CPX-351 as a Novel Approach for the Treatment of Older Patients With AML and MDS

Lower Doses of CPX-351 as a Novel Approach for the Treatment of Older Patients With Relapsed or Refractory Acute Myeloid Leukemia and Myelodysplastic Syndromes

The purpose of this study is to evaluate how effective lower doses of CPX-351 are in older participants with relapsed/refractory acute myeloid leukemia (AML) who are not eligible to receive intensive chemotherapy and in participants with myelodysplastic syndromes (MDS) after Hypomethylating Agents (HMA) failure.

Study Overview

• Status: Active, not recruiting
• Conditions: Myelodysplastic Syndromes; Refractory Acute Myeloid Leukemia; Relapsed Acute Myelomonocytic Leukemia
• Intervention / Treatment: Drug: CPX-351

Detailed Description

Currently, elderly patients with AML and high risk MDS, who are ineligible to receive induction chemotherapy and fail HMA +/- combination, have very poor outcomes and there is no FDA-approved therapy outside of some targeted therapies which can only be applied to a small patient population. CPX-351 is an investigational (experimental) drug that works by combining two anti-cancer drugs cytarabine and daunorubicin. CPX-351 is experimental because it is only FDA approved for the treatment of adults with two types of AML: newly diagnosed therapy-related AML or AML with myelodysplasia-related changes.

This is an open label clinical trial of lower doses of CPX-351 in relapsed/primary refractory older AML and MDS patients ineligible to receive intensive chemotherapy. The first arm is for particpants with primary refractory/relapsed AML and the second arm is for higher risk MDS participants after HMA failure.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44106-5065
      • Cleveland Clinic, Case Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Primary refractory or relapsed AML (defined by 2016 World Health Organization [WHO] criteria) patients who are not suitable for or not willing to receive intensive chemotherapy as evaluated by the treating physician. Primary refractory disease is defined as:

  • Failure to achieve a CR, CRi, or mLFS (defined as <5% Bone Marrow (BM) blasts) after receiving 1 or 2 cycles of remission induction chemotherapy.
  • Failure to achieve a CR, CRi, or MLFS (defined as <5% BM blasts) after receiving 4 cycles of non-intensive chemotherapy or whose disease progressed at any time point during the treatment.
• Participants with MDS (according to 2016 WHO criteria) who did not respond to treatment with azacitidine, decitabine, or combination of HMA with another drug or lost their response to initial therapy with HMA.
• Eastern Cooperative Oncology Group (ECOG) performance status <=2
• Adequate hepatic (serum total bilirubin < 1.5 x ULN, Serum glutamic pyruvic transaminase (SGPT) and/or serum glutamate oxaloacetate transaminase (SGOT) <2.5 x ULN) and renal function (creatinine < 1.5mg/dL).
• Participants must be willing and able to review, understand, and provide written consent before starting therapy.

Exclusion Criteria:

• Active signs or symptoms of central nervous system (CNS) involvement by malignancy (lumbar puncture [LP] not required).
• Prior 7+3 remission induction chemotherapy for MDS or AML
• More than 2 lines of prior non-intensive therapy.
• New York Heart Association (NYHA) class III or IV heart disease, active ischemia or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia on rhythm control strategy or on pacemaker, uncontrolled hypertension (blood pressure > 160 systolic and > 110 diastolic not responsive to antihypertensive medication)
• Acute myocardial infarction in the previous 12 weeks (from the start of treatment).
• Any serious medical condition, laboratory abnormality, or psychiatric illness that, in the view of the treating physician, would place the participant at an unacceptable risk if he or she were to participate in the study or would prevent that person from giving informed consent.
• Any active malignancy (unrelated, non-hematological malignancy) diagnosed within the past 6 months of starting the study drug (other than curatively treated carcinoma-in-situ of the cervix or non-melanoma skin cancer).
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to CPX-351.
• Subjects with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Known history of HIV or active hepatitis B or C.
• No major surgery within 2 weeks prior to study enrollment.
• Pregnant or breast feeding
• Male and female participants who are fertile who do not agree to use an effective barrier methods of birth control (i.e. abstinence) to avoid pregnancy while receiving study treatment and for 30 days after last dose of study treatment. Non-childbearing is defined as > 1 year postmenopausal or surgically sterilized.
• Acute promyelocytic leukemia (APL)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Primary refractory/relapsed AML; Lower dose CPX-351 in participants with primary refractory/relapsed AML. Participants will receive an induction and maintenance phase of CPX-351	Drug: CPX-351; Induction phase: CPX-351 15 mg/m^2 on days 1 and 3 of each 28-day cycle for up to a total of 6 cycles in the absence of unacceptable toxicity Maintenance phase: CPX-351 7.5 mg/m^2 on days 1 and 3 for two cycles alternating with 15 mg/m^2 for one cycle. Participants may receive up to 12 cycles of maintenance phase in the absence of unacceptable toxicity.
Experimental: MDS after HMA failure; Lower dose CPX-351 in participants with MDS after HMA failure. Participants will receive an induction and maintenance phase of CPX-351	Drug: CPX-351; Induction phase: CPX-351 15 mg/m^2 on days 1 and 3 of each 28-day cycle for up to a total of 6 cycles in the absence of unacceptable toxicity Maintenance phase: CPX-351 7.5 mg/m^2 on days 1 and 3 for two cycles alternating with 15 mg/m^2 for one cycle. Participants may receive up to 12 cycles of maintenance phase in the absence of unacceptable toxicity.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (ORR) per 2003 International Working Group (IWG) criteria	ORR = complete response (CR) + CR with incomplete blood count recovery (CRi) + partial remission (PR) as defined by 2003 IWG criteria for AML patients, and ORR = CR + PR + hematologic improvement (HI) and as defined per 2006 IWG criteria for MDS patients	At 6 months
Overall response rate (ORR) per 2003 IWG criteria	ORR = complete response (CR) + CR with incomplete blood count recovery (CRi) + partial remission (PR) as defined by 2003 IWG criteria for AML patients, and ORR = CR + PR + hematologic improvement (HI) and as defined per 2006 IWG criteria for MDS patients	At 1 year
Overall response rate (ORR) per 2003 IWG criteria	ORR = complete response (CR) + CR with incomplete blood count recovery (CRi) + partial remission (PR) as defined by 2003 IWG criteria for AML patients, and ORR = CR + PR + hematologic improvement (HI) and as defined per 2006 IWG criteria for MDS patients	At 1.5 years
Overall response rate (ORR) per 2003 IWG criteria	ORR = complete response (CR) + CR with incomplete blood count recovery (CRi) + partial remission (PR) as defined by 2003 IWG criteria for AML patients, and ORR = CR + PR + hematologic improvement (HI) and as defined per 2006 IWG criteria for MDS patients	At 2 years
Overall response rate (ORR) per 2003 IWG criteria	ORR = complete response (CR) + CR with incomplete blood count recovery (CRi) + partial remission (PR) as defined by 2003 IWG criteria for AML patients, and ORR = CR + PR + hematologic improvement (HI) and as defined per 2006 IWG criteria for MDS patients	At 2.5 years
Overall response rate (ORR) per 2003 IWG criteria	ORR = complete response (CR) + CR with incomplete blood count recovery (CRi) + partial remission (PR) as defined by 2003 IWG criteria for AML patients, and ORR = CR + PR + hematologic improvement (HI) and as defined per 2006 IWG criteria for MDS patients	At 3 years
Overall response rate (ORR) per 2003 IWG criteria	ORR = complete response (CR) + CR with incomplete blood count recovery (CRi) + partial remission (PR) as defined by 2003 IWG criteria for AML patients, and ORR = CR + PR + hematologic improvement (HI) and as defined per 2006 IWG criteria for MDS patients	At 3.5 years
Overall response rate (ORR) per 2003 IWG criteria	ORR = complete response (CR) + CR with incomplete blood count recovery (CRi) + partial remission (PR) as defined by 2003 IWG criteria for AML patients, and ORR = CR + PR + hematologic improvement (HI) and as defined per 2006 IWG criteria for MDS patients	At 4 years
Overall response rate (ORR) per 2003 IWG criteria	ORR = complete response (CR) + CR with incomplete blood count recovery (CRi) + partial remission (PR) as defined by 2003 IWG criteria for AML patients, and ORR = CR + PR + hematologic improvement (HI) and as defined per 2006 IWG criteria for MDS patients	At 4.5 years
Overall response rate (ORR) per 2003 IWG criteria	ORR = complete response (CR) + CR with incomplete blood count recovery (CRi) + partial remission (PR) as defined by 2003 IWG criteria for AML patients, and ORR = CR + PR + hematologic improvement (HI) and as defined per 2006 IWG criteria for MDS patients	At 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to response (TTR)	TTR is measured from start of treatment to the date of achieving a response. Wilcoxon rank test will be used for comparison of continuous variables.	At 6 months
Time to response (TTR)	TTR is measured from start of treatment to the date of achieving a response. Wilcoxon rank test will be used for comparison of continuous variables.	At 1 year
Time to response (TTR)	TTR is measured from start of treatment to the date of achieving a response. Wilcoxon rank test will be used for comparison of continuous variables.	At 1.5 years
Time to response (TTR)	TTR is measured from start of treatment to the date of achieving a response. Wilcoxon rank test will be used for comparison of continuous variables.	At 2 years
Time to response (TTR)	TTR is measured from start of treatment to the date of achieving a response. Wilcoxon rank test will be used for comparison of continuous variables.	At 2.5 years
Time to response (TTR)	TTR is measured from start of treatment to the date of achieving a response. Wilcoxon rank test will be used for comparison of continuous variables.	At 3 years
Time to response (TTR)	TTR is measured from start of treatment to the date of achieving a response. Wilcoxon rank test will be used for comparison of continuous variables.	At 3.5 years
Time to response (TTR)	TTR is measured from start of treatment to the date of achieving a response. Wilcoxon rank test will be used for comparison of continuous variables.	At 4 years
Time to response (TTR)	TTR is measured from start of treatment to the date of achieving a response. Wilcoxon rank test will be used for comparison of continuous variables.	At 4.5 years
Time to response (TTR)	TTR is measured from start of treatment to the date of achieving a response. Wilcoxon rank test will be used for comparison of continuous variables.	At 5 years
Duration of response (DOR)	DOR measured from the time of achieving a response to time of disease progression. Wilcoxon rank test will be used for comparison of continuous variables.	At 6 months
Duration of response (DOR)	DOR measured from the time of achieving a response to time of disease progression. Wilcoxon rank test will be used for comparison of continuous variables.	At 1 year
Duration of response (DOR)	DOR measured from the time of achieving a response to time of disease progression. Wilcoxon rank test will be used for comparison of continuous variables.	At 1.5 years
Duration of response (DOR)	DOR measured from the time of achieving a response to time of disease progression. Wilcoxon rank test will be used for comparison of continuous variables.	At 2 years
Duration of response (DOR)	DOR measured from the time of achieving a response to time of disease progression. Wilcoxon rank test will be used for comparison of continuous variables.	At 2.5 years
Duration of response (DOR)	DOR measured from the time of achieving a response to time of disease progression. Wilcoxon rank test will be used for comparison of continuous variables.	At 3 years
Duration of response (DOR)	DOR measured from the time of achieving a response to time of disease progression. Wilcoxon rank test will be used for comparison of continuous variables.	At 3.5 years
Duration of response (DOR)	DOR measured from the time of achieving a response to time of disease progression. Wilcoxon rank test will be used for comparison of continuous variables.	At 4 years
Duration of response (DOR)	DOR measured from the time of achieving a response to time of disease progression. Wilcoxon rank test will be used for comparison of continuous variables.	At 4.5 years
Duration of response (DOR)	DOR measured from the time of achieving a response to time of disease progression. Wilcoxon rank test will be used for comparison of continuous variables.	At 5 years
Event-free survival (EFS)	EFS measured from date of first dose to the date of treatment failure, relapse, or death from any cause. Wilcoxon rank test will be used for comparison of continuous variables	At 6 months
Event-free survival (EFS)	EFS measured from date of first dose to the date of treatment failure, relapse, or death from any cause. Wilcoxon rank test will be used for comparison of continuous variables	At 1 year
Event-free survival (EFS)	EFS measured from date of first dose to the date of treatment failure, relapse, or death from any cause. Wilcoxon rank test will be used for comparison of continuous variables	At 1.5 years
Event-free survival (EFS)	EFS measured from date of first dose to the date of treatment failure, relapse, or death from any cause. Wilcoxon rank test will be used for comparison of continuous variables	At 2 years
Event-free survival (EFS)	EFS measured from date of first dose to the date of treatment failure, relapse, or death from any cause. Wilcoxon rank test will be used for comparison of continuous variables	At 2.5 years
Event-free survival (EFS)	EFS measured from date of first dose to the date of treatment failure, relapse, or death from any cause. Wilcoxon rank test will be used for comparison of continuous variables	At 3 years
Event-free survival (EFS)	EFS measured from date of first dose to the date of treatment failure, relapse, or death from any cause. Wilcoxon rank test will be used for comparison of continuous variables	At 3.5 years
Event-free survival (EFS)	EFS measured from date of first dose to the date of treatment failure, relapse, or death from any cause. Wilcoxon rank test will be used for comparison of continuous variables	At 4 years
Event-free survival (EFS)	EFS measured from date of first dose to the date of treatment failure, relapse, or death from any cause. Wilcoxon rank test will be used for comparison of continuous variables	At 4.5 years
Event-free survival (EFS)	EFS measured from date of first dose to the date of treatment failure, relapse, or death from any cause. Wilcoxon rank test will be used for comparison of continuous variables	At 5 years
Overall Survival (OS)	OS measured from start of treatment to death or last follow up. OS function will be estimated using the Kaplan-Meier method	At 6 months
Overall Survival (OS)	OS measured from start of treatment to death or last follow up. OS function will be estimated using the Kaplan-Meier method	At 1 year
Overall Survival (OS)	OS measured from start of treatment to death or last follow up. OS function will be estimated using the Kaplan-Meier method	At 1.5 years
Overall Survival (OS)	OS measured from start of treatment to death or last follow up. OS function will be estimated using the Kaplan-Meier method	At 2 years
Overall Survival (OS)	OS measured from start of treatment to death or last follow up. OS function will be estimated using the Kaplan-Meier method	At 2.5 years
Overall Survival (OS)	OS measured from start of treatment to death or last follow up. OS function will be estimated using the Kaplan-Meier method	At 3 years
Overall Survival (OS)	OS measured from start of treatment to death or last follow up. OS function will be estimated using the Kaplan-Meier method	At 3.5 years
Overall Survival (OS)	OS measured from start of treatment to death or last follow up. OS function will be estimated using the Kaplan-Meier method	At 4 years
Overall Survival (OS)	OS measured from start of treatment to death or last follow up. OS function will be estimated using the Kaplan-Meier method	At 4.5 years
Overall Survival (OS)	OS measured from start of treatment to death or last follow up. OS function will be estimated using the Kaplan-Meier method	At 5 years

Collaborators and Investigators

• Sponsor: Case Comprehensive Cancer Center
• Investigators: Principal Investigator: Sudipto Mukherjee, MD, PhD, Cleveland Clinic, Case Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): January 14, 2021
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: December 9, 2020
• First Submitted That Met QC Criteria: December 14, 2020
• First Posted (Actual): December 16, 2020

Study Record Updates

• Last Update Posted (Estimated): November 14, 2023
• Last Update Submitted That Met QC Criteria: November 13, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Leukemia, Myelomonocytic, Acute
• Other Study ID Numbers: CASE1920

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: There are no plans to share individual patient data in order to protect the confidentiality of the participants who enroll on this study

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No