A Study of Venetoclax and Alvocidib in Patients With Relapsed/Refractory Acute Myeloid Leukemia

Phase 1

Completed

Brief Summary: An open-label, dose-escalation study to assess the safety and pharmacokinetics (PK), to determine the dose limiting toxicity (DLT) and the recommended Phase 2 dose (RPTD), and to assess the preliminary efficacy of alvocidib with venetoclax when co-administered in participants with relapsed or refractory (R/R) acute myeloid leukemia (AML).

Recruitment & Eligibility

Inclusion Criteria

Must have adequate coagulation, hematology, kidney, and liver function, per protocol.
Diagnosis of relapsed or refractory (R/R) acute myeloid leukemia (AML)
Meet the following disease activity criteria:
an established, confirmed diagnosis of AML by World Health Organization criteria excluding acute promyelocytic leukemia (APL)-M3; and
an Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.
If male participant is sexually active, he must agree from day 1 through 6 months after the last dose of alvocidib or 90 days after the last dose of venetoclax, whichever is longer, to practice the protocol-specified protection.

Exclusion Criteria

History of any malignancy within the last 6 months except for those specified in this protocol and low-grade malignancies not requiring active treatment such as non-melanoma skin cancer, cervical intraepithelial neoplasia, or prostate cancer in situ.
Prior allogeneic stem cell transplant within 6 months of study drug administration and no requirement for graft versus host therapy.
History of previous enrollment in Studies NCT02993523 or NCT03069352.
History of exposure to alvocidib or any other cyclin-dependent kinase 9 (CDK9) inhibitor.
History of Tumor Lysis Syndrome (TLS) due to previous exposure to venetoclax.

Arm && Interventions

Group	Intervention	Description
Venetoclax + Alvocidib	Venetoclax	Venetoclax administered orally once daily (QD) and Alvocidib administered as an intravenous infusion on Days 1, 2, and 3 for all 28-day treatment cycles. Different combinations of dose levels for venetoclax and alvocidib may be explored.
Venetoclax + Alvocidib	Alvocidib	Venetoclax administered orally once daily (QD) and Alvocidib administered as an intravenous infusion on Days 1, 2, and 3 for all 28-day treatment cycles. Different combinations of dose levels for venetoclax and alvocidib may be explored.

Primary Outcome Measures

Name	Time	Method
Tmax of venetoclax	Approximately 32 days after first dose of study drug	Time to maximum plasma concentration (Tmax) of venetoclax
Clearance of Alvocidib	Approximately 32 days after first dose of study drug	Clearance (CL) of alvocidib
AUC0-∞ of Alvocidib	Approximately 32 days after first dose of study drug	Area under the plasma concentration-time curve from 0 to infinity (AUC0-∞) post-dose of alvocidib
Cmax of Venetoclax	Approximately 32 days after first dose of study drug	Maximum plasma concentration (Cmax) of venetoclax
Half-life (t1/2) of Alvocidib	Approximately 32 days after first dose of study drug	Half-life (t1/2) of alvocidib
AUC0-24 Post-dose of Venetoclax	Approximately 32 days after first dose of study drug	Area under the plasma concentration-time curve from 0 to 24 hours (AUC24) post-dose of venetoclax.
Cmax of Alvocidib	Approximately 32 days after first dose of study drug	Maximum plasma concentration (Cmax) of alvocidib.
AUCt Post-dose of Alvocidib	Approximately 32 days after first dose of study drug	Area under the plasma concentration-time curve from time zero to time t (AUCt) post-dose alvocidib.
Dose Escalation Phase: Recommended Phase 2 dose (RPTD) for Venetoclax and Alvocidib	Minimum first cycle of dosing (up to 28 days)	RPTD will be determined using available safety and pharmacokinetics data upon completion of the dose escalation phase.

Secondary Outcome Measures

Name	Time	Method
Complete Response (CR) Rate	Up to approximately 8 months	CR is defined as the proportion of participants with documented complete response (CR) based on International Working Group (IWG) criteria.
Combined CR Rate	Up to approximately 8 months	Combined CR rate is defined as CR + CRi (CR with incomplete blood count recovery) based on IWG criteria.
Objective Response Rate (ORR)	Up to approximately 18 months	ORR is defined as the proportion of participants with documented partial response (PR) or better based on IWG criteria.

Locations (14): Univ Klinik Eppendorf Hamburg /ID# 168633
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Hamburg, Germany
NYU Langone Medical Center /ID# 201559
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New York, New York, United States
University of Pittsburgh Medic /ID# 170790
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Pittsburgh, Pennsylvania, United States
University Hospital of Wales /ID# 202302
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Cardiff, United Kingdom
Universitaetsklinikum Dresden /ID# 168636
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Dresden, Germany
Weill Cornell Medical College /ID# 170800
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New York, New York, United States
St. James University Hospital /ID# 202303
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Leeds, United Kingdom
University of California, Davis Comprehensive Cancer Center /ID# 170799
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Sacramento, California, United States
Sylvester Comprehensive Cancer /ID# 170761
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Miami, Florida, United States
Ninewells Hospital /ID# 202304
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Dundee, United Kingdom
Indiana Blood & Marrow Transpl /ID# 170793
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Indianapolis, Indiana, United States
USC Norris Cancer Center /ID# 170844
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Los Angeles, California, United States
UC Irvine /ID# 201093
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Orange, California, United States
Duke University Medical Center /ID# 170842
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Durham, North Carolina, United States