Clinical Trial 18973

Cancer Type: Malignant Hematology
Interventions:APR-246; azacitidine (5-azacitidine)

Study Type: Treatment
Phase of Study: Phase I/II
Investigators:

  • David Sallman

Overview

Study 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

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.

Objective

Primary Objective (Phase1b): 1. 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): 2. To determine the proportion of patients with TP53 mutant myeloid neoplasms alive at 8 months. Secondary Objectives: 3. To determine overall best response rates as measured by the international working group criteria (IWG 2006). 4. To determine if mutant TP53 variant allele frequency (VAF) or p53 protein expression predicts response to APR-246 with azacitidine. 5. To determine if p53 protein expression correlates with TP53 VAF. 6. To determine if APR-246 with azacitidine treatment leads to mutant TP53 clonal suppression. 7. To determine if TP53 clonal suppression correlates with outcomes. 8. To determine if APR-246 treatment upregulates p53 target genes. 9. To determine if APR-246 induces reactive oxygen species (ROS) production. 10. To determine the rate and time to acute myeloid leukemia (AML) transformation. 11. To determine the median overall survival (OS). 12. To determine the duration of response. 13. To determine whether recurrent genetic mutations are predictive of response.

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.