Milademetan Tosylate and Low-Dose Cytarabine in Treating Participants with Recurrent or Refractory Acute Myeloid Leukemia

Status: Active


This phase I / II trial studies the side effects and best dose of milademetan tosylate and to see how well it works with cytarabine in treating participants with acute myeloid leukemia that has come back (recurrent) or that does not respond to treatment (refractory). Milademetan tosylate 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 milademetan tosylate and low-dose cytarabine may work better in treating participants with recurrent or refractory acute myeloid leukemia.

Eligibility Criteria

Inclusion Criteria

  • Subjects must have refractory or relapsed AML (salvage 1, 2, and 3)
  • 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 (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)
  • Patient receiving treatment with a strong inhibitor or inducer of CYP3A4; patient receiving drugs that are strong CYP3A inhibitors within 7 days prior to the first dose and during treatment; patient receiving drugs that are strong inducers of CYP3A within 14 days prior to the first dose and during treatment
  • 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

Locations & Contacts


M D Anderson Cancer Center
Status: Active
Contact: Kiran Naqvi
Phone: 713-745-6877

Trial Objectives and Outline


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) in relapsed/refractory (non-TP53 mutant) patient population.


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 (milademetan tosylate) 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 milademetan tosylate, followed by a phase II study.

Participants receive low dose cytarabine subcutaneously (SC) twice daily (BID) on days 1-7 and receive milademetan tosylate orally (PO) once daily (QD) on days 8-21. 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 Phase & Type

Trial Phase

Phase I/II

Trial Type


Lead Organization

Lead Organization
M D Anderson Cancer Center

Principal Investigator
Kiran Naqvi

Trial IDs

Primary ID 2018-0333
Secondary IDs NCI-2018-01612 ID NCT03634228