Clinical trial NCT03072043: Phase 1b/2 Safety and Efficacy of APR-246 w/Azacitidine for tx of TP53 Mutant Myeloid Neoplasms
Official 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
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)
Lead sponsor: H. Lee Moffitt Cancer Center and Research Institute
Sponsor class: OTHER
Collaborators: name: Aprea Therapeutics
First posted: 2017-03-07
Enrollment: 55
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: 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.
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Phase 1b: Maximum Tolerated Dose (MTD)
timeFrame: Up to 12 months
measure: Phase 2: Complete Response (CR) Rate
timeFrame: Up to 12 months
Secondary outcomes:
measure: Phase 2: Duration of Response
timeFrame: Up to 24 months
measure: Overall Survival (OS)
timeFrame: Up to 24 months
measure: Phase 2: Overall Response Rate
timeFrame: Up to 24 months
Other outcomes:
Locations:
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Baltimore
country: United States
facility: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: Weill Medical College of Cornell University
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic Taussig Cancer Center
state: Ohio
city: Houston
country: United States
facility: University of Texas M.D. Anderson Cancer Center
state: Texas
Study officials:
affiliation: H. Lee Moffitt Cancer Center and Research Institute
name: David Sallman, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.