Combining decitabine and venetoclax with olutasidenib for treating AML with IDH1 mutation

Phase 1b/2 Study of Decitabine and Venetoclax in Combination With the Targeted Mutant IDH1 Inhibitor Olutasidenib

This study is testing a new combination of three medications to see if it can safely help people with acute myeloid leukemia who have an IDH1 mutation achieve remission.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 78 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: M.D. Anderson Cancer Center (Academic / other)
• Drugs / interventions: chemotherapy, immunotherapy
• Locations: 2 sites (Buffalo, New York and 1 other locations)
• Trial ID: NCT06445959 on ClinicalTrials.gov

What this trial studies

This clinical trial aims to determine the safety and optimal dosing of a combination of decitabine and venetoclax alongside the targeted mutant IDH1 inhibitor olutasidenib in patients with acute myeloid leukemia (AML) harboring IDH1 mutations. The study is divided into two phases: the first phase focuses on establishing a recommended dose and assessing safety, while the second phase evaluates the effectiveness of this combination in achieving remission in newly diagnosed or relapsed/refractory patients. Additionally, the trial will explore various prognostic markers and the pharmacokinetics of the drugs involved.

Who should consider this trial

Good fit: Ideal candidates include adults over 18 with documented IDH1 gene mutations and either relapsed/refractory AML or newly diagnosed AML not suitable for intensive chemotherapy.

Not a fit: Patients without an IDH1 mutation or those who are eligible for intensive chemotherapy may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new effective option for patients with AML who have IDH1 mutations.

How similar studies have performed: Other studies have shown promising results with similar combinations of targeted therapies and chemotherapy in treating AML, indicating potential for success.

Eligibility criteria

Inclusion Criteria:

1. Age \> 18 years
2. Participants must have a documented IDH1 gene mutation
3. Participants with a diagnosis of relapsed or refractory AML (including biphenotypic or bilineage leukemia including a myeloid component or isolated extramedullary AML), high-risk MDS by IPSS-R or IPSS-M; OR
4. Participants with newly diagnosed AML not eligible or appropriate for intensive chemotherapy are also eligible. (Phase 2 portion only)
5. 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:

   1. Severe cardiac disorder (eg, congestive heart failure requiring treatment, ejection fraction ≤50%, or chronic stable angina).
   2. Severe pulmonary disorder (eg, DLCO ≤65% or forced expiratory volume in 1 second \[FEV1\] ≤65%).
   3. Creatinine clearance ≥30 mL/min to \<45 mL/min.
   4. Moderate hepatic impairment with total bilirubin \>1.5 to .3.0 x upper limit of normal (ULN)
   5. ECOG performance status of 2 or 3
   6. Any other comorbidity that per the investigator renders a patient inappropriate for intensive chemotherapy
6. Eastern Cooperative Oncology Group (ECOG) Performance Status \</=2 (unless age 18 to 74 years of age with newly diagnosed AML not eligible for intensive chemotherapy as per 5e above)
7. Adequate renal function including creatinine \< 1.5, unless related to the disease or unless age 18 to 74 years of age with newly diagnosed AML not eligible for intensive chemotherapy as per 5c above.
8. Adequate hepatic function (direct bilirubin \< 2x upper limit of normal (ULN) unless increase is due to Gilbert fs disease or leukemic involvement, and AST and/or ALT \< 3x ULN unless considered due to leukemic involvement, in which case direct bilirubin or AST and/or ALT \< 5x ULN will be considered eligible, or unless age 18 to 74 years of age with newly diagnosed AML not eligible for intensive chemotherapy as per 5d above)
9. In the absence of rapidly proliferative disease, the interval from prior treatment to time of initiation will be at least 14 days for cytotoxic or non-cytotoxic (immunotherapy agent(s), or an interval of 5 half-lives of the prior therapy. Oral hydroxyurea and/or cytarabine (up to 2 g/m2) for patients with rapidly proliferative disease is allowed before the start of study therapy, as needed, for clinical benefit and after discussion with the PI. Concurrent intrathecal therapy for central nervous system (CNS) prophylaxis or continuation of therapy for controlled CNS disease is permitted.
10. Male participants who are sexually active with a women of childbearing potential (WOCBP) and who have not had vasectomies must be willing to use a barrier method of contraception and refrain from sperm donation from initial study drug until 90 days after last dose of study drug.
11. Willing and able to provide informed consent.

Exclusion Criteria:

1. Participants with t(15;17) karyotypic abnormality or acute promyelocytic leukemia (French-American-British \[FAB\] class M3-AML).
2. Participants with any concurrent uncontrolled clinically significant medical condition including life-threatening severe infection, or psychiatric illness, which could place the participants at unacceptable risk of study treatment.
3. Participants with active, uncontrolled leukemia involvement of the CNS
4. Participants with active graft-versus-host-disease (GVHD) status post stem cell transplant including active cGVHD requiring topic therapy. Patients must have discontinued calcineurin inhibitors at least 4 weeks prior to start of study treatment.
5. Participants with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications.
6. Known active hepatitis B (HBV) or Hepatitis C (HCV) infection or known HIV infection.
7. Participant has a white blood cell count \> 25 x 10\^9/L. (Note: Hydroxyurea and cytarabine is permitted to meet this criterion.)
8. 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.

A) Appropriate highly effective method(s) of contraception include oral or injectable hormonal birth control, IUD, and double barrier methods (for example a condom in combination with a spermicide).

Where this trial is running

Buffalo, New York and 1 other locations

• Roswell Park — Buffalo, New York, United States (Recruiting)
• MD Anderson Cancer Center — Houston, Texas, United States (Recruiting)

Study contacts

• Principal investigator: Courtney DiNardo, MD — M.D. Anderson Cancer Center
• Study coordinator: Courtney DiNardo, MD

Conditions Mutant IDH1 Inhibitor Olutasidenib