Clinical Trial to Assess the Efficacy and Toxicity of Induction and Consolidation With CPX-351 for Patients Aged 60 to 75 Years With Secondary or High-risk Acute Myeloid Leukemia

This protocol corresponds to a prospective, multicentre, open label, phase II study designed to evaluate the efficacy of CPX-351 in elderly patients with secondary or high-risk AML. The clinical trial is divided into pre-treatment, treatment (induction and consolidation cycles) and follow-up periods and consists of a single arm group. Patients will be enrolled at diagnosis to follow the treatment arm. After that will start induction chemotherapy with CPX-351 regimen (14 days maximum screening period). Once a patient have been evaluated for response and recovered from major complications, he/she will start second course (consolidation 1), unless the bone marrow and peripheral blood assessment is showing less than a complete response, then a second induction may be offered. If a CR or CRi is obtained after the second induction course, patients will start the third course after a rest and recovery period. Patients aged between 60 and 65 years old are recommended to undergo an allo-SCT after first consolidation if they are considered fit for this procedure and they have a full matched related or unrelated donor. Patients aged between 65 and 70 years old can be proposed for an allo-SCT in CR/CRi if they have a composite HSCT co-morbidity index /age less than 4 and a suitable fully matched related donor. In patients over 70 years old, an allo-SCT in first CR should be avoided although the decision should be taken on an individual basis. Patients with CR/CRi who are not considered for an allo-SCT, will follow 6 maintenance cycles with modified courses of CPX-351 schedule. Patients showing unacceptable toxicity along all therapeutic phases that, in consideration of the investigator, will be prematurely discontinued. All patients will be followed-up for survival. The study will be analyzed on an intention to treat basis. Bone marrow and response assessments will be done after each induction and consolidation course, and every 3 months during the first 12 months after starting maintenance therapy. Patients will be followed-up for a minimum period of 1 year after the enrolment of the last patient. Additionally, after the end of the trial, patients will be followed-up for 2 years in order to verify survival and the evolution of the disease. Study design allows a maximum of 59 patients.

This is a prospective, multicenter, open-label, phase II study to assess efficacy of CPX-351 in elderly patients (60 to 75 years of age) with newly diagnosed high risk AML. The study includes a single arm group. The primary endpoint of the study is to assess the CR/CRi rate after induction with CPX-351.

Patients will be enrolled at diagnosis to follow the treatment arm. After that they will start induction chemotherapy with CPX-351 regimen (14 days maximum screening period). Once a patient has been evaluated for response and recovered from major complications (minimum 42 days and maximum 80 days after starting the first course), he/she will start second course (consolidation 1), unless the bone marrow and peripheral blood assessment is showing less than a partial response. If a CR or CRi is obtained after the second course, patients will start the third course after a rest and recovery period (minimum 42 days and maximum 80 days after starting the second course). After the third course an assessment of response will be done.

Patients aged between 60 and 65 years old are recommended to undergo an allo-SCT after first consolidation if they are considered fit for this procedure and they have a full matched related or unrelated donor. Patients with age less than 65-70 years old can be proposed for an allogeneic HSCT in CR/CRi if they have a composite HSCT co-morbidity index /age less than 4 and a suitable fully matched related donor. In patients over 70 years old, an allo-SCT in first CR should be avoided although the decision should be taken on an individual basis.

Patients with CR/CRi who are not considered for an allo-SCT, will follow 6 maintenance cycles with modified courses of CPX-351 schedule. Patients showing unacceptable toxicity along all therapeutic phases that, in consideration of the investigator, will be prematurely discontinued. All patients will be followed-up for survival. The study will be analyzed on an intention to treat basis. Bone marrow and response assessments will be done after each induction and consolidation course, and every 3 months after starting maintenance therapy. Patients will be followed-up for a minimum period of 3 years after the enrollment of the last patient in order to know OS, disease-free, and relapse free survival (RFS), as well as on the duration of remission and cumulative incidence of relapse. Patients may be admitted in hospital to receive the experimental treatment.

The clinical trial is divided into pre-treatment (screening), treatment periods (induction, consolidation and maintenance cycles) and follow-up:

Induction cycle (1 cycle):

It will consist of priming with daily administration of G-CSF on days -1, 1 and 2 (300 mcg/m2/day) subcutaneously, CPX-351 day 1, 3 and 5 (100 units/m2/day) IV in 90 minutes infusion, and subcutaneous G-CSF from day 10 to recovery (5 mg/kg/day). The chemotherapy course may be administered in hospital. If a complete response is obtained after the first cycle of treatment, the patient will receive consolidation cycle. If a partial response is obtained after the first cycle of treatment, the patient will receive induction 2. Response to treatment will be determined by the local investigator and will be the basis for treatment decisions. However, if there is any doubt, it should be discussed with the Study coordinator.

Induction 2 (1 cycle, only for patients with PR after induction 1):

It will consist of priming with daily administration of G-CSF on days -1, 1 and 2 (300 mcg/m2/day) subcutaneously, CPX-351 day 1 and 3 (100 units/m2/day) IV in 90 minutes infusion, and subcutaneous G-CSF from day 10 to recovery (5 mg/kg/day). The chemotherapy course may be administered in hospital.

Consolidation cycle (up to 2 cycles):

It will consist of priming with daily administration of G-CSF on days -1, 1 and 2 (300 mcg/m2/day) subcutaneously, CPX-351 day 1 and 3 (65 units/m2/day) IV in 90 minutes infusion, and subcutaneous G-CSF from day 10 to recovery (5 mg/kg/day). The chemotherapy course may be administered in hospital. Patients aged between 60 and 65 years old are recommended to undergo an allo-SCT after first consolidation if they are considered fit for this procedure and they have a full matched related or unrelated donor. Patients with age between 65-70 years old can be proposed for an allogeneic HSCT in CR/CRi if they have a composite HSCT co-morbidity index /age less than 4 and a suitable fully matched related donor. In patients over 70 years old, an allo-SCT in first CR should be avoided although the decision should be taken on an individual basis.

Maintenance cycle (up to 6 cycles):

For patients in CR and when an allo-SCT is not feasible or recommended, a maintenance treatment could be started for up to 6 additional cycles, on every 4 to 8 weeks courses, according to hematologic recovery.

It will consist of CPX-351 day 1 (50 units/m2/day) IV in 90 minutes infusion. Subcutaneous G-CSF may be used to recovery (5 mg/kg/day) in patients with grade 4 neutropenia and confirmed CR.

Eligibility Criteria:
Inclusion Criteria:

1. Written informed consent in accordance with national, local, and institutional guidelines. The patient must provide informed consent prior to the first screening procedure. Informed consent form must be signed by the patient and the investigator.
2. Age 60 to 75 years at the time of diagnosis of AML.
3. Newly confirmed diagnosed of AML according to WHO 2008 criteria.
4. Secondary or high risk AML, defined as one of the following:

   * t-AML: documentation of prior cytotoxic therapy or radiation therapy for an unrelated disease in a discharge summary or pharmacy records or radiation therapy records
   * MDSAML: bone marrow documentation of MDS prior to diagnosis of AML (could have been treated previously with hypomethylating or standard chemotherapy)
   * CMMoLAML: bone marrow documentation of CMMoL prior to diagnosis of AML (could have been treated previously with hypomethylating or standard chemotherapy)
   * de novoAML with FISH or cytogenetic changes linked to MDS per WHO 2016 criteria.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
6. Ability to adhere to the study visit schedule and other protocol requirements.
7. Laboratory values fulfilling the following:

   * Serum creatinine \< 2.0 mg/mL
   * Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) or total bilirubin \< 3 times the upper limit of normal (ULN, subjects with elevated liver enzymes related to disease were instructed to contact the Sponsor) (subjects with Gilbert's Syndrome were instructed to contact the sponsor).
8. Subjects with second malignancies in remission may have been eligible if there was clinical evidence of disease stability for a period ≥ 6 months off cytotoxic chemotherapy, documented by imaging, tumor marker studies at screening. Subjects maintained on long-term nonchemotherapy treatment such as hormonal therapy were eligible.
9. Cardiac ejection fraction ≥ 50% assessed by echocardiography or MUGA.
10. Eligible to receive intensive chemotherapy.
11. Female patients of child-bearing potential must have a negative serum pregnancy test at screening and agree to use reliable methods of contraception for three months after their last dose of medication. Male patients must use a reliable method of contraception (if sexually active with a female of child-bearing potential).
12. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures

Exclusion Criteria:

1. Patients with genetic diagnosis of acute promyelocytic leukemia.
2. Age \<60 years or \>75 years.
3. Blastic phase of bcr/abl chronic myeloid leukemia.
4. Patients with de novo AML without FISH or cytogenetic changes linked to MDS per WHO 2016 criteria.
5. Clinical evidence of active central nervous system (CNS) leukemia.
6. Subjects with active (uncontrolled, metastatic) second malignancies.
7. Any major surgery or radiation therapy in 4 weeks.
8. Subjects with myocardial impairment of any cause (eg, 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).
9. Uncontrolled infection; subjects with an infection receiving treatment (antibiotic, antifungal, or antiviral treatment) could be entered into the study provided the subject was respiratory and hemodynamically stable for ≥ 72 hours.
10. Current evidence of invasive fungal infection (blood or tissue culture); subjects with recent fungal infection must have had 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).
11. Hypersensitivity to cytarabine, daunorubicin or liposomal products.
12. Presence of any severe psychiatric disease or physical condition that, according to the physician´s criteria, contraindicates the inclusion of the patient into the clinical trial.
13. Serum creatinine ≥ 20 mg/dL (unless it is attributable to AML activity).
14. Bilirubin, alkaline phosphatase, or SGOT \> 3 times the ULN (unless it is attributable to AML activity).
15. Subjects with prior cumulative anthracycline exposure of greater than 368 mg/m2 daunorubicin (or equivalent).
16. History of Wilson's disease or other copper-metabolism disorder.
17. Patients who have received an investigational agent (for any indication) within 5 half-lives of the agent and until toxicity from this has resolved to grade 1 or less; if the half-life of the agent is unknown, patients must wait 4 weeks prior to first dose of study treatment.