Phase III Study of CPX-351 Versus 7+3 in Patients 60-75 Years Old With Untreated High Risk (Secondary) Acute Myeloid Leukemia

Study Overview
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Brief Summary
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To confirm the efficacy of CPX-351 compared to 7+3 as first line therapy in elderly patients (60-75 yrs) with high risk (secondary) Acute Myeloid Leukemia. The primary efficacy endpoint will be overall survival.

Official Title
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Phase III, Multicenter, Randomized, Trial of CPX-351 (Cytarabine:Daunorubicin) Liposome Injection Versus Cytarabine and Daunorubicin in Patients 60-75 Years of Age With Untreated High Risk (Secondary) AML

Conditions
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High Risk Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: CPX-351
* Drug: 7+3 (cytarabine and daunorubicin)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to understand and voluntarily give informed consent Age 60-75 years at the time of diagnosis of AML Pathological diagnosis of AML according to WHO criteria (with at least 20% blasts in the peripheral blood or bone marrow) Confirmation of: Therapy related AML: t-AML must have a documented history of prior cytotoxic therapy or ionizing radiotherapy for an unrelated disease AML with a history of myelodysplasia: MDSAML must have bone marrow documentation of prior MDS AML with a history of CMMoL: CMMoLAML must have bone marrow documentation of prior CMMoL De novo AML with karyotypic abnormalities characteristic of MDS: de novoAML must have cytogenetics with abnormalities per WHO. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Able to adhere to the study visit schedule and other protocol requirements Laboratory values fulfilling the following: Serum creatinine < 2.0 mg/dL Serum total bilirubin < 2.0 mg/dL, patients with Gilbert's Syndrome should contact the medical monitor Serum alanine aminotransferase or aspartate aminotransferase < 3 times the ULN Note: If elevated liver enzymes, above the ULN, are related to disease; contact medical monitor to discuss. Cardiac ejection fraction ≥ 50% by echocardiography or MUGA Patients with second malignancies in remission may be eligible if there is clinical evidence of disease stability for a period of greater than 6 months off cytotoxic chemotherapy, documented by imaging, tumor marker studies, etc., at screening. Patients maintained on long-term non-chemotherapy treatment, e.g., hormonal therapy, are eligible. Exclusion Criteria: Except for CMMoL, patients with history of myeloproliferative neoplasms (MPN) (defined as a history of essential thrombocytosis or polycythemia vera, or idiopathic myelofibrosis prior to the diagnosis of AML) or combined MDS/MPN are not eligible. Acute promyelocytic leukemia [t(15;17)] or favorable cytogenetics, including t(8;21) or inv16 if known at the time of randomization. Clinical evidence of active CNS leukemia Patients with active (uncontrolled, metastatic) second malignancies are excluded. Prior treatment intended for induction therapy of AML; only hydroxyurea is permitted for control of blood counts. For example, a patient with MDS that changes HMA dose and schedule after the diagnosis of AML is excluded. AML-type therapy, such as cytarabine alone (>1g/m2/day) or cytarabine plus an anthracycline as well as prior HSCT are also excluded. Administration of any therapy for MDS (conventional or investigational) must be completed by 2 weeks prior to of the first dose of study drug; in the event of rapidly proliferative disease use of hydroxyurea is permitted until 24 hours before the start of study treatment. Toxicities associated with prior MDS therapy must have recovered to grade 1 or less prior to start of treatment. Any major surgery or radiation therapy within four weeks. Patients with prior cumulative anthracycline exposure of greater than 368 mg/m2 daunorubicin (or equivalent). Any serious medical condition, laboratory abnormality or psychiatric illness that would prevent obtaining informed consent Patients with myocardial impairment of any cause (e.g. cardiomyopathy, ischemic heart disease, significant valvular dysfunction, hypertensive heart disease, and congestive heart failure) resulting in heart failure by New York Heart Association Criteria (Class III or IV staging) Active or uncontrolled infection. Patients with an infection receiving treatment (antibiotic, antifungal or antiviral treatment) may be entered into the study but must be afebrile and hemodynamically stable for ≥72 hrs. Current evidence of invasive fungal infection (blood or tissue culture); patients with recent fungal infection must have a subsequent negative cultures to be eligible; known HIV (new testing not required) or evidence of active hepatitis B or C infection (with rising transaminase values) Hypersensitivity to cytarabine, daunorubicin or liposomal products History of Wilson's disease or other copper-metabolism disorder

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (CPX-351)<br>Subjects are eligible to receive up to 2 inductions and up to 2 consolidations with CPX-351. The number of inductions and consolidations a subject received depended on response. | Drug: CPX-351<br>* First induction: 100 units/m2 by 90-minute IV infusion on Days 1, 3, 5. Second induction: 100 units/m2 by 90-minute IV infusion on Days 1 and 3. Consolidation therapy: 65 units/m2 by 90-minute IV infusion on Days 1 and 3.<br>|
| Active Comparator: Arm B (7+3)<br>Subjects are eligible to receive up to 2 inductions and up to 2 consolidations with cytarabine and daunorubicin given as a 7 + 3, or 5 days of continuous infusion of cytarabine and 2 days of daunorubicin (5+2, second induction, consolidation courses) therapy. The number of inductions and consolidations a subject received depended on response. | Drug: 7+3 (cytarabine and daunorubicin)<br>* First induction: 7+3 was administered as: cytarabine at a dose of 100 mg/m2/day on Days 1 through 7 by continuous infusion, and daunorubicin at a dose of 60 mg/m2/day on Days 1, 2, and 3. Second induction: 5+2 was administered as: cytarabine at a dose of 100 mg/m2/day on Days 1 through 5 by continuous infusion and daunorubicin at a dose of 60 mg/m2/day on Days 1 and 2. Consolidation therapy: 5+2 was administered as: cytarabine at a dose of 100 mg/m2/day on Days 1 through 5 by continuous infusion, and daunorubicin at a dose of 60 mg/m2/day on Days 1 and 2.<br>* Other names: cytarabine and daunorubicin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival was measured from the date of randomization to death from any cause, subjects not known to have died by the last follow-up were censored on the date they were last known to be alive. | From the date of randomization to death from any cause | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Subjects With a Response | Complete Remission (CR) | Post Induction | 
| Event-free Survival | All randomized subjects were assessed for event-free survival (EFS). EFS was defined as the time from study randomization to the date of induction treatment failure (persistent disease), relapse from CR or CRi or death from any cause, whichever came first. Subjects alive and not known to have any of these events were censored on thee date they were last examined on study. | From the date of randomization to the date that persistent disease was documented or the date of relapse after CR or death, whichever came first | 
| Remission Duration | Only subjects achieving CR or CRi were assessed for remission duration. | From the date of achievement of a remission until the date of relapse or death from any cause | 
| Rate of Achieving Morphologic Leukemia-free State | All randomized subjects with at least 1 evaluable postrandomization bone marrow assessment performed on or after Day 14 after the last induction were assessed for MLFS. | Day 14 | 
| Proportion of Subjects Receiving a Stem Cell Transplant | The number and percentage of subjects transferred for HSCT after induction treatment was recorded. | Post Induction | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, Acute Myeloid Leukemia, high risk AML, secondary AML, AML in elderly