Pinkal Desai, Sagar Lonial, Amanda Cashen, Manali Kamdar, Ian Flinn, Susan O'Brien, Jacqueline S Garcia, Neha Korde, Javid Moslehi, Margaret Wey, Patricia Cheung, Shringi Sharma, Damilola Olabode, Hong Chen, Firasath Ali Syed, Mary Liu, Jamal Saeh, Marcio Andrade-Campos, Tapan M Kadia, James S Blachly
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引用次数: 0
Abstract
Purpose: AZD5991, a human MCL-1 inhibitor, was assessed for safety, tolerability, pharmacokinetics, and antitumor activity as monotherapy and in combination with venetoclax in patients with relapsed or refractory hematologic malignancies.
Patients and methods: In the monotherapy cohort (n = 61), patients with hematologic malignancies received AZD5991 intravenously in escalating doses either once or twice weekly, following intrapatient dose escalation, during a 3-week cycle. In the combination cohort (n = 17), patients with acute myeloid leukemia and myelodysplastic syndrome received escalating doses of AZD5991 and venetoclax during either a 3- or 4-week cycle. Primary objectives were safety and maximum tolerated dose; secondary objectives included plasma pharmacokinetics and antitumor activity.
Results: The most common (≥30%) adverse events were diarrhea (59.0%), nausea (55.1%), and vomiting (47.4%). Four deaths occurred because of adverse events: cardiac arrest, sepsis, tumor lysis syndrome, and acute respiratory failure; only tumor lysis syndrome was related to AZD5991. Dose-limiting toxicities occurred in five patients. Three patients with myelodysplastic syndrome achieved an objective response: one marrow complete remission without hematologic improvement, one partial remission with AZD5991 monotherapy, and one marrow complete remission with AZD5991 + venetoclax. Asymptomatic elevations of troponin I or T were observed in eight (10.3%) patients. Post hoc retrospective analysis revealed elevated troponin T in 14/31 patients before any AZD5991 dose and in 54/65 patients after any AZD5991 dose at or after Cycle 1. No associations were found between elevated troponin and cardiovascular risk factors.
Conclusions: Treatment with AZD5991 was associated with high incidence of laboratory troponin elevation and a low overall response rate.
期刊介绍:
Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.