Decitabine/Cedazuridine and Venetoclax in Combination With Ivosidenib or Enasidenib for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia

NCT04774393 | Recruiting Phase 1 FDA Drug

• 2 other identifiers: 2020-1220NCI-2021-00893
• Study Type: interventional
• Target: 84
• Locations: 1 country
• Sites: 1

Brief Summary

This phase Ib/II trials studies the side effects of decitabine/cedazuridine (ASTX727) and venetoclax in combination with ivosidenib or enasidenib, and how well they work in treating patients with acute myeloid leukemia that has come back (relapsed) or does not respond to treatment (refractory). ASTX727 is the combination of a fixed dose of 2 drugs, cedazuridine and decitabine. Cedazuridine may slow down how fast decitabine is broken down by the body, and decitabine may block abnormal cells or cancer cells from growing. Venetoclax may stop the growth of cancer cells by blocking BCL-2, a protein needed for cancer cell survival. Enasidenib and ivosidenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving decitabine/cedazuridine and venetoclax in combination with ivosidenib or enasidenib may help control acute myeloid leukemia.

Conditions

Acute Myeloid Leukemia; Recurrent Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (3)

• Dose limiting toxicity (Phase Ib)

  Will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5 by organ system.

  Up to 1 cycle (1 cycle = 28 days)

• Overall response rate (ORR) (Phase II)

  Defined as complete remission (CR), CR with incomplete hematologic recovery, CR with incomplete count recovery, partial response or marrow clearance of blasts. Will estimate the ORR for the combination treatmen1t, along with the Bayesian 95% credible interval.

  Within 4 months of treatment

• Incidence of adverse events (Phase II)

  Assessed using Common Toxicity Criteria version 5.0. Safety data will be summarized using frequency and percentage, by category and severity.

  Within 4 months of treatment

Secondary Outcomes (4)

• Event-free survival (EFS)

  Time interval between treatment start until disease progression, relapse/refractory, or death due to any cause, assessed up to 3 years

• Overall survival (OS)

  Time interval between treatment start until death due to any cause, assessed up to 3 years

• Duration of response

  Up to 3 years

• Minimal residual disease negative status

  Up to 3 years

Study Arms (2)

Arm A (decitabine/cedazuridine, venetoclax, ivosidenib)

EXPERIMENTAL

Patients receive decitabine/cedazuridine PO daily on days 1-5, venetoclax PO daily on days 1-14, and ivosidenib PO daily on days 1-28. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.

Drug: Decitabine and Cedazuridine; Drug: Ivosidenib; Drug: Venetoclax

Arm B (decitabine/cedazuridine, venetoclax, enasidenib)

EXPERIMENTAL

Patients receive decitabine/cedazuridine PO daily on days 1-5, venetoclax PO daily on days 1-14, and enasidenib PO daily on days 1-28. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.

Drug: Decitabine and Cedazuridine; Drug: Enasidenib; Drug: Venetoclax

Interventions

Decitabine and Cedazuridine DRUG

Given PO

Also known as: ASTX727, CDA Inhibitor E7727/Decitabine Combination Agent ASTX727, Cedazuridine/Decitabine Combination Agent ASTX727, Cedazuridine/Decitabine Tablet, Inqovi

Arm A (decitabine/cedazuridine, venetoclax, ivosidenib); Arm B (decitabine/cedazuridine, venetoclax, enasidenib)

Enasidenib DRUG

Given PO

Also known as: AG-221, CC-90007 Free Base

Arm B (decitabine/cedazuridine, venetoclax, enasidenib)

Ivosidenib DRUG

Given PO

Also known as: AG-120, Tibsovo

Arm A (decitabine/cedazuridine, venetoclax, ivosidenib)

Venetoclax DRUG

Given PO

Also known as: ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, Venclyxto

Arm A (decitabine/cedazuridine, venetoclax, ivosidenib); Arm B (decitabine/cedazuridine, venetoclax, enasidenib)

Eligibility Criteria

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

You may qualify if:

• Patients with a diagnosis of relapsed or refractory acute myeloid leukemia (AML) (including biphenotypic or bilineage leukemia including a myeloid component or isolated extramedullary AML); OR
• Patients (\> 60 year old) with newly diagnosed AML not eligible for intensive chemotherapy are also eligible
• To be considered not eligible for intensive chemotherapy, participants must be defined by the following: Age 75 years or older, or Age 18 to 74 years with at least one of the following comorbidities:
• Severe cardiac disorder (eg, congestive heart failure requiring treatment, ejection fraction ≤50%, or chronic stable angina).
• Severe pulmonary disorder (eg, DLCO ≤65% or forced expiratory volume in 1 second \[FEV1\] ≤65%).
• Creatinine clearance ≥30 mL/min to \<45 mL/min.
• Moderate hepatic impairment with total bilirubin \>1.5 to ≤3.0 × upper limit of normal (ULN)
• ECOG performance status of 2 or 3
• Age \>= 18 years
• Subjects must have documented IDH1 or IDH2 gene mutation
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 2
• Adequate renal function including creatinine \< 2 unless related to the disease
• Direct bilirubin \< 2 x upper limit of normal (ULN) unless increase is due to Gilbert's disease or leukemic involvement
• Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) \< 3 x ULN unless considered due to leukemic involvement, in which case direct bilirubin or AST and/or ALT \< 5 x ULN will be considered eligible)
• In the absence of rapidly proliferative disease, the interval from prior treatment to time of initiation will be at least 7 days for cytotoxic or non-cytotoxic (immunotherapy agent(s). Oral hydroxyurea and/or cytarabine (up to 2 g/m\^2) for patients with rapidly proliferative disease is allowed before the start of study therapy, as needed, for clinical benefit and after discussion with the principle investigator (PI). Concurrent therapy for central nervous system (CNS) prophylaxis or continuation of therapy for controlled CNS disease is permitted

You may not qualify if:

• Patients with t(15;17) karyotypic abnormality or acute promyelocytic leukemia (French-American-British \[FAB\] class M3-AML)
• Patients with any concurrent uncontrolled clinically significant medical condition including life-threatening severe infection, or psychiatric illness, which could place the patient at unacceptable risk of study treatment
• Patients with active graft-versus-host-disease (GVHD) status post stem cell transplant (patients without active GVHD on chronic suppressive immunosuppression and/or phototherapy for chronic skin GVHD are permitted after discussion with the PI)
• Patients with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications
• Corrected QT (QTc) interval using Fridericia's formula (QTcF) \>= 450 msec. Bundle branch block and prolonged QTc interval are permitted after discussion with the PI
• Known active hepatitis B (HBV) or hepatitis C (HCV) infection or known human immunodeficiency virus (HIV) infection
• Subject has a white blood cell count \> 25 x 10\^9/L. (Note: Hydroxyurea is permitted to meet this criterion)
• Nursing women, women of childbearing potential (WOCBP) with positive urine pregnancy test, or women of childbearing potential who are not willing to maintain adequate contraception
• Appropriate highly effective method(s) of contraception include oral or injectable hormonal birth control, intrauterine device (IUD), and double barrier methods (for example a condom in combination with a spermicide)

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

RECRUITING

Related Publications (1)

• DiNardo CD, Marvin-Peek J, Loghavi S, Takahashi K, Issa GC, Jen WY, Daver NG, Reville PK, Short NJ, Sasaki K, Mullin JK, Bradley CA, Borthakur G, Maiti A, Alvarado Y, Pemmaraju N, Abbas HA, Hammond DE, Haddad F, Bravo GM, Chien KS, Yilmaz M, Kornblau SM, Jabbour E, Ravandi F, Kadia T, Garcia-Manero G, Konopleva MY, Kantarjian HM. Outcomes of Frontline Triplet Regimens With a Hypomethylating Agent, Venetoclax, and Isocitrate Dehydrogenase Inhibitor for Intensive Chemotherapy-Ineligible Patients With Isocitrate Dehydrogenase-Mutated AML. J Clin Oncol. 2025 Aug 20;43(24):2692-2699. doi: 10.1200/JCO-25-00640. Epub 2025 Jun 13.

  PMID: 40513054 DERIVED

Related Links

• MD Anderson Cancer Center

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

decitabine and cedazuridine drug combination; enasidenib; ivosidenib; venetoclax

Condition Hierarchy (Ancestors)

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

Study Officials

• Courtney DiNardo, MD

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Courtney DiNardo, MD

CONTACT

713-794-1141; cdinardo@mdanderson.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 24, 2021
• First Posted: March 1, 2021
• Study Start: May 24, 2021
• Primary Completion (Estimated): November 29, 2027
• Study Completion (Estimated): November 29, 2027
• Last Updated: November 10, 2025

Record last verified: 2025-11

Locations

US (1)