CPX-351 and Ivosidenib for the Treatment of IDH1 Mutated Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

  • STATUS
    Recruiting
  • days left to enroll
    63
  • participants needed
    30
  • sponsor
    M.D. Anderson Cancer Center
Updated on 8 July 2022
cancer
myeloid leukemia
cytarabine
direct bilirubin
leukemia
refractory acute myeloid leukemia (aml)

Summary

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.

Description

PRIMARY OBJECTIVE:

I. To determine the overall response rate (ORR) including 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) of the combination of liposome-encapsulated daunorubicin-cytarabine (CPX-351) and ivosidenib in IDH1-mutated patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS).

SECONDARY OBJECTIVES:

I. To assess safety of CPX-351 in combination with ivosidenib. II. To determine time to event endpoints including duration of response (DOR), event free survival (EFS) and overall survival (OS).

EXPLORATORY OBJECTIVES:

I. Evaluate minimal residual disease (MRD) using multiparameter flow cytometry, cytogenetics and molecular evaluation.

II. To evaluate molecular and cellular biomarkers that may be predictive of antitumor activity and/or resistance to treatment including evaluation of 2HG, IDH1 and other co-occurring mutations and VAF levels before, during and after treatment.

OUTLINE

INDUCTION: Patients receive CPX-351 intravenously (IV) over 90 minutes on days 1, 3, and 5, and ivosidenib orally (PO) once daily (QD) on days 1-28. Patients who do not achieve complete remission may receive a second cycle of induction therapy in the absence of disease progression or unacceptable toxicity. Patients achieving complete remission proceed to consolidation.

CONSOLIDATION: Patients receive CPX-351 IV over 90 minutes on days 1 and 3, and ivosidenib PO QD on days 1-28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients receive ivosidenib PO QD for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients who are experiencing clinical benefit and who have not experienced excessive toxicity after completion of 2 years of maintenance may be eligible to continue therapy after discussion with the principal investigator.

After completion of study treatment, patients are followed up at 30 days, then monthly for 3 years.

Details
Condition Acute Myeloid Leukemia With Gene Mutations, Myelodysplastic Syndrome, Myeloproliferative Neoplasm, Recurrent Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia
Treatment Ivosidenib, Liposome-encapsulated Daunorubicin-Cytarabine
Clinical Study IdentifierNCT04493164
SponsorM.D. Anderson Cancer Center
Last Modified on8 July 2022

Eligibility

Yes No Not Sure

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 >= 10% bone marrow blasts, or intermediate or high risk by International Prognostic Scoring System [IPSS], revised [R]-IPSS or dynamic [D]-IPSS) may also be eligible after discussion with the PI
Direct bilirubin =< 2 x upper limit of normal (ULN) unless deemed to be related to underlying leukemia
Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) =< 3 x ULN unless deemed to be related to underlying leukemia
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 either ivosidenib or 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 central nervous system (CNS) leukemia. (2) use of hydroxyurea, and/or cytarabine (1 or 2 doses; up to 2 g/m^2) 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 (New York Heart Association [NYHA] class III or IV), unstable angina, or an ejection fraction < 45%
Patients with prior anthracycline exposure of > 360 mg/m^2 daunorubicin (or equivalent) or > 210 mg/m^2 daunorubicin (or equivalent) in patients with prior mediastinal radiation
Corrected QT (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
Appropriate highly effective method(s) of contraception include oral or injectable hormonal birth control, intrauterine device (IUD), and double barrier methods (for example a condom in combination with a spermicide)
Subjects with a known medical history of progressive multifocal leukoencephalopathy
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
(PML)
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
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