This phase II trial investigates how well CPX-351 and ivosidenib work in treating patients with acute myeloid leukemia or high-risk myelodysplastic syndrome that has IDH1 mutation. The safety of this drug combination will also be studied. IDH1 is a type of genetic mutation (change). Chemotherapy drugs, such as CPX-351, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Ivosidenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. The purpose of this trial is to learn if CPX-351 in combination with ivosidenib can help to control IDH1-mutated acute myeloid leukemia or high-risk myelodysplastic syndrome.
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
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).
Single group
Ivosidenib
DrugGiven PO
Liposome-encapsulated Daunorubicin-Cytarabine
DrugGiven IV
Overall response rate (ORR)
Defined as complete remission (CR) + complete remission with hematologic recovery (CRh) + complete remission with incomplete blood count recovery (CRi) + morphologic leukemia-free state (MLFS) + and partial remission (PR). Will be assessed based on revised International Working Group (IWG) response criteria for acute myeloid leukemia (AML). Estimated along 95% confidence interval.
Duration of response
Defined as the number of days from the date of initial response (PR or better) to the date of first documented disease progression/relapse or death, whichever occurs first.
Event-free survival
Defined as the number of days from the date of treatment initiation (i.e., cycle 1 days 1 \[C1D1\]) to the date of documented treatment failure, relapses from CR, or death from any cause, whichever occurs first, and will be calculated for all patients. Will be estimated using the method of Kaplan and Meier.
Overall survival
Will be estimated using the method of Kaplan and Meier.
Incidence of adverse events
The severity of the adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. The number and percent of subjects with treatment-emergent adverse events will be summarized according to intensity and drug relationship, and categorized by System Organ Class and preferred term by dose level/part.
Minimal residual disease (MRD) status
The association between cellular biomarker, MRD, etc. and antitumor activity will be compared using Wilcoxon's rank sum test or Fisher's exact test, as appropriate. MRD negative status and exploratory biomarkers will be summarized graphically and with descriptive statistics.
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