TY - JOUR
T1 - A Phase 1 First-in-Human Study of the MCL-1 Inhibitor AZD5991 in Patients with Relapsed/Refractory Hematologic Malignancies
AU - Desai, Pinkal
AU - Lonial, Sagar
AU - Cashen, Amanda
AU - Kamdar, Manali
AU - Flinn, Ian
AU - O'Brien, Susan
AU - Garcia, Jacqueline S.
AU - Korde, Neha
AU - Moslehi, Javid
AU - Wey, Margaret
AU - Cheung, Patricia
AU - Sharma, Shringi
AU - Olabode, Damilola
AU - Chen, Hong
AU - Syed, Firasath Ali
AU - Liu, Mary
AU - Saeh, Jamal
AU - Andrade-Campos, Marcio
AU - Kadia, Tapan M.
AU - Blachly, James S.
N1 - Publisher Copyright:
© 2024 The Authors; Published by the American Association for Cancer Research.
PY - 2024/11/1
Y1 - 2024/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85208227333&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-24-0028
DO - 10.1158/1078-0432.CCR-24-0028
M3 - Article
C2 - 39167622
AN - SCOPUS:85208227333
SN - 1078-0432
VL - 30
SP - 4844
EP - 4855
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 21
ER -