An Open Label Phase II Pharmacokinetic and Pharmacodynamic Assessment of the Potential for QTc Prolongation Following First Induction Treatment With CPX-351 (Cytarabine:Daunorubicin) Liposome Injection in Acute Leukemias and MDS Patients

Study Overview
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Brief Summary
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The purpose of this study is to assess the effects of CPX-351 on cardiac repolarization, assess plasma drug levels, asses serum copper levels, and assess drug levels in urine. Efficacy and Safety will be assessed in all patients enrolled to the study.

Detailed Description
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This study is an open-label, single-arm, Phase II, PK and pharmacodynamic (PD) trial of CPX-351 in patients with documented acute leukemia (AML or ALL) or MDS (IPSS score ≥ 1.5) and suitable for treatment with intensive chemotherapy. Each patient will be screened for hepatic impairment. Hepatic impairment will be assessed using the Child-Pugh system and only patients with a Child-Pugh score <7 points will be eligible for this study. Patients will receive up to two inductions and four consolidation courses. Patients will be monitored for safety (early deaths, adverse events, metabolic changes, etc.) and efficacy (response for AML, ALL, and MDS) while on the study.

Official Title
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An Open Label Phase II Pharmacokinetic and Pharmacodynamic Assessment of the Potential for QTc Prolongation Following First Induction Treatment With CPX-351 (Cytarabine:Daunorubicin) Liposome Injection in Acute Leukemias and MDS Patients

Conditions
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Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), Myelodysplastic Syndrome (MDS)

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 sign an informed consent form Age ≥ 18 to ≤ 80 years at the time of signing the informed consent form Life expectancy of at least 3 months Pathological confirmation by bone marrow documenting the following: Newly Diagnosed De novo AML according to WHO criteria except for Acute Promyelocytic Leukemia or patients with known favorable cytogenetics (see exclusion) Newly Diagnosed Secondary AML age <60 years and ≥76 to 80 years, defined as having a history of an antecedent hematologic disorder (myelodysplastic syndromes [MDS], myeloproliferative disease [MPD]or history of cytotoxic treatment for non-hematologic malignancy) Patients with relapsed/refractory AML regardless of cytogenetic risk Patients with relapsed/refractory ALL Patients with MDS (IPSS score ≥ 1.5) Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2 Able to adhere to the study visit schedule and other protocol requirements Laboratory values fulfilling the following: Serum Creatinine ≤ 2.0mg/dL Hepatic function with a score of < 7 points according to the Child-Pugh System Serum alanine aminotransferase or aspartate aminotransferase < 3 times the ULN. Note: If elevated liver enzymes are related to disease; contact medical monitor to discuss. Cardiac ejection fraction ≥50% by ECHO or MUGA Screening and Baseline QTcF (Fridericia's) less than 470 msec 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. All men and women must agree to practice effective contraception during the study period if not otherwise documented to be infertile. Exclusion Criteria: Patients eligible for participation in Study CLTR0310-301 (Phase III study of CPX-351 NCT01696084) or who have already participated in that study are not eligible for this study. Patients taking medications known to prolong the QTc interval directly or that interact pharmacodynamically with medicines to prolong the QTc interval. Rhythm abnormalities (other than sinus bradycardia with HR < 50 bpm) AV block (other than 1o AV Block with PR > 200 msec) Bundle branch block or QRS ≥ 120 msec Abnormal T wave morphology (other than slight flattening) Pathological U waves Other QRS or T/U morphology preventing accurate determination of QT interval Patients with unexplained syncope, history of or known risk factors for torsade des pointes, including congenital long QT syndrome, or family history of LQTS. Patients with history of and/or current evidence of myocardial impairment (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) Newly diagnosed patients with Acute promyelocytic leukemia [t(15;17)] or favorable cytogenetics, including t(8;21) or inv16 Clinical evidence of active CNS leukemic involvement Chemotherapy or other investigational anticancer therapeutic drugs within 1 week prior to study entry unless AEs have resolved and there is no interference with the assessment of efficacy or safety; in the event of rapidly proliferative disease, however, the use of hydroxyurea is permitted up to 12 hours before study entry. Patients with prior bone marrow or stem cell transplant, considered for inclusion, should be discussed with the medical monitor first. Any serious medical condition or psychiatric illness that would prevent the patient from providing informed consent Patients with prior cumulative anthracycline exposure of greater than 368 mg/m2 daunorubicin (or equivalent) Active or uncontrolled infection. Patients with any 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 fevers believed to be due to leukemia or MDS are eligible provided a thorough infection work-up is negative and the patient is clinically and hemodynamically stable. Pregnant or lactating women Hypersensitivity to cytarabine, daunorubicin or liposomal products History of Wilson's disease or other copper-related metabolic disorder

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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<br>Single Arm Study (Patients may receive up to 2 Inductions and 4 Consolidations): Induction 1: CPX-351 will be given intravenously at 100units/m2 on days 1, 3, and 5 over a 90 minute infusion. Induction 2: CPX-351 will be given intravenously at 100units/m2 on days 1 and 3 over a 90 minute infusion. Consolidations 1-4: CPX-351 will be given intravenously at 65units/m2 on days 1 and 3 over a 90 minute infusion. | Drug: CPX-351<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of CPX-351 on Cardiac Ventricular Repolarization (QTcF) | Time-matched QTcF Changes From Baseline after the start of first infusion | 21 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Copper Levels Change From Baseline | Change from Baseline to Induction 1, Day 5 | During 1st induction (up to 5 days) | 
| Complete Response Rate |  | Following 1st induction, following 2nd induction if applicable | 
| Tmax |  | Induction 1, Day 5 | 
| Cmax |  | Induction 1, Day 5 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Newly Diagnosed AML, Secondary AML, Relapsed/Refractory AML, Relapsed/Refractory ALL, MDS