Combination of GTI-2040 and Cytarabine in the Treatment of Refractory and Relapsed Acute Myeloid Leukemia (AML)

Study Overview
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Brief Summary
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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).

Official Title
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A Phase II Simon Two-stage Multicenter Study and Pilot Pharmacodynamic Investigation of GTI 2040 in Combination With High Dose Cytarabine (HiDAC) in Refractory and Relapsed Acute Myeloid Leukemia (AML)

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Biological: GTI-2040


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pilot<br>Pilot PD Study (Delayed GTI-2040) Group: In the Pilot PD Study Group, addition of GTI-2040 is delayed until 24 hours after initiation of HiDAC. | Biological: GTI-2040<br>* 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<br>|
| Experimental: Phase II arm<br>Phase II PD Study (Early GTI-2040) Group: In the Phase II PD Study Group, GTI-2040 is given 24 hours prior to addition of HiDAC. | Biological: GTI-2040<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate of GTI-2040 Combined With HiDAC in Refractory or Relapsed AML | Overall Response was defined as whether or not the patient achieved complete remission (CR) and CR with incomplete blood count recovery (CRi) while on the study. | at 29-35 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summary of Treatment Emergent Adverse Events | An adverse event (AE) was defined as any unintended or undesirable experience that occurred during the course of the clinical investigation, regardless of whether or not it was considered to be study drug-related. This included any newly occurring event or a previous condition that had increased in severity or frequency since the administration of study drug. | 30 days after the last dose |