Details

Details

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.

IRB MCC1917

CC 17-1021

Hospital Main Campus

Phase Phase 1, Phase 2

Disease Leukemia - Acute Myeloid (AML), Leukemia - Chronic Myeloid (CML), Myelofibrosis, Myeloproliferative Neoplasms

Drug APR-246 , Azacitidine

Description

Description

Primary Objective (Phase1b):
  • To determine the safe and recommended Phase 2 dose (RP2D) of APR-246 in combination with azacitidine as determined by dose-limiting toxicities (DLTs)
Primary Objective (Phase 2):
  • To determine the proportion of patients with TP53 mutant myeloid neoplasms alive at 8 months
Secondary Objectives:
  1. To determine overall best response rates as measured by the international working group criteria (IWG 2006)
  2. To determine if mutant TP53 variant allele frequency (VAF) or p53 protein expression predicts response to APR-246 with azacitidine
  3. To determine if p53 protein expression correlates with TP53 VAF
  4. To determine if APR-246 with azacitidine treatment leads to mutant TP53 clonal suppression
  5. To determine if TP53 clonal suppression correlates with outcomes.
  6. To determine if APR-246 treatment upregulates p53 target genes
  7. To determine if APR-246 induces reactive oxygen species (ROS) production
  8. To determine the rate and time to acute myeloid leukemia (AML) transformation
  9. To determine the median overall survival (OS)
  10. To determine the duration of response
  11. To determine whether recurrent genetic mutations are predictive of response
Inclusion Criteria

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:
    • Serum creatinine ≤ 2 x upper limit of normal (ULN)
    • 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
    • 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 WHO criteria or AML with 20-30% myeloblasts (refractory anemia with excess blasts in transformation (RAEB-T) by French-American-British (FAB) criteria)
  5. Documentation of a TP53 gene mutation by 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 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

Exclusion Criteria

  1. Patient has a known history of HIV or active hepatitis B or active hepatitis C infection (testing notmandatory).
  2. Patient has any of the following cardiac abnormalities (as determined by treating MD):
    • Symptomatic congestive heart failure
    • Myocardial infarction ≤ 6 months prior to enrollment
    • Unstable angina pectoris
    • Serious uncontrolled cardiac arrhythmia
    • QTc ≥ 480 msec
  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, 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.
  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.