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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03072043
Recruitment Status : Active, not recruiting
First Posted : March 7, 2017
Results First Posted : February 25, 2021
Last Update Posted : May 4, 2021
Aprea Therapeutics
Information provided by (Responsible Party):
H. Lee Moffitt Cancer Center and Research Institute

Tracking Information
First Submitted Date  ICMJE March 2, 2017
First Posted Date  ICMJE March 7, 2017
Results First Submitted Date  ICMJE November 13, 2020
Results First Posted Date  ICMJE February 25, 2021
Last Update Posted Date May 4, 2021
Actual Study Start Date  ICMJE May 18, 2017
Actual Primary Completion Date November 15, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 4, 2021)
  • Phase 1b: Maximum Tolerated Dose (MTD) [ Time Frame: Up to 12 months ]
    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.
  • Phase 2: Complete Response (CR) Rate [ Time Frame: Up to 12 months ]
    Complete Response Rate as defined by the 2006 International Working Group (IWG) criteria.
Original Primary Outcome Measures  ICMJE
 (submitted: March 2, 2017)
  • Phase 1b: Maximum Tolerated Dose (MTD) [ Time Frame: 8 weeks ]
    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.
  • Phase 2: Overall Survival (OS) [ Time Frame: 8 months ]
    Overall survival at 8 months. OS:The length of time from the start of treatment until death by any cause.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 4, 2021)
  • Phase 2: Duration of Response [ Time Frame: Up to 24 months ]
    Duration of response defined as the time between achieving response and progression of disease.
  • Overall Survival (OS) [ Time Frame: Up to 24 months ]
    OS:The length of time from the start of treatment until death by any cause.
  • Phase 2: Overall Response Rate [ Time Frame: Up to 24 months ]
    Proportion of participants achieving hematological improvement (HI), partial response (PR), complete response (CR), and/or marrow CR (mCR) by the IWG 2006 criteria.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Phase 1b/2 Safety and Efficacy of APR-246 w/Azacitidine for tx of TP53 Mutant Myeloid Neoplasms
Official Title  ICMJE 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
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:
Phase 1b Dose Escalation followed by Phase 2 treatment. Participants will be evaluable for inclusion in the Phase 1b and Phase 2 portions of the study if they receive at least one dose of protocol therapy.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Myelodysplastic Syndrome
  • Acute Myeloid Leukemia
  • Myeloproliferative Neoplasm
  • Chronic Myelomonocytic Leukemia
Intervention  ICMJE
  • Drug: APR-246
    Phase 1b: Dose escalation of APR-246 via intravenous (IV) infusion, with starting dose of 50 mg/kg lean body weight (LBW). Phase 2: APR-246 at maximum tolerated dose (MTD).
    Other Names:
    • PRIMA-1MET
    • Methylated analogue to PRIMA-1
  • Drug: Azacitidine
    Azacitidine is administered subcutaneously (SC) or via IV at 75 mg/m^2.
    Other Names:
    • Mylosar
    • Vidaza
Study Arms  ICMJE
  • Experimental: Phase 1b Dose Escalation
    Participants 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.
    • Drug: APR-246
    • Drug: Azacitidine
  • Experimental: Phase 2 Treatment
    Participants 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.
    • Drug: APR-246
    • Drug: Azacitidine
Publications * Sallman DA, DeZern AE, Garcia-Manero G, Steensma DP, Roboz GJ, Sekeres MA, Cluzeau T, Sweet KL, McLemore A, McGraw KL, Puskas J, Zhang L, Yao J, Mo Q, Nardelli L, Al Ali NH, Padron E, Korbel G, Attar EC, Kantarjian HM, Lancet JE, Fenaux P, List AF, Komrokji RS. Eprenetapopt (APR-246) and Azacitidine in TP53-Mutant Myelodysplastic Syndromes. J Clin Oncol. 2021 May 10;39(14):1584-1594. doi: 10.1200/JCO.20.02341. Epub 2021 Jan 15.

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: November 17, 2020)
Original Estimated Enrollment  ICMJE
 (submitted: March 2, 2017)
Estimated Study Completion Date  ICMJE June 2021
Actual Primary Completion Date November 15, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries France
Administrative Information
NCT Number  ICMJE NCT03072043
Other Study ID Numbers  ICMJE MCC-18973
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party H. Lee Moffitt Cancer Center and Research Institute
Study Sponsor  ICMJE H. Lee Moffitt Cancer Center and Research Institute
Collaborators  ICMJE Aprea Therapeutics
Investigators  ICMJE
Principal Investigator: David Sallman, M.D. H. Lee Moffitt Cancer Center and Research Institute
PRS Account H. Lee Moffitt Cancer Center and Research Institute
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP