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

NCT03072043 | Completed Phase 1 Results FDA Drug

• 1 other identifier: MCC-18973
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 6

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.

Conditions

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

Keywords

myelodysplastic syndrome (MDS); TP53 mutant myelodysplastic syndrome; MDS/myeloproliferative neoplasm (MPN); chronic myelomonocytic leukemia (CMML); acute myeloid leukemia (AML)

Outcome Measures

Primary Outcomes (2)

• Phase 1b: Maximum Tolerated Dose (MTD)

  Maximum Tolerated Dose, defined as the dose level below which dose limiting toxicity (DLT) is manifested in ≥33% of the patients or at dose level 3 if DLT is manifested in \<33% of the patients.

  Up to 12 months

• Phase 2: Complete Response (CR) Rate

  Complete Response Rate as defined by the 2006 International Working Group (IWG) criteria.

  Up to 12 months

Secondary Outcomes (3)

• Phase 2: Duration of Response

  Up to 24 months

• Overall Survival (OS)

  Up to 24 months

• Phase 2: Overall Response Rate

  Up to 24 months

Study Arms (2)

Phase 1b Dose Escalation

EXPERIMENTAL

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.

Drug: APR-246; Drug: Azacitidine

Phase 2 Treatment

EXPERIMENTAL

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.

Drug: APR-246; Drug: Azacitidine

Interventions

APR-246 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).

Also known as: PRIMA-1MET, Methylated analogue to PRIMA-1

Phase 1b Dose Escalation; Phase 2 Treatment

Azacitidine DRUG

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

Also known as: Mylosar, Vidaza

Phase 1b Dose Escalation; Phase 2 Treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• H. Lee Moffitt Cancer Center and Research Institute: lead
• Aprea Therapeutics: collaborator

Study Sites (6)

H. Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, 33612, United States

Location

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, 21231, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Weill Medical College of Cornell University

New York, New York, 10065, United States

Location

Cleveland Clinic Taussig Cancer Center

Cleveland, Ohio, 44195, United States

Location

University of Texas M.D. Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• 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.

  PMID: 33449813 DERIVED

Related Links

• Moffitt Cancer Center Clinical Trials website

MeSH Terms

Conditions

Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Myeloproliferative Disorders; Leukemia, Myelomonocytic, Chronic

Interventions

eprenetapopt; Azacitidine

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myelodysplastic-Myeloproliferative Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Results Point of Contact

• Title: David Sallman, MD
• Organization: Moffitt Cancer Center

David.Sallman@moffitt.org

813-745-6841

Study Officials

• David Sallman, M.D.

  H. Lee Moffitt Cancer Center and Research Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Phase 1b Dose Escalation followed by Phase 2 treatment. Participants will be evaluable for inclusion in the Phase 1b and Phase 2 portions of the study if they receive at least one dose of protocol therapy.

Study Record Dates

• First Submitted: March 2, 2017
• First Posted: March 7, 2017
• Study Start: May 18, 2017
• Primary Completion: November 15, 2019
• Study Completion: December 8, 2021
• Last Updated: January 24, 2022
• Results First Posted: February 25, 2021

Record last verified: 2022-01

Locations

US (6)