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

Primary Purpose

Acute Myeloid Leukemia With Gene Mutations, Myelodysplastic Syndrome, Myeloproliferative Neoplasm

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Ivosidenib
Liposome-encapsulated Daunorubicin-Cytarabine
Sponsored by
M.D. Anderson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia With Gene Mutations

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 (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

Sites / Locations

  • M D Anderson Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (CPX-351, ivosidenib)

Arm Description

INDUCTION: 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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

Full Information

First Posted
July 27, 2020
Last Updated
August 29, 2023
Sponsor
M.D. Anderson Cancer Center
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1. Study Identification

Unique Protocol Identification Number
NCT04493164
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
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
December 30, 2020 (Actual)
Primary Completion Date
June 1, 2024 (Anticipated)
Study Completion Date
June 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
M.D. Anderson Cancer Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia With Gene Mutations, Myelodysplastic Syndrome, Myeloproliferative Neoplasm, Recurrent Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment (CPX-351, ivosidenib)
Arm Type
Experimental
Arm Description
INDUCTION: 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.
Intervention Type
Drug
Intervention Name(s)
Ivosidenib
Other Intervention Name(s)
AG-120, Tibsovo
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
Liposome-encapsulated Daunorubicin-Cytarabine
Other Intervention Name(s)
CPX-351, Cytarabine-Daunorubicin Liposome for Injection, Liposomal AraC-Daunorubicin CPX-351, Liposomal Cytarabine-Daunorubicin, Liposome-encapsulated Combination of Daunorubicin and Cytarabine, Vyxeos
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
Overall response rate (ORR)
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.
Time Frame
Up to 3 years
Secondary Outcome Measure Information:
Title
Duration of response
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.
Time Frame
Up to 3 years
Title
Event-free survival
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.
Time Frame
Up to 3 years
Title
Overall survival
Description
Will be estimated using the method of Kaplan and Meier.
Time Frame
Up to 3 years
Title
Incidence of adverse events
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.
Time Frame
Up to 3 years
Other Pre-specified Outcome Measures:
Title
Minimal residual disease (MRD) status
Description
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.
Time Frame
Up to 3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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 > 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 (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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Courtney DiNardo
Phone
713-794-1141
Email
cdinardo@mdanderson.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Courtney DiNardo
Organizational Affiliation
M.D. Anderson Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
M D Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Courtney DiNardo
Phone
713-794-1141
Email
cdinardo@mdanderson.org
First Name & Middle Initial & Last Name & Degree
Courtney DiNardo

12. IPD Sharing Statement

Links:
URL
http://www.mdanderson.org
Description
http://www.mdanderson.org

Learn more about this trial

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

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