GTI-2040 and Gemcitabine in Treating Patients With Metastatic or Unresectable Solid Tumors

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 gemcitabine in treating patients with metastatic or unresectable solid tumors. Drugs used in chemotherapy, such as gemcitabine, work in different ways to stop tumor cells from dividing so they stop growing or die. GTI-2040 may stop the growth of tumor cells by blocking the enzymes necessary for their growth and by making tumor cells more sensitive to gemcitabine

Detailed Description
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OBJECTIVES: Primary I. Determine the toxicity profile and maximum tolerated dose of GTI-2040 and gemcitabine in patients with metastatic or unresectable solid tumors. Secondary I. Determine the pharmacokinetics and pharmacodynamics of this regimen in these patients. OUTLINE: This is an open-label, dose-escalation study. Patients receive GTI-2040 IV continuously on days 2-16 of course 1 and on days 1-16 of all subsequent courses and gemcitabine IV over 30 minutes on days 1, 8, and 15 of course 1 and on days 2, 9, and 16 of all subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of GTI-2040 and gemcitabine 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. Once the MTD is determined, 10 additional patients are treated at that dose. PROJECTED ACCRUAL: Approximately 18-40 patients will be accrued for this study within 6-20 months.

Official Title
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A Phase I Pharmacokinetics and Pharmacodynamic Study of GTI2040 in Combination With Gemcitabine in Patients With Solid Tumors

Conditions
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Unspecified Adult Solid Tumor, Protocol Specific

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed solid tumor Metastatic or unresectable disease for which standard curative or palliative measures do not exist or are no longer effective Measurable or evaluable disease No known active or progressive brain metastases or primary brain tumors Performance status - ECOG 0-2 Performance status - Karnofsky 60-100% More than 12 weeks Hemoglobin > 9 g/dL Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Bilirubin ≤ 2 times upper limit of normal (ULN) AST and ALT ≤ 3 times ULN (5 times ULN if hepatic metastases are present) Creatinine ≤ 2.0 mg/dL Creatinine clearance ≥ 50 mL/min No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No prior allergic reaction attributed to compounds of similar chemical or biological composition to study drugs No ongoing or active infection No psychiatric illness or social situation that would preclude study compliance No other condition (e.g., dementia or developmental delay) that would preclude giving informed consent No other concurrent uncontrolled illness that would preclude study participation Prior biologic therapy allowed No concurrent biologic therapy No concurrent immunotherapy No concurrent routine filgrastim (G-CSF) or sargramostim (GM-CSF) Prior gemcitabine allowed Prior investigational chemotherapy allowed At least 4 weeks since prior chemotherapy (6 weeks for mitomycin, carmustine, or nitrosoureas) and recovered No other concurrent chemotherapy Concurrent hormonal therapy (e.g., luteinizing hormone-releasing hormone agonists) for prostate cancer is allowed At least 4 weeks since prior radiotherapy and recovered No prior radiotherapy to more than 25% of bone marrow No concurrent radiotherapy Recovered from prior surgery No other concurrent investigational therapy No other concurrent anticancer therapy No concurrent combination antiretroviral therapy for HIV-positive patients No concurrent long-term oral anticoagulation therapy (e.g., warfarin) Prophylactic warfarin to maintain central venous access patency allowed

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: Treatment (GTI-2040, gemcitabine hydrochloride)<br>Patients receive GTI-2040 IV continuously on days 2-16 of course 1 and on days 1-16 of all subsequent courses and gemcitabine IV over 30 minutes on days 1, 8, and 15 of course 1 and on days 2, 9, and 16 of all subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of GTI-2040 and gemcitabine until the 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. Once the MTD is determined, 10 additional patients are treated at that dose. | Biological: GTI-2040<br>* Given IV<br>Drug: gemcitabine hydrochloride<br>* Given IV<br>* Other names: Gemzar;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) of GTI-2040 and gemcitabine hydrochloride, graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) v3.0 |  | Up to day 28 | 
| Adverse events, graded according to the NCI CTC v3.0 |  | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Levels of gemcitabine triphosphate (dFdCTP) in terms of pharmacokinetics of gemcitabine hydrochloride |  | Days 1, 2, 8, and 15 (course 1), days 1, 2, 9, and 16 (course 2) | 
| Levels of ribonucleotide reductase R2 and protein expression | Student t-tests will be employed. | Days 1, 2, 8, and 15 (course 1), days 1, 2, 9, and 16 (course 2) | 
| Levels of apoptotic markers and cell cycle regulatory proteins | Student t-tests will be employed. | Days 1, 2, 8, and 15 (course 1), days 1, 2, 9, and 16 (course 2) |