Study of Alvocidib in Patients With Relapsed/Refractory AML Following Treatment With Venetoclax Combination Therapy

Study Overview
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Brief Summary
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This study will evaluate the safety and efficacy of alvocidib in patients with AML who have either relapsed from or are refractory to venetoclax in combination with azacytidine or decitabine.

Official Title
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A Phase 2, Open-label, Randomized, Two-stage Clinical Study of Alvocidib in Patients With Relapsed/Refractory Acute Myeloid Leukemia Following Treatment With Venetoclax Combination Therapy

Conditions
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Acute Myeloid Leukemia (AML)

Intervention / Treatment
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* Drug: Alvocidib (flavopiridol) and cytarabine (Ara-C)
* Drug: Alvocidib (flavopiridol)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be ≥18 years of age. Have an established, pathologically confirmed diagnosis of AML by World Health Organization (WHO) criteria, excluding acute promyelocytic leukemia (APL-M3) with a bone marrow of >5% blasts based on histology or flow cytometry. Have received initial induction therapy with venetoclax in combination with azacytidine or decitabine (with or without other investigational agents as part of a clinical trial; requires Medical Monitor review) and were either refractory (failed to achieve a CR/CRi or achieved a CR/CRi with duration <90 days) or have relapsed (reoccurrence of disease following a CR/CRi with duration ≥90 days). Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2. Have a glomerular filtration rate (GFR) ≥30 mL/min using the Cockcroft-Gault equation. Have an alanine aminotransferase (ALT)/aspartate aminotransferase (AST) level ≤5 times upper limit of normal (ULN). Have a total bilirubin level ≤2.0 mg/dL (unless secondary to Gilbert syndrome, hemolysis, or leukemia). Be infertile or agree to use an adequate method of contraception:sexually active patients and their partners must use an effective method of contraception associated with a low failure rate prior to study entry, for the duration of study participation, and for at least 3 months (males) and 6 months (females) after the last dose of study drug. Be able to comply with the requirements of the entire study. Provide written informed consent prior to any study related procedure: in the event that the patient is re-screened for study participation or a protocol amendment alters the care of an ongoing patient, a new informed consent form must be signed. Exclusion Criteria: Received any previous treatment with alvocidib or any other CDK inhibitor or received prior anti-leukemic therapy other than first-line venetoclax in combination with azacytidine or decitabine. Require concomitant chemotherapy, radiation therapy, or immunotherapy. Hydroxyurea is allowed up to the evening before starting (but not within 12 hours) of starting treatment on either arm. Received an allogeneic stem cell transplant within 60 days of the start of study treatment. Patients who received an allogeneic stem cell transplant must be off all immunosuppressants at the time of study treatment Are receiving or have received systemic therapy for graft-versus-host disease. Have a peripheral blast count of >30,000/mm3 (may use hydroxyurea as in #2 above). Received antileukemic therapy within the last 2 weeks or 3-5 half lives of the prior therapy (with the exception of hydroxyurea or if the patient has definite refractory disease), whichever is less. Refractory patients who received therapy within the last 2 weeks may be eligible with prior approval of the Medical Monitor. Diagnosed with acute promyelocytic leukemia (APL-M3). Have active central nervous system (CNS) leukemia. Have evidence of uncontrolled disseminated intravascular coagulation. Have an active, uncontrolled infection. Have other life-threatening illness. Have other active malignancies requiring treatment or diagnosed with other malignancies within the last 6 months, except nonmelanoma skin cancer or cervical intraepithelial neoplasia. Have mental deficits and/or psychiatric history that may compromise the ability to give written informed consent or to comply with the study protocol. Are pregnant and/or nursing. Have received any live vaccine within 14 days prior to first study drug administration.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, Two-stage
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lead-In Cohort: Arm 1<br>Refractory (i.e., failed to achieve a CR/CRi or achieved a CR/CRi with duration <90 days) | Drug: Alvocidib (flavopiridol) and cytarabine (Ara-C)<br>* Alvocidib (flavopiridol), administered intravenously, + cytarabine (Ara-C), administered by subcutaneous injection<br>|
| Experimental: Lead-In Cohort: Arm 2<br>Relapsed (i.e., reoccurrence of disease following a CR/CRi with duration ≥90 days). | Drug: Alvocidib (flavopiridol)<br>* Administered intravenously<br>|
| Experimental: Stage 1: Arm 1<br>Refractory (i.e., failed to achieve a CR/CRi or achieved a CR/CRi with duration <90 days) | Drug: Alvocidib (flavopiridol) and cytarabine (Ara-C)<br>* Alvocidib (flavopiridol), administered intravenously, + cytarabine (Ara-C), administered by subcutaneous injection<br>|
| Experimental: Stage 1: Arm 2<br>Relapsed (i.e., reoccurrence of disease following a CR/CRi with duration ≥90 days). | Drug: Alvocidib (flavopiridol)<br>* Administered intravenously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Combined Complete Remission | Rate of combined complete remission (complete remission (CR) + CR with incomplete hematological recovery (CRi)), as defined by the International Working Group Criteria and 2017 European LeukemiaNet). Combined complete remissions (patients with a best response of CR or CRi), complete remissions, composite complete remissions (patients with a best response of CR, CRi or CRh), and combined responses (patients with a best response of CR, CRi, CRh, MLFS or PR) will be summarized by observed response rates and estimated 95% CIs. | Response assessments were measured from date of first dose through End of Treatment date, an average of 3 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Overall Survival | Time from treatment (Day 1) until death from any cause | From first dose until disease progression or death; through study termination, an average of 10 months | 
| Complete Response Rate | Percentage of patients achieving complete response (CR) whose bone marrow is determined to be negative for minimal residual disease (MRD) using standardized techniques (ie, multiparametric flow cytometry [MPFC] and molecular testing including next generation sequencing [NGS] | Response assessments were measured from date of first dose through end of treatment date, an average of 3 months | 
| Composite CR Rate | Patients with a best response of CR + CRi + CRh (CR + partial recovery of both blood cell types) | Response assessments were measured from date of first dose through end of treatment date, an average of 3 months | 
| Combined Response Rate | Combined Percentage of Patients Achieving One of the Following: CR < CRi, CRh, MLFS, PR Morphologic leukemia-free state (MLFS) = Bone marrow blasts <5%; absence of blasts with Auer rods; absence of extramedullary disease; no hematologic recovery required; Partial Response (PR) = Meets all hematologic values required for CR but with a decrease of at least 50% in the percentage of blasts to ≥5% to ≤25% in bone marrow | Response assessments were measured from date of first dose through end of treatment date, an average of 3 months | 
| Event Free Survival (EFS) | Event Free Survival - time from first treatment (D1) until (a) treatment failure, (b) relapse after CR/Cri or CRh, or (c) death from any cause, whichever occurs first | From first dose until disease progression or death; through study termination, an average of 10 months | 
| Duration of Composite Complete Remission (CR) | Duration of Composite CR, defined as the time from first documented response of CR, CRi or CRhi to relapse or death from any cause | Response assessments were measured from date of first dose through end of treatment date, an average of 3 months | 
| Transfusion Independence | Rates of 28- and 56-day Transfusion Independence (TI) = Percentages of patients who do not receive red blood cell (RBC) transfusions, platelet (PLT) transfusions, and neither RBC nor PLT transfusions for 28 and 56 days; comprised of 6 secondary endpoints | Transfusion dependence was measured from 28 days prior to first dose through 56 days after last dose, an average of 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tolero, Phase 2, AML, Relapsed, Refractory, Alvocidib, Venetoclax