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Study of the Safety and Efficacy of APR-246 in Combination With Azacitidine

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ClinicalTrials.gov Identifier: NCT03588078
Recruitment Status : Unknown
Verified January 2020 by Groupe Francophone des Myelodysplasies.
Recruitment status was:  Active, not recruiting
First Posted : July 17, 2018
Last Update Posted : January 30, 2020
Aprea Therapeutics
Information provided by (Responsible Party):
Groupe Francophone des Myelodysplasies

Tracking Information
First Submitted Date  ICMJE June 20, 2018
First Posted Date  ICMJE July 17, 2018
Last Update Posted Date January 30, 2020
Actual Study Start Date  ICMJE September 15, 2018
Estimated Primary Completion Date May 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 3, 2018)
Overall Survival [ Time Frame: 8 months ]
overall survival at complete remission
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 3, 2018)
Duration of response [ Time Frame: minimum 24 months it is defined as the time between achieving response and progression of disease ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Study of the Safety and Efficacy of APR-246 in Combination With Azacitidine
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 Mutation TP53 (TP53) Mutant Myeloid Neoplasms
Brief Summary The main purpose of this study is to determine the safe and efficacy of APR-246 in combination with azacitidine as well as to see complete remission of this patients
Detailed Description

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

  • Inter-current illness that prevent further administration of treatment
  • Unacceptable adverse event(s)
  • Participant decides to withdraw from the study,
  • 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 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: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:
Participants will receive one dose of protocol therapy
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Myelodysplastic Syndrome With Gene Mutation
  • Acute Myeloid Leukemia With Gene Mutations
  • Myeloproliferative Neoplasm
  • Chronic Myelomonocytic Leukemia
Intervention  ICMJE
  • Drug: APR-246
    Azacitidine at maximum tolerated dose. APR246 at the Dose limited Toxicity (DLT) dose
    Other Names:
    • PRIMA-1MET
    • Methylated analogue to PRIMA-1
  • Drug: Azacitidine
    azacitidine is administered subcutaneously (SC) or via IV at 75 mg/m2
    Other Names:
    • Mylosar
    • Vidaza
Study Arms  ICMJE Experimental: combination of APR246 and azacitidine
Following completion of the Dose Finding Phase, we will conduct a dose expansion, whereby patients will be treated with APR-246 administered at the maximum tolerated dose (MTD) with azacitidine on a 28 day cycle utilizing the same dosing as in Phase 1b
  • Drug: APR-246
  • Drug: Azacitidine
Publications * Cluzeau T, Sebert M, Rahmé R, Cuzzubbo S, Lehmann-Che J, Madelaine I, Peterlin P, Bève B, Attalah H, Chermat F, Miekoutima E, Rauzy OB, Recher C, Stamatoullas A, Willems L, Raffoux E, Berthon C, Quesnel B, Loschi M, Carpentier AF, Sallman DA, Komrokji R, Walter-Petrich A, Chevret S, Ades L, Fenaux P. Eprenetapopt Plus Azacitidine in TP53-Mutated Myelodysplastic Syndromes and Acute Myeloid Leukemia: A Phase II Study by the Groupe Francophone des Myélodysplasies (GFM). J Clin Oncol. 2021 May 10;39(14):1575-1583. doi: 10.1200/JCO.20.02342. Epub 2021 Feb 18.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Unknown status
Actual Enrollment  ICMJE
 (submitted: August 9, 2019)
Original Estimated Enrollment  ICMJE
 (submitted: July 3, 2018)
Estimated Study Completion Date  ICMJE May 15, 2021
Estimated Primary Completion Date May 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Patient has signed the Informed Consent (ICF) and is able to comply with protocol requirements.
  2. Patient has adequate organ function as defined by the following laboratory values:

    1. Serum creatinine ≤ 2 x upper limit of normal (ULN)
    2. Total serum bilirubin < 1.5 x ULN or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert's Syndrome or hemolysis or who required regular blood transfusions
    3. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x ULN
  3. Age ≥18 years at the time of signing the informed consent form
  4. Documented diagnosis of myelodysplastic syndrome (MDS), MDS/ myeloproliferative neoplasm (MPN), chronic myelomonocytic leukemia (CMML) by World Health organization (WHO) criteria or non-proliferative AML (ie with WBC < 20 G/l)
  5. Documentation of a TP53 gene mutation by next-generation sequencing (NGS) based on central or local evaluation.
  6. Revised International Prognostic Scoring System (IPSS-R) criteria for Intermediate, High-risk or Very High-risk.
  7. An Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 is required.
  8. If of childbearing potential, negative pre-treatment urine or serum pregnancy test.
  9. If of childbearing potential (males and females), willing to use an effective form of contraception such as latex condom, hormonal birth control, intrauterine device or double barrier method during chemotherapy treatment and for at least six months thereafter.

Exclusion Criteria:

  1. Patient has a known history of HIV or active hepatitis B or active hepatitis C infection (testing not mandatory).
  2. Patient has any of the following cardiac abnormalities (as determined by treating MD):

    1. symptomatic congestive heart failure
    2. myocardial infarction ≤ 6 months prior to enrollment
    3. unstable angina pectoris
    4. serious uncontrolled cardiac arrhythmia
    5. QTc ≥ 470 msec (≥ 500 msec in the presence of RBBB) calculated from a mean of 3 ECG readings using Fridericia's correction (QTcF = QT/RR0.33)
    6. bradycardia (<40 bpm)
    7. known left ventricular ejection fraction (LVEF) < the institution lower limit of normal as assessed by ECHO
    8. clinically significant pericardial disease
    9. electrocardiographic evidence of acute ischemia
    10. familial history of long QT syndrome
  3. Concomitant malignancies or previous malignancies with less than a 1-year disease free interval at the time of signing consent. Patients 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.
  4. Prior exposure to azacitidine, decitabine or investigational hypomethylating agent
  5. 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.
  6. No concurrent use of erythroid stimulating agents, Granulocyte-colony stimulating Factor (G-CSF), Granulocyte Macrophage-colony stimulating factor (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.
  7. Patients with history of allogeneic stem cell transplantation.
  8. Pregnant women are excluded from this study because APR-246 has not been studied in pregnant subjects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with APR-246, breastfeeding should be discontinued if the mother is treated with APR-246.
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 France
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT03588078
Other Study ID Numbers  ICMJE GFM-APR246
Has Data Monitoring Committee Yes
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
Plan to Share IPD: No
Current Responsible Party Groupe Francophone des Myelodysplasies
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Groupe Francophone des Myelodysplasies
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Aprea Therapeutics
Investigators  ICMJE
Principal Investigator: Pierre Fenaux service Hématologie Séniors Hôpital Saint Louis
PRS Account Groupe Francophone des Myelodysplasies
Verification Date January 2020

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