Alvocidib Biomarker-driven Phase 2 AML Study

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

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.

Study Overview

• Status: Terminated
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Mitoxantrone; Drug: Cytarabine; Drug: Alvocidib

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 104
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Center
• Spain
  • Albacete, Spain, 02006
    • Complejo Hospitalario Universitario de Albacete
  • Badalona, Spain
    • Institut Catala D'oncologia
  • Barcelona, Spain, 08036
    • Hospital Clinic De Barcelona
  • Cáceres, Spain
    • Hospital San Pedro de Alcantara
  • Oviedo, Spain, 33011
    • Hospital Universitario Central de Asturias - HUCA
  • Salamanca, Spain, 37007
    • Hospital Clinico Universitario de Salamanca
  • Valencia, Spain
    • Hospital Universitari i Politecnic La Fe
  • Malaga
    • Málaga, Malaga, Spain, 29010
      • Hospital Regional Universitario de Malaga
• United Kingdom
  • Bristol, United Kingdom
    • Univ Hospital of Bristol
  • London, United Kingdom
    • Guys Hospital St. Thomas
  • Wales
    • Cardiff, Wales, United Kingdom, CF10 3NS
      • University Hospitals of Wales
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • Honor Health Research Institute
  • California
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles (UCLA)
    • San Diego, California, United States, 92093-2024
      • University of California San Diego UCSD
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Florida
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Northside Hospital
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern Memorial Hospital
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Kansas
    • Westwood, Kansas, United States, 66205
      • University of Kansas Medical Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Clinic Foundation
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Sidney Kimmel Cancer Center at Johns Hopkins
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Rochester
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • New Jersey
    • Morristown, New Jersey, United States, 07960
      • Morristown Cancer Center
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Center Institute
    • Hawthorne, New York, United States, 10532
      • Hudson Valley Cancer Center
    • New York, New York, United States, 10032
      • Columbia University Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke
    • Greenville, North Carolina, United States, 27858
      • East Carolina University
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Columbus, Ohio, United States, 43210
      • Ohio State University
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • West Penn Allegheny Hospital
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor Sammons Cancer Center
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Be between the ages of ≥18 and ≤65 years
2. 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

3. 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.

4. Demonstrate MCL-1 dependence of ≥30% by mitochondrial profiling in bone marrow.
5. Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2
6. Have a serum creatinine level ≤1.8 mg/dL
7. Have an alanine aminotransferase (ALT)/aspartate aminotransferase (AST) level ≤5 times upper limit of normal (ULN)
8. Have a total bilirubin level ≤2.0 mg/dL (unless secondary to Gilbert syndrome, hemolysis, or leukemia)
9. Have a left ventricular ejection fraction (LVEF) >45% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan
10. 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.
11. Be able to comply with the requirements of the entire study.
12. Provide written informed consent prior to any study related procedure.

Exclusion Criteria:

1. 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).
2. Received any previous treatment with alvocidib or any other CDK inhibitor
3. Received a hematopoietic stem cell transplant within the previous 2 months
4. Have clinically significant graft versus host disease (GVHD), or GVHD requiring initiation or escalation of treatment within the last 21 days
5. 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.
6. Received >360 mg/m2 equivalents of daunorubicin
7. Have a peripheral blast count of >30,000/mm3 (may use hydroxyurea as in #5 above)
8. 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.
9. Diagnosed with acute promyelocytic leukemia (APL, M3)
10. Have active central nervous system (CNS) leukemia
11. Have evidence of uncontrolled disseminated intravascular coagulation
12. Have an active, uncontrolled infection
13. Have other life-threatening illness
14. Have other active malignancies or diagnosed with other malignancies within the last 6 months, except nonmelanoma skin cancer or cervical intraepithelial neoplasia
15. Have mental deficits and/or psychiatric history that may compromise the ability to give written informed consent or to comply with the study protocol.
16. Are pregnant and/or nursing
17. Have received any live vaccine within 14 days prior to first study drug administration.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ACM (Stage 1 / Stage 2); 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: Mitoxantrone; Other Names: mitoxantrone hydrochloride; Drug: Cytarabine; Other Names: ara-c; Drug: Alvocidib
Active Comparator: CM (Stage 2); 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: Mitoxantrone; Other Names: mitoxantrone hydrochloride; Drug: Cytarabine; Other Names: ara-c

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response to Treatment	To determine if treatment with ACM can induce CR in patients with relapsed or refractory AML with MCL-1 dependence of >30% who failed to achieve CR following 1 cycle of CM	Best response after at least 1 cycle through study completion approximately 4 years

Collaborators and Investigators

• Sponsor: Sumitomo Pharma America, Inc.
• Investigators: Study Director: Stephen Anthony, DO, Sumitomo Pharma America, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): March 14, 2016
• Primary Completion (Actual): February 12, 2020
• Study Completion (Actual): February 12, 2020

Study Registration Dates

• First Submitted: August 6, 2015
• First Submitted That Met QC Criteria: August 6, 2015
• First Posted (Estimated): August 11, 2015

Study Record Updates

• Last Update Posted (Actual): November 15, 2023
• Last Update Submitted That Met QC Criteria: November 13, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: AML; Relapsed AML; Refractory AML
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Cytarabine; Mitoxantrone; Alvocidib
• Other Study ID Numbers: TPI-ALV-201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No