S0342: Paclitaxel, Carboplatin, and Cetuximab in Treating Patients With Stage IIIB or Stage IV Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies such as cetuximab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Combining more than one chemotherapy drug with a monoclonal antibody may kill more tumor cells. It is not yet known whether cetuximab is more effective when given at the same time as chemotherapy or following chemotherapy. PURPOSE: This randomized phase II trial is studying how well giving cetuximab at the same time as combination chemotherapy works compared to giving cetuximab after combination chemotherapy in treating patients with stage IIIB or stage IV non-small cell lung cancer.

Detailed Description
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OBJECTIVES: Primary Compare overall survival of patients with selected stage IIIB or stage IV non-small cell lung cancer treated with concurrent vs sequential paclitaxel, carboplatin, and cetuximab. Secondary Compare response rates (confirmed and unconfirmed, complete and partial) in patients treated with these regimens. Compare the toxic effects of these regimens in these patients. Correlate epidermal growth factor receptor polymorphisms and downstream biomarkers with response to cetuximab in these patients. OUTLINE: This is a randomized, multicenter study. Patients are randomized to 1 of 2 treatment arms. Arm I (concurrent cetuximab): Patients receive cetuximab IV over 1 hour (over 2 hours on day 1 of course 1 only) on days 1, 8, and 15 and paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on day 8. Treatment repeats every 21 days for a total of 4 courses (12 weeks) in the absence of disease progression or unacceptable toxicity. Beginning on week 13, patients receive single-agent cetuximab IV over 1 hour once weekly in the absence of disease progression or unacceptable toxicity. Arm II (sequential cetuximab): Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for a total of 4 courses (12 weeks) in the absence of disease progression or unacceptable toxicity. Beginning on week 13, patients receive single-agent cetuximab IV over 1 hour (over 2 hours on week 13 only) once weekly in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 1 year and then every 6 months for 2 years. PROJECTED ACCRUAL: A total of 180 patients (90 per treatment arm) will be accrued for this study within 9 months.

Official Title
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Phase II Selection Design Trial Of Concurrent Chemotherapy + Cetuximab Vs. Chemotherapy Followed By Cetuximab In Advanced Non-Small Cell Lung Cancer (NSCLC)

Conditions
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Lung Cancer

Intervention / Treatment
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* Drug: cetuximab
* Drug: carboplatin
* Drug: paclitaxel


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed non-small cell lung cancer (NSCLC) of one of the following stages: Newly diagnosed selected stage IIIB disease (T4 lesion due to malignant pleural effusion, any N, M0) Newly diagnosed stage IV disease (any T, any N, M1) Recurrent stage IV disease after prior surgery or radiotherapy The following subtypes are eligible: Adenocarcinoma Squamous cell carcinoma Large cell carcinoma Unspecified Measurable disease by CT scan, MRI, x-ray, or physical exam Pleural effusions, ascites, or laboratory parameters are not acceptable as the only evidence of disease Not within prior radiotherapy field unless a new lesion is present Not within area of prior surgical resection No known brain metastases by CT scan or MRI PATIENT CHARACTERISTICS: Age 18 and over Performance status Zubrod 0-1 Life expectancy Not specified Hematopoietic Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Hemoglobin ≥ 9 mg/dL Hepatic Bilirubin ≤ 2 times upper limit of normal (ULN) SGOT or SGPT ≤ 2 times ULN Alkaline phosphatase ≤ 2 times ULN No known acute hepatitis Renal Creatinine ≤ ULN Creatinine clearance ≥ 50 mL/min Cardiovascular No significant cardiac disease No uncontrolled hypertension No unstable angina No congestive heart failure Other No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or adequately treated stage I or II cancer currently in complete remission No active or uncontrolled infection No sensory neuropathy ≥ grade 2 No known human anti-mouse antibodies Not pregnant or nursing Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy No prior biologic therapy for NSCLC No prior chimeric or murine monoclonal antibody therapy No prior cetuximab Chemotherapy No prior systemic chemotherapy for NSCLC Endocrine therapy Not specified Radiotherapy See Disease Characteristics At least 3 weeks since prior radiotherapy and recovered Surgery See Disease Characteristics At least 2 weeks since prior thoracic or major surgery and recovered Other No prior gefitinib or other investigational agents that target the epidermal growth factor receptor pathway

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br> | Drug: cetuximab<br>* Arm 1: 400 mg/m2 (Initial dose), 2 hour IV infusion on Day 1, Week 1 only. 250 mg/m2 (Subsequent doses), 1 hour IV infusion, on Day 1 weekly starting at Week 2. Arm 2: 400 mg/m2 (Initial dose), 2 hour IV infusion on Week 13 ONLY 250 mg/m2 (Subsequent doses), 1 hour IV infusion, weekly starting at Week 14.<br>Drug: carboplatin<br>* Arm 1: AUC=6 30 minute IV infusion immediately following paclitaxel on Day 1 q 21 days x 4 starting at Week 2 Arm 2: AUC=6 30 minute IV infusion immediately following paclitaxel on Day 1 q 21 days x 4 starting at Week 1<br>Drug: paclitaxel<br>* Arm 1: 225 mg/m2 3 hour IV infusion 1 hour following cetuximab on Day 1, q 21 days x 4 Starting at Week 4. Arm 2: 225 mg/m2 3 hour IV infusion 1 hour following cetuximab on Day 1, q 21 days x 4 Starting at Week 1.<br>|
| Active Comparator: 2<br> | Drug: cetuximab<br>* Arm 1: 400 mg/m2 (Initial dose), 2 hour IV infusion on Day 1, Week 1 only. 250 mg/m2 (Subsequent doses), 1 hour IV infusion, on Day 1 weekly starting at Week 2. Arm 2: 400 mg/m2 (Initial dose), 2 hour IV infusion on Week 13 ONLY 250 mg/m2 (Subsequent doses), 1 hour IV infusion, weekly starting at Week 14.<br>Drug: carboplatin<br>* Arm 1: AUC=6 30 minute IV infusion immediately following paclitaxel on Day 1 q 21 days x 4 starting at Week 2 Arm 2: AUC=6 30 minute IV infusion immediately following paclitaxel on Day 1 q 21 days x 4 starting at Week 1<br>Drug: paclitaxel<br>* Arm 1: 225 mg/m2 3 hour IV infusion 1 hour following cetuximab on Day 1, q 21 days x 4 Starting at Week 4. Arm 2: 225 mg/m2 3 hour IV infusion 1 hour following cetuximab on Day 1, q 21 days x 4 Starting at Week 1.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Select a regimen based on overall survival | To select a regimen based on overall survival via a Phase II selection design of chemotherapy in conjunction with cetuximab (concurrent vs. sequential) for Phase III testing against chemotherapy alone in Stage IIIB and Stage IV non-small cell lung cancer. | From date of registration until the date of progression or date of death from any cause, whichever came first, assessed up to 3 years | 
| Response rate (confirmed and unconfirmed, complete and partial response) | To evaluate response rates (confirmed and unconfirmed, complete and partial) of patients with selected Stage IIIB and Stage IV NSCLC treated with paclitaxel and carboplatin with concurrent cetuximab or paclitaxel and carboplatin followed by cetuximab. | From date of registration until the date of progression or date of death from any cause, whichever came first, assessed up to 3 years | 
| Toxicities | To evaluate the toxicities of the two treatment regimens in patients with selected Stage IIIB and Stage IV NSCLC. | From date of registration until the date of progression or date of death from any cause, whichever came first, assessed up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation of epidermal growth factor receptor polymorphisms and downstream biomarkers with response | To conduct exploratory molecular correlative studies of the EGFR-HER signaling pathways examining activated phosphoproteins, oncogenic mutations and rates of proliferation and apoptosis in patient tissues (see S9925 for details). | At prestudy | 
| Evaluate EGFR polymorphisms | To evaluate EGFR polymorphisms as a potential correlate for response to cetuximab (see S9925 for details). | At prestudy and week 5 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent non-small cell lung cancer, stage IIIB non-small cell lung cancer, stage IV non-small cell lung cancer, adenocarcinoma of the lung, squamous cell lung cancer, large cell lung cancer