresib, use was limited by gastrointestinal and thrombocytopenia toxicities. Investigations of molibresib as part of combination regimens may be warranted.
AB - Purpose: Molibresib is a selective, small molecule inhibitor of the bromodomain and extra-terminal (BET) protein family. This was an open-label, two-part, Phase I/II study investigating molibresib monotherapy for the treatment of hematological malignancies (NCT01943851). Patients and Methods: Part 1 (dose escalation) determined the recommended Phase 2 dose (RP2D) of molibresib in patients with acute myeloid leukemia (AML), Non-Hodgkin lymphoma (NHL), or multiple myeloma. Part 2 (dose expansion) investigated the safety and efficacy of molibresib at the RP2D in patients with relapsed/refractory myelodysplastic syndrome (MDS; as well as AML evolved from antecedent MDS) or cutaneous T-cell lymphoma (CTCL). The primary endpoint in Part 1 was safety and the primary endpoint in Part 2 was objective response rate (ORR). Results: There were 111 patients enrolled (87 in Part 1, 24 in Part 2). Molibresib RP2Ds of 75 mg daily (for MDS) and 60 mg daily (for CTCL) were selected. Most common Grade 3+ adverse events included thrombocytopenia (37%), anemia (15%), and febrile neutropenia (15%). Six patients achieved complete responses [3 in Part 1 (2 AML, 1 NHL), 3 in Part 2 (MDS)], and 7 patients achieved partial responses [6 in Part 1 (4 AML, 2 NHL), 1 in Part 2 (MDS)]. The ORRs for Part 1, Part 2, and the total study population were 10% [95% confidence interval (CI), 4.8-18.7], 25% (95% CI, 7.3-52.4), and 13% (95% CI, 6.9-20.6), respectively. Conclusions: While antitumor activity was observed with molibresib, use was limited by gastrointestinal and thrombocytopenia toxicities. Investigations of molibresib as part of combination regimens may be warranted.
UR - http://www.scopus.com/inward/record.url?scp=85148250544&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-22-1284
DO - 10.1158/1078-0432.CCR-22-1284
M3 - Article
C2 - 36350312
AN - SCOPUS:85148250544
SN - 1078-0432
VL - 29
SP - 711
EP - 722
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 4
ER -