Investigator Initiated Trial of CPX-351 for Untreated Acute Myeloid Leukemia

Study Overview
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Brief Summary
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This is an open label study to assess the suitability of CPX-351 as first intensive therapy in elderly (age ≥60 years) patients with AML. Patients may have received prior AML treatment with non-intensive regimens, e.g. hypomethylating agents, low dose Ara C or lenolidomide, but may not have received intensive AML treatment with anthracyclines and/or cytarabine prior to enrollment on this trial. The outcome of elderly patients following intensive treatment with CPX-351 will be measured by clinical endpoints for efficacy and safety and by biological/functional response.

Official Title
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Phase II Trial of CPX (Cytarabine:Daunorubicin) Liposome Injection in Patients >/=60 Years of Age With AML Previously Untreated By Intensive Chemotherapy

Conditions
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Leukemia, Myeloid, Acute

Intervention / Treatment
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* Drug: CPX-351


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to understand and voluntarily give informed consent Age≥60 years at the time of study treatment Pathological diagnosis of AML according to WHO criteria (with >20% blasts in the peripheral blood or bone marrow) including: De novo AML with normal karyotype or adverse karyotypes (including patients with karyotypic abnormalities characteristic of MDS) Secondary AML: transformed from prior MDS or MPN, confirmed by bone marrow documentation of prior antecedent hematologic disorder Therapy-related AML: t-AML, requires documented history of prior cytotoxic therapy or ionizing radiotherapy for an unrelated disease Performance status >50% KPS, ECOG 0-2 Laboratory values fulfilling the following: Serum creatinine < 2.5 mg/dL Serum total bilirubin < 2.5 mg/dL, Serum alanine aminotransferase or aspartate aminotransferase < 3 times the ULN Patients with elevated liver enzymes and serum creatinine values secondary to AML are eligible after discussion with PI Cardiac ejection fraction ≥ 50% by echocardiography or MUGA Patients with history of second malignancies in remission may be eligible if there is clinical evidence of disease stability 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: Acute promyelocytic leukemia [t(15;17)] Clinical evidence of active CNS leukemia Prior intensive chemotherapy for AML with anthracycline/cytarabine-based regimens and/ or prior HSCT. Patients may have been treated with commercially available or investigational hypomethylating agents (e.g. decitabine, azacitidine, SGI-110), lenalidomide, or low-dose cytarabine (not to exceed 20 mg/m2 daily for 14 days for ≤ 6 cycles) Prior treatment including HMA, systemic chemotherapy, surgery, or radiation therapy must have been completed at least 7 days before start of study treatment or after discussion with PI. Treatment with investigational agents must have been completed at least 14 days prior to study drug treatment. Hydroxyurea is permitted for control of blood counts before the start of study treatment. Toxicities associated with prior therapies must have recovered to grade 1 or less prior to start of study treatment. 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. Patients with current or recent 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 History of prior bone marrow or solid organ transplantation

Ages Eligible for Study
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Minimum Age: 60 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CPX-351 (Cytarabine:Daunorubicin) Injection<br>Dosing for first induction: CPX-351 • CPX-351 at 100u/m2 will be administered on study days 1, 3 and 5 Dosing for second induction: • CPX-351 at 100 u/m2 will be administered on days 1 and 3 Dosing for consolidation: • CPX-351 at 65 u/m2 will be administered on days 1 and 3 | Drug: CPX-351<br>* Cytarabine:Daunorubicin Liposome Injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety assessment | Safety of CPX-351 as first intensive therapy in older (age ≥60 years) patients with AML based on the 30 day mortality | 30 days | 
| Efficacy assessment | The primary efficacy endpoint will be overall survival (OS) | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy assessment by response rate | Efficacy of CPX-351 will be assessed by treatment response rate, as determined by bone marrow analysis at Day 14 of each induction and consolidation, and as needed thereafter, up to 5 years. | Up to 5 years, as needed. | 
| Efficacy assessment by response duration | Efficacy of CPX-351 will be assessed by treatment response duration, as determined by bone marrow analysis at Day 14 of each induction and consolidation, and as needed thereafter, up to 5 years. | Up to 5 years, as needed. | 
| Efficacy assessment by event free survival (EFS) | Efficacy of CPX-351 will be assessed by treatment event free survival, as determined by bone marrow analysis at Day 14 of each induction and consolidation, and as needed thereafter, up to 5 years. | Up to 5 years, as needed. | 
| Safety assessment | The safety of CPX-351 in this population will be assessed by evaluation of the frequency of adverse events. | 30 days | 
| Safety assessment | The safety of CPX-351 in this population will be assessed by evaluation of the severity of adverse events. | 30 days | 
| Safety assessment | The safety of CPX-351 in this population will be assessed by evaluation of the severity of serious adverse events. | 30 days | 
| Safety assessment | The safety of CPX-351 in this population will be assessed by evaluation of the frequency of serious adverse events. | 30 days | 
| Quality of Life Assessment using the Functional Assessment of Cancer Therapy-Leukemia (FACT-LEU) | The higher the score, the better the QOL. Physical Well-Being (PWB): Range:0-28. To derive: Subtract the answer from 4 for each of 7 questions. Add scores, multiply by 7 and divide by # of questions answered. Social/Family Well-Being (SWB): Range:0-28. To derive: Add answers of 7 questions, multiply by 7 and divide by # of questions answered. Emotional Well-Being (EWB): Range:0-24. To derive: Subtract the answers from 4 for each of the 6 questions, except #2 (added without modification). Add values, multiply by 6 and divide by # of questions answered. Functional Well-Being (FWB): Range:0-28. To derive: Add answers of 7 questions, multiply by 7 and divide by # of questions answered. Leukemia Subscale (LeuS): Range:0-68. To derive: Subtract the answers from 4 for each of the 17 questions, except #s 11 and 12 (these are added without modification). Add values, multiply by 17 and divide by # of questions answered. FACT-Leu total =PWB+SWB+EWB+FWB+LeuS. Range: 0-176. | At the start of treatment and one month after treatment completion. | 
| Cognitive function | The relationship of cognitive function to outcome will be assessed using the Blessed Orientation-Memory-Concentration Test | 5 years | 
| Cognitive function | The relationship of cognitive function to outcome will be assessed using the Montreal Cognitive Assessment. | At the start of treatment and one month after completion of therapy. | 
| Rate of morphologic leukemia-free state (MLFS) | The rate of morphologic leukemia-free state (MLFS) will be determined to supplement the efficacy assessment of CPX-351. Morphologic leukemia-free state is defined as bone marrow blasts <5% AND absence of Auer rods and/or extramedullary disease. All registered patients that have at least one evaluable post registration bone marrow assessment performed on or after Day 14 after the last induction will be assessed for morphologic leukemia-free state | 30 days |