Combination of GTI-2040 and Cytarabine in the Treatment of Refractory and Relapsed Acute Myeloid Leukemia (AML)
Condition: Acute Myeloid Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Intervention: GTI-2040
Intervention description: GTI-2040 will be administered one day after HiDAC in the pilot PD study and one day before HiDAC in the Phase II study for a cycle. Those who achieve a complete remission (CR) will be permitted to receive one cycle of consolidation of GTI-2040 and HiDAC
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 27.0
Sex: All
Minimum age: 18 Years
Maximum age: 60 Years
Healthy volunteers: No

Summary:

      This is a Phase II trial conducted at multiple centers for evaluation of the pharmacodynamic
      activity and the overall response rate contributed by the combination agents of GTI-2040 and
      High Dose Cytarabine (HiDAC) in Refractory and Relapsed Acute Myeloid Leukemia (AML).
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must have unequivocal histologic diagnosis of AML according to WHO
             classification.

          -  Patients must have (1) refractory AML, defined as a disease unresponsive to the
             initial treatment; or (2) relapsed AML, defined as disease that re-occurs after
             treatment with conventional or high dose chemotherapy, with or without autologous stem
             cell support.

          -  Patients previously treated with antisense oligonucleotides remain eligible in absence
             of significant or dose-limiting documented toxicities directly attributable to the
             antisense agents.

          -  Age 18-59 years old.

          -  Because no dosing or adverse event data are currently available on the use of GTI-2040
             in combination with cytarabine in patients <18 years of age, children are excluded
             from this study but will be eligible for future pediatric Phase 2 combination trials.

          -  Eastern Cooperative Oncology Group (ECOG) performance status <= 2 (Karnofsky >60%).

          -  Patients with central nervous system (CNS) involvement will be considered eligible for
             this study if no residual leukemic cells are detectable in the cerebral spinal fluid
             following intrathecal or radiation therapy.

          -  Central line catheter for administration of GTI-2040 infusion is required for all
             patients enrolled in the study.

          -  Ability to understand and the willingness to sign a written informed consent document.
             Written informed consent is required prior to any study procedures for screening or
             enrollment.

        Exclusion Criteria:

          -  Patients who have had chemotherapy (with the exception of hydroxyurea) or radiotherapy
             within 4 weeks prior to entering the study or those who have not recovered from
             adverse events due to agents administered more than 4 weeks earlier. Patients who have
             received mitomycin C or nitrosurea require a 6 week recovery period before enrollment.

          -  Patients who have had prior allogeneic stem cell transplant.

          -  Patients may not be receiving any other investigational agents as part of ongoing
             treatment.

          -  Patients with the following abnormal clinical values (unless abnormalities in these
             parameters are directly attributable to malignancy):

               -  Resting cardiac ejection fraction < 50%

               -  Serum creatinine > 1.5 mg/dL

               -  Total bilirubin > 2x upper limits of normal (ULN) (unless due to Gilbert's
                  syndrome)

               -  aspartate aminotransferase (AST) and alanine aminotransferase (ALT) > 3x ULN

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to GTI-2040 or other agents used in the study.

          -  Patients who require chronic systemic anticoagulant therapy for medical conditions
             (e.g., previous history of deep venous thrombosis, atrial fibrillation etc.). Heparin
             administration to maintain central line patency (i.e. catheter flush) is not an
             exclusion.

          -  Patients with uncontrolled intercurrent illness including, but not limited to, ongoing
             or active infection requiring IV antibiotics, symptomatic congestive heart failure,
             unstable angina pectoris, or cardiac arrhythmia.

          -  Serious medical or psychiatric illness that would prevent informed consent or limit
             survival to < 4 weeks.

          -  Pregnancy or breastfeeding women. The potential for teratogenic effects and other
             risks for GTI-2040 in nursing infants are unknown. Women of childbearing potential and
             men must agree to use adequate contraception (hormonal or barrier method of birth
             control) prior to study entry and for the duration of study participation.

          -  HIV-positive patients on combination antiretroviral therapy are ineligible because
             these patients are at increased risk of lethal infections when treated with
             marrow-suppressive therapy. Appropriate studies will be undertaken in patients
             receiving combination antiretroviral therapy when indicated.