Combining CPX-351 and ivosidenib for treating IDH1 mutated acute myeloid leukemia and high-risk myelodysplastic syndrome

Phase II Investigator Sponsored Study of CPX-351 in Combination With Ivosidenib for Patients With IDH1 Mutated Acute Myeloid Leukemia or High-Risk MDS

This study is testing a combination of two treatments, CPX-351 and ivosidenib, to see if they can help people with acute myeloid leukemia or high-risk myelodysplastic syndrome who have an IDH1 mutation.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 30 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: M.D. Anderson Cancer Center (Academic / other)
• Drugs / interventions: chemotherapy, immunotherapy, radiation
• Locations: 1 site (Houston, Texas)
• Trial ID: NCT04493164 on ClinicalTrials.gov

What this trial studies

This phase II trial evaluates the effectiveness of CPX-351, a chemotherapy drug, in combination with ivosidenib, a targeted therapy, for patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) that have an IDH1 mutation. The study aims to determine the overall response rate to this treatment combination, assess its safety, and evaluate various time-to-event endpoints such as duration of response and overall survival. Patients will receive CPX-351 intravenously and ivosidenib orally over a specified treatment schedule, with the possibility of maintenance therapy for up to two years. The trial also includes exploratory objectives to evaluate biomarkers that may predict treatment response.

Who should consider this trial

Good fit: Ideal candidates include patients with IDH1-R132 mutated AML or high-risk MDS who are treatment naive or have relapsed/refractory disease and are eligible for intensive chemotherapy.

Not a fit: Patients without IDH1 mutations or those with rapidly proliferative disease may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment combination could improve outcomes for patients with IDH1 mutated AML or high-risk MDS.

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

Eligibility criteria

Inclusion Criteria:

* Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
* IDH1-R132 mutated disease status as assessed by local laboratory. 2HG-producing IDH1 variants outside of R132 (i.e. R100) may be eligible after discussion with the principal investigator (PI)
* Treatment naive or relapsed/refractory AML who are eligible for intensive chemotherapy. Patients with high-risk MDS or MPN (defined as International Prognostic Scoring System Revised \[IPSS-R\] score ≥ 4 or dynamic \[D\]-IPSS ≥ 3) may also be eligible after discussion with the PI
* Adequate hepatic function (direct bilirubin ≤ 2 x upper limit of normal (ULN), Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 3 x ULN unless deemed to be related to underlying leukemia
* Adequate renal function including creatinine clearance ≥ 30 ml/min based on the Cockcroft-Gault equation.
* Willing and able to provide informed consent
* In the absence of rapidly proliferative disease, the interval from prior treatment to time of initiation will be at least 7 days for cytotoxic or non-cytotoxic (immunotherapy) agents.
* Male subjects must agree to refrain from unprotected sex and sperm donation from initial study drug administration until 90 days after the last dose of study drug

Exclusion Criteria:

* Patients who have previously received CPX-351.
* Patients with any concurrent uncontrolled clinically significant medical condition including infection, laboratory abnormality, or psychiatric illness, which could place the patient at unacceptable risk of study treatment.
* The use of other chemotherapeutic agents or anti-leukemic agents is not permitted during study with the following exceptions (1) intrathecal chemotherapy for prophylactic use or for controlled CNS leukemia. (2) use of hydroxyurea, and/or cytarabine (1 or 2 doses; up to 2 g/m2) for patients with rapidly proliferative disease is allowed before the start of study therapy.
* Patients with active graft-versus-host-disease (GVHD) status post stem cell transplant (patients without active GVHD on chronic suppressive immunosuppression and/or phototherapy for chronic skin GVHD are permitted after discussion with the PI).
* Patients with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications.
* Patients with symptomatic congestive heart failure (NYHA Class III or IV), unstable angina, or an ejection fraction \< 45%.
* Patients with prior anthracycline exposure of \> 360 mg/m2 daunorubicin (or equivalent), or \> 210 mg/m2 daunorubicin (or equivalent) in patients with prior mediastinal radiation.
* QTc interval using Fridericia's formula (QTcF) \> 470 msec. A prolonged QTc interval in the setting of right bundle branch block is permitted after discussion with the PI.
* Nursing women, women of childbearing potential (WOCBP) with positive urine or serum 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).
* Subjects with a known medical history of progressive multifocal leukoencephalopathy (PML).
* Subjects taking strong CYP3A4 inducers are excluded from the study unless they can be transferred to other medications within ≥ 5 half-lives prior to dosing
* Patients with a diagnosis of acute promyelocytic leukemia (APL).
* Unresolved toxicities \> grade 1 from prior treatment including chemotherapy, targeted therapy, immunotherapy, experimental agents, radiation, or surgery.

Where this trial is running

Houston, Texas

• M D 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 Acute Myeloid Leukemia With Gene Mutations; Myelodysplastic Syndrome; Myeloproliferative Neoplasm; Recurrent Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia