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

Phase 1
18 Years
Open (Enrolling)
Leukemia, Myelogenous, Acute, Myelodysplastic Syndromes

Thank you

Trial Information

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

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.

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

- 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

- 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

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

- History of ventricular arrhythmia (excluding premature ventricular contractions,

- 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 stroke or transient ischemic attack;

- 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

- 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.

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To determine the safety and establish the maximum tolerated dose (MTD) of OXi4503 in patients with relapsed and refractory AML and MDS.

Outcome Time Frame:

3 years

Safety Issue:


Principal Investigator

Christopher R. Cogle, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Florida


United States: Food and Drug Administration

Study ID:




Start Date:

February 2011

Completion Date:

January 2015

Related Keywords:

  • Leukemia, Myelogenous, Acute
  • Myelodysplastic Syndromes
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Myelodysplastic Syndromes
  • Preleukemia



Shands Cancer Hospital at the University of Florida Gainesville, Florida  32608