GTI-2040 and High-Dose Cytarabine in Treating Patients With Refractory or Relapsed Acute Myeloid Leukemia

Study Overview
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Brief Summary
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This phase I trial is studying the side effects and best dose of GTI-2040 and high-dose cytarabine in treating patients with refractory or relapsed acute myeloid leukemia. GTI-2040 may stop the growth of cancer cells by blocking the enzymes necessary for cancer cell growth. Drugs used in chemotherapy, such as cytarabine, use different ways to stop cancer cells from dividing so they stop growing or die. Giving GTI-2040 together with cytarabine may kill more cancer cells.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose and recommended phase II dose of GTI-2040 and high-dose cytarabine in patients with relapsed or refractory acute myeloid leukemia. SECONDARY OBJECTIVES: I. Determine the therapeutic response in patients treated with this regimen. II. Determine the pharmacokinetics of this regimen in these patients. OUTLINE: This is a dose-escalation study. Patients are stratified according to age (under age 60 vs age 60 and over). Patients are assigned to 1 of 2 strata. Stratum I (under age 60): Patients receive GTI-2040 IV continuously on days 1-6 and high-dose cytarabine IV over 2 hours twice daily on days 2, 4, and 6. Stratum II (age 60 and over): Patients receive GTI-2040 IV continuously on days 1-6 and high-dose cytarabine IV over 4 hours once daily on days 2-6. In both strata, treatment continues in the absence of unacceptable toxicity. Cohorts of 3-6 patients per stratum receive escalating doses of GTI-2040 and high-dose cytarabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. PROJECTED ACCRUAL: A total of 6-51patients will be accrued for this study within 2-16 months.

Official Title
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A Phase I Study of GTI2040 (NSC 722929; IND 67368) in Combination With High-dose Cytarabine in Refractory or Relapsed Acute Myeloid Leukemia (AML)

Conditions
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Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Recurrent Adult Acute Myeloid Leukemia

Intervention / Treatment
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* Biological: GTI-2040
* Drug: cytarabine
* Other: pharmacological study
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed acute myeloid leukemia according to the WHO classification Relapsed or refractory disease, meeting 1 of the following criteria: Unresponsive to initial treatment Recurrent disease after treatment with prior conventional or high-dose chemotherapy with or without stem cell support CNS involvement allowed provided there are no residual leukemic cells detected in the cerebrospinal fluid after intrathecal or radiation chemotherapy Performance status - ECOG 0-2 At least 4 weeks Bilirubin no greater than 2 times upper limit of normal* (ULN) (unless due to Gilbert's syndrome) AST and ALT no greater than 3 times ULN* Creatinine no greater than 1.5 mg/dL* No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia Resting ejection fraction at least 50%* Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No prior allergy to study medications No ongoing or active infection requiring IV antibiotics No other concurrent uncontrolled illness No serious medical or psychiatric illness that would preclude giving informed consent More than 4 weeks since prior chemotherapy (except hydroxyurea) (6 weeks for nitrosoureas or mitomycin) No other concurrent chemotherapy No concurrent hormonal therapy except steroids for adrenal failure and hormones for non-disease-related conditions (e.g., insulin for diabetes) More than 4 weeks since prior radiotherapy No concurrent palliative radiotherapy Prior therapy with antisense oligonucleotides allowed provided no toxic effects were experienced that were directly attributable to the antisense agents No other concurrent investigational agents No other concurrent anticancer therapy No concurrent chronic systemic anticoagulant therapy for medical conditions (e.g., prior deep vein thrombosis or atrial fibrillation) Concurrent heparin to maintain central line patency (i.e., catheter flush) is allowed No concurrent combination antiretroviral therapy for HIV-positive patients

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stratum I (GTI-2040, cytarabine)<br>Patients receive GTI-2040 IV continuously on days 1-6 and high-dose cytarabine IV over 2 hours twice daily on days 2, 4, and 6. | Biological: GTI-2040<br>* Given IV<br>Drug: cytarabine<br>* Given IV<br>* Other names: cytosine arabinoside;Other: pharmacological study<br>* Optional correlative studies<br>* Other names: pharmacological studies;Other: laboratory biomarker analysis<br>* Optional correlative studies<br>|
| Experimental: Stratum II (GTI-2040, cytarabine)<br>Patients receive GTI-2040 IV continuously on days 1-6 and high-dose cytarabine IV over 4 hours once daily on days 2-6. In both strata, treatment continues in the absence of unacceptable toxicity. | Biological: GTI-2040<br>* Given IV<br>Drug: cytarabine<br>* Given IV<br>* Other names: cytosine arabinoside;Other: pharmacological study<br>* Optional correlative studies<br>* Other names: pharmacological studies;Other: laboratory biomarker analysis<br>* Optional correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum-tolerated dose (MTD) as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 |  | Up to day 42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Therapeutic response | Standard paired statistical tests, parametric and nonparametric, will be used to baseline with treatment values. With data collected serially over time, repeated measures analysis of variance will be used to analyze data. | Up to 6 years | 
| Change in R2 expression in circulating and marrow leukemia cells | Standard paired statistical tests, parametric and nonparametric, will be used to baseline with treatment values. With data collected serially over time, repeated measures analysis of variance will be used to analyze data. | From baseline to up to 6 years |