A phase 1b study of venetoclax and alvocidib in patients with relapsed/refractory acute myeloid leukemia
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A phase 1b study of venetoclax and alvocidib in patients with relapsed/refractory acute myeloid leukemia. / Jonas, Brian A; Hou, Jing-Zhou; Roboz, Gail J; Alvares, Caroline L; Jeyakumar, Deepa; Edwards, John R; Erba, Harry P; Kelly, Richard J; Röllig, Christoph; Fiedler, Walter; Brackman, Deanna; Siddani, Satya R; Chyla, Brenda; Hilger-Rolfe, Jacqueline; Watts, Justin M.
In: HEMATOL ONCOL, Vol. 41, No. 4, 10.2023, p. 743-752.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - A phase 1b study of venetoclax and alvocidib in patients with relapsed/refractory acute myeloid leukemia
AU - Jonas, Brian A
AU - Hou, Jing-Zhou
AU - Roboz, Gail J
AU - Alvares, Caroline L
AU - Jeyakumar, Deepa
AU - Edwards, John R
AU - Erba, Harry P
AU - Kelly, Richard J
AU - Röllig, Christoph
AU - Fiedler, Walter
AU - Brackman, Deanna
AU - Siddani, Satya R
AU - Chyla, Brenda
AU - Hilger-Rolfe, Jacqueline
AU - Watts, Justin M
N1 - © 2023 AbbVie Inc. Hematological Oncology published by John Wiley & Sons Ltd.
PY - 2023/10
Y1 - 2023/10
N2 - Relapsed/refractory (R/R) Acute Myeloid Leukemia (AML) is a genetically complex and heterogeneous disease with a poor prognosis and limited treatment options. Thus, there is an urgent need to develop therapeutic combinations to overcome drug resistance in AML. This open-label, multicenter, international, phase 1b study evaluated the safety, efficacy, and pharmacokinetics of venetoclax in combination with alvocidib in patients with R/R AML. Patients were treated with escalating doses of venetoclax (400, 600, and 800 mg QD, orally, days 1-28) and alvocidib (45 and 60 mg/m2 , intravenously, days 1-3) in 28-day cycles. The combination was found to be safe and tolerable, with no maximum tolerated dose reached. Drug-related Grade ≥3 adverse events were reported in 23 (65.7%) for venetoclax and 24 (68.6%) for alvocidib. No drug-related AEs were fatal. Gastrointestinal toxicities, including diarrhea, nausea, and vomiting were notable and frequent; otherwise, the toxicities reported were consistent with the safety profile of both agents. The response rate was modest (complete remission [CR] + incomplete CR [CRi], 11.4%; CR + CRi + partial response rate + morphologic leukemia-free state, 20%). There was no change in alvocidib pharmacokinetics with increasing doses of venetoclax. However, when venetoclax was administered with alvocidib, AUC24 and Cmax decreased by 18% and 19%, respectively. A recommended phase 2 dose was not established due to lack of meaningful increase in efficacy across all cohorts compared to what was previously observed with each agent alone. Future studies could consider the role of the sequence, dosing, and the use of a more selective MCL1 inhibitor for the R/R AML population.
AB - Relapsed/refractory (R/R) Acute Myeloid Leukemia (AML) is a genetically complex and heterogeneous disease with a poor prognosis and limited treatment options. Thus, there is an urgent need to develop therapeutic combinations to overcome drug resistance in AML. This open-label, multicenter, international, phase 1b study evaluated the safety, efficacy, and pharmacokinetics of venetoclax in combination with alvocidib in patients with R/R AML. Patients were treated with escalating doses of venetoclax (400, 600, and 800 mg QD, orally, days 1-28) and alvocidib (45 and 60 mg/m2 , intravenously, days 1-3) in 28-day cycles. The combination was found to be safe and tolerable, with no maximum tolerated dose reached. Drug-related Grade ≥3 adverse events were reported in 23 (65.7%) for venetoclax and 24 (68.6%) for alvocidib. No drug-related AEs were fatal. Gastrointestinal toxicities, including diarrhea, nausea, and vomiting were notable and frequent; otherwise, the toxicities reported were consistent with the safety profile of both agents. The response rate was modest (complete remission [CR] + incomplete CR [CRi], 11.4%; CR + CRi + partial response rate + morphologic leukemia-free state, 20%). There was no change in alvocidib pharmacokinetics with increasing doses of venetoclax. However, when venetoclax was administered with alvocidib, AUC24 and Cmax decreased by 18% and 19%, respectively. A recommended phase 2 dose was not established due to lack of meaningful increase in efficacy across all cohorts compared to what was previously observed with each agent alone. Future studies could consider the role of the sequence, dosing, and the use of a more selective MCL1 inhibitor for the R/R AML population.
U2 - 10.1002/hon.3159
DO - 10.1002/hon.3159
M3 - SCORING: Journal article
C2 - 37086447
VL - 41
SP - 743
EP - 752
JO - HEMATOL ONCOL
JF - HEMATOL ONCOL
SN - 0278-0232
IS - 4
ER -