Combination Chemotherapy, Bev, RT, and Erlotinib in Treating Patients With Stage III Non-Small Cell Lung Cancer

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy, such as carboplatin and paclitaxel, 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 bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of non-small cell lung cancer by blocking blood flow to the tumor. Radiation therapy uses high energy x-rays to kill tumor cells. Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving combination chemotherapy together with bevacizumab, radiation therapy, and erlotinib may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of bevacizumab and erlotinib when given together with combination chemotherapy and radiation therapy and to see how well they work in treating patients with stage III non-small cell lung cancer.

Detailed Description
-----------------
OBJECTIVES: Primary Determine the maximum tolerated dose of bevacizumab and erlotinib hydrochloride when given together with carboplatin, paclitaxel, and thoracic conformal radiotherapy in patients with stage IIIA or IIIB non-small cell lung cancer. (Phase I [closed to accrual as of 1/3/2008]) Determine the safety and toxicity profile of this regimen in these patients. (Phase I [closed to accrual as of 1/3/2008]) Determine the progression-free survival of patients treated with induction therapy comprising carboplatin, paclitaxel, and bevacizumab followed by chemoradiotherapy comprising thoracic conformal radiotherapy, carboplatin, paclitaxel, bevacizumab, and erlotinib hydrochloride and consolidation therapy comprising bevacizumab and erlotinib hydrochloride. (Phase II) Determine the overall toxicity profile of this regimen in these patients. (Phase II) Secondary Determine the response rate in patients treated with induction therapy comprising carboplatin, paclitaxel, and bevacizumab. (Phase I[closed to accrual as of 1/3/2008] and II) Determine the toxicity profile of induction therapy in these patients. (Phase I [closed to accrual as of 1/3/2008] and II) Determine the overall response rate and survival profile in patients treated with this regimen. (Phase I [closed to accrual as of 1/3/2008] and II) Determine the feasibility and tolerability of administering consolidation therapy comprising erlotinib hydrochloride and bevacizumab after treatment with combined modality therapy (induction therapy and chemoradiotherapy) in these patients. (Phase I [closed to accrual as of 1/3/2008] and II) Collect tumor and blood samples from these patients for future analysis of correlation between molecular markers and clinical benefit. (Phase I [closed to accrual as of 1/3/2008] and II) OUTLINE: This is a nonrandomized, open-label, controlled, phase I (closed to accrual as of 1/3/2008), dose-escalation study of bevacizumab and erlotinib hydrochloride, followed by a phase II study. Phase I (closed to accrual as of 1/3/2008): Induction therapy: Patients receive paclitaxel IV over 3 hours, carboplatin IV over 15-30 minutes, and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 2 courses. Patients with stable or responding disease proceed to chemoradiotherapy. Chemoradiotherapy: Patients receive chemoradiotherapy according to their assigned dose cohort: Cohort 1: Patients undergo thoracic conformal radiotherapy (TCRT) on days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40, and 43-47. Patients also receive carboplatin IV and paclitaxel IV on days 1, 8, 15, 22, 29, 36, and 43 and bevacizumab IV over 30-90 minutes on days 1, 15, 29, and 43. Cohort 2: Patients undergo TCRT and receive carboplatin, paclitaxel, and bevacizumab as in cohort 1. Patients also receive oral erlotinib hydrochloride on days 2-5, 9-12, 16-19, 23-26, 30-33, 37-40, and 44-47. Cohort 3: Patients undergo TCRT and receive carboplatin, paclitaxel, and bevacizumab as in cohort 1. Patients also receive higher doses of oral erlotinib hydrochloride on days 2-5, 9-12, 16-19, 23-26, 30-33, 37-40, and 44-47. Cohorts of 5 patients receive chemoradiotherapy as described above until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 (with grade 4 toxicity) or 3 (with grade 3 toxicity) of 5 patients experience dose-limiting toxicity. Three to 6 weeks after completion of chemoradiotherapy, patients proceed to consolidation therapy. Consolidation therapy: Patients receive bevacizumab IV on day 1 and oral erlotinib hydrochloride on days 1-21. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Phase II: Induction therapy: Patients receive induction therapy as in phase I (closed to accrual as of 1/3/2008). Chemoradiotherapy: Patients undergo TCRT and receive carboplatin and paclitaxel as in phase I (closed to accrual as of 1/3/2008). Patients also receive bevacizumab and erlotinib hydrochloride as in phase I (closed to accrual as of 1/3/2008) at the MTD/drug combination determined in phase I (closed to accrual as of 1/3/2008). Consolidation therapy: Patients receive consolidation therapy as in phase I (closed to accrual as of 1/3/2008). Tumor tissue and peripheral blood is collected at baseline for future correlative and biomarker studies. After completion of study therapy, patients are followed every 2 months for 2 years, every 4 months for 2 years, every 6 months for 2 years, and then annually thereafter.

Official Title
-----------------
Phase I/II Trial of Induction Carboplatin/Paclitaxel With Bevacizumab Followed by Concurrent Thoracic Conformal Radiation Therapy With Carboplatin/Paclitaxel, Bevacizumab and Erlotinib in Stage IIIA/B Non-Small Cell Lung Cancer

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

Intervention / Treatment
-----------------
* Biological: bevacizumab
* Drug: carboplatin
* Drug: erlotinib hydrochloride
* Drug: paclitaxel
* Radiation: 3-dimensional conformal radiation therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Diagnosis of non-small cell lung cancer Stage IIIA or IIIB disease No malignant pleural or pericardial effusions No palpable supraclavicular adenopathy Squamous cell histology allowed provided there is no hemoptysis and no central invasive lesions that abut or invade major blood vessels in the chest (with or without cavitation) Considered suitable and appropriate for combined modality therapy and thoracic conformal radiotherapy, as determined by the treating medical and radiation oncologist PATIENT CHARACTERISTICS: Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Hemoglobin ≥ 9.0 mg/dL Platelet count ≥ 100,000/mm³ Absolute neutrophil count (ANC) ≥ 1,500/mm³ Forced expiratory volume 1 (FEV_1) ≥ 1 L Creatinine ≤ 1.5 times upper limit of normal (ULN) Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≤ 2.5 times ULN Bilirubin normal Partial thromboplastin time (PTT) and international normalized ratio (INR) normal Urine protein:creatinine ratio < 1.0 Blood pressure ≤ 150/100 mm Hg on 3 separate occasions Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No significant recent hemoptysis (> ½ teaspoon of bright red blood) No unstable angina No New York Heart Association (NYHA) congestive heart failure ≥ class II No myocardial infarction or stroke within the past 6 months No clinically significant peripheral vascular disease No evidence of bleeding diathesis or coagulopathy No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months No serious, non-healing wound, ulcer, or bone fracture No thrombosis requiring therapeutic anticoagulation No significant traumatic injury within the last 28 days PRIOR CONCURRENT THERAPY: Recovered from prior surgery At least 4 weeks since prior and no concurrent participation in another experimental drug study At least 4 weeks since prior and no concurrent major surgical procedure or open biopsy At least 2 weeks since prior mediastinoscopy or mediastinotomy At least 1 week since prior fine needle aspirations or core biopsies No other concurrent antineoplastic or antitumor agents, including chemotherapy, radiotherapy, immunotherapy, or hormonal anticancer therapy No other concurrent investigational agents

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 120 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Bevacizumab 10 mg + Chemoradiotherapy (carboplatin, paclitaxel, and 3-dimensional conformal radiation therapy) | Biological: bevacizumab<br>* Given IV<br>Drug: carboplatin<br>* Given IV<br>Drug: paclitaxel<br>* Given IV<br>Radiation: 3-dimensional conformal radiation therapy<br>* Given 5 days a week for 7 weeks<br>|
| Experimental: Cohort 2<br>Bevacizumab 10 mg + Erlotinib 100 mg + Chemoradiotherapy (carboplatin, paclitaxel, and 3-dimensional conformal radiation therapy) | Biological: bevacizumab<br>* Given IV<br>Drug: carboplatin<br>* Given IV<br>Drug: erlotinib hydrochloride<br>* Given orally<br>Drug: paclitaxel<br>* Given IV<br>Radiation: 3-dimensional conformal radiation therapy<br>* Given 5 days a week for 7 weeks<br>|
| Experimental: Cohort 3<br>Bevacizumab + Erlotinib 150 mg + Chemoradiotherapy (carboplatin, paclitaxel, and 3-dimensional conformal radiation therapy) | Biological: bevacizumab<br>* Given IV<br>Drug: carboplatin<br>* Given IV<br>Drug: erlotinib hydrochloride<br>* Given orally<br>Drug: paclitaxel<br>* Given IV<br>Radiation: 3-dimensional conformal radiation therapy<br>* Given 5 days a week for 7 weeks<br>|
| Experimental: Phase II<br>Bevacizumab + Erlotinib 100 mg + Chemoradiotherapy (carboplatin, paclitaxel, and 3-dimensional conformal radiation therapy) | Biological: bevacizumab<br>* Given IV<br>Drug: carboplatin<br>* Given IV<br>Drug: erlotinib hydrochloride<br>* Given orally<br>Drug: paclitaxel<br>* Given IV<br>Radiation: 3-dimensional conformal radiation therapy<br>* Given 5 days a week for 7 weeks<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Dose of Erlotinib When Given Together With Carboplatin, Paclitaxel, and Thoracic Conformal Radiotherapy (Phase I [Closed to Accrual as of 1/3/2008]) | Dose-limiting toxicities (DLTs) were used to establish which cohort would be used for the phase II portion of the trial. DLTs were defined as any grade 3 or 4 nonhematologic toxicity with the exception of esophagitis, which had to be grade 4; grade 4 neutropenia lasting greater than or equal to 7 days and thrombocytopenia to less than 20,000/microliter. | 6 weeks after completion of therapy | 
| Safety and Toxicity Profile of Combining Both Bevacizumab and Erlotinib Hydrochloride With Carboplatin, Paclitaxel, and Thoracic Conformal Radiotherapy | A list of Hematologic and nonhematologic toxicities associated with induction and concurrent therapy. This includes the percentage of patients who experienced grades 2-4 based on the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0). | 6 weeks after completion of therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | The length of time during and after the treatment of a stage IIIA/B NSCLC that a patient lives with the disease but it does not get worse. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | 5 years | 
| Response Rate to Induction Therapy (Phase I [Closed to Accrual as of 1/3/2008] and II) | Measurable lesions must be accurately measured in at least one dimension (longest diameter to be recorded) as > 20 mm with conventional techniques or as > 10mm with spiral CT scan or nonmeasurable, but evaluable. Evaluable is nonmeasurable disease that includes ascites, malignant pleural/pericardial effusion, bone lesions, or marrow involvement. The same method of assessment and the same techniques should be used to characterize each identified and reported lesion at baseline and during follow-up. Complete Response (CR)- Disappearance of all target lesions | 5 years | 
| Overall Response Rate and Survival Profile | The overall response rate (ORR) to the two cycles of induction therapy plus bevacizumab in stage IIIA/B NSCLC. ORR is the portion of patients with a tumor size reduction for a minimum time period. Response duration is measured from the time of initial response until documented tumor progression. | 5 years | 
| Feasibility and Tolerability of Administering Consolidation Therapy | The proportion of patients who were able to complete consolidation therapy after induction therapy and chemoradiotherapy | 6 cycles | 

 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, recurrent non-small cell lung cancer, squamous cell lung cancer