GTI-2040 in Treating Patients With Relapsed, Refractory, or High-Risk Acute Leukemia, High-Grade Myelodysplastic Syndromes, or Refractory or Blastic Phase Chronic Myelogenous 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 in treating patients with relapsed, refractory, or high-risk acute leukemia, high-grade myelodysplastic syndromes, or refractory or blastic phase chronic myelogenous leukemia. Drugs used in chemotherapy, such as GTI-2040, work in different ways to stop the growth of cancer or abnormal cells, either by killing the cells or by stopping them from dividing.

Detailed Description
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OBJECTIVES: I. Determine the maximum tolerated dose of GTI-2040 in patients with relapsed, refractory, or high-risk acute leukemia, high-grade myelodysplastic syndromes, or refractory or blastic phase chronic myelogenous leukemia. II. Assess the toxicity and efficacy of this drug in these patients. III. Assess plasma and intracellular pharmacokinetics of this drug in these patients. OUTLINE: This is a multicenter, dose-escalation study. Patients receive GTI-2040 IV continuously on days 1-4 and 15-18. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of GTI-2040 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. Blood samples are collected on days 1, 4, 15, and 19 of course 1 for pharmacokinetic studies. Samples are analyzed by proteomic assay, dCTP pool measurement, and real-time polymerase chain reaction for mRNA of RRM2, RRM1, and p53R2.

Official Title
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Phase I and Pharmacodynamic Study of GTI-2040 (NSC 722929, IND 67368) in Acute Leukemias

Conditions
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Acute Undifferentiated Leukemia, 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), Blastic Phase Chronic Myelogenous Leukemia, de Novo Myelodysplastic Syndromes, Previously Treated Myelodysplastic Syndromes, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Relapsing Chronic Myelogenous Leukemia, Secondary Acute Myeloid Leukemia, Secondary Myelodysplastic Syndromes, Untreated Adult Acute Lymphoblastic Leukemia, Untreated Adult Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: GTI-2040
* Procedure: pharmacological study
* Procedure: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of 1 of the following: Acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) refractory to primary standard induction therapy Relapsed or refractory acute leukemia Chronic myelogenous leukemia (CML) in blast crisis at diagnosis OR that failed prior aggressive induction chemotherapy Diagnosis of 1 of the following: Acute leukemia secondary to preexisting hematologic condition or prior chemotherapy at diagnosis OR that failed prior aggressive induction chemotherapy Advanced myelodysplastic syndromes (intermediate-1 or greater) De novo acute leukemia (myeloid or nonmyeloid) Not a candidate for aggressive standard induction chemotherapy De novo AML or ALL (patients > 60 years of age) No suspected or proven active CNS leukemia ECOG performance status (PS) 0-2 OR Karnofsky PS 50-100% Life expectancy >= 8 weeks Bilirubin =< 1.5 mg/dL AST and ALT < 3 times upper limit of normal (ULN) Creatinine =< 1.5 times ULN No HIV positivity Fertile patients must use effective contraception No history of allergic reactions attributed to other phosphorothiolated oligonucleotides No uncontrolled intercurrent illness including, but not limited to, any of the following: Ongoing, active, or poorly controlled infection Symptomatic congestive heart failure Unstable angina pectoris No uncontrolled intercurrent illness including, but not limited to, any of the following: Cardiac arrhythmia Poorly controlled pulmonary disease Psychiatric illness or social situation that would preclude study compliance Recovered from all prior therapies Prior autologous or allogeneic stem cell transplantation allowed (No active graft-vs-host disease > grade 2) At least 2 weeks since prior and no concurrent cytotoxic chemotherapy At least 2 weeks since prior and no concurrent biologic therapy At least 2 weeks since any other prior investigational agent No other concurrent anticancer therapy, including radiotherapy or hormonal therapy Concurrent imatinib mesylate for CML allowed Not pregnant or nursing Negative pregancy test

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive GTI-2040 IV continuously on days 1-4 and 15-18. | Drug: GTI-2040<br>* Given IV<br>Procedure: pharmacological study<br>* Correlative study<br>* Other names: pharmacological studies;Procedure: laboratory biomarker analysis<br>* Correlative study<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) determined according to dose-limiting toxicities (DLTs) graded using Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0) |  | 28 days | 
| Change in dCTP levels in PBMC and bone marrow by Real-Time PCR |  | Days 1, 4, 15, and 19 of course 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective tumor response |  | Up to 3 years | 
| Overall survival |  | Up to 3 years | 
| Time to failure |  | Up to 3 years | 
| Duration of response |  | Up to 3 years | 
| Change in expression levels of R1, R2, and p53R2 mRNA in PBMC by Real-Time PCR |  | Day 1, 4, 15, and 19 of course 1 | 
| Change in intracellular levels of GTI-2040 by ELISA |  | Day 1, 4, 15, and 19 of course 1 | 
| Incidence of grade 3 or higher toxicity assessed by CTCAE v3.0 |  | Up to 3 years |