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

Acute Myeloid Leukemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03072043
• Other study ID #: MCC-18973
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: May 18, 2017
• Est. completion date: December 8, 2021

Study information

• Verified date: January 2022
• Source: H. Lee Moffitt Cancer Center and Research Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 55
• Est. completion date: December 8, 2021
• Est. primary completion date: November 15, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Chronic Myelomonocytic Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Leukemia, Myelomonocytic, Chronic
• Leukemia, Myelomonocytic, Juvenile
• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Myeloproliferative Disorders
• Myeloproliferative Neoplasm
• Neoplasms
• Preleukemia
• Syndrome

Intervention

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

Locations

Country	Name	City	State
United States	The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio
United States	University of Texas M.D. Anderson Cancer Center	Houston	Texas
United States	Weill Medical College of Cornell University	New York	New York
United States	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida

Sponsors (2)

Lead Sponsor	Collaborator
H. Lee Moffitt Cancer Center and Research Institute	Aprea Therapeutics

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Phase 2: Complete Response (CR) Rate	Complete Response Rate as defined by the 2006 International Working Group (IWG) criteria.	Up to 12 months
Secondary	Phase 2: Duration of Response	Duration of response defined as the time between achieving response and progression of disease.	Up to 24 months
Secondary	Overall Survival (OS)	OS:The length of time from the start of treatment until death by any cause.	Up to 24 months
Secondary	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

External Links

•   Moffitt Cancer Center Clinical Trials website