Pharmacokinetics, Safety, and Efficacy of ASTX727 in Combination With Venetoclax in Acute Myeloid Leukemia (AML)

NCT04657081 | Active Not Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: ASTX727-07
• Study Type: interventional
• Target: 101
• Locations: 3 countries
• Sites: 34

Brief Summary

The Phase 1 portion of this study is a single-arm, open-label, multicenter, non-randomized interventional study to evaluate the pharmacokinetic (PK) interaction, safety, and efficacy of ASTX727 when given in combination with venetoclax for the treatment of newly diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. The primary purpose of the study is to rule out drug-drug interactions between ASTX727 and venetoclax combination therapy by evaluating area under the curve (AUC) and maximum plasma concentration (Cmax) exposure. The Phase 2 portion of the study is to assess the efficacy of ASTX727 and venetoclax when given in combination and to evaluate potential PK interactions. Phase 2 will follow the same overall study design as Phase 1 and has two parts, Part A and Part B.

Conditions

Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (3)

• Pharmacokinetic parameter: AUC0-24

  Venetoclax area under the curve from time 0 to 24 hours (AUC0-24) with and without ASTX727 in Phase 1 and Phase 2, Part A.

  On Days 5 and 15 in Cycle 2 (28 days per cycle)

• Pharmacokinetic parameter: Cmax

  Venetoclax maximum observed concentration (Cmax) with and without ASTX727 in Phase 1 and Phase 2, Part A.

  On Days 5 and 15 in Cycle 2 (28 days per cycle)

• Complete Response (CR)

  Number of participants with CR in Phase 2, Parts A and B.

  Up to 36 months

Secondary Outcomes (13)

• Pharmacokinetic parameter: AUC0-24

  Cycle 1, 2 and 3 (28 days per cycle)

• Pharmacokinetic parameter: Cmax

  Cycle 1, 2 and 3 (28 days per cycle)

• Pharmacokinetic parameter: AUC0-8

  Cycle 1, 2 and 3 (28 days per cycle)

• Pharmacokinetic parameter: AUC0-inf

  Cycle 1, 2 and 3 (28 days per cycle)

• Pharmacokinetic parameter: 5-day AUC

  Cycle 2 (28 days per cycle)

Study Arms (1)

Oral administration of ASTX727 and Venetoclax combination

EXPERIMENTAL

Cycle 1: ASTX727 according to a prescribed dosing regimen and venetoclax on day 1 (100 mg daily), day 2 (200 mg daily), and days 3-28 (400 mg daily) of a 28-day cycle. Cycle 2 and beyond: ASTX727 according to a prescribed dosing regimen and venetoclax on days 1-28 (400 mg daily) of a 28-day cycle.

Drug: Decitabine and Cedazuridine (ASTX727); Drug: Venetoclax

Interventions

Decitabine and Cedazuridine (ASTX727) DRUG

Route of administration: oral in the form of a tablet

Also known as: INQOVI

Oral administration of ASTX727 and Venetoclax combination

Venetoclax DRUG

Route of administration: oral in the form of a tablet

Also known as: Venclexta

Oral administration of ASTX727 and Venetoclax combination

Eligibility Criteria

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

You may qualify if:

• Participant must be 18 years of age or older.
• Histological confirmation of newly diagnosed AML by World Health Organization (WHO) 2016 criteria.
• Projected life expectancy of at least 3 months.
• Participants must be considered ineligible for intensive induction chemotherapy defined by the following: a) Age 75 years or older, or b) Age 18 to 74 years with at least one of the following comorbidities: i) Severe cardiac disorder (eg, congestive heart failure requiring treatment, ejection fraction ≤50%, or chronic stable angina), ii) Severe pulmonary disorder (eg, diffusing lung capacity for carbon monoxide DLCO ≤65% or forced expiratory volume in 1 second \[FEV1\] ≤65%), iii) Creatinine clearance ≥30 mL/min to \<45 mL/min, iv) Moderate hepatic impairment with total bilirubin \>1.5 to ≤3.0 × upper limit of normal (ULN), v) Phase 1: Eastern Cooperative Oncology Group (ECOG) Performance Status of 2 (participants with ECOG ≥3 are not eligible); Phase 2, Parts A and B: ECOG Performance Status of 2 or 3 (participants with ECOG 4 are not eligible).
• Phase 1: ECOG Performance Status of 0-2; Phase 2, Parts A and B: ECOG 0-3.
• Women of child-bearing potential (according to recommendations of the Clinical Trial Facilitation Group \[CTFG\]) must not be pregnant or breastfeeding and must have a negative pregnancy test at screening.
• Participants and their partners with reproductive potential must agree to use a highly effective contraceptive measure during the study and for 3 months after the last dose of study treatment, including refraining from sperm donation. Effective contraception includes methods such as oral contraceptives or double-barrier method (eg, use of a condom AND diaphragm, with spermicide).
• Capable of giving legally effective informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form and protocol, and willing to participate in the study.

You may not qualify if:

• History of myeloproliferative neoplasm including myelofibrosis, essential thrombocythemia, polycythemia vera, chronic myeloid leukemia with or without BCR-ABL1 translocation and AML with BCR-ABL1 translocation.
• The following karyotype abnormalities: t(8;21), inv(16) or t(15;17), or other acute promyelocytic leukemia variants that remain sensitive to all-trans retinoic acid (ATRA) therapy.
• Known active central nervous system involvement from AML.
• Known human immunodeficiency virus (HIV) infection (due to potential drug-drug interactions between antiretroviral medications and venetoclax). Human immunodeficiency virus testing will be performed at Screening, only if indicated per local guidelines or institutional standards.
• Known active hepatitis B or C infection (detectable viral load). Hepatitis B or C testing will be performed at Screening, only if indicated per local guidelines or institutional standards.
• Severe hepatic impairment defined as: bilirubin \>1.5×upper limit of normal (ULN) for participants ≥75 years or \>3×ULN for participants \<75 years; or aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) or alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) \>3×ULN (unless considered to be due to leukemic organ involvement).
• Severe renal impairment defined as: calculated creatinine clearance or glomerular filtration rate \<30 mL/min.
• A malabsorption syndrome or other condition that precludes enteral route of administration.
• Cardiovascular disability status of New York Heart Association Class \>2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain.
• Chronic respiratory disease that requires continuous oxygen, or significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, any other medical condition or known hypersensitivity to any of the study medications that in the opinion of the investigator would adversely affect his/her participating in this study.
• Clinically significant uncontrolled systemic infection requiring therapy (viral, bacterial, or fungal).
• History of other malignancies prior to study entry, with the exception of adequately treated in situ carcinoma of the breast or cervix uteri; localized basal cell carcinoma or squamous cell carcinoma of the skin; previous malignancy confined and surgically resected (or adequately treated and controlled with other modalities); and any early stage malignancy for which no definitive therapy is required.
• White blood cell (WBC) count \>25,000/μL (Hydroxyurea treatment is permitted to meet this criterion).
• Treatment with the following: a) A hypomethylating agent (azacitidine or decitabine), or venetoclax including prior treatment for myelodysplastic syndrome (MDS), b) Chimeric Antigen Receptor (CAR)-T cell therapy, c) Investigational therapies for MDS or AML.
• Participants who cannot discontinue concomitant prophylactic antifungal therapy with CYP3A inhibitor activity or other concomitant medications with moderate or strong CYP3A inhibitor activity ≥7 days or 5 half-lives, whichever is greater, prior to cycle 1 day 1 (C1D1).

Sponsors & Collaborators

• Taiho Oncology, Inc.: lead

Study Sites (34)

USC Norris Comprehensive Cancer Center

Los Angeles, California, 90033, United States

Location

Stanford University

Palo Alto, California, 94306, United States

Location

Yale University

New Haven, Connecticut, 06510, United States

Location

Baptist MD Anderson Cancer Center

Jacksonville, Florida, 32207, United States

Location

Boca Raton Clinical Research

Plantation, Florida, 33322, United States

Location

The University of Chicago Medical Center

Chicago, Illinois, 60637, United States

Location

Indiana University Simon Cancer Center

Indianapolis, Indiana, 46202, United States

Location

Tufts Medical Center

Boston, Massachusetts, 02111, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

University of Massachusetts, Memorial Medical Center

Worcester, Massachusetts, 01655, United States

Location

Health Midwest Ventures Group, Inc.

Kansas City, Missouri, 64132, United States

Location

Hackensack University of Medical Center

Hackensack, New Jersey, 07601, United States

Location

Roswell Park Comprehensive Cancer Center

Buffalo, New York, 14263, United States

Location

Weill Cornell Medical College

New York, New York, 10065, United States

Location

University of Rochester

Rochester, New York, 14627, United States

Location

The Research Foundation of the State University of New York (SUNY)

Syracuse, New York, 13210, United States

Location

East Carolina University

Greenville, North Carolina, 27834, United States

Location

The Ohio State University

Columbus, Ohio, 43210, United States

Location

Penn State Milton S. Hershey Medical Center

Hershey, Pennsylvania, 17033, United States

Location

UPMC Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232-6307, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Baylor Scott & White Research Institute

Temple, Texas, 76508, United States

Location

Seattle Cancer Care Alliance

Seattle, Washington, 98109, United States

Location

University of Calgary - Health Sciences Centre

Calgary, Alberta, T2N 4N1, Canada

Location

University of Alberta

Edmonton, Alberta, T6G 2R3, Canada

Location

The Ottawa Hospital, General Campus

Ottawa, Ontario, K1H 8L6, Canada

Location

Jewish General Hospital

Montreal, H3T 1E2, Canada

Location

Hospital Universitario Central de Asturias

Oviedo, Austrias, 33011, Spain

Location

Institut Catala d'Oncologia-Hospital Duran i Reynals

L'Hospitalet de Llobregat, Barcelona, 08908, Spain

Location

Clinica Universidad de Navarra, Pamplona

Pamplona, Navarre, 31008, Spain

Location

Universitario Gregorio Marañon

Madrid, 28007, Spain

Location

Hospital Universitario de Salamanca

Salamanca, 37007, Spain

Location

Hospital Universitari i Politecnic La Fe

Valencia, 46026, Spain

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

Decitabine; cedazuridine; decitabine and cedazuridine drug combination; venetoclax

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

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

Study Design

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

Study Record Dates

• First Submitted: December 1, 2020
• First Posted: December 8, 2020
• Study Start: February 9, 2021
• Primary Completion: September 30, 2024
• Study Completion (Estimated): December 31, 2026
• Last Updated: December 8, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

CA (4); US (24); ES (6)