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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Myelodysplastic Syndrome, Acute Myeloid Leukemia, Myeloproliferative Neoplasm, Chronic Myelomonocytic Leukemia

Intervention / Treatment
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* Drug: APR-246
* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b Dose Escalation<br>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<br>* 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).<br>* Other names: Methylated analogue to PRIMA-1;Drug: Azacitidine<br>* Azacitidine is administered subcutaneously (SC) or via IV at 75 mg/m^2.<br>* Other names: Vidaza;|
| Experimental: Phase 2 Treatment<br>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<br>* 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).<br>* Other names: Methylated analogue to PRIMA-1;Drug: Azacitidine<br>* Azacitidine is administered subcutaneously (SC) or via IV at 75 mg/m^2.<br>* Other names: Vidaza;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: Duration of Response | Duration of response defined as the time between achieving response and progression of disease. | Up to 24 months | 
| Overall Survival (OS) | OS:The length of time from the start of treatment until death by any cause. | Up to 24 months | 
| Phase 2: Overall Response Rate | Proportion of participants achieving hematological improvement (HI), partial response (PR), complete response (CR), and/or marrow CR (mCR) by the IWG 2006 criteria. | Up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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myelodysplastic syndrome (MDS), TP53 mutant myelodysplastic syndrome, MDS/myeloproliferative neoplasm (MPN), chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML)