A phase 1b study of venetoclax and alvocidib in patients with relapsed/refractory acute myeloid leukemia

Abstract

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 C_max 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.

Keywords: BCL-2; MCL-1; acute myeloid leukemia; alvocidib; drug resistance; venetoclax.

Figure 1.

Swimmer plot of best treatment response and survival for all patients since the first dose of study drug. Each lane represents one patient in the study, with the colored bars indicating the drug exposure. The numbers on the left indicate the treatment cohort each patient was a part of: 1, Ven 400 Alvo 45 “no ramp-up”; 2, Ven 400 Alvo 45; 3, Ven 400 Alvo 60. 4, Ven 600 Alvo 60. 5, Ven 800 Alvo 60. Note: #, prior venetoclax.

Figure 2.

Co-administration with alvocidib reduced venetoclax exposure. A) C_max or B) AUC₂₄ of venetoclax by each patient when given alone, or in combination with alvocidib.

Figure 3.

Molecular patterns of response. Heatmap showing the frequency of molecular markers detected at baseline for each patient as it relates to best response on study, which is color coded on the bottom. The molecular marker is on the right and the frequency is on the left, with the colors indicating the type of alteration. CR, complete response; CRi, CR with incomplete hematologic recovery; PR, partial response; MLFS, morphologic leukemia-free state; RD, resistant disease; PD, progressive disease; DS, discontinued with no response data.