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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 16, 2018
Sponsor:
Information provided by (Responsible Party):
Tolero Pharmaceuticals, Inc.

August 6, 2015
August 11, 2015
October 16, 2018
March 14, 2016
March 2019   (Final data collection date for primary outcome measure)
Complete Remission (CR) rate = Percentage of patients achieving CR [ Time Frame: 3 months ]
Same as current
Complete list of historical versions of study NCT02520011 on ClinicalTrials.gov Archive Site
  • Overall Survival (OS) Rate [ Time Frame: 2 years ]
    Day 1 until death from any cause
  • Combined CR Rate = Percentage of patients achieving CR, CRi, CRp [ Time Frame: 3 months ]
  • Combined Response Rate = Percentage of patients achieving CR, CRi, CRp, PR [ Time Frame: 3 months ]
  • Rate of Stem Cell Transplantation [ Time Frame: 6 months ]
  • Event-Free Survival [ Time Frame: 2 years ]
  • Combined CR Rate = Percentage of patients achieving CR, CRi, CRp [ Time Frame: 3 months ]
  • Combined Response Rate = Percentage of patients achieving CR, CRi, CRp, PR [ Time Frame: 3 months ]
  • Event-Free Survival [ Time Frame: 2 years ]
  • Relapse-Free Survival [ Time Frame: 2 years ]
Mortality [ Time Frame: 30 and 60 days ]
Same as current
 
Alvocidib Biomarker-driven Phase 2 AML Study
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
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.

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.

Interventional
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Acute Myeloid Leukemia
  • Drug: Alvocidib
  • Drug: Cytarabine
    Other Name: ara-c
  • Drug: Mitoxantrone
    Other Name: mitoxantrone hydrochloride
  • 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
    Interventions:
    • Drug: Alvocidib
    • Drug: Cytarabine
    • Drug: Mitoxantrone
  • 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
    Interventions:
    • Drug: Cytarabine
    • Drug: Mitoxantrone
  • 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
    Interventions:
    • Drug: Alvocidib
    • Drug: Cytarabine
    • Drug: Mitoxantrone
  • 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
    Interventions:
    • Drug: Alvocidib
    • Drug: Cytarabine
    • Drug: Mitoxantrone
  • 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
    Interventions:
    • Drug: Alvocidib
    • Drug: Cytarabine
    • Drug: Mitoxantrone
  • 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
    Interventions:
    • Drug: Alvocidib
    • Drug: Cytarabine
    • Drug: Mitoxantrone
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
209
79
December 2019
March 2019   (Final data collection date for primary outcome measure)

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.
Sexes Eligible for Study: All
18 Years to 65 Years   (Adult, Older Adult)
No
Contact: Judy Costas, BSN 361-649-9176 jcostas@toleropharma.com
Canada,   Spain,   United Kingdom,   United States
 
 
NCT02520011
TPI-ALV-201
Yes
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Plan to Share IPD: No
Tolero Pharmaceuticals, Inc.
Tolero Pharmaceuticals, Inc.
Not Provided
Study Director: Stephen Anthony, DO Tolero Pharmaceuticals
Tolero Pharmaceuticals, Inc.
October 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP