Alvocidib Biomarker-driven Phase 2 AML Study
- Conditions
- Acute Myeloid Leukemia
- Interventions
- Registration Number
- NCT02520011
- Lead Sponsor
- Sumitomo Pharma America, Inc.
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 104
-
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.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description CM (Stage 2) Mitoxantrone 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 CM (Stage 2) Cytarabine 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 ACM (Stage 1 / Stage 2) Cytarabine 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 ACM (Stage 1 / Stage 2) Mitoxantrone 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 ACM (Stage 1 / Stage 2) Alvocidib 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
- Primary Outcome Measures
Name Time Method Complete Response (CR) Rate in Patients With Relapsed or Refractory AML Best response after at least 1 cycle through study completion approximately 4 years 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.
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (38)
Honor Health Research Institute
🇺🇸Scottsdale, Arizona, United States
Mayo Clinic Florida
🇺🇸Jacksonville, Florida, United States
Morristown Cancer Center
🇺🇸Morristown, New Jersey, United States
Hospital Regional Universitario de Malaga
🇪🇸Málaga, Malaga, Spain
Institut Catala d'Oncologia
🇪🇸Badalona, Spain
Hospital Clinic de Barcelona
🇪🇸Barcelona, Spain
Hospital Universitario Central de Asturias - HUCA
🇪🇸Oviedo, Spain
Hospital Clinico Universitario de Salamanca
🇪🇸Salamanca, Spain
Hospital Universitari i Politècnic La Fe
🇪🇸Valencia, Spain
University Hospitals of Wales
🇬🇧Cardiff, Wales, United Kingdom
Univ Hospital of Bristol
🇬🇧Bristol, United Kingdom
Guys Hospital St. Thomas
🇬🇧London, United Kingdom
Northwestern Memorial Hospital
🇺🇸Chicago, Illinois, United States
Sidney Kimmel Cancer Center at Johns Hopkins
🇺🇸Baltimore, Maryland, United States
East Carolina University
🇺🇸Greenville, North Carolina, United States
Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States
Ohio State University
🇺🇸Columbus, Ohio, United States
Baylor Sammons Cancer Center
🇺🇸Dallas, Texas, United States
Princess Margaret Cancer Center
🇨🇦Toronto, Ontario, Canada
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
University of California Los Angeles (UCLA)
🇺🇸Los Angeles, California, United States
Northside Hospital
🇺🇸Atlanta, Georgia, United States
University of Iowa
🇺🇸Iowa City, Iowa, United States
Roswell Park Cancer Center Institute
🇺🇸Buffalo, New York, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
West Penn Allegheny Hospital
🇺🇸Pittsburgh, Pennsylvania, United States
University of California San Diego UCSD
🇺🇸San Diego, California, United States
Mayo Clinic Rochester
🇺🇸Rochester, Minnesota, United States
University of Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
Duke
🇺🇸Durham, North Carolina, United States
Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
Hudson Valley Cancer Center
🇺🇸Hawthorne, New York, United States
Complejo Hospitalario Universitario de Albacete
🇪🇸Albacete, Spain
Hospital San Pedro de Alcantara
🇪🇸Cáceres, Spain
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
Ochsner Clinic Foundation
🇺🇸New Orleans, Louisiana, United States
University of North Carolina
🇺🇸Chapel Hill, North Carolina, United States
University of Kansas Medical Center
🇺🇸Westwood, Kansas, United States