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

NCT ID: NCT03072043

Last Updated: 2022-01-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 55 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-05-18
• Study Completion Date: 2021-12-08

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.

Conditions

Myelodysplastic Syndrome; Acute Myeloid Leukemia; Myeloproliferative Neoplasm; Chronic Myelomonocytic Leukemia

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

APR-246

Intervention Type: DRUG

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).

Azacitidine

Intervention Type: DRUG

Azacitidine is administered subcutaneously (SC) or via IV at 75 mg/m\^2.

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.

Group Type: EXPERIMENTAL

APR-246

Intervention Type: DRUG

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).

Azacitidine

Intervention Type: DRUG

Azacitidine is administered subcutaneously (SC) or via IV at 75 mg/m\^2.

Interventions

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).

Intervention Type: DRUG

Azacitidine

Azacitidine is administered subcutaneously (SC) or via IV at 75 mg/m\^2.

Intervention Type: DRUG

Other Intervention Names

PRIMA-1MET; Methylated analogue to PRIMA-1; Mylosar; Vidaza

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Aprea Therapeutics

INDUSTRY

Sponsor Role: collaborator

H. Lee Moffitt Cancer Center and Research Institute

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

David Sallman, M.D.

Role: PRINCIPAL_INVESTIGATOR

H. Lee Moffitt Cancer Center and Research Institute

Locations

H. Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, United States

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Weill Medical College of Cornell University

New York, New York, United States

Cleveland Clinic Taussig Cancer Center

Cleveland, Ohio, United States

University of Texas M.D. Anderson Cancer Center

Houston, Texas, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 33449813 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

MCC-18973

Identifier Type: -

Identifier Source: org_study_id