| 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. © 2024 The Authors; Published by the American Association for Cancer Research. |
| Keywords: |
adult; human tissue; treatment outcome; aged; aged, 80 and over; middle aged; unclassified drug; overall survival; leukemia, myeloid, acute; lenalidomide; clinical trial; constipation; drug tolerability; fatigue; neutropenia; diarrhea; drug safety; hepatitis b; hepatitis c; monotherapy; chemotherapy; primary central nervous system lymphoma; human immunodeficiency virus infection; nuclear magnetic resonance imaging; antineoplastic agent; anorexia; edema; progression free survival; proteasome inhibitor; mantle cell lymphoma; multiple myeloma; neutrophil count; neoplasm recurrence, local; anemia; bleeding; nausea; thrombocytopenia; vomiting; antineoplastic combined chemotherapy protocols; relapse; creatinine; waldenstroem macroglobulinemia; antineoplastic activity; drug effect; drug resistance; drug resistance, neoplasm; pyrimidines; retrospective study; histology; abdominal pain; appetite; asthenia; dyspnea; febrile neutropenia; fever; hyperuricemia; hypomagnesemia; tumor lysis syndrome; coronary artery bypass graft; alanine aminotransferase; aspartate aminotransferase; bilirubin; hypokalemia; cutaneous t cell lymphoma; hematologic malignancy; myelodysplastic syndrome; hematologic neoplasms; immunotherapy; sulfonamide; heart failure; heart infarction; multicenter study; tumor recurrence; sulfonamides; protein mcl 1; pancreatitis; spinal cord compression; sepsis; liver disease; headache; maximum tolerated dose; phase 1 clinical trial; aniline compounds; urinalysis; drug therapy; indoles; pyrimidine derivative; fused heterocyclic rings; indole derivative; electrocardiography; follicular lymphoma; mycosis fungoides; ethnicity; cytomegalovirus infection; amylase; hematologic disease; heart arrest; myelodysplastic syndromes; pharmacokinetics; platelet count; cardiovascular risk factor; acute respiratory failure; sezary syndrome; inhibitor protein; angina pectoris; pyrexia idiopathica; acute myeloid leukemia; hyperphosphatemia; diffuse large b cell lymphoma; myocarditis; troponin t; acrylamides; aniline derivative; bleeding disorder; richter syndrome; angioplasty; very elderly; myeloid cell leukemia sequence 1 protein; humans; human; male; female; article; acrylamide derivative; venetoclax; osimertinib; daratumumab; mild renal impairment; bridged bicyclo compounds, heterocyclic; azd5991; mcl1 protein, human; refractory hematologic malignancy
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