Clinical Trials /

Milademetan Tosylate and Low-Dose Cytarabine With or Without Venetoclax in Treating Participants With Recurrent or Refractory Acute Myeloid Leukemia

NCT03634228

Description:

This phase I/II trial studies the side effects and best dose of milademetan tosylate and to see how well it works with cytarabine with or without ventoclax in treating participants with acute myeloid leukemia that has come back (recurrent) or that does not respond to treatment (refractory). Milademetan tosylate and ventoclax may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known if giving milademetan tosylate and low-dose cytarabine with or without ventoclax will work better in treating participants with recurrent or refractory acute myeloid leukemia.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Milademetan Tosylate and Low-Dose Cytarabine With or Without Venetoclax in Treating Participants With Recurrent or Refractory Acute Myeloid Leukemia
  • Official Title: A Phase I/II Study of the Oral MDM2 Inhibitor DS-3032b (Milademetan) in Combination With Low Dose Cytarabine (LDAC) in Patients With Newly Diagnosed or Relapsed/Refractory Acute Myeloid Leukemia (AML)

Clinical Trial IDs

  • ORG STUDY ID: 2018-0333
  • SECONDARY ID: NCI-2018-01612
  • SECONDARY ID: 2018-0333
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03634228

Conditions

  • Acute Myeloid Leukemia
  • Recurrent Acute Myeloid Leukemia
  • Refractory Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Cytarabine.beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-Beta-D-arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453Arm A (low dose cytarabine, MDM2 inhibitor DS-3032b)
Milademetan TosylateDS-3032 Tosylate, DS-3032b, DS-3032b TosylateArm A (low dose cytarabine, MDM2 inhibitor DS-3032b)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, VenclyxtoArm B (low dose cytarabine, MDM2 inhibitor DS-3032b)

Purpose

This phase I/II trial studies the side effects and best dose of milademetan tosylate and to see how well it works with cytarabine with or without ventoclax in treating participants with acute myeloid leukemia that has come back (recurrent) or that does not respond to treatment (refractory). Milademetan tosylate and ventoclax may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known if giving milademetan tosylate and low-dose cytarabine with or without ventoclax will work better in treating participants with recurrent or refractory acute myeloid leukemia.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the safety and tolerability. (Phase 1) II. To determine the recommended phase
      II dose. (Phase I) III. To evaluate the efficacy (by International Working Group [IWG]
      criteria - Phase 2) of the MDM2 inhibitor, milademetan tosylate (DS-3032b), in combination
      with low dose cytarabine (LDAC), with or without the addition of venetoclax in both the
      frontline and in relapsed/refractory (non-TP53 mutant) patient population.

      SECONDARY OBJECTIVES:

      I. Evaluation of time to response variables including overall survival (OS), event-free
      survival (EFS) and duration of response (DOR).

      II. Determine biomarkers that may be predictive of DS-3032b activity. III. Molecular
      profiling at screening, on study, and at relapse to determine genomic predictors of response
      and resistance.

      OUTLINE: This is a phase I, dose escalation study of milademetan tosylate, followed by a
      phase II study. Patients are assigned to 1 of 2 arms.

      ARM A: Patients receive low dose cytarabine subcutaneously (SC) twice daily (BID) on days
      1-10 and milademetan tosylate orally (PO) once daily (QD) on days 8-14, 8-21, or 5-7 and
      15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable
      toxicity.

      ARM B: Patients receive low dose cytarabine SC BID on days 1-10, milademetan tosylate PO QD
      on days 8-14, 8-21, or 5-7 and 15-17, and venetoclax PO QD on days 1-14. Cycles repeat every
      28 days in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment participants are followed up at 30 days.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (low dose cytarabine, MDM2 inhibitor DS-3032b)ExperimentalPatients receive low dose cytarabine SC BID on days 1-10 and milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Cytarabine
  • Milademetan Tosylate
Arm B (low dose cytarabine, MDM2 inhibitor DS-3032b)ExperimentalPatients receive low dose cytarabine SC BID on days 1-10, milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17, and venetoclax PO QD on days 1-14. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Cytarabine
  • Milademetan Tosylate
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis of acute myeloid leukemia (AML) by World Health Organization (WHO) 2016
             criteria. Patients will be divided into 2 arms during the phase 2 portion:

               -  Arm A: Subjects must have newly diagnosed AML

               -  Arm B: Subjects must have refractory or relapsed AML

          -  TP53 wild-type status on molecular testing performed within the last 3 months

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 3

          -  Creatinine clearance >= 60 mL/min, as calculated using the modified Cockcroft-Gault
             equation OR creatinine =< 1.5 x upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN

          -  Bilirubin =< 1.5 x ULN, unless resulting from hemolysis, Gilbert's disease or
             considered to be due to leukemic involvement

          -  No gastrointestinal issues to interfere with oral medication absorption

          -  No active uncontrolled infection or comorbidity that would interfere with therapy or
             place patient at increased risk

          -  Subject (male and female) of childbearing/reproductive potential must agree to use
             double-barrier contraceptive measures or avoid intercourse during the study and for 90
             days after the last dose of study drug

          -  Subject must sign and date an Institutional Review Board-approved informed consent
             form (including Health Insurance Portability and Accountability Act authorization, if
             applicable) before performance of any study-specific procedures or tests

          -  Able and willing to provide bone marrow biopsies/aspirates as requested by the
             protocol

          -  Willing to undergo malignancy genotyping for TP53 mutation, insertion, or deletion at
             screening

          -  Use of hydroxyurea is allowed prior to and during the first cycle of study treatment.
             1‐2 doses of cytarabine are also permitted if needed for cytoreduction prior to
             initiating study treatment

        Exclusion Criteria:

          -  Patient with t(15;17) karyotypic abnormality or a diagnosis of acute promyelocytic
             leukemia

          -  Patient with other malignancy that contains a non-synonymous mutation, insertion, or
             deletion in the TP53 gene determined previously or at screening

          -  Prior treatment with an MDM2 inhibitor

          -  Presence of central nervous system involvement of leukemia. History of prior
             leptomeningeal leukemia/disease that has fully resolved is eligible

          -  A second concurrent primary malignancy that has required systemic anti‐neoplastic
             treatment within the previous 6 months, except for localized cancers that have
             apparently been cured, for example non‐melanoma skin cancer, superficial bladder
             cancer, or carcinoma in situ of the cervix or breast

          -  Any condition that would preclude adequate absorption of DS-3032b, including
             refractory vomiting, malabsorption, biliary shunt, significant bowel resection, and/or
             graft-versus-host disease (GVHD) affecting the gut

          -  Any active uncontrolled infection, known human immunodeficiency virus infection, or
             active hepatitis B or C infection

          -  Any concomitant medical condition that would in the opinion of the investigator
             increase the risk of toxicity

          -  Unresolved toxicities from previous anticancer therapy, defined as toxicities (other
             than alopecia) not yet resolved to National Cancer Institute (NCI)-Common Terminology
             Criteria for Adverse Events (CTCAE) version (v) 5, grade =< 1 or baseline. Subjects
             with chronic grade 2 toxicities may be eligible per discretion of the investigator and
             sponsor (e.g., grade 2 chemotherapy-induced neuropathy)

          -  Patient having received hematopoietic stem cell transplantation (HSCT) within 60 days
             of the first dose of DS-3032b, is on immuno-suppressive therapy post-HSCT at the time
             of screening, or has clinically significant GVHD (use of topical steroids for ongoing
             skin GVHD will be permitted)

          -  Prolongation of corrected QT interval using Fridericia's method (QTcF) at rest, where
             the mean QTcF interval is >= 450 ms for males or >= 470 ms for females based on
             electrocardiograms (ECGs). Patients with right bundle branch block (RBBB) will be
             eligible after discussion with principal investigator (PI)

          -  Pregnant or breastfeeding

          -  Substance abuse or medical, psychological, or social conditions that, in the opinion
             of the investigator, may interfere with the subject's participation in the clinical
             study or evaluation of the clinical study results
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events (Phase I)
Time Frame:Up to 1 year
Safety Issue:
Description:Graded according to Common Terminology Criteria for Adverse Events version 5.0.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

May 29, 2020