Clinical Trials /

MDM2 Inhibitor DS-3032b and Low-Dose Cytarabine in Treating Participants With Newly Diagnosed Recurrent or Refractory Acute Myeloid Leukemia

NCT03634228

Description:

There are 2 phases in this study: Phase 1 (dose escalation) and Phase 2 (dose expansion). The goal of Phase 1 of this clinical research study is to find the highest tolerable dose of DS-3032b that can be given in combination with low-dose cytarabine (LDAC) to patients with relapsed (has come back)/refractory (has stopped responding to treatment) acute myeloid leukemia (AML). The goal of Phase 2 is to learn if the dose of DS-3032b and LDAC found in Phase 1 can help to control the disease. The safety of this drug combination will also be studied in both phases. This is an investigational study. DS-3032b is not FDA approved or commercially available. It is currently being used for research purposes only. LDAC is FDA approved and commercially available for the treatment of AML. It is considered investigational to give DS-3032b in combination with LDAC to treat AML. The study doctor can explain how the study drugs are designed to work. Up to 32 participants will be enrolled in this study. All will take part at MD Anderson.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: MDM2 Inhibitor DS-3032b and Low-Dose Cytarabine in Treating Participants With Newly Diagnosed Recurrent or Refractory Acute Myeloid Leukemia
  • Official Title: A Phase I/II Study of the Oral MDM2 Inhibitor DS-3032b 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 Arising From Previous Myelodysplastic Syndrome
  • Recurrent Acute Myeloid Leukemia
  • Refractory Acute Myeloid Leukemia
  • TP53 Gene Mutation Negative

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-28453Treatment (low dose cytarabine, MDM2 inhibitor DS-3032b)
MDM2 Inhibitor DS-3032bDS-3032 TOSYLATE, DS-3032b, HDM2 Inhibitor DS-3032bTreatment (low dose cytarabine, MDM2 inhibitor DS-3032b)

Purpose

This phase I/II trial studies the side effects of MDM2 inhibitor DS-3032b and low-dose cytarabine and to see how well they work in treating participants with newly diagnosed acute myeloid leukemia that has come back or that does not respond to treatment. MDM2 inhibitor DS-3032b 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. Giving MDM2 inhibitor DS-3032b and low-dose cytarabine may work better in treating participants with recurrent or refractory newly diagnosed acute myeloid leukemia.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the safety and tolerability. (Phase 1) II. To evaluate the efficacy (by
      International Working Group [IWG] criteria - Phase 2) of the MDM2 inhibitor, DS-3032b, in
      combination with low dose cytarabine (LDAC) in both the frontline and 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 (MDM2 inhibitor 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 dose escalation study of MDM2 inhibitor DS-3032b, followed by a phase II
      study.

      Participants receive low dose cytarabine subcutaneously (SC) twice daily (BID) on days 1-7
      and receive MDM2 inhibitor DS-3032b orally (PO) once daily (QD) on days 8-21. Courses 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
Treatment (low dose cytarabine, MDM2 inhibitor DS-3032b)ExperimentalParticipants receive low dose cytarabine SC BID on days 1-7 and receive MDM2 inhibitor DS-3032b PO QD on days 8-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Cytarabine
  • MDM2 Inhibitor DS-3032b

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis of acute myeloid leukemia (AML) by World Health Organization (WHO) 2017
             criteria. Patients will be divided into 2 arms during the Phase 2 portion: Arm A:
             Subjects must have newly diagnosed AML arising from previously-treated myelodysplastic
             syndrome. 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 =< 2

          -  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

          -  A life expectancy of at least 3 months

        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 active treatment within the
             previous 2 years, 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 (eg, 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)

          -  Patient receiving concomitant treatment with a strong inhibitor or inducer of CYP3A4

          -  Received any therapies intended to treat malignancy within 14 days of first receipt of
             DS-3032b (except for hydroxyurea, which is allowed for control prior to and during the
             first cycle of study treatment

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

          -  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 graded according to Common Terminology Criteria for Adverse Events version 5.0 (Phase I)
Time Frame:Up to 1 year
Safety Issue:
Description:MTD is defined the highest dose at which no more than one patient out of 6 patients experience DLTs in the first cycle. A 3+3 algorithm will be applied for dose escalation or dose de-escalation.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated