Combining entrectinib and ASTX727 for treating relapsed or refractory TP53 mutated acute myeloid leukemia

A Phase I Study of Entrectinib in Combination With ASTX727 (35 mg Decitabine and 100 mg Cedazuridine) in Patients With Relapsed/Refractory TP53 Mutated Acute Myeloid Leukemia (AML)

This study is testing a new combination of two drugs, entrectinib and ASTX727, to see if they can help people with relapsed or hard-to-treat acute myeloid leukemia that has a TP53 mutation.

Quick facts

• Phase: PHASE1
• Study type: Interventional
• Enrollment: 12 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: OHSU Knight Cancer Institute (other)
• Drugs / interventions: entrectinib
• Locations: 1 site (Portland, Oregon)
• Trial ID: NCT05396859 on ClinicalTrials.gov

What this trial studies

This phase I trial evaluates the safety and effectiveness of entrectinib in combination with ASTX727 for patients with relapsed or refractory acute myeloid leukemia (AML) that has a TP53 mutation. The study aims to determine the maximum tolerated dose of this combination therapy while assessing its overall safety and preliminary anti-AML activity. Patients will receive entrectinib daily for 28 days alongside ASTX727 for the first five days of each treatment cycle, with follow-up assessments conducted for up to one year post-treatment.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with relapsed or refractory AML and a documented TP53 mutation.

Not a fit: Patients without a TP53 mutation or those with other types of AML may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for patients with difficult-to-treat TP53 mutated AML.

How similar studies have performed: While this approach is novel in combining these specific agents for TP53 mutated AML, similar studies have shown promise in targeting genetic mutations in cancer therapies.

Eligibility criteria

Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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.

Where this trial is running

Portland, Oregon

• OHSU Knight Cancer Institute — Portland, Oregon, United States (RECRUITING)

Study contacts

• Principal investigator: Ronan T Swords, M.D. — OHSU Knight Cancer Institute

Conditions: Acute Myeloid Leukemia, Recurrent Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia