Phase I/II trial to study the effectiveness of combining GTI-2040 with docetaxel in treating patients who have recurrent, metastatic, or unresectable locally advanced non-small cell lung cancer, prostate cancer, or other solid tumors. GTI-2040 may stop the growth of cancer cells by blocking the enzymes necessary for their growth. It may also increase the effectiveness of docetaxel by making the tumor cells more sensitive to the drug. Combining GTI-2040 with docetaxel may kill more tumor cells
OBJECTIVES: I. Determine the recommended phase II dose of GTI-2040 and docetaxel in patients with recurrent, metastatic, or unresectable locally advanced non-small cell lung cancer, prostate cancer, or other solid tumors (phase I study closed to accrual as of 8/5/2004). II. Determine the toxicity of this regimen in these patients. III. Determine the objective tumor response rate in patients treated with this regimen. IV. Determine the stable disease rate, time to disease progression, objective response duration, and duration of stable disease in patients treated with this regimen. V. Determine the pharmacokinetics of GTI-2040 when administered in combination with docetaxel in these patients. VI. Correlate the pharmacokinetics of GTI-2040 with the biological and toxic effects of this regimen in these patients. VII. Correlate baseline and post-treatment levels of ribonucleotide reductase activity in tumor biopsies and peripheral blood mononuclear cells and tumoral expression of c-myc, ras, pRAF1, pMAPK, and markers of apoptosis with clinical outcome in patients treated with this regimen. OUTLINE: This is an open-label, dose-escalation, multicenter study. Phase I (closed to accrual as of 8/5/2004): Patients receive GTI-2040 IV continuously on days 1-14. Patients also receive docetaxel IV over 1 hour on day 3 during course 1 and on day 1 for all subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of GTI-2040 and docetaxel until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. The recommended phase II dose (RP2D) is defined as the dose preceding the MTD. Phase II: Patients receive GTI-2040 and docetaxel at the RP2D as in phase I. Patients are followed every 3 months. PROJECTED ACCRUAL: A total of 12-48 patients (12-18 for phase I \[closed to accrual as of 8/5/2004\] and 15-30 for phase II) will be accrued for this study within 4-16 months.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
48
Princess Margaret Hospital Phase 2 Consortium
Toronto, Ontario, Canada
Number of patients experiencing dose limiting toxicities (DLTs), graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) v2.0 (Phase I)
Time frame: Up to day 21
Objective tumor response as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) (Phase II)
The 95% confidence intervals will be provided.
Time frame: Up to day 42
Stable disease rate
Time frame: Up to 6 weeks
Response duration
The 95% confidence intervals will be provided.
Time frame: Up to 4 years
Toxicities of GTI-2040 combined with docetaxel, graded according to the NCI CTC v2.0
Time frame: Up to 4 years
Time to disease progression
Time frame: Up to 4 years
Duration of stable disease
Time frame: Up to 6 weeks
Level of ribonucleotide reductase (RNR) activity
Logistic regression and descriptive statistics will be used.
Time frame: Up to week 10
Tumoral expression in terms of c-myc, R2 subunit protein levels and markers of proliferation (cyclin B1) and apoptosis (activated caspase 3)
Logistic regression and descriptive statistics will be used.
Time frame: Up to week 10
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