Combination Chemotherapy Plus Radiation Therapy With or Without AE-941 in Treating Patients With Stage III Non-small Cell Lung Cancer That Cannot Be Removed By Surgery

Study Overview
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Brief Summary
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Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. Radiation therapy uses high-energy x-rays to damage tumor cells. AE-941 may help shrink or slow the growth of non-small cell lung cancer cells. It is not yet known if combination chemotherapy plus radiation therapy is more effective with or without AE-941 for non-small cell lung cancer. This randomized phase III trial is studying combination chemotherapy and radiation therapy given with AE-941 to see how well they work compared to combination chemotherapy and radiation therapy alone in treating patients with stage III non-small cell lung cancer that cannot be removed by surgery

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the overall survival of patients with unresectable stage IIIA or IIIB non-small cell lung cancer treated with induction platinum-based chemotherapy and radiotherapy with or without AE-941 (Neovastat). II. Determine the progression-free survival, tumor response, tumor response duration, and metastasis-free survival of patients treated with these regimens. III. Determine the tolerability of this regimen in these patients. OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to stage (IIIA vs IIIB), type of platinum-based induction chemotherapy to be received (cisplatin and vinorelbine vs carboplatin and paclitaxel), and gender. Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive oral AE-941 (Neovastat) twice daily beginning on day 1 or within 10 days of initiation of chemotherapy. Arm II: Patients receive oral placebo twice daily beginning on day 1 or within 10 days of initiation of chemotherapy. All patients receive induction chemotherapy with 1 of the following platinum-based regimens: cisplatin IV on days 1, 22, 50, and 71 and vinorelbine IV on days 1, 8, 22, 29, 50, 57, 71, and 78 carboplatin IV over 30 minutes and paclitaxel IV over 3 hours on days 1, 22, 50, 57, 64, 71, 78, and 85. All patients receive radiotherapy beginning on day 50 for 6 weeks. Treatment in both arms continues in the absence of unacceptable toxicity. Patients are followed every 3 months. PROJECTED ACCRUAL: A total of 756 patients (378 per treatment arm) will be accrued for this study within 36 months.

Official Title
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Multicenter, Open-Ended, Double-Blind, Placebo-Controlled, Phase III Study of AE-941 in Addition to Combined Modality Treatment (Chemotherapy/Radiotherapy) for Locally Advanced Unresectable Non-Small Cell Lung Cancer

Conditions
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Adenocarcinoma of the Lung, Adenosquamous Cell Lung Cancer, Large Cell Lung Cancer, Squamous Cell Lung Cancer, Stage IIIA Non-small Cell Lung Cancer, Stage IIIB Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: shark cartilage extract AE-941
* Other: placebo
* Drug: cisplatin
* Drug: vinorelbine tartrate
* Drug: carboplatin
* Drug: paclitaxel
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed newly diagnosed, untreated, unresectable stage IIIA or stage IIIB non-small cell lung cancer Squamous cell carcinoma, adenocarcinoma, or large cell carcinoma of the lung Mixed tumors allowed if non-small cell elements identified Contralateral supraclavicular and/or scalene lymph node involvement allowed No disease extending into the cervical region At least 1 bidimensionally or unidimensionally measurable lesion No pleural effusion unless cytologically negative or too small to safely aspirate Not scheduled for curative cancer surgery Performance status - ECOG 0-1 Absolute neutrophil count greater than 1,500/mm^3 Platelet count greater than 100,000/mm^3 Hematocrit greater than 30% SGOT or SGPT less than 1.5 times upper limit of normal Bilirubin normal Creatinine less than 1.5 mg/dL Creatinine clearance greater than 60 mL/min No other major medical or psychiatric illness that would preclude study participation or consent No medical condition that interferes with oral medication intake and/or absorption (gastrectomy or major intestinal resection) No grade 2 or greater peripheral neuropathy unless secondary to mechanical etiology No hypersensitivity to fish products No more than 10% weight loss within past 3 months No other malignancy within past 3 years except inactive carcinoma in situ of the cervix or nonmelanoma skin cancer Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception At least 30 days since prior chemotherapy See Disease Characteristics Recovered from prior major surgery At least 30 days since prior shark cartilage products No other concurrent investigational anticancer agents No other concurrent cartilage products No other concurrent investigational agents No concurrent amifostine or other radioprotectants No concurrent enrollment in other clinical trials

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 (shark cartilage extract AE-941)<br>Patients receive oral AE-941 (Neovastat) twice daily beginning on day 1 or within 10 days of initiation of chemotherapy. All patients receive induction chemotherapy with 1 of the following platinum-based regimens: cisplatin IV on days 1, 22, 50, and 71 and vinorelbine IV on days 1, 8, 22, 29, 50, 57, 71, and 78 carboplatin IV over 30 minutes and paclitaxel IV over 3 hours on days 1, 22, 50, 57, 64, 71, 78, and 85. All patients receive radiotherapy beginning on day 50 for 6 weeks. Treatment in both arms continues in the absence of unacceptable toxicity. | Drug: shark cartilage extract AE-941<br>* Given orally<br>* Other names: Neovastat/AE-941;Drug: cisplatin<br>* Given IV<br>* Other names: DDP;Drug: vinorelbine tartrate<br>* Given IV<br>* Other names: VNB;Drug: carboplatin<br>* Given IV<br>* Other names: Paraplatin;Drug: paclitaxel<br>* Given IV<br>* Other names: Taxol;Radiation: radiation therapy<br>* Undergo radiotherapy<br>* Other names: therapy, radiation;|
| Placebo Comparator: Arm II (placebo)<br>Patients receive oral placebo twice daily beginning on day 1 or within 10 days of initiation of chemotherapy. All patients receive induction chemotherapy with 1 of the following platinum-based regimens: cisplatin IV on days 1, 22, 50, and 71 and vinorelbine IV on days 1, 8, 22, 29, 50, 57, 71, and 78 carboplatin IV over 30 minutes and paclitaxel IV over 3 hours on days 1, 22, 50, 57, 64, 71, 78, and 85. All patients receive radiotherapy beginning on day 50 for 6 weeks. Treatment in both arms continues in the absence of unacceptable toxicity. | Other: placebo<br>* Given orally<br>* Other names: PLCB;Drug: cisplatin<br>* Given IV<br>* Other names: DDP;Drug: vinorelbine tartrate<br>* Given IV<br>* Other names: VNB;Drug: carboplatin<br>* Given IV<br>* Other names: Paraplatin;Drug: paclitaxel<br>* Given IV<br>* Other names: Taxol;Radiation: radiation therapy<br>* Undergo radiotherapy<br>* Other names: therapy, radiation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Survival distributions will be compared by use of the log-rank test. The stratified log-rank test (nominal or categorical covariates) may be used to simultaneously control for important prognostic factors. Kaplan-Meier curves will also be plotted to illustrate the comparative survival experience of both groups over the entire study period. | From randomization until date of death or last follow-up, assessed up to 7 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival every 3 months | Will be compared by use of the log-rank test. The stratified log-rank test (nominal or categorical covariates) may be used to simultaneously control for important prognostic factors. Kaplan-Meier curves will also be plotted. | From randomization until disease progression, assessed up to 7 years | 
| Tumor response rate | Will be compared by chi-square test. | Up to 7 years | 
| Tumor response duration | Will be compared by use of the log-rank test. The stratified log-rank test (nominal or categorical covariates) may be used to simultaneously control for important prognostic factors. Kaplan-Meier curves will also be plotted. | From first observation of at least a partial response to detection of disease progression or death due to any cause, assessed up to 7 years | 
| Metastasis-free survival | Will be compared by use of the log-rank test. The stratified log-rank test (nominal or categorical covariates) may be used to simultaneously control for important prognostic factors. Kaplan-Meier curves will also be plotted. | From randomization until metastasis documented by imaging procedures, assessed up to 7 years |