Entrectinib in Combination With ASTX727 for the Treatment of Relapsed/Refractory TP53 Mutated Acute Myeloid Leukemia

NCT05396859 | Active Not Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: STUDY00023205NCI-2022-02156
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I trial tests the safety, side effects, and best dose of entrectinib when given with ASTX727 in treating patients with acute myeloid leukemia (AML) that has come back (relapsed) or that does not respond to treatment (refractory) and has a genetic change (mutation) in the TP53 gene. ASTX727 is a combination of cedazuridine and decitabine. Cedazuridine is in a class of medications called cytidine deaminase inhibitors. It prevents the breakdown of decitabine, making it more available in the body so that decitabine will have a greater effect. Decitabine is in a class of medications called hypomethylation agents. It works by helping the bone marrow produce normal blood cells and by killing abnormal cells in the bone marrow. Entrectinib is in a class of medications called kinase inhibitors. It works by blocking the action of the abnormal protein that signals cancer cells to multiply. This helps to stop or slow the spread of cancer cells. Giving ASTX727 and entrectinib together may kill more tumor cells in patients with AML.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• Incidence of dose limiting toxicities (DLTs)

  Toxicities will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version \[v\] 5.0).

  From first dose of study drug (day 1 of cycle 0) to end of cycle 1 (each cycle = 28 days)

Secondary Outcomes (8)

• Incidence of treatment-related grade >= 3 adverse events

  From first dose of study drug (day 1 of cycle 0) up to 30 days post end of therapy (each cycle = 28 days)

• Composite complete remission (CCR) rate

  From first dose of study drug up to 2 weeks after last dose of study drug, start of new cancer therapy, or transplant, end of study follow up, death (whichever is first), assessed up to 6 months

• Overall response rate (ORR)

  From first dose of study drug up to 2 weeks after last dose of study drug, start of new cancer therapy, or transplant (whichever is first), assessed up to 6 months

• Clinical benefit rate (CBR)

  From first dose of study drug up to 2 weeks after last dose of study drug, start of new cancer therapy, or transplant (whichever is first), assessed up to 6 months

• Proportion transplanted

  From first dose of study drug up to end of follow-up or death, assessed up to 6 months

Other Outcomes (7)

• Genomic analysis

  Pre-dose Cycle 0; At Cycle 1 day 1; Cycle 1, Day 8; Cycle 1, Day 28 (each cycle = 28 days)

• Total NTRK protein levels

  Pre-dose Cycle 0; At Cycle 1 day 1; Cycle 1, Day 8; Cycle 1, Day 28 (each cycle = 28 days)

• NTRK phosphorylation levels

  Pre-dose Cycle 0; At Cycle 1 day 1; Cycle 1, Day 8; Cycle 1, Day 28 (each cycle = 28 days)

Study Arms (1)

Treatment (ASTX727, entrectinib)

EXPERIMENTAL

Patients receive entrectinib PO QD on days 1-28 and ASTX727 PO QD on days 1-5. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Decitabine and Cedazuridine; Drug: Entrectinib; Other: Laboratory Biomarker Analysis

Interventions

Decitabine and Cedazuridine DRUG

Given PO

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

Treatment (ASTX727, entrectinib)

Entrectinib DRUG

Given PO

Also known as: Rozlytrek, RXDX 101, RXDX-101, RXDX101

Treatment (ASTX727, entrectinib)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (ASTX727, entrectinib)

Eligibility Criteria

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

You may qualify if:

• Must be able to understand and willing to sign an informed consent document.
• Participants aged 18 years or older.
• Morphologically documented AML in patients with relapsed/refractory disease, defined as having \>= 20% blasts in bone marrow or peripheral blood.
• Documented TP53 mutation as seen on standard diagnostics in AML.
• Aspartate aminotransferase (AST) \< 3 × upper limit of normal (ULN).
• Alanine aminotransferase (ALT) \< 3 × ULN.
• Total bilirubin \< 1.5 × ULN (except for patients with known Gilbert's syndrome).
• Adequate renal function as defined by calculated creatinine clearance (according to the Cockcroft-Gault equation) \> 40 mL/min OR serum creatinine \< 1.5 × ULN.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) =\< 2.
• Must be able to take oral medication.
• Individuals of childbearing potential (IOCBP) must agree to use highly-effective method(s) of contraception during the study and six months after the last dose of study drugs. IOCBP must have a negative pregnancy test prior to study enrollment.
• Sperm producing individuals must agree to use an adequate method of contraception starting with the first dose of study therapy through 3 months after the last dose of study drugs.
• Participants must be recovered from any clinically relevant toxic effects of any prior surgery, radiotherapy, or other therapy intended for the treatment of their cancer.

You may not qualify if:

• Isolated myeloid sarcoma (patients must have blood or marrow involvement with AML to enter the study).
• Acute promyelocytic leukemia (M3).
• Active central nervous system (CNS) involvement by AML.
• Clinical signs/symptoms of leukostasis which has failed urgent therapy of at least 3 days duration, which may have included hydroxyurea or leukapheresis.
• Known active human immunodeficiency virus (HIV), active hepatitis B or active hepatitis C infection.
• Disseminated intravascular coagulopathy with active bleeding or signs of thrombosis.
• Patients who have received an investigational agent (for any indication) within 5 half-lives of the agent or who have agent-related toxicity that has not resolved to grade 1 or less. If the half-life of an investigational agent is unknown, patients must wait 1 week after discontinuing it before receiving the first dose of study treatment. An investigational agent is one for which there is no approved indication by the United States (US) Food and Drug Administration (FDA).
• Prior entrectinib for other malignancies (prior decitabine therapy will not be excluded).
• Patients with psychological, familial, social, or geographic factors that otherwise preclude them from giving informed consent, following the protocol, or potentially hamper compliance with study treatment and follow-up.
• Patients who are otherwise felt unable to comply with the protocol, in the opinion of the investigator.
• Any other significant medical condition, including psychiatric illness or laboratory abnormality, that would preclude the patient participating in the trial or would confound the interpretation of the results of the trial.
• Patients with the following will be excluded: uncontrolled intercurrent illness including, but not limited to, symptomatic (New York Heart Association \[NYHA\] class III or IV) congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, myocardial infarction at presentation of AML, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Patients with medical comorbidities that will preclude safety evaluation of the combination should not be enrolled.
• Patients with uncontrolled infection shall not be enrolled until infection is treated and controlled.
• Participants with prior documented history of malabsorption syndrome (e.g., short gut syndrome) that might limit the bioavailability of study medications will be excluded.

Sponsors & Collaborators

• OHSU Knight Cancer Institute: lead
• Oregon Health and Science University: collaborator
• Genentech, Inc.: collaborator
• Taiho Oncology, Inc.: collaborator

Study Sites (1)

OHSU Knight Cancer Institute

Portland, Oregon, 97239, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

decitabine and cedazuridine drug combination; entrectinib

Condition Hierarchy (Ancestors)

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

Study Officials

• Ronan T Swords, M.D.

  OHSU Knight Cancer Institute

  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: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: April 20, 2022
• First Posted: May 31, 2022
• Study Start: October 28, 2022
• Primary Completion: June 10, 2024
• Study Completion (Estimated): December 31, 2026
• Last Updated: April 27, 2026

Record last verified: 2025-10

Locations

US (1)