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Alvocidib Biomarker-driven Phase 2 AML Study

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ClinicalTrials.gov Identifier: NCT02520011
Recruitment Status : Recruiting
First Posted : August 11, 2015
Last Update Posted : October 30, 2018
Sponsor:
Information provided by (Responsible Party):
Tolero Pharmaceuticals, 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 ≥ 40% by mitochondrial profiling in bone marrow.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: Alvocidib Drug: Cytarabine Drug: Mitoxantrone Phase 2

Detailed Description:

In Stage 1 of the study, all eligible AML patients with demonstrated MCL-1 dependence of ≥ 40% by mitochondrial profiling in bone marrow will receive treatment with ACM.

In Stage 2, all eligible AML patients with demonstrated MCL-1 dependence of ≥ 40% by mitochondrial profiling in bone marrow will be randomized 1:1 to receive either treatment with ACM or CM.

In the NDHR exploratory arm, all eligible patients with newly diagnosed high-risk (NDHR) AML with MCL-1 dependence of ≥40% by mitochondrial profiling in bone marrow will receive treatment with ACM.

In the MCL-1 dependency exploratory arms, all eligible AML patients with demonstrated MCL-1 dependence of ≥ 30 - <40% (Arm A), 15% - <30% (Arm B), or 0 - <15% (Arm C) by mitochondrial profiling in bone marrow who are either in first relapse (within 24 months of CR) or have primary refractory AML (ie, no CR or CRi after 2 cycles of intensive anthracycline/cytarabine ± etoposide or cladribine induction) will receive treatment with ACM.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 209 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 2, Randomized, Biomarker-driven Study in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With an Exploratory Arm in Patients With Newly Diagnosed High-Risk AML and Exploratory Arms With Varying Levels of MCL-1 Dependence
Actual Study Start Date : March 14, 2016
Estimated Primary Completion Date : March 2019
Estimated Study Completion Date : December 2019


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: Alvocidib
Drug: Cytarabine
Other Name: ara-c

Drug: Mitoxantrone
Other Name: mitoxantrone hydrochloride

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: Cytarabine
Other Name: ara-c

Drug: Mitoxantrone
Other Name: mitoxantrone hydrochloride

Experimental: Exploratory Arm - NDHR
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
Drug: Cytarabine
Other Name: ara-c

Drug: Mitoxantrone
Other Name: mitoxantrone hydrochloride

Experimental: Exploratory Arm A - MCL-1 Dependence 30-<40%
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
Drug: Cytarabine
Other Name: ara-c

Drug: Mitoxantrone
Other Name: mitoxantrone hydrochloride

Experimental: Exploratory Arm B - MCL-1 Dependence 15-<30%
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
Drug: Cytarabine
Other Name: ara-c

Drug: Mitoxantrone
Other Name: mitoxantrone hydrochloride

Experimental: Exploratory Arm C - MCL-1 Dependence 0-<15%
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
Drug: Cytarabine
Other Name: ara-c

Drug: Mitoxantrone
Other Name: mitoxantrone hydrochloride




Primary Outcome Measures :
  1. Complete Remission (CR) rate = Percentage of patients achieving CR [ Time Frame: 3 months ]

Secondary Outcome Measures :
  1. Overall Survival (OS) Rate [ Time Frame: 2 years ]
    Day 1 until death from any cause

  2. Combined CR Rate = Percentage of patients achieving CR, CRi, CRp [ Time Frame: 3 months ]
  3. Combined Response Rate = Percentage of patients achieving CR, CRi, CRp, PR [ Time Frame: 3 months ]
  4. Rate of Stem Cell Transplantation [ Time Frame: 6 months ]
  5. Event-Free Survival [ Time Frame: 2 years ]

Other Outcome Measures:
  1. Mortality [ Time Frame: 30 and 60 days ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 primary refractory AML (no CR or CRi after 2 cycles of intensive anthracycline/cytarabine ± etoposide or cladribine induction) or have NDHR AML as defined in this protocol.
  4. Demonstrate MCL-1 dependence of ≥40% by mitochondrial profiling in bone marrow, 30 - <40% for MCL-1 Dependency Exploratory Arm A, 15% - <30% (MCL-1 Dependency Exploratory Arm B), or 0 - <15% (MCL-1 Dependency Exploratory Arm C)
  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 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02520011


Contacts
Contact: Judy Costas, BSN 361-649-9176 jcostas@toleropharma.com

  Show 29 Study Locations
Sponsors and Collaborators
Tolero Pharmaceuticals, Inc.
Investigators
Study Director: Stephen Anthony, DO Tolero Pharmaceuticals

Responsible Party: Tolero Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT02520011     History of Changes
Other Study ID Numbers: TPI-ALV-201
First Posted: August 11, 2015    Key Record Dates
Last Update Posted: October 30, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Tolero Pharmaceuticals, Inc.:
Refractory AML
Relapsed AML
AML
Newly diagnosed high-risk AML

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Alvocidib
Mitoxantrone
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Growth Inhibitors
Growth Substances
Protein Kinase Inhibitors