TY - JOUR
T1 - Safety, pharmacokinetic, pharmacodynamic and clinical activity of molibresib for the treatment of nuclear protein of the testis carcinoma and other cancers
T2 - Results of a Phase I/II open-label, dose escalation study
AU - Cousin, Sophie
AU - Blay, Jean Yves
AU - Garcia, Irene Braña
AU - de Bono, Johann S.
AU - Le Tourneau, Christophe
AU - Moreno, Victor
AU - Trigo, Jose
AU - Hann, Christine L.
AU - Azad, Arun A.
AU - Im, Seock Ah
AU - Cassier, Philippe A.
AU - French, Christopher A.
AU - Italiano, Antoine
AU - Keedy, Vicki L.
AU - Plummer, Ruth
AU - Sablin, Marie Paule
AU - Hemming, Matthew L.
AU - Ferron-Brady, Geraldine
AU - Wyce, Anastasia
AU - Khaled, Ahmed
AU - Datta, Antara
AU - Foley, Shawn W.
AU - McCabe, Michael T.
AU - Wu, Yuehui
AU - Horner, Thierry
AU - Kremer, Brandon E.
AU - Dhar, Arindam
AU - O'Dwyer, Peter J.
AU - Shapiro, Geoffrey I.
AU - Piha-Paul, Sarina A.
N1 - Publisher Copyright:
© 2021 UICC.
PY - 2022/3/15
Y1 - 2022/3/15
N2 - Molibresib is an orally bioavailable, selective, small molecule BET protein inhibitor. Results from a first time in human study in solid tumors resulted in the selection of a 75 mg once daily dose of the besylate formulation of molibresib as the recommended Phase 2 dose (RP2D). Here we present the results of Part 2 of our study, investigating safety, pharmacokinetics, pharmacodynamics and clinical activity of molibresib at the RP2D for nuclear protein in testis carcinoma (NC), small cell lung cancer, castration-resistant prostate cancer (CRPC), triple-negative breast cancer, estrogen receptor-positive breast cancer and gastrointestinal stromal tumor. The primary safety endpoints were incidence of adverse events (AEs) and serious AEs; the primary efficacy endpoint was overall response rate. Secondary endpoints included plasma concentrations and gene set enrichment analysis (GSEA). Molibresib 75 mg once daily demonstrated no unexpected toxicities. The most common treatment-related AEs (any grade) were thrombocytopenia (64%), nausea (43%) and decreased appetite (37%); 83% of patients required dose interruptions and 29% required dose reductions due to AEs. Antitumor activity was observed in NC and CRPC (one confirmed partial response each, with observed reductions in tumor size), although predefined clinically meaningful response rates were not met for any tumor type. Total active moiety median plasma concentrations after single and repeated administration were similar across tumor cohorts. GSEA revealed that gene expression changes with molibresib varied by patient, response status and tumor type. Investigations into combinatorial approaches that use BET inhibition to eliminate resistance to other targeted therapies are warranted.
AB - Molibresib is an orally bioavailable, selective, small molecule BET protein inhibitor. Results from a first time in human study in solid tumors resulted in the selection of a 75 mg once daily dose of the besylate formulation of molibresib as the recommended Phase 2 dose (RP2D). Here we present the results of Part 2 of our study, investigating safety, pharmacokinetics, pharmacodynamics and clinical activity of molibresib at the RP2D for nuclear protein in testis carcinoma (NC), small cell lung cancer, castration-resistant prostate cancer (CRPC), triple-negative breast cancer, estrogen receptor-positive breast cancer and gastrointestinal stromal tumor. The primary safety endpoints were incidence of adverse events (AEs) and serious AEs; the primary efficacy endpoint was overall response rate. Secondary endpoints included plasma concentrations and gene set enrichment analysis (GSEA). Molibresib 75 mg once daily demonstrated no unexpected toxicities. The most common treatment-related AEs (any grade) were thrombocytopenia (64%), nausea (43%) and decreased appetite (37%); 83% of patients required dose interruptions and 29% required dose reductions due to AEs. Antitumor activity was observed in NC and CRPC (one confirmed partial response each, with observed reductions in tumor size), although predefined clinically meaningful response rates were not met for any tumor type. Total active moiety median plasma concentrations after single and repeated administration were similar across tumor cohorts. GSEA revealed that gene expression changes with molibresib varied by patient, response status and tumor type. Investigations into combinatorial approaches that use BET inhibition to eliminate resistance to other targeted therapies are warranted.
UR - http://www.scopus.com/inward/record.url?scp=85119982365&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85119982365&partnerID=8YFLogxK
U2 - 10.1002/ijc.33861
DO - 10.1002/ijc.33861
M3 - Article
C2 - 34724226
AN - SCOPUS:85119982365
SN - 0020-7136
VL - 150
SP - 993
EP - 1006
JO - International journal of cancer
JF - International journal of cancer
IS - 6
ER -