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 applies:

- 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 requirements.

- 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 required.

- If of childbearing potential, negative pre-treatment 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 ≥ 480 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:8 weeks
Safety Issue:
Description:Participants will be evaluated for dose limiting toxicities (DLTs) during the first 2 cycles of therapy, i.e., 8 weeks for purpose of deciding the dose for next cohort. DLT is defined as follows based on the Common Terminology Criteria for Adverse Events (CTCAE) v 4.03: Treatment related non-hematological CTCAE grade 3-4 toxicity that lead to dose modification or withdrawal; Grade 3 metabolic/electrolyte abnormalities that are not clinically significant, and are adequately controlled within 72 hours are not to be considered DLT; Grade 3 nausea/vomiting/diarrhea despite maximum medical therapy; Grade 3 central nervous system (CNS) toxicity despite maximal medical therapy.

Secondary Outcome Measures


Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet 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

March 2, 2017