Study of the Safety and Efficacy of APR-246 in Combination With Azacitidine

NCT03588078 | Unknown Phase 1 DMC FDA Drug

• 1 other identifier: GFM-APR246
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 7

Brief Summary

The main purpose of this study is to determine the safe and efficacy of APR-246 in combination with azacitidine as well as to see complete remission of this patients

Conditions

Myelodysplastic Syndrome With Gene Mutation; Acute Myeloid Leukemia With Gene Mutations; Myeloproliferative Neoplasm; Chronic Myelomonocytic Leukemia

Keywords

Azacitidine

Outcome Measures

Primary Outcomes (1)

• Overall Survival

  overall survival at complete remission

  8 months

Secondary Outcomes (1)

• Duration of response

  minimum 24 months it is defined as the time between achieving response and progression of disease

Study Arms (1)

combination of APR246 and azacitidine

EXPERIMENTAL

Following completion of the Dose Finding Phase, we will conduct a dose expansion, whereby patients will be treated with APR-246 administered at the maximum tolerated dose (MTD) with azacitidine on a 28 day cycle utilizing the same dosing as in Phase 1b

Drug: APR-246; Drug: Azacitidine

Interventions

APR-246 DRUG

Azacitidine at maximum tolerated dose. APR246 at the Dose limited Toxicity (DLT) dose

Also known as: PRIMA-1MET, Methylated analogue to PRIMA-1

combination of APR246 and azacitidine

Azacitidine DRUG

azacitidine is administered subcutaneously (SC) or via IV at 75 mg/m2

Also known as: Mylosar, Vidaza

combination of APR246 and azacitidine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient has signed the Informed Consent (ICF) and is able to comply with protocol requirements.
• Patient has adequate organ function as defined by the following laboratory values:
• Serum creatinine ≤ 2 x upper limit of normal (ULN)
• Total serum bilirubin \< 1.5 x ULN or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert's Syndrome or hemolysis or who required regular blood transfusions
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 2.5 x ULN
• 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) by World Health organization (WHO) criteria or non-proliferative AML (ie with WBC \< 20 G/l)
• Documentation of a TP53 gene mutation by next-generation sequencing (NGS) based on central or local evaluation.
• Revised International Prognostic Scoring System (IPSS-R) criteria for Intermediate, High-risk or Very High-risk.
• 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 (males and females), willing to use an effective form of contraception such as latex condom, hormonal birth control, intrauterine device or double barrier method during chemotherapy treatment and for at least six months thereafter.

You may not qualify if:

• Patient has a known history of HIV or active hepatitis B or active hepatitis C infection (testing not mandatory).
• Patient has any of the following cardiac abnormalities (as determined by treating MD):
• symptomatic congestive heart failure
• myocardial infarction ≤ 6 months prior to enrollment
• unstable angina pectoris
• serious uncontrolled cardiac arrhythmia
• QTc ≥ 470 msec (≥ 500 msec in the presence of RBBB) calculated from a mean of 3 ECG readings using Fridericia's correction (QTcF = QT/RR0.33)
• bradycardia (\<40 bpm)
• known left ventricular ejection fraction (LVEF) \< the institution lower limit of normal as assessed by ECHO
• clinically significant pericardial disease
• electrocardiographic evidence of acute ischemia
• familial history of long QT syndrome
• Concomitant malignancies or previous malignancies with less than a 1-year disease free interval at the time of signing consent. Patients 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.
• Prior exposure to azacitidine, decitabine or investigational hypomethylating agent
• 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.

Sponsors & Collaborators

• Groupe Francophone des Myelodysplasies: lead
• Aprea Therapeutics: collaborator

Study Sites (7)

Bruno Quesnel

Lille, 59037, France

Location

Dr Pierre Peterlin and Pr Patrice Chevalier

Nantes, 44093, France

Location

Hôpital Archet 1

Nice, 06200, France

Location

Hôpital Saint Louis - Hématologie Séniors

Paris, 75010, France

Location

Hôpital Cochin/Service d'Hématologie

Paris, 75679, France

Location

Aspasia Stamatoullas

Rouen, 76038, France

Location

Odile Beyne Rosy

Toulouse, 31059, France

Location

Related Publications (1)

• Cluzeau T, Sebert M, Rahme R, Cuzzubbo S, Lehmann-Che J, Madelaine I, Peterlin P, Beve B, Attalah H, Chermat F, Miekoutima E, Rauzy OB, Recher C, Stamatoullas A, Willems L, Raffoux E, Berthon C, Quesnel B, Loschi M, Carpentier AF, Sallman DA, Komrokji R, Walter-Petrich A, Chevret S, Ades L, Fenaux P. Eprenetapopt Plus Azacitidine in TP53-Mutated Myelodysplastic Syndromes and Acute Myeloid Leukemia: A Phase II Study by the Groupe Francophone des Myelodysplasies (GFM). J Clin Oncol. 2021 May 10;39(14):1575-1583. doi: 10.1200/JCO.20.02342. Epub 2021 Feb 18.

  PMID: 33600210 DERIVED

MeSH Terms

Conditions

Myeloproliferative Disorders; Leukemia, Myelomonocytic, Chronic

Interventions

eprenetapopt; Azacitidine

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myelodysplastic-Myeloproliferative Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Pierre Fenaux

  service Hématologie Séniors Hôpital Saint Louis

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Participants will receive one dose of protocol therapy

Study Record Dates

• First Submitted: June 20, 2018
• First Posted: July 17, 2018
• Study Start: September 15, 2018
• Primary Completion: May 1, 2020
• Study Completion: May 15, 2021
• Last Updated: January 30, 2020

Record last verified: 2020-01

Data Sharing

• IPD Sharing: Will not share

Locations

FR (7)