Clinical Trials /

Alvocidib Biomarker-driven Phase 2 AML Study

NCT02520011

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Alvocidib Biomarker-driven Phase 2 AML Study
  • Official Title: Phase 2, Randomized, Biomarker-driven Clinical Study in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With MCL-1 Dependence ≥40%

Clinical Trial IDs

  • ORG STUDY ID: TPI-ALV-201
  • NCT ID: NCT02520011

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
AlvocidibACM (Stage 1 / Stage 2)
Cytarabineara-cACM (Stage 1 / Stage 2)
Mitoxantronemitoxantrone hydrochlorideACM (Stage 1 / Stage 2)

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
ACM (Stage 1 / Stage 2)ExperimentalA: 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
  • Alvocidib
  • Cytarabine
  • Mitoxantrone
CM (Stage 2)Active ComparatorC: 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
  • Cytarabine
  • Mitoxantrone

Eligibility 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 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 ≥40% 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 prior to study entry, for the duration of study participation,
             and for at least 3 months (males) and 6 months (females) after the last dose of study
             drug.

         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.
      
Maximum Eligible Age:65 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete Remission (CR) rate = Percentage of patients achieving CR after Cycle 1 as defined in Stage 1 by the International Working Group Criteria and 2010 European LeukemiaNet (ELN) criteria and in Stage 2 by the 2017 ELN criteria.
Time Frame:3 months
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Overall Survival (OS) Rate
Time Frame:2 years
Safety Issue:
Description:Day 1 until death from any cause
Measure:Combined CR Rate = Percentage of patients achieving CR, CRi, CRp (CRp is kept in definitions for Combined CR Rate / Combined Remission Rate as Stage-1 patients were assessed by IWG criteria. CRp won't be used for assessing Stage-2 patients.)
Time Frame:3 months
Safety Issue:
Description:
Measure:Combined Response Rate = Percentage of patients achieving CR, CRi, CRp, PR
Time Frame:3 months
Safety Issue:
Description:
Measure:Rate of Stem Cell Transplantation
Time Frame:6 months
Safety Issue:
Description:
Measure:Event-Free Survival
Time Frame:2 years
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Tolero Pharmaceuticals, Inc.

Trial Keywords

  • Refractory AML
  • Relapsed AML
  • AML

Last Updated

May 21, 2019