NCT03072043 · REGISTRY CONDITION SEARCH

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

Found through the registry condition index, not selected as a treatment recommendation. This discovery collection was restricted to studies with posted results.

Phase: PHASE1, PHASE2
Status at capture: COMPLETED
Registry last update: 2022-01-24

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.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Phase 1b: Maximum Tolerated Dose (MTD)

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outcome · POSTED

Phase 2: Complete Response (CR) Rate

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outcome · POSTED

Phase 2: Duration of Response

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outcome · POSTED

Overall Survival (OS)

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outcome · POSTED

Phase 2: Overall Response Rate

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

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.
healthy Volunteers: false
minimum Age: 18 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
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.
intervention Names
Drug: APR-246
Drug: Azacitidine
label
Phase 1b Dose Escalation
type
EXPERIMENTAL
description
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.
intervention Names
Drug: APR-246
Drug: Azacitidine
label
Phase 2 Treatment
type
EXPERIMENTAL

interventions

arm Group Labels
Phase 1b Dose Escalation
Phase 2 Treatment
description
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).
name
APR-246
other Names
PRIMA-1MET
Methylated analogue to PRIMA-1
type
DRUG
arm Group Labels
Phase 1b Dose Escalation
Phase 2 Treatment
description
Azacitidine is administered subcutaneously (SC) or via IV at 75 mg/m\^2.
name
Azacitidine
other Names
Mylosar
Vidaza
type
DRUG

Study design

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.

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 55
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
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.
measure
Phase 1b: Maximum Tolerated Dose (MTD)
time Frame
Up to 12 months
description
Complete Response Rate as defined by the 2006 International Working Group (IWG) criteria.
measure
Phase 2: Complete Response (CR) Rate
time Frame
Up to 12 months

secondary Outcomes

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

Full study description

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.

Source references

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.
pmid
33449813
type
DERIVED