A phase 1b study of venetoclax and alvocidib in patients with relapsed/refractory acute myeloid leukemia.
Brian A Jonas, Jing-Zhou Hou, Gail J Roboz, Caroline L Alvares, Deepa Jeyakumar, John R Edwards, Harry P Erba, Richard J Kelly, Christoph Röllig, Walter Fiedler, Deanna Brackman, Satya R Siddani, Brenda Chyla, Jacqueline Hilger-Rolfe, Justin M Watts
Author Information
Brian A Jonas: Department of Internal Medicine, Division of Malignant Hematology, Cell Therapy and Transplantation, University of California Davis, Davis, California, USA.
Jing-Zhou Hou: University of Pittsburgh Medical Center Cancer Center, Pittsburgh, Pennsylvania, USA.
Gail J Roboz: Weill Cornell Medicine and New York-Presbyterian Hospital, New York, New York, USA.
Caroline L Alvares: Department of Haematology, University Hospital of Wales, Cardiff, UK.
Deepa Jeyakumar: Chao Comprehensive Cancer Center, University of California Irvine, Irvine, California, USA. ORCID
John R Edwards: Indiana Blood and Marrow Transplantation, Indianapolis, Indiana, USA.
Harry P Erba: Duke University School of Medicine, Durham, North Carolina, USA.
Richard J Kelly: Department of Haematology, St. James's University Hospital, Leeds, UK.
Christoph Röllig: Universitätsklinikum TU, Dresden, Germany.
Walter Fiedler: University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Deanna Brackman: AbbVie Inc., North Chicago, Illinois, USA. ORCID
Satya R Siddani: AbbVie Inc., North Chicago, Illinois, USA.
Brenda Chyla: AbbVie Inc., North Chicago, Illinois, USA.
Jacqueline Hilger-Rolfe: AbbVie Inc., North Chicago, Illinois, USA.
Justin M Watts: Division of Hematology, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA.
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/m , 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, AUC and C 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.
