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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03072043
Recruitment Status : Active, not recruiting
First Posted : March 7, 2017
Last Update Posted : May 27, 2020
Aprea Therapeutics
Information provided by (Responsible Party):
H. Lee Moffitt Cancer Center and Research Institute

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.

Condition or disease Intervention/treatment Phase
Myelodysplastic Syndrome Acute Myeloid Leukemia Myeloproliferative Neoplasm Chronic Myelomonocytic Leukemia Drug: APR-246 Drug: Azacitidine Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 56 participants
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
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.
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : May 5, 2017
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : June 2021

Arm Intervention/treatment
Experimental: 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.
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).
Other Names:
  • Methylated analogue to PRIMA-1

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

Experimental: 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.
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).
Other Names:
  • Methylated analogue to PRIMA-1

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

Primary Outcome Measures :
  1. Phase 1b: Maximum Tolerated Dose (MTD) [ Time Frame: Up to 12 months ]
    Participants will be evaluated for dose limiting toxicities (DLTs) during the first 2 cycles of therapy, i.e., 8 weeks for purpose of deciding the dose for next cohort. DLT is defined as follows based on the Common Terminology Criteria for Adverse Events (CTCAE) v 4.03: Treatment related non-hematological CTCAE grade 3-4 toxicity that lead to dose modification or withdrawal; Grade 3 metabolic/electrolyte abnormalities that are not clinically significant, and are adequately controlled within 72 hours are not to be considered DLT; Grade 3 nausea/vomiting/diarrhea despite maximum medical therapy; Grade 3 central nervous system (CNS) toxicity despite maximal medical therapy.

  2. Phase 2: Complete Response (CR) Rate [ Time Frame: Up to 12 months ]
    CR rate by International Working Group (IWG) 2006 criteria.

Secondary Outcome Measures :
  1. Duration of Response [ Time Frame: Up to 24 months ]
    Duration of response defined as the time between achieving response and progression of disease.

  2. Overall Survival (OS) [ Time Frame: 8 months post treatment ]
    Overall survival at 8 months. OS:The length of time from the start of treatment until death by any cause.

  3. Overall Response Rate [ Time Frame: Up to 24 months ]
    Proportion of participants achieving hematological improvement (HI), partial response (PR), complete response (CR), and/or marrow CR (mCR) by the IWG 2006 criteria.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03072043

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United States, Florida
H. Lee Moffitt Cancer Center and Research Institute
Tampa, Florida, United States, 33612
United States, Maryland
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States, 21231
United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, New York
Weill Medical College of Cornell University
New York, New York, United States, 10065
United States, Ohio
Cleveland Clinic Taussig Cancer Center
Cleveland, Ohio, United States, 44195
United States, Texas
University of Texas M.D. Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
H. Lee Moffitt Cancer Center and Research Institute
Aprea Therapeutics
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Principal Investigator: David Sallman, M.D. H. Lee Moffitt Cancer Center and Research Institute
Additional Information:
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Responsible Party: H. Lee Moffitt Cancer Center and Research Institute Identifier: NCT03072043    
Other Study ID Numbers: MCC-18973
First Posted: March 7, 2017    Key Record Dates
Last Update Posted: May 27, 2020
Last Verified: April 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by H. Lee Moffitt Cancer Center and Research Institute:
myelodysplastic syndrome (MDS)
TP53 mutant myelodysplastic syndrome
MDS/myeloproliferative neoplasm (MPN)
chronic myelomonocytic leukemia (CMML)
acute myeloid leukemia (AML)
Additional relevant MeSH terms:
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Leukemia, Myeloid, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Myelodysplastic Syndromes
Myeloproliferative Disorders
Pathologic Processes
Neoplasms by Histologic Type
Leukemia, Myeloid
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Myelodysplastic-Myeloproliferative Diseases
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors