Erlotinib, Paclitaxel, and Carboplatin Combined With Radiation Therapy for Stage III Non-Small Cell Lung Cancer

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving erlotinib, paclitaxel, and carboplatin together with radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving these treatments after surgery may kill any tumor cells that remain after surgery. PURPOSE: This phase I/II trial is studying the best dose of erlotinib and the side effects of erlotinib, paclitaxel, and carboplatin when given together with radiation therapy and to see how well they work in treating patients who are undergoing surgery for stage III non-small cell lung cancer.

Detailed Description
-----------------
OBJECTIVES: Primary Assess the safety and feasibility of erlotinib hydrochloride, paclitaxel, and carboplatin in combination with accelerated hyperfractionated radiotherapy in patients with stage IIIA or IIIB non-small cell lung cancer. Determine the maximum tolerated dose and recommended phase II dose of erlotinib hydrochloride in these patients. Assess the safety and tolerability of long-term maintenance erlotinib hydrochloride after completion of adjuvant chemoradiotherapy in these patients. Secondary Evaluate the clinical and pathological response rate in these patients after neoadjuvant erlotinib hydrochloride, paclitaxel, carboplatin, and radiotherapy. Assess the impact of erlotinib hydrochloride on disease-free survival, overall survival, locoregional control, and distant metastatic control in these patients. OUTLINE: This is an open-label, phase I dose-escalation study of erlotinib hydrochloride followed by a non-randomized phase II study. Cohorts of 3-6 patients receive escalating doses of erlotinib hydrochloride until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Phase I: Neoadjuvant chemoradiotherapy: Patients receive oral erlotinib hydrochloride once daily on days 1-28 and paclitaxel IV over 1 hour and carboplatin IV over 30 minutes on days 1, 8, and 15 in the absence of disease progression or unacceptable toxicity. Patients concurrently undergo radiotherapy twice daily on days 1-5 and 8-12. Patients with complete response, partial response, or stable disease proceed to surgery. Patients who develop a medical contraindication to surgery (i.e., medically unresectable) receive a second course of erlotinib hydrochloride, paclitaxel, carboplatin, and radiotherapy as above within 2 weeks after completion of neoadjuvant chemoradiotherapy. Cohorts of 3-6 patients receive escalating doses of erlotinib hydrochloride until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Surgery: Within 4 weeks after completion of neoadjuvant chemoradiotherapy, patients undergo surgical resection and then proceed to adjuvant chemoradiotherapy. Adjuvant chemoradiotherapy: Within 6-8 weeks after surgery, patients receive a second course of erlotinib hydrochloride, paclitaxel, carboplatin, and radiotherapy as in neoadjuvant chemoradiotherapy. Maintenance therapy: All patients receive oral erlotinib hydrochloride once daily for 2 years in the absence of disease progression or unacceptable toxicity. Phase II: Patients receive treatment as in phase I with erlotinib hydrochloride at the MTD. After completion of study treatment, patients are followed periodically. PROJECTED ACCRUAL: A total of 42 patients will be accrued for this study.

Official Title
-----------------
A Phase I/II Trial of Neoadjuvant Paclitaxel, Carboplatin and OSI-774 (Tarceva) With Concurrent Accelerated Hyperfractionation Radiation Followed by Maintenance Therapy With OSI-774 for Stage III Non-Small Cell Lung Cancer

Conditions
-----------------
Lung Cancer

Intervention / Treatment
-----------------
* Drug: carboplatin
* Drug: Erlotinib
* Drug: paclitaxel
* Procedure: conventional surgery
* Radiation: radiation therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically or cytologically confirmed non-small cell lung cancer Surgically determined stage IIIA or IIIB disease Histology from an involved mediastinal or supraclavicular lymph nodes alone will be allowed if a separate distal primary lesion is clearly evident on radiographs Histological or cytological proof of mediastinal nodal involvement by mediastinoscopy, Chamberlain procedure, thoracoscopy, thoracotomy, or CT-guided biopsy is required except for cases of paralysis of left true vocal cord with separate left lung primary distinct from enlarged nodes > 1 cm in the anterior-posterior window seen on the CT scan Patients with N3 or T4 status must be evaluated and deemed potentially resectable after induction chemotherapy and radiation therapy Measurable and evaluable disease No malignant pleural effusion except for effusion visible only on CT scan and deemed too small to tap No pericardial effusion No small or mixed small cell/non-small cell lung cancer No massive lesions requiring radiation to the entire lung No metastatic cancer to the lungs PATIENT CHARACTERISTICS: ECOG performance status 0-1 WBC ≥ 3,000/mm^3 Platelet count > 100,000/mm^3 Serum creatinine ≤ 2.0 mg/dL Alkaline phosphatase, AST, and ALT < 2 times upper limit of normal Albumin > 3.0 g/dL Serum bilirubin < 1.5 mg/dL Adequate pulmonary function No clinical evidence of another uncontrolled malignancy No requirement for urgent therapy for severe local symptoms such as post-obstructive pneumonia PRIOR CONCURRENT THERAPY: No prior chemotherapy, radiation therapy, or immunotherapy for lung cancer No prior surgery to treat the cancer

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Level A<br>Erlotinib, Paclitaxel, and Carboplatin with Radiation Dose Level A: 50 mg OSI-774/50 mg/m2 Paclitaxel/2 AUC Carboplatin | Drug: carboplatin<br>* AUC2 weekly x 3 weeks<br>* Other names: Carbo;Drug: Erlotinib<br>* Daily<br>* Other names: Tarceva;Drug: paclitaxel<br>* 50mg/m2/weekly x 3 weeks<br>Procedure: conventional surgery<br>* conventional surgery<br>Radiation: radiation therapy<br>* 150 cGy bid<br>|
| Experimental: Dose Level B<br>Erlotinib, Paclitaxel, and Carboplatin with Radiation Dose Level B: 100 mg OSI-774/50 mg/m2 Paclitaxel/2 AUC Carboplatin | Drug: carboplatin<br>* AUC2 weekly x 3 weeks<br>* Other names: Carbo;Drug: Erlotinib<br>* Daily<br>* Other names: Tarceva;Drug: paclitaxel<br>* 50mg/m2/weekly x 3 weeks<br>Procedure: conventional surgery<br>* conventional surgery<br>Radiation: radiation therapy<br>* 150 cGy bid<br>|
| Experimental: Dose Level C<br>Erlotinib, Paclitaxel, and Carboplatin with Radiation Dose Level C: 150 mg OSI-774/50 mg/m2 Paclitaxel/2 AUC Carboplatin | Drug: carboplatin<br>* AUC2 weekly x 3 weeks<br>* Other names: Carbo;Drug: Erlotinib<br>* Daily<br>* Other names: Tarceva;Drug: paclitaxel<br>* 50mg/m2/weekly x 3 weeks<br>Procedure: conventional surgery<br>* conventional surgery<br>Radiation: radiation therapy<br>* 150 cGy bid<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose of Erlotinib Hydrochloride (Phase I) | The Phase I portion of this study is to determine the Maximum Tolerated Dose (MTD) of combining OSI-774 with the paclitaxel-carboplatin chemoradiation protocol and to assess the safety and feasiblity of this combination. | 2 weeks after surgery | 
| Tolerability of Long-term OSI-774 (Phase II) | Number of patients who experienced grade >/= 3 toxicities on maintanance erolotinib (OSI-774) | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological Complete Response Rate | Number of participants with an pathological complete response rate using the RECIST criteria. Complete response: Disappearance of all measurable and evaluable disease Partial response: A 30% or greater decline in the sum of the longest diameter of target lesions compared to the baseline measurement. Progressive disease: A 20% or greater increase in the sum of the longest diameter of the target lesions compared to the baseline. Stable disease: Disease that did not meet the criteria for a CR / PR or progressive disease. | 2 years | 
| Overall Survival | Percent of participants still alive from the date of study entry to the date of the corresponding event (recurrence of death) or the date of final follow-up. | 3 years | 
| Progression Free Survival (PFS) | Months from the date of study entry to the date of the corresponding event (recurrence of death) or the date of final follow-up | 3 years | 
| Locoregional Control | Estimated by the Kaplan-Meier method and summarized at various follow-up points as the number of patients remaining at risk, the event estimate, standard error, and median.From the date of study entry to the date of the corresponding event (recurrence of death) or the date of final follow-up, assessed up to 2 years | 2 years | 
| Distant Control | Estimated by the Kaplan-Meier method and summarized at various follow-up points as the number of patients remaining at risk, the event estimate, standard error, and median.From the date of study entry to the date of the corresponding event (recurrence of death) or the date of final follow-up, assessed up to 2 years | 2 years | 

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