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

Sponsor
Groupe Francophone des Myelodysplasies (Other)
Overall Status
Unknown status
CT.gov ID
NCT03588078
Collaborator
Aprea Therapeutics (Industry)
53
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32
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Study Details

Study Description

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 Design

Study Type:
Interventional
Actual Enrollment :
53 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Intervention Model Description:
Participants will receive one dose of protocol therapyParticipants will receive one dose of protocol therapy
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
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
Actual Study Start Date :
Sep 15, 2018
Anticipated Primary Completion Date :
May 1, 2020
Anticipated Study Completion Date :
May 15, 2021

Arms and Interventions

Arm Intervention/Treatment
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
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
  • Outcome Measures

    Primary Outcome Measures

    1. Overall Survival [8 months]

      overall survival at complete remission

    Secondary Outcome Measures

    1. Duration of response [minimum 24 months it is defined as the time between achieving response and progression of disease]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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:

    3. Serum creatinine ≤ 2 x upper limit of normal (ULN)

    4. 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

    5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x ULN

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

    7. 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)

    8. Documentation of a TP53 gene mutation by next-generation sequencing (NGS) based on central or local evaluation.

    9. Revised International Prognostic Scoring System (IPSS-R) criteria for Intermediate, High-risk or Very High-risk.

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

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

    12. 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):

    3. symptomatic congestive heart failure

    4. myocardial infarction ≤ 6 months prior to enrollment

    5. unstable angina pectoris

    6. serious uncontrolled cardiac arrhythmia

    7. 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)

    8. bradycardia (<40 bpm)

    9. known left ventricular ejection fraction (LVEF) < the institution lower limit of normal as assessed by ECHO

    10. clinically significant pericardial disease

    11. electrocardiographic evidence of acute ischemia

    12. familial history of long QT syndrome

    13. 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.

    14. Prior exposure to azacitidine, decitabine or investigational hypomethylating agent

    15. 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.

    16. 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.

    17. Patients with history of allogeneic stem cell transplantation.

    18. 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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Bruno Quesnel Lille France 59037
    2 Dr Pierre Peterlin and Pr Patrice Chevalier Nantes France 44093
    3 Hôpital Archet 1 Nice France 06200
    4 Hôpital Saint Louis - Hématologie Séniors Paris France 75010
    5 Hôpital Cochin/Service d'Hématologie Paris France 75679
    6 Aspasia Stamatoullas Rouen France 76038
    7 Odile Beyne Rosy Toulouse France 31059

    Sponsors and Collaborators

    • Groupe Francophone des Myelodysplasies
    • Aprea Therapeutics

    Investigators

    • Principal Investigator: Pierre Fenaux, service Hématologie Séniors Hôpital Saint Louis

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Groupe Francophone des Myelodysplasies
    ClinicalTrials.gov Identifier:
    NCT03588078
    Other Study ID Numbers:
    • GFM-APR246
    First Posted:
    Jul 17, 2018
    Last Update Posted:
    Jan 30, 2020
    Last Verified:
    Jan 1, 2020
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Groupe Francophone des Myelodysplasies
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Jan 30, 2020