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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

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ClinicalTrials.gov Identifier: NCT02238925
Recruitment Status : Completed
First Posted : September 12, 2014
Results First Posted : November 30, 2017
Last Update Posted : November 30, 2017
Sponsor:
Information provided by (Responsible Party):
Jazz Pharmaceuticals

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Myelodysplastic Syndrome (MDS) Drug: CPX-351 Phase 2

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 26 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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 Start Date : July 2014
Actual Primary Completion Date : May 2015
Actual Study Completion Date : January 2016


Arm Intervention/treatment
Experimental: CPX-351

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



Primary Outcome Measures :
  1. Effect of CPX-351 on Cardiac Ventricular Repolarization (QTcF) [ Time Frame: 21 days ]
    Time-matched QTcF Changes From Baseline after the start of first infusion


Secondary Outcome Measures :
  1. Serum Copper Levels Change From Baseline [ Time Frame: During 1st induction (up to 5 days) ]
    Change from Baseline to Induction 1, Day 5

  2. Complete Response Rate [ Time Frame: Following 1st induction, following 2nd induction if applicable ]
  3. Tmax [ Time Frame: Induction 1, Day 5 ]
  4. Cmax [ Time Frame: Induction 1, Day 5 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02238925


Locations
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United States, Indiana
Franciscan Saint Francis Health
Indianapolis, Indiana, United States, 46237
United States, Kansas
University of Kansas Cancer Center
Westwood, Kansas, United States, 66205
United States, Oregon
Oregon Health & Science University
Portland, Oregon, United States, 97239
United States, South Carolina
Medical University of South Carolina
Charleston, South Carolina, United States, 29425
United States, Wisconsin
Medical College of Wisconsin
Milwaukee, Wisconsin, United States, 53226
Sponsors and Collaborators
Jazz Pharmaceuticals

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Jazz Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02238925     History of Changes
Other Study ID Numbers: CLTR0310-206
First Posted: September 12, 2014    Key Record Dates
Results First Posted: November 30, 2017
Last Update Posted: November 30, 2017
Last Verified: October 2017
Keywords provided by Jazz Pharmaceuticals:
Newly Diagnosed AML
Secondary AML
Relapsed/Refractory AML
Relapsed/Refractory ALL
MDS
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid, Acute
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Myelodysplastic Syndromes
Neoplasms by Histologic Type
Neoplasms
Leukemia, Myeloid
Bone Marrow Diseases
Hematologic Diseases
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cytarabine
Daunorubicin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors