Clinical Trials /

Phase 1b/2 Safety and Efficacy of APR-246 w/Azacitidine for tx of TP53 Mutant Myeloid Neoplasms



The main purpose of this study is to determine the safe and recommended dose of APR-246 in combination with azacitidine as well as to see if this combination of therapy improves overall survival.

Related Conditions:
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndromes
  • Myelodysplastic/Myeloproliferative Neoplasm
Recruiting Status:

Active, not recruiting


Phase 1/Phase 2

Trial Eligibility



  • Brief Title: Phase 1b/2 Safety and Efficacy of APR-246 w/Azacitidine for tx of TP53 Mutant Myeloid Neoplasms
  • Official Title: A Phase 1b/2 Study to Evaluate the Safety and Efficacy of APR-246 in Combination With Azacitidine for the Treatment of TP53 Mutant Myeloid Neoplasms

Clinical Trial IDs

  • ORG STUDY ID: MCC-18973
  • NCT ID: NCT03072043


  • Myelodysplastic Syndrome
  • Acute Myeloid Leukemia
  • Myeloproliferative Neoplasm
  • Chronic Myelomonocytic Leukemia


APR-246PRIMA-1MET, Methylated analogue to PRIMA-1Phase 1b Dose Escalation
AzacitidineMylosar, VidazaPhase 1b Dose Escalation


The main purpose of this study is to determine the safe and recommended dose of APR-246 in combination with azacitidine as well as to see if this combination of therapy improves overall survival.

Detailed Description

      Participants will be treated for a total of 6 cycles. For participants responding or who have
      stable disease following cycle 6, treatment may continue until one of the following criteria

        -  Inter-current illness that prevents further administration of treatment,

        -  Unacceptable adverse event(s),

        -  Participant decides to withdraw from the study, or

        -  General or specific changes in the participant's condition render the participant
           unacceptable for further treatment in the judgment of the investigator.

        -  Evidence of disease progression by the International Working Group (IWG) 2006 criteria.

      Participants who wish not to continue treatment at time of disease assessment at end of cycle
      6 will complete their end of treatment visit upon completion of cycle 6.

Trial Arms

Phase 1b Dose EscalationExperimentalParticipants will receive intravenous infusions of APR-246 as a lead-in phase on days -14 to -11 starting at Dose Level 1 prior to starting cycle #1 of combination therapy with azacitidine. Combination therapy will consist of APR-246 on days 1-4 and azacitidine on days 4-10 (or days 4-5 and 8-12) of a 28 day cycle.
  • APR-246
  • Azacitidine
Phase 2 TreatmentExperimentalParticipants will be treated with APR-246 administered at the maximum tolerated dose (MTD) with azacitidine on a 28 day cycle utilizing the same dosing schedule as in Phase 1b.
  • APR-246
  • Azacitidine

Eligibility Criteria

        Inclusion Criteria:

          -  Has signed the Informed Consent (ICF) and is able to comply with protocol

          -  Has adequate organ function according to study protocol guidelines.

          -  Age ≥18 years at the time of signing the informed consent form.

          -  Documented diagnosis of myelodysplastic syndrome (MDS), MDS/ myeloproliferative
             neoplasm (MPN), chronic myelomonocytic leukemia (CMML) or oligoblastic AML (20-30%
             myeloblasts) by World Health Organization (WHO) criteria.

          -  Documentation of a TP53 gene mutation by NGS based on central or local evaluation.

          -  For TP53 mutant patients with lower risk MDS (i.e., low or intermediate-1 risk by the
             International Prognostic Scoring System (IPSS)) and isolated deletion of 5q (del(5q)),
             failure of prior treatment with at least 4 full cycles of lenalidomide defined as no
             response to treatment, loss of response at any time point, progressive disease, or
             intolerance to therapy.

          -  An Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 is

          -  If of childbearing potential, negative pre-treatment urine or serum pregnancy test.

          -  If of childbearing potential, willing to use an effective form of contraception such
             as hormonal birth control, intrauterine device or double barrier method during
             chemotherapy treatment and for at least six months thereafter.

        Exclusion Criteria:

          -  Known history of HIV or active hepatitis B or active hepatitis C infection (testing
             not mandatory).

          -  Has any of the following cardiac abnormalities (as determined by treating MD): a.
             Symptomatic congestive heart failure; b. Myocardial infarction less than or equal to 6
             months prior to enrollment; c. Unstable angina pectoris; d. Serious uncontrolled
             cardiac arrhythmia; e. QTc ≥ 470 msec

          -  Concomitant malignancies or previous malignancies with less than a 1-year disease free
             interval at the time of signing consent. Potential participants with adequately
             resected basal or squamous cell carcinoma of the skin, or adequately resected
             carcinoma in situ (e.g., cervix) may enroll irrespective of the time of diagnosis.

          -  Use of cytotoxic chemotherapeutic agents, or experimental agents (agents that are not
             commercially available) for the treatment of MDS, MDS/MPN, CMML or AML within 14 days
             of the first day of study drug treatment.

          -  No concurrent use of erythroid stimulating agents, G-CSF, GM-CSF is allowed during
             study except in cases of febrile neutropenia where G-CSF can be used for short term.
             Growth factors must be stopped 14 days prior to study.

          -  Women who are pregnant or breastfeeding.
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1b: Maximum Tolerated Dose (MTD)
Time Frame:Up to 12 months
Safety Issue:
Description:Maximum Tolerated Dose, defined as the dose level below which dose limiting toxicity (DLT) is manifested in ≥33% of the patients or at dose level 3 if DLT is manifested in <33% of the patients.

Secondary Outcome Measures

Measure:Phase 2: Duration of Response
Time Frame:Up to 24 months
Safety Issue:
Description:Duration of response defined as the time between achieving response and progression of disease.
Measure:Overall Survival (OS)
Time Frame:Up to 24 months
Safety Issue:
Description:OS:The length of time from the start of treatment until death by any cause.
Measure:Phase 2: Overall Response Rate
Time Frame:Up to 24 months
Safety Issue:
Description:Proportion of participants achieving hematological improvement (HI), partial response (PR), complete response (CR), and/or marrow CR (mCR) by the IWG 2006 criteria.


Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:H. Lee Moffitt Cancer Center and Research Institute

Trial Keywords

  • myelodysplastic syndrome (MDS)
  • TP53 mutant myelodysplastic syndrome
  • MDS/myeloproliferative neoplasm (MPN)
  • chronic myelomonocytic leukemia (CMML)
  • acute myeloid leukemia (AML)

Last Updated

July 28, 2021