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

Study Overview
=================
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).

Official Title
-----------------
Phase 1b Study of Venetoclax and Alvocidib in Patients With Relapsed/Refractory Acute Myeloid Leukemia

Conditions
-----------------
Acute Myeloid Leukemia (AML)

Intervention / Treatment
-----------------
* Drug: Venetoclax
* Drug: Alvocidib


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Venetoclax + Alvocidib<br>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. | Drug: Venetoclax<br>* tablet, oral<br>* Other names: ABT-199;Drug: Alvocidib<br>* Intravenous<br>* Other names: Flavopiridol;|

What is the study measuring?
-----------------
Primary Outcome Measures

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

Secondary Outcome Measures

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

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Acute Myeloid Leukemia (AML), relapsed Acute Myeloid Leukemia, refractory Acute Myeloid Leukemia, Cancer