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
Condition: Acute Myeloid Leukemia (AML); Acute Lymphoblastic Leukemia (ALL); Myelodysplastic Syndrome (MDS)
MeSH terms: Leukemia; Leukemia, Myeloid, Acute; Preleukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Myelodysplastic Syndromes
Intervention: CPX-351
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 26.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Newly Diagnosed AML; Secondary AML; Relapsed/Refractory AML; Relapsed/Refractory ALL; MDS

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.
    

Eligibility 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