GTI-2040 and Docetaxel in Treating Patients With Recurrent, Metastatic, or Unresectable Locally Advanced Non-Small Cell Lung Cancer, Prostate Cancer, or Other Solid Tumors

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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A Phase I/2 Study of GTI-2040 Combined With Docetaxel In Metastatic Or Unresectable Locally Advanced Non-Small Cell Lung Cancer

Conditions
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Recurrent Non-small Cell Lung Cancer, Recurrent Prostate Cancer, Stage III Prostate Cancer, Stage IIIA Non-small Cell Lung Cancer, Stage IIIB Non-small Cell Lung Cancer, Stage IV Non-small Cell Lung Cancer, Stage IV Prostate Cancer, Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Biological: GTI-2040
* Drug: docetaxel
* 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 diagnosis of 1 of the following: Solid tumor malignancy (phase I only)* Prostate cancer (phase I only)* Non-small cell lung cancer (phase I and II)* 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 Must have measurable disease other than bone lesions 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 Asymptomatic brain metastases allowed 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 Neoadjuvant/adjuvant chemotherapy 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 Concurrent low-dose warfarin for central line thrombosis prophylaxis allowed 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

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, docetaxel)<br>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 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 RP2D is defined as the dose preceding the MTD. Phase II: Patients receive GTI-2040 and docetaxel at the RP2D as in phase I. | Biological: GTI-2040<br>* Given IV<br>Drug: docetaxel<br>* Given IV<br>* Other names: TXT;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 |
| --- | --- | --- |
| Number of patients experiencing dose limiting toxicities (DLTs), graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) v2.0 (Phase I) |  | 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. | Up to day 42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stable disease rate |  | Up to 6 weeks | 
| Response duration | The 95% confidence intervals will be provided. | Up to 4 years | 
| Toxicities of GTI-2040 combined with docetaxel, graded according to the NCI CTC v2.0 |  | Up to 4 years | 
| Time to disease progression |  | Up to 4 years | 
| Duration of stable disease |  | Up to 6 weeks | 
| Level of ribonucleotide reductase (RNR) activity | Logistic regression and descriptive statistics will be used. | 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. | Up to week 10 |