A Phase I Pharmacokinetics and Pharmacodynamic Study of GTI2040 in Combination With Gemcitabine in Patients With Solid Tumors
A Phase I Pharmacokinetics and Pharmacodynamic Study of GTI2040 in Combination With Gemcitabine in Patients With Solid Tumors
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
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.
Inclusion Criteria:
Histologically or cytologically confirmed solid tumor
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)