Clinical Trials /

A Phase I Clinical Trial of OXi4503 for Relapsed and Refractory AML and MDS

NCT01085656

Description:

This study is intended to determine the safety and maximum tolerated dose of a drug, OXi4503 (combretastatin A1 diphosphate, CA1P, OXiGENE), in patients with relapsed and refractory AML and MDS.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Terminated

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Phase I Clinical Trial of OXi4503 for Relapsed and Refractory AML and MDS
  • Official Title: A Phase I Clinical Trial of OXi4503 for Relapsed and Refractory Acute Myelogenous Leukemia (AML) and Myelodysplastic Syndromes (MDS)

Clinical Trial IDs

  • ORG STUDY ID: UF OXi4503 AML MDS
  • NCT ID: NCT01085656

Conditions

  • Leukemia, Myelogenous, Acute
  • Myelodysplastic Syndromes

Interventions

DrugSynonymsArms
OXi4503Combretastatin A1 Diphosphate, CA1POXi4503

Purpose

This study is intended to determine the safety and maximum tolerated dose of a drug, OXi4503 (combretastatin A1 diphosphate, CA1P, OXiGENE), in patients with relapsed and refractory AML and MDS.

Detailed Description

      Despite initial disease remissions with cytotoxic chemotherapies, patients with AML and MDS
      often relapse and die of their disease. Novel strategies for targeting dependent pathways are
      needed. AML and MDS depend on blood vessels for survival and proliferation. OXi4503 is a
      novel microtubule targeting agent that selectively destroys cancer-associated blood vessels,
      induces cancer cell apoptosis via an ortho-quinone moiety and results in significant
      regressions of solid tumors. OXi4503 is currently being tested in phase I clinical trials of
      advanced solid tumors. In preclinical studies with human AML, OXi4503 was cytotoxic to
      leukemia cells, decreased size of chloromas, regressed leukemic cell engraftment in bone
      marrow and brought about phenotypic and molecular remissions. Given these results, we
      hypothesize that OXi4503 has disease remitting effects in myeloid malignancies such as AML
      and MDS. Before evaluating efficacy, safety and maximum tolerated dose of OXi4503 will be
      defined in AML and MDS patients. In addition, assessments of pharmacokinetic (PK) and
      pharmacokinetic (PD) parameters will be made, and relationships between dose and biologic
      activity will be defined. Results from this trial will provide new clinical data and biologic
      insight regarding the effects of OXi4503 in AML and MDS, and will serve as the basis for
      future efficacy trials.
    

Trial Arms

NameTypeDescriptionInterventions
OXi4503ExperimentalDosing of OXi4503 will be an intravenous infusion (IV) over 10 minutes on Days 1, 8, 15, and 22 of each 28 day cycle.
  • OXi4503

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must be at least 18 years of age;

          -  Patients must have either:

               -  AML (de novo or secondary, and any WHO 2008 classification excluding acute
                  promyelocytic leukemia) that has failed to achieve CR or CRi (IWG 2003) after at
                  least 1 cycle of induction chemotherapy, or has relapsed after any duration of CR
                  or CRi; or,

               -  MDS (RAEB-1 or RAEB-2 WHO 2008 classification) that has failed to achieve any
                  hematologic improvement (IWG 2006 criteria) after at least 4 cycles of induction
                  therapy (e.g., azacitidine, decitabine), or has relapsed after any duration of CR
                  or PR.;

          -  Patient performance status must be Eastern Cooperative Oncology Group (ECOG) 0, 1 or
             2;

          -  Patients must have a life expectancy of greater than 14 days;

          -  Patients must have total bilirubin ≤ 2;

          -  Patients must have serum AST and ALT levels ≤ 2.5 times upper limit of normal;

          -  Patients must have serum creatinine less than or equal to 2.5 times upper limit of
             normal;

          -  Patients must have PT/INR and PTT in normal range ± 25%;

          -  Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically
             sterile) may participate, provided they meet the following conditions:

               -  Must agree to use physician-approved contraceptive methods (e.g., abstinence,
                  intrauterine device, oral contraceptive, double barrier device) throughout the
                  study and for three months following the last dose of OXi4503; and

               -  Must have a negative serum or urine pregnancy test within 7 days prior to
                  beginning treatment on this trial;

          -  Males with female partners of child-bearing potential must agree to use
             physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy)
             throughout the study and should avoid conceiving children for 6 months following the
             last dose of OXi4503;

          -  Written informed consent, willingness, and ability to comply with all study
             procedures.

        Exclusion Criteria:

          -  Acute promyelocytic leukemia (APL) with t(15;17);

          -  Absolute peripheral blood myeloblast count greater than 25,000/mm3;

          -  Uncontrolled hypertension, defined as blood pressure 140/90 mm Hg despite maximum
             medical intervention;

          -  History of congenital long QT syndrome or torsades de pointes;

          -  Pathologic bradycardia or heart block (excluding first degree heart block);

          -  Prolonged baseline QTc, defined as QTc interval > 470 msec in women and > 450 msec in
             men;

          -  History of ventricular arrhythmia (excluding premature ventricular contractions,
             PVCs);

          -  Major operative surgery within 28 days;

          -  Unstable angina pectoris within 28 days;

          -  Myocardial infarction and/or new ST elevation or depression or new Q wave on ECG
             within 28 days;

          -  Any history of hemorrhagic stroke;

          -  Symptomatic congestive heart failure Class III or greater (New York Heart Association
             Functional Classification);

          -  On full dose anti-coagulation defined as warfarin intended to raise the INR to 2-3, or
             enoxaparin 1 mg/kg twice a day or unfractionated heparin intended to raise the PTT to
             60-90 seconds;

          -  Major hemorrhagic event within 28 days requiring transfusion of packed red blood
             cells;

          -  Prior history of hypertensive crisis or hypertensive encephalopathy;

          -  Active, uncontrolled, clinical significant infection;

          -  Any open wound;

          -  Pregnant and nursing patients are excluded because the effects of OXi4503 on a fetus
             or nursing child are unknown.

          -  Treatment with any anticancer therapy (standard or investigational) within the
             previous 21 days prior to the first dose of study drug or less than full recovery
             (CTCAE grade 1) from the clinically significant toxic effects of that treatment. The
             use of hydroxyurea may be used for two weeks after dosing in Cycle 1 (e.g., Days 1-14
             dosed with hydroxyurea).

        Relative Exclusion Criteria:

          -  Patients on concurrent medications known to prolong the QTc interval may participate
             as long as their screening QTc interval meets eligibility criteria.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:To determine the safety and establish the maximum tolerated dose (MTD) of OXi4503 in patients with relapsed and refractory AML and MDS.
Time Frame:28 days
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Terminated
Lead Sponsor:University of Florida

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