A Phase I/2 Study of GTI-2040 Combined With Docetaxel In Metastatic Or Unresectable Locally Advanced Non-Small Cell Lung Cancer
A Phase I/2 Study of GTI-2040 Combined With Docetaxel In Metastatic Or Unresectable Locally Advanced Non-Small Cell Lung Cancer
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.
Inclusion Criteria:
Histologically or cytologically confirmed diagnosis of 1 of the following:
Recurrent, metastatic, locally advanced unresectable, or treatment-refractory disease
Measurable disease
At least 1 unidimensionally measurable lesion at least 20 mm by conventional techniques OR at least 10 mm by spiral CT scan
Previously irradiated lesions are considered measurable provided they have demonstrated progression before study entry
No bone-only disease
No stage IIIA or IIIB non-small cell lung cancer without a malignant pleural or pericardial effusion that is eligible for first-line radical combined chemotherapy and radiotherapy
No known progressive or symptomatic brain metastases
Performance status - ECOG 0-2
Performance status - Karnofsky 60-100%
More than 3 months
WBC at least 3,000/mm^3
Absolute neutrophil count at least 1,500/mm^3
Platelet count at least 100,000/mm^3
No history of coagulopathy
Bilirubin no greater than 1.5 times upper limit of normal (ULN)
AST/ALT no greater than 2 times ULN (3.5 times ULN if liver metastases are present)
INR no greater than 1.3
APTT no greater than 1.25 times ULN
Creatinine no greater than 1.5 times ULN
Creatinine clearance at least 50 mL/min
No symptomatic congestive heart failure
No evidence of cardiac dysfunction
No unstable angina pectoris
No cardiac arrhythmia
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No active peptic ulcer disease
No poorly controlled diabetes mellitus
No pre-existing grade 2 or greater neuropathy
No ongoing or active infection
No contraindication to corticosteroids
No psychiatric illness or social situation that would limit compliance with study requirements
No prior allergic reaction attributed to compounds of similar chemical or biological composition to study drugs
No other concurrent uncontrolled illness
One, and only one, prior chemotherapy regimen for advanced disease (not including adjuvant therapy) allowed
More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas and mitomycin) and recovered
Prior multiple lines of endocrine therapy for advanced solid tumors allowed
More than 4 weeks since prior endocrine therapy and recovered
Concurrent steroids allowed
See Disease Characteristics
More than 4 weeks since prior radiotherapy and recovered
No concurrent radiotherapy to sole site of measurable disease
Prior surgery allowed
No concurrent anticoagulant therapy
No concurrent combination antiretroviral therapy for HIV-positive patients
No other concurrent investigational or commercial agents or therapies intended to treat the malignancy
Concurrent bisphosphonates allowed