Carboxyamidotriazole in Treating Patients With Stage III or Stage IV Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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Randomized phase III trial to determine the effectiveness of carboxyamidotriazole in treating patients who have stage III or stage IV non-small cell lung cancer. Chemotherapeutic agents are modestly effective for the treatment of advanced lung cancer, with rapid tumor relapse and growth even after initial response to therapy. It is not yet known whether carboxyamidotriazole is more effective than no further treatment after standard chemotherapy for non-small cell lung cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine whether oral administration of the carboxyaminoimidazole (CAI) is more effective than placebo in prolonging the overall survival in patients with non-small cell lung cancer stage III or stage IV non-small cell lung cancer who have been stable or had tumor regression following chemotherapy. SECONDARY OBJECTIVES: I. To evaluate the safety and tolerability of oral CAI following chemotherapy. II. To determine whether CAI prolongs time-to-disease progression relative to a placebo. III. To evaluate whether a substantive effect in quality of life (QOL) can be detected between the CAI and placebo groups using the FACT-L and the UNISCALE. IV. To document the response rate to CAI in patients with measurable or evaluable disease. TERTIARY OBJECTIVES: I. To evaluate genotypes at GSH-related loci as predictors of overall survival. OUTLINE: This is a randomized, double-blind, multicenter study. Patients are stratified according to timing of first-line therapy (prior to registration vs after registration), disease stage (IIIA vs IIIB vs IV), therapy components (chemotherapy and thoracic radiotherapy vs chemotherapy only), ECOG performance status (0 vs 1 vs 2) and participating center. Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive oral carboxyamidotriazole daily. ARM II: Patients receive oral placebo daily. Treatment continues in the absence of disease progression or unacceptable toxicity. Quality of life is assessed at baseline and then monthly during study. Patients are followed every 3 months for 5 years.

Official Title
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Phase III Randomized, Double-Blind Study of CAI and Placebo in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)

Conditions
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Stage IIIA Non-small Cell Lung Cancer, Stage IIIB Non-small Cell Lung Cancer, Stage IV Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: carboxyamidotriazole
* Other: placebo
* Procedure: quality-of-life assessment
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: TRACK I: Histologically or cytologically confirmed NSCLC stage III or IV; disease must be stable or responding after standard chemotherapy (with or without TRT) for a minimum of 3 or a maximum of 6 months TRACK I: Not required to have measurable or evaluable disease at study entry TRACK I: Must have had one and only one prior chemotherapy regimen for NSCLC (radiosensitizers are allowed) TRACK I: =< 6 weeks from last dose of chemotherapy or TRT TRACK I: ECOG PS 0, 1, or 2 TRACK I: ANC >= 1500/mm^3 TRACK I: PLT >= 100,000/mm^3 TRACK I: HgB >= 10.0 g/dL TRACK I: Total bilirubin =< 1.5 x UNL TRACK I: Alkaline phosphatase =< 3 x UNL TRACK I: AST =< 3 x UNL TRACK I: Creatinine =< 1.5 x UNL TRACK I: Expected survival of at least three months TRACK II AT REGISTRATION: Histologically or cytologically confirmed NSCLC stage III or IV TRACK II AT REGISTRATION: No prior chemotherapy for NSCLC TRACK II AT REGISTRATION: Expected survival of at least six months TRACK II AT REGISTRATION: Willingness to provide blood sample TRACK II AT RANDOMIZATION: STAB, PR, CR, REGR following 3-6 months of chemotherapy with or without radiation therapy TRACK II AT RANDOMIZATION: Must have had one and only one prior chemotherapy regimen for NSCLC (radiosensitizers are allowed) TRACK II AT RANDOMIZATION: =< 6 weeks from last dose of chemotherapy or TRT TRACK II AT RANDOMIZATION: ECOG PS 0, 1, or 2 TRACK II AT RANDOMIZATION: ANC >= 1500/mm^3 TRACK II AT RANDOMIZATION: PLT >= 100,000/mm^3 TRACK II AT RANDOMIZATION: HgB >= 10.0 g/dL TRACK II AT RANDOMIZATION: Total bilirubin =< 1.5 x UNL TRACK II AT RANDOMIZATION: Alkaline phosphatase =< 3 x UNL TRACK II AT RANDOMIZATION: AST =< 3 x UNL TRACK II AT RANDOMIZATION: Creatinine =< 1.5 x UNL TRACK II AT RANDOMIZATION: Expected survival of at least three months Exclusion Criteria: TRACK I: Pregnant, nursing women, females or sexual partners of childbearing potential not using adequate contraception (condoms, diaphragm, birth control pills, injections, intrauterine device [IUD], or abstinence, etc.) while on study treatment and for two months after discontinuing study treatment as this regimen may be harmful to a developing fetus or nursing child TRACK I: Untreated brain metastases TRACK I: Concomitant participation in a phase III lung cancer treatment trial TRACK I: Planned concurrent chemotherapy, immunotherapy or radiotherapy TRACK II AT RANDOMIZATION: Pregnant, nursing women, females or sexual partners of childbearing potential not using adequate contraception (condoms, diaphragm, birth control pills, injections, intrauterine device [IUD], or abstinence, etc.) while on study treatment and for two months after discontinuing study treatment as this regimen may be harmful to a developing fetus or nursing child TRACK II AT RANDOMIZATION: Untreated brain metastases TRACK II AT RANDOMIZATION: Planned concurrent chemotherapy, immunotherapy, or radiotherapy

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (CAI)<br>Patients receive oral carboxyamidotriazole daily. | Drug: carboxyamidotriazole<br>* Given PO<br>* Other names: carboxyaminoimidazole;Procedure: quality-of-life assessment<br>* Ancillary studies<br>* Other names: quality of life assessment;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Placebo Comparator: Arm II (placebo)<br>Patients receive oral placebo daily | Other: placebo<br>* Given PO<br>* Other names: PLCB;Procedure: quality-of-life assessment<br>* Ancillary studies<br>* Other names: quality of life assessment;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS was defined as the time from randomization to death of any cause. Participants who did not die or were lost to follow-up were censored at the time of last evaluation/follow-up date. Patients were followed for a maximum of 5 years from randomization. The median OS with 95%CI was estimated using the Kaplan Meier method. | up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With Severe Non-hematologic Adverse Events | Severe non-hematologic adverse events were defined as adverse events grade 3 or higher, regardless of attribution to study drug. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC version 2.0) | every cycle during treatment | 
| Time to Disease Progression (TTP) | TTP is defined as the time from randomization to first documented disease progression(PD). Patients who were lost to follow-up were censored at the time of last evaluation. For patients who died without clear documentation, PD was assumed at the midpoint of the time interval between last evaluation and death. Median TTP was estimated using the Kaplan Meier method. Measurable PD: ≥25% increase in the sum of the products of two greatest perpendicular diameters of all indicator lesions or appearance of new lesion(s). Evaluable PD: definite increase in tumor size or appearance of new lesion(s) | up to 5 years | 
| Clinically Significant (10-point) Decrease in UNISCALE Quality of Life (QOL)Assessment From Baseline to Week 8 | The UNISCALE was used to assess QOL. UNISCALE is a single item global measure of QOL. Participant were to complete the questionnaire at baseline and every 8 weeks, prior to assessment by the treating physician. A high score indicates a higher quality of life while a low score represents a lower quality of life. A 10 point or greater decline (from baseline to week 8) in UNISCALE QOL score was considered clinically significant. | Baseline to week 8 | 
| Clinically Significant (10-point) Decrease in Functional Assessment of Cancer Therapy for Lung Cancer (FACT-L) Quality of Life (QOL)Assessment From Baseline to Week 8 | The FACT-L is a 36-item Likert instrument that combines frequency of symptomatic/QOL problems with perceived relative importance of each issue. It includes 4 constructs of well being: physical, social/family, emotional and functional, and a fifth construct, additional concerns, dealing solely with tumor related symptoms. Questionnaires were completed at baseline and 8 weeks. Questions within each construct were summated to obtain a construct score. A higher score relates to higher quality of life. A 10 point or greater decline (from baseline to week 8) was considered clinically significant. | Baseline to week 8 | 
| Number of Patients With a Confirmed Tumor Responses Treated With CAI. | Confirmed response was defined as a complete response (CR) or partial response (PR) for patients with measurable disease or as a CR or regression (REGR) for patients with evaluable disease noted on 2 consecutive evaluations at least 4 weeks apart. CR: total disappearance of all tumor; PR: >=50% reduction of the sum of the products of the two greatest perpendicular diameters of all indicator lesions; REGR: Definite decrease in tumor size and no new lesion(s). | During Treatment (up to 5 years) |