Olutasidenib in Relapsed IDH1 Mutated AML Patients Who Have Previously Received Venetoclax

Pilot Single Arm Phase 2 Study of Olutasidenib in Relapsed IDH1 Mutated AML Patients Who Have Previously Received Venetoclax

This is a prospective, single-arm phase 2 pilot study to assess the response rate of IDH1 mutated relapsed/refractory acute myeloid leukemia (AML) patients who receive olutasidenib after progressing on venetoclax based regimens. Each cycle will last for 28 days. Patients will receive olutasidenib 150 mg orally twice daily Day 1 through Day 28. After 3 cycles of olutasidenib, azacitidine 75 mg/m2 given on Day 1 through Day 7 may be added at the discretion of the treating investigator if the patient has not achieved a complete remission. Subjects with at least a PR after 6 cycles of treatment will continue treatment as previously described. Subjects without at least a partial response (PR) after 6 cycles of treatment will move to long term follow up.

Study Overview

• Status: Not yet recruiting
• Conditions: IDH1 Mutation; Relapsed / Refractory AML
• Intervention / Treatment: Drug: Olutasidenib; Drug: Azacitidine (AZA)

• Study Type: Interventional
• Enrollment (Estimated): 25
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ahran Lee; Phone Number: 14 317-634-5842; Email: alee@hoosiercancer.org
• Study Contact Backup: Name: Timothy Pardee; Phone Number: MD, PhD; Email: tspardee@wakehealth.edu

Study Locations

• United States
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Atrium Health Wake Forest Baptist Medical Center
      • Principal Investigator: Timothy Pardee, MD, PhD
      • Contact: Sarah Davis; Phone Number: 803-325-4205; Email: Sarah.Davis@advocatehealth.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
2. Age ≥ 18 years at the time of consent.
3. ECOG Performance Status of ≤ 2 within 28 days prior to registration.
4. Must have histologically or cytologically documented relapsed and/or refractory Acute Myeloid Leukemia (Refractory is defined as failure to achieve a CR after induction chemotherapy or a minimum of two cycles of HMA plus venetoclax)
5. Acute Myeloid Leukemia with a documented IDH1 mutation.
6. No more than 2 lines of prior therapy. NOTE: One line of therapy must have contained venetoclax.
7. Persisting, non-hematologic and non-infectious toxicities from prior treatment must be Grade ≤ 2. NOTE: Documentation of these criteria is required at screening.

8. Demonstrate adequate organ function as defined in the table below. All screening labs to be obtained within 14 days prior to registration.

   • Renal
   • Calculated creatinine clearance (Cockcroft-Gault formula will be used to calculate creatinine clearance) ≥ 30 mL/min
   • Hepatic
   • Total bilirubin2 ≤ 2× upper limit of normal (ULN); ≤ 3 times ULN in patients with Gilbert Syndrome
   • Aspartate aminotransferase (AST) ≤ 5 × ULN
   • Alanine aminotransferase (ALT) ≤ 5× ULN
9. Participants of childbearing potential must have a negative serum pregnancy test within 7 days prior to initiation of treatment.
10. Participants of childbearing potential who are having penile-vaginal intercourse with a person able to father a child must be willing to abstain from penile-vaginal intercourse or must use an effective method(s) of contraception. A participant able to father a child who is having penile-vaginal intercourse with a person of childbearing potential must be willing to abstain from penile-vaginal intercourse or use an effective method(s) of contraception.
11. Subjects with known HIV infection may be eligible if they are on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration. Testing is not required at screening.
12. Subjects with known chronic hepatitis B virus (HBV) infection may be eligible if they have an undetectable HBV viral load on suppressive therapy, if indicated. Subjects with a history of hepatitis C virus (HCV) infection may be eligible if they have been treated and cured. Subjects with an HCV infection who are currently on treatment must have an undetectable HCV viral load to be eligible for this trial. Testing is not required at screening.
13. As determined by the investigator or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study.

Exclusion Criteria:

1. Previous exposure to ivosidenib or any IDH1 inhibitor.
2. Active infection requiring IV systemic therapy. NOTE: Subjects receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.
3. Known CNS involvement with AML.
4. Previous allogeneic stem cell transplant within 60 days prior to registration.
5. Treatment with any investigational drug within 21 days or 2 half-life's prior to registration.
6. History of severe allergic anaphylactic reactions to olutasidenib or any of their excipients.
7. Pregnant or breastfeeding. NOTE: breast milk cannot be stored for future use while the subject is being treated on study.
8. Prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen, per treating physician discretion.
9. Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout period prior to starting olutasidenib is 2 weeks or 5 half-lives (whichever is longer) prior to initiation of treatment.
10. Concomitant use of known sensitive CYP3A substrates (e.g. Midazolam, simvastatin, fluticasone, budesonide). The required washout period prior to starting olutasidenib is 2 weeks or 5 half-lives (whichever is longer) prior to initiation of treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Olutasidenib and Azacitidine; Each cycle will last for 28 days. Patients will receive olutasidenib 150 mg orally twice daily Day 1 through Day 28. After 3 cycles of olutasidenib, azacitidine 75 mg/m2 given on Day 1 through Day 7 may be added at the discretion of the treating investigator if the patient has not achieved a complete remission or for whom loss of response is suspected. Subjects with at least a PR after 6 cycles of treatment will continue treatment.. Subjects without at least a PR after 6 cycles of treatment will move to long term follow up.

Drug: Olutasidenib; Olutasidenib 150 mg orally twice a day; Drug: Azacitidine (AZA); Azacitidine 75 mg/m2 subcutaneously or IV (over 10-40 minutes)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite complete remission rate	Composite complete remission (CRc) rate is defined as patients that meet the criteria for CR + CRh + CRi per the modified European LeukemiaNet (mELN) 2022.; Complete Remission (CR) is defined as absence of leukemia cells in the bone marrow (< 5% blasts), normal blood counts (absolute neutrophil count ≥ 1000/μL and platelet count ≥ 100,000/μL), and the absence of circulating blasts, and extramedullary disease; Complete Remission with Hematologic recovery (CRh) is defined as meeting all criteria for CR as Bone marrow myeloblasts < 5%; absence of circulating blasts; absence of extramedullary disease; both ANC ≥ 0.5x109/L (500/µL) and platelet count ≥ 50×109/L (50 000/µL); Complete Remission with Incomplete hematologic recovery (CRi) is defined as meeting all criteria for Complete Remission (CR) except for either a low neutrophil count (neutropenia) or a low platelet count (thrombocytopenia)	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (ORR)	ORR is defined as the proportion of patients achieving CR + CRh + CRi + Partial Remission (PR) + morphologic leukemia-free state [MLFS] per ELN 2022. PR is defined as all hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; and decrease of pretreatment bone marrow blast percentage by at least 50%. MLFS is defined as bone marrow blasts < 5%, absence of circulating blasts, and no hematologic recovery.	2 years
Overall survival	OS is defined as the time from registration to death from any cause or last known follow-up.	2 years
Duration of response (DoR)	DoR is defined as the time between the first achieved response (CR, CRh, CRi, PR, MLFS) and the earliest evidence of relapse (blasts ≥ 5%) per ELN 2022 or death or date of last follow up.	2 years
Time to hematologic improvement (hemoglobin)	Improvement of Hgb is defined as the time it takes for an individual's hemoglobin level to increase by ≥ 1g/dL from Cycle 1 Day 1 without transfusion	2 years
Time to hematologic improvement (platelet count)	Improvement of PLT is defined as the time it takes for an individual's platelet count to increase by ≥ 50 x 10^9/L from Cycle 1 Day 1 without transfusion	2 years
Time to hematologic improvement (neutrophil count)	Improvement of ANC is defined as the time it takes for an individual's neutrophil count to increase to ≥ 1,500 cells/µL for 3 days.	2 years
Rate of transfusion independence	The rate of transfusion independence is defined as the absence of red blood cell (RBC) transfusions for ≥ 8 weeks following the start of treatment	2 years
Rate of allogeneic transplant	The rate of allogeneic transplant is defined as the proportion of patients who undergo allogeneic transplant following response to olutasidenib.	2 years

Collaborators and Investigators

• Sponsor: Timothy Pardee
• Collaborators: Rigel Pharmaceuticals; Atrium Health Wake Forest Baptist
• Investigators: Principal Investigator: Timothy Pardee, MD, PhD, Atrium Health Wake Forest Baptist

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2029

Study Registration Dates

• First Submitted: March 10, 2026
• First Submitted That Met QC Criteria: March 10, 2026
• First Posted (Actual): March 13, 2026

Study Record Updates

• Last Update Posted (Actual): March 13, 2026
• Last Update Submitted That Met QC Criteria: March 10, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Aza Compounds; Nucleosides; Ribonucleosides; Azacitidine; olutasidenib
• Other Study ID Numbers: HCRN-AML24-687

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No