S0429: Docetaxel, Cetuximab, and Radiation Therapy in Treating Patients With Stage III Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some find tumor cells and kill them or carry tumor-killing substances to them. Others interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving docetaxel and cetuximab together with radiation therapy may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of docetaxel when given together with cetuximab and radiation therapy in treating patients with stage III non-small cell lung cancer.

Detailed Description
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OBJECTIVES: Primary Test the feasibility and toxicity of combined cetuximab, weekly docetaxel, and concurrent radiotherapy in patients with poor-risk stage III non-small cell lung cancer (NSCLC). Secondary Evaluate response rates (confirmed and unconfirmed, complete and partial) as well as overall and progression-free survival. Correlate EGFR mutations, KRAS mutations, EGFR/HER2 gene copy number detected by FISH, and protein expression by immunohistochemistry of EGFR-HER signaling pathways, phosphorylation, proliferative markers, apoptotic markers, selected oncogene markers, and markers for angiogenesis in biopsied pre-treatment tumor tissues with response and survival outcomes. Explore possible associations between changes in plasma angiogenic factors (VEGF, IL-8, bFGF) and cytokine levels (IL-6, IL-1α, ICAM, TGF-β, and others) and the risk of treatment-related pneumonitis and esophagitis. OUTLINE: Patients are enrolled sequentially to 1 of 2 treatment groups. Cohort 1: Patients receive cetuximab IV over 1-2 hours on days 1, 8, 15, and 22. Cohort 2: Patients receive cetuximab as in group 1 followed by docetaxel IV over 15-30 minutes on days 8, 15, and 22 of course 1 and on days 1, 8, 15, and 22 of course 2. Initially, 27 patients will be enrolled in Cohort 1. Once all patients in Cohort 1 have discontinued treatment, if toxicity rates are acceptable per protocol specifications, an additional 27 patients will be enrolled to Cohort 2. Treatment in both cohorts repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. All patients also undergo radiotherapy once daily, 5 days a week, beginning on day 8 of course 1 and continuing through course 2 (approximately 7 weeks). Patients with no progressive disease then receive cetuximab alone once weekly. Treatment with cetuximab alone continues in the absence of disease progression for up to 2 years. After completion of study treatment, patients are followed periodically for up to 3 years. PROJECTED ACCRUAL: A total of 54 patients will be accrued for this study.

Official Title
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A Pilot (Phase I) Study of Weekly Docetaxel and Cetuximab Chemoradiation for Poor Risk Stage III Non-Small Cell Lung Cancer

Conditions
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Lung Cancer

Intervention / Treatment
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* Biological: cetuximab
* Drug: docetaxel
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically proven newly diagnosed single, primary, bronchogenic stage IIIA or selected stage IIIB (excluding malignant pleural effusion) non-small cell lung cancer (NSCLC) of one of the following cellular types: Adenocarcinoma Large cell carcinoma Squamous cell carcinoma Unspecified Histology or cytology from involved mediastinal or supraclavicular nodes will be sufficient for diagnosis if a separate primary lesion of the lung parenchyma is clearly evident on radiographs (i.e., a second biopsy will not be required) Underwent positron emission tomography (PET) scan within the past 42 days N2 or N3 mediastinal disease by PET scan OR enlarged nodes on CT scan determined to be N2 or N3 by biopsy Measurable disease, defined as lesions that can be accurately measured in at least one dimension as ≥ 2 cm by conventional techniques or ≥ 1 cm by spiral CT scan Pleural effusion, ascites, bone lesions, and laboratory parameters are not considered measurable disease No brain metastases Malignant pleural effusion allowed provided 1 of the following is true: Present before mediastinoscopy or exploratory thoracotomy AND the pleural fluid is transudate with negative cytology Present only after but not before exploratory or staging thoracotomy AND the pleural fluid is either transudate or exudate with negative cytology Present only on CT scan but not on decubitus chest x-ray AND deemed too small to tap under either CT scan or ultrasound guidance PATIENT CHARACTERISTICS: Zubrod performance status 0-1, meeting ≥ 1 of the following criteria OR Zubrod performance status 2 with no co-morbidities or meeting 1 of the following criteria: No co-morbidities FEV_1 < 2 L OR < 1 L with estimated contralateral FEV_1 ≥ 0.6 L DLCO > 10 mL/mm Hg/min Albumin < 0.85 times lower limit of normal Unintentional weight loss > 10% within the past 6 months Controlled congestive heart failure which, in the opinion of the investigator, may become decompensated due to radiotherapy FEV_1 < 2 L OR < 1 L with estimated contralateral FEV_1 ≥ 0.6 L Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Serum creatinine ≤ 1.5 times upper limit of normal (ULN) Must provide prior smoking history Serum bilirubin normal Meets one of the following criteria: Alkaline phosphatase (AP) ≤ 4 times ULN AND SGOT or SGPT normal AP normal AND SGOT or SGPT ≤ 2.5 times ULN No other prior malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or adequately treated stage I or II cancer from which the patient is currently in complete remission No pregnant or nursing patients Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: No prior chemotherapy or curative surgery for this cancer No prior radiotherapy to the neck and/or thorax for any reason No prior therapy which specifically targets the EGFR pathway No concurrent growth factors (e.g., filgrastim [G-CSF], epoetin alfa, or pegfilgrastim) or amifostine No concurrent intensity-modulated radiotherapy No concurrent prophylactic mediastinal, contralateral hilar, or supraclavicular lymph node 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cetuximab + Radiotherapy (no Docetaxel)<br> | Biological: cetuximab<br>* Cohorts 1 and 2: 400 mg/m2 (initial dose) 2 hour IV infusion on Day 1, Cycle 1 only. 250 mg/m2, 1 hour IV infusion on Days 8 , 15 and 22 during Cycle 1. 250 mg/m2 (subsequent doses), 1 hour IV infusion on Days 1, 8 , 15 and 22 during subsequent cycles.<br>Radiation: radiation therapy<br>* Radiation therapy should begin on Day 8 of Cycle 1 and continue through the end of Cycle 2. Refer to Section 12.1 for Radiation Therapy Review. RT prescription should be PTV (GTV + 2-cm margins on CT scan) to 6,480 cGy in 36 fractions given 5 days a week, 180 cGy per day. The dose is prescribed to the isocenter. The entire treatment should be planned prior to starting treatment to ensure that the plan meets protocol specifications.<br>|
| Experimental: Cetuximab + Radiotherapy + Docetaxel<br> | Biological: cetuximab<br>* Cohorts 1 and 2: 400 mg/m2 (initial dose) 2 hour IV infusion on Day 1, Cycle 1 only. 250 mg/m2, 1 hour IV infusion on Days 8 , 15 and 22 during Cycle 1. 250 mg/m2 (subsequent doses), 1 hour IV infusion on Days 1, 8 , 15 and 22 during subsequent cycles.<br>Drug: docetaxel<br>* Cohort 2 ONLY: 20 mg/m2 IV over 15 - 30 minutes on Days 8, 15 and 22 of Cycle 1. Concurrent with RT and cetuximab starting at Week 2. 20 mg/m2 IV over 15 - 30 minutes on Days 1, 8, 15 and 22 of Cycle 2.<br>Radiation: radiation therapy<br>* Radiation therapy should begin on Day 8 of Cycle 1 and continue through the end of Cycle 2. Refer to Section 12.1 for Radiation Therapy Review. RT prescription should be PTV (GTV + 2-cm margins on CT scan) to 6,480 cGy in 36 fractions given 5 days a week, 180 cGy per day. The dose is prescribed to the isocenter. The entire treatment should be planned prior to starting treatment to ensure that the plan meets protocol specifications.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-related Esophagitis or Pneumonitis | The primary endpoint will be the rate of Grade 3 or greater esophagitis and/or pneumonitis within 4 months after discontinuation of radiation therapy. | Weekly for the first 8 weeks, then every 4 weeks thereafter for up to 4 months after complettion of radiotherapy. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity | Only adverse events that are possibly, probably or definitely related to study drug are reported. | Weekly for the first 8 weeks, then every 4 weeks while subject on protocol treatment. | 
| Overall Survival | The duration form the date of enrollment until the date of death due to any cause. Patients last known to be alive are censored at the date of last contact. | weekly while patient is on protocol treatment, then monthly thereafter. | 
| Progression-free Survival. | Duration from the date of enrollment until the date of progression (as defined by RECIST: >= 20% increase over baseline in the sum of longest diameters, or appearance of new lesions, or non-measurable disease that is clearly worsening in the opinion of the treating investigator, or symptomatic deterioration) or death due to any cause. Patients last known to be alive and free of disease progression are censored at the date of last contact. | At week 10, week 22, and then every 3 months until progression for up to 3 years after enrollment. | 
| Response Rate | Confirmed and unconfirmed complete and partial responses in the subset of patients with measurable disease (as defined per RECIST). A confirmed complete response (CR) is defined as disappearance of all disease, confirmed by a second determination of CR at least 4 weeks later. A confirmed partial response (PR) is defined as a >= 30% decrease from baseline in the sum of longest diameters, confirmed by a second determination of PR at least 4 weeks later. A patient is considered to have measurable disease if they have at least one lesion with a longest diameter of >= 2 cm by conventional CT, or >= 1 cm by spiral CT. | Week 10 and week 22 | 

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