Clinical Trials /

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

NCT04493164

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
  • Myeloproliferative Neoplasm
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: CPX-351 and Ivosidenib for the Treatment of IDH1 Mutated Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome
  • Official Title: Phase II Investigator Sponsored Study of CPX-351 in Combination With Ivosidenib for Patients With IDH1 Mutated Acute Myeloid Leukemia or High-Risk MDS

Clinical Trial IDs

  • ORG STUDY ID: 2020-0096
  • SECONDARY ID: NCI-2020-05258
  • SECONDARY ID: 2020-0096
  • NCT ID: NCT04493164

Conditions

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

Interventions

DrugSynonymsArms
IvosidenibAG-120, TibsovoTreatment (CPX-351, ivosidenib)
Liposome-encapsulated Daunorubicin-CytarabineCPX-351, Cytarabine-Daunorubicin Liposome for Injection, Liposomal AraC-Daunorubicin CPX-351, Liposomal Cytarabine-Daunorubicin, Liposome-encapsulated Combination of Daunorubicin and Cytarabine, VyxeosTreatment (CPX-351, ivosidenib)

Purpose

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.

Detailed 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (CPX-351, ivosidenib)ExperimentalINDUCTION: Patients receive CPX-351 IV over 90 minutes on days 1, 3, and 5, and ivosidenib PO 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.
  • Ivosidenib
  • Liposome-encapsulated Daunorubicin-Cytarabine

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 >= 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 > 368 mg/m^2 daunorubicin (or equivalent) are excluded

          -  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
             (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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:Up to 3 years
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Duration of response
Time Frame:Up to 3 years
Safety Issue:
Description: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.
Measure:Event-free survival
Time Frame:Up to 3 years
Safety Issue:
Description: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.
Measure:Overall survival
Time Frame:Up to 3 years
Safety Issue:
Description:Will be estimated using the method of Kaplan and Meier.
Measure:Incidence of adverse events
Time Frame:Up to 3 years
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

July 27, 2020