Alvocidib Biomarker-driven Phase 2 AML Study

Study Overview
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Brief Summary
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The purpose of this two-stage Phase 2 study is to assess the clinical response (Complete Remission) of ACM (Alvocidib/Cytarabine/Mitoxantrone) compared to CM (Cytarabine/Mitoxantrone) treatment in refractory or relapsed AML patients with demonstrated MCL-1 dependence of ≥ 30% by mitochondrial profiling in bone marrow.

Detailed Description
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In Stage 1 of the study, all eligible AML patients with demonstrated MCL-1 dependence of ≥ 30% by mitochondrial profiling in bone marrow will receive treatment with ACM. In Stage 2, all eligible AML patients with demonstrated MCL-1 dependence of ≥ 30% by mitochondrial profiling in bone marrow will be randomized 1:1 to receive either treatment with ACM or CM.

Official Title
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Phase 2, Randomized, Biomarker-driven Clinical Study in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With MCL-1 Dependence ≥30%

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Alvocidib
* Drug: Cytarabine
* Drug: Mitoxantrone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be between the ages of ≥18 and ≤65 years Have an established, pathologically confirmed diagnoses 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 Be in first relapse (within 24 months of CR) or have failed induction therapy* (no CR or CRi after treatment with an intensive regimen (eg, anthracycline/cytarabine ± etoposide, gemtuzumab ozogamicin, or cladribine). *Induction therapy may involve 1 or 2 cycles of the same regimen. Efficacy assessment of induction therapy must be >21 days from the start of the previous induction cycle. Demonstrate MCL-1 dependence of ≥30% by mitochondrial profiling in bone marrow. Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2 Have a serum creatinine level ≤1.8 mg/dL 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) Have a left ventricular ejection fraction (LVEF) >45% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan Be nonfertile 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 during and for at least 6 months after completion of study therapy. Be able to comply with the requirements of the entire study. Provide written informed consent prior to any study related procedure. Exclusion Criteria: Received more than 2 cycles of induction therapy for AML. Investigational agents as part of front-line therapy for AML may by acceptable following discussion with the Medical Monitor. Hydroxyurea is permitted (see #5 below). Received any previous treatment with alvocidib or any other CDK inhibitor Received a hematopoietic stem cell transplant within the previous 2 months Have clinically significant graft versus host disease (GVHD), or GVHD requiring initiation or escalation of treatment within the last 21 days 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 >360 mg/m2 equivalents of daunorubicin Have a peripheral blast count of >30,000/mm3 (may use hydroxyurea as in #5 above) Received antileukemic therapy within the last 3 weeks (with the exception of hydroxyurea or if the patient has definite refractory disease). Refractory patients who received therapy within the last 3 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 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
Maximum Age: 65 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ACM (Stage 1 / Stage 2)<br>A: alvocidib, 30 mg/m2 as a 30 minute intravenous (IV) bolus followed by 60 mg/m2 over 4 hours as an IV infusion administered daily on Days 1-3; C: cytarabine (ara-c), 2 gm/m2 by continuous IV infusion over 72 hours on Days 6-8; M: mitoxantrone (mitoxantrone hydrochloride), 40 mg/m2 by IV infusion over 1-2 hours starting 12 hours after completing cytarabine | Drug: Alvocidib<br> <br> Drug: Cytarabine<br> <br> * Other names: ara-c;Drug: Mitoxantrone<br> <br> * Other names: mitoxantrone hydrochloride;|
| Active Comparator: CM (Stage 2)<br>C: cytarabine (ara-c), 2 gm/m2 by continuous IV infusion over 72 hours on Days 1-3; M: mitoxantrone (mitoxantrone hydrochloride), 40 mg/m2 by IV infusion over 1-2 hours starting 12 hours after completing cytarabine | Drug: Cytarabine<br> <br> * Other names: ara-c;Drug: Mitoxantrone<br> <br> * Other names: mitoxantrone hydrochloride;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR) Rate in Patients With Relapsed or Refractory AML | Complete Remission (CR) rate = Percentage of patients achieving CR after Cycle 1 as defined in Stage 1 by the International Working Group (IWG) Criteria and 2010 European LeukemiaNet (EN) criteria in patients with relapsed or refractory AML with MCL-1 dependence >30% and in Stage 2 by the 2017 ELN criteria. The study was terminated in January 2020 due to a steady and marked reduction in enrollment. Thus, the efficacy endpoints could not be analyzed. As sufficient efficacy results were not available to analyze patients based on the percentage of MCL-1 dependency the treatment efficacy was summarized by distributing the safety population into 6 groups based on whether the patients received the ACM vs CM regimen and their disease stages at study entry. | Best response after at least 1 cycle through study completion approximately 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Refractory AML, Relapsed AML, AML