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

Study Overview
=================
Brief Summary
-----------------
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.

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.

Official Title
-----------------
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

Conditions
-----------------
Refractory Acute Myeloid Leukemia, Relapsed Acute Myelomonocytic Leukemia, Myelodysplastic Syndromes

Intervention / Treatment
-----------------
* Drug: CPX-351


Participation Criteria
=================
Eligibility Criteria
-----------------
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)

Ages Eligible for Study
-----------------
Minimum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Primary refractory/relapsed AML<br>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<br>* 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.<br>|
| Experimental: MDS after HMA failure<br>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<br>* 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.<br>|

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 |