Olutasidenib with azacitidine followed by olutasidenib maintenance for IDH1‑mutated acute myeloid leukemia after venetoclax plus HMA

A Phase 2 Study of Olutasidenib in Combination With Azacitidine Followed by Olutasidenib Maintenance After Venetoclax Plus a Hypomethylating Agent Regimen (HMA-VEN) for IDH1-Mutated Acute Myeloid Leukemia (AML)

This trial will test whether giving olutasidenib with azacitidine, then continuing olutasidenib alone, helps people with IDH1‑mutated AML who previously received venetoclax plus a hypomethylating agent.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 28 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: University of California, Davis (other)
• Drugs / interventions: radiation
• Locations: 1 site (Sacramento, California)
• Trial ID: NCT07304011 on ClinicalTrials.gov

What this trial studies

Participants receive oral olutasidenib twice daily on days 1–28 plus azacitidine by IV or SC for seven days of each 28‑day cycle for up to four cycles, followed by olutasidenib maintenance given orally twice daily on days 1–28 of each 28‑day cycle. Treatment continues until disease progression or unacceptable toxicity, with scheduled bone marrow biopsies and blood draws to monitor response and safety. After treatment ends, patients are followed up within 30 days and then every four months until withdrawal, loss to follow‑up, study termination, or death. The trial enrolls adults with AML carrying an IDH1‑R132 mutation who achieved a CR or CRi to first‑line venetoclax plus an HMA.

Who should consider this trial

Good fit: Ideal candidates are adults with AML carrying an IDH1‑R132 mutation who achieved a CR or CRi to first‑line venetoclax plus an HMA (≤4 cycles), are candidates for azacitidine, have ECOG ≤2, and have discontinued venetoclax at least one week before starting study treatment.

Not a fit: Patients without an IDH1 mutation, those who did not respond to first‑line venetoclax plus HMA, those who received more than four cycles of prior HMA‑Ven, or those with poor performance status (ECOG >2) are unlikely to benefit from this regimen.

Why it matters

Potential benefit: If effective, this approach could prolong remission and delay relapse for patients with IDH1‑mutated AML who previously received venetoclax plus an HMA.

How similar studies have performed: Other IDH1 inhibitors and early combination studies of IDH1 inhibitors with azacitidine have shown activity in AML, but this specific olutasidenib-plus-azacitidine followed by maintenance sequence is being tested in this population.

Eligibility criteria

Inclusion Criteria:

* Pathologically documented AML (except acute promyelocytic leukemia with the t(15;17) translocation) as defined by the World Health Organization (WHO) or International Consensus Classification criteria
* Achieved complete response (CR)/complete remission with incomplete count recovery (CRi) response to first line HMA-Ven according to the European Leukemia Net (ELN) recommendations for diagnosis as determined by investigator review
* Documented IDH1-R132 mutations (≥ 0.01%) detected in the bone marrow or blood. Mutation must be present at the time of AML diagnosis or after initiating HMA-Ven
* Receiving first-line HMA-Ven with less than or equal to 4 cycles of HMA-Ven at the time of enrollment. Participants must discontinue venetoclax (Ven) at least 1 week (or 5 half-lives, whichever is shorter) from initiating study treatment
* Candidate for standard of care azacitidine
* Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 50%)
* No prior solid organ allograft
* Recovery from the non-hematologic toxic effects of prior treatment to grade ≤ 1, or baseline value according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) classification (excluding infertility or alopecia)
* Aged ≥ 18 at the time of consent
* Creatinine clearance ≥ 40 mL/min (calculated by the Cockcroft-Gault formula or measured by 24-hour urine collection)
* Serum alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN)
* Serum aspartate aminotransferase (AST) ≤ 3 × ULN
* Bilirubin ≤ 2 x ULN unless due to Gilbert's syndrome or controlled autoimmune hemolytic anemia (not requiring immunosuppressive other than ≤ 20 mg of prednisolone daily)

  * Note: Patients with Gilbert's syndrome may be included if total bilirubin is ≤ 3 × ULN and direct bilirubin is ≤ 2 × ULN
* Prothrombin time (PT) or international normalized ratio (INR)/activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN
* Women of child-bearing potential, men, and their respective partners, must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days after the last dose of olutasidenib
* Must sign and date the informed consent form prior to undergoing any study procedures

Exclusion Criteria:

* Prior IDH1 inhibitor (IDH1i) targeted therapy
* Prior AML therapy except for HMA-Ven
* History of a different malignancy unless they have been disease-free for at least 12 months and are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with a history of other malignancies within 12 months and without any evidence of disease progression or requiring therapy may be considered, but only after consideration and approval by the Overall Principal Investigator (PI). Individuals with the following cancers are eligible if diagnosed and/or treated within the past 12 months: cervical cancer in situ, breast ductal carcinoma in situ (DCIS), and basal cell or squamous cell carcinoma of the skin
* Patients with symptomatic central nervous system (CNS) metastases or other tumor location (such as spinal cord compression, other compressive mass, uncontrolled painful lesion, bone fracture, etc.) necessitating an urgent therapeutic intervention, palliative care, surgery or radiation therapy
* Patients with previous allogeneic hematopoietic stem cell transplantation (HSCT) for non-AML indications, if they meet any of the following criteria: \< 100 days from time of HSCT; active acute or chronic graft versus (vs.) host disease (GvHD); or receiving immunosuppressive therapy as treatment or prophylaxis against GvHD

  * Note: Doses \< 20 mg methylprednisolone (or its equivalent) daily are not an exclusion criterion
* Treatment with radiation therapy or major surgery (requiring general anesthesia) within 2 weeks prior to study drug dosing
* Patients unable to swallow oral medications, or patients with gastrointestinal conditions (e.g., malabsorption, resection, etc.) deemed by the Investigator to jeopardize intestinal absorption
* Congestive heart failure (New York Heart Association Class III or IV) or unstable angina pectoris; previous history of myocardial infarction within one year prior to study entry, uncontrolled hypertension, or uncontrolled arrhythmias
* Patients with a baseline corrected QT interval by Fridericia's formula (QTcF) of \> 480 msec

  * Note: This criterion does not apply to patients with a bundle branch block (BBB); for participants with BBB, a cardiology consult is recommended to ensure that QTcF is not prolonged
* Concomitant medication(s) known to cause Torsades de Pointes (TdP) initiated less than the duration required to reach steady-state plasma concentration (approximately five half-lives) before first dose of study drug. Medications used as needed (PRN), e.g. Zofran, and common AML supportive care drugs (e.g. levofloxacin, azoles, etc.) are exempt
* Concurrent treatment with chronic corticosteroids except if chronic treatment with \< 20 mg of methylprednisolone daily or equivalent (pulse steroids for treatment or prophylaxis are allowed \[e.g., for transfusion or medication reactions\])
* Known history of seropositivity for HIV infection
* Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy (prophylactic systemic antimicrobials permitted)
* Uncontrolled disease-related metabolic disorder (e.g., hypercalcemia)
* Pregnant, breastfeeding, or planning to become pregnant while enrolled in this trial or within 90 days after the last dose of olutasidenib. Pregnant or breastfeeding

  * NOTE: Breast milk cannot be stored for future use while the mother is being treated on study)
* Plans to donate sperm or conceive a child through intercourse while enrolled in this trial or within 90 days after the last dose of olutasidenib
* Unwillingness or inability to comply with procedures either required in this protocol or considered standard of care
* Medical, uncontrolled disease-related metabolic disorder, psychiatric, cognitive, or other conditions that may, in the opinion of the investigator, compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol, or complete the study

Where this trial is running

Sacramento, California

• University of California Davis Comprehensive Cancer Center — Sacramento, California, United States (RECRUITING)

Study contacts

• Principal investigator: Brian Jonas, MD — University of California, Davis
• Study coordinator: OCR Referral Team

Conditions: Acute Myeloid Leukemia