Proton Beam Radiation With Concurrent Chemotherapy and Nelfinavir for Inoperable Stage III Non Small Cell Lung Cancer (NSCLC)

Study Overview
=================
Brief Summary
-----------------
Seventy two patients are being asked to take part in this research study because they have been diagnosed with Stage IIIA or IIIB non-small cell lung cancer (NSCLC). This study is being done to determine the highest safe dose of proton beam radiotherapy and/or study drug (called Nelfinavir) that can be given with concurrent chemoradiotherapy to patients with cancer without causing bad side effects; and to develop biomarker for clinical outcome. This study will be done in two phases. In the first phase, feasibility will be established. We will follow patients treatment courses and record side effects at the standard proton radiation dose that can be given together with Cisplatinum + Etoposide or Carboplatin + Paclitaxel. In the second phase, we will see if it is possible to increase the total proton radiation dose or study drug without increasing the number of bad side effects while treated together with chemotherapy drugs.

Detailed Description
-----------------
Overall objectives: Determine MTD of proton beam radiotherapy with concurrent cisplatin and etoposide for stage III NSCLC. Determine MTD of proton beam radiotherapy with concurrent carboplatin and paclitaxel for stage III NSCLC in non-cisplatin candidates. Determine MTD of Nelfinavir with concurrent chemoradiotherapy for stage III NSCLC at RPTD of proton beam radiotherapy. Develop biomarker for clinical outcome with concurrent chemoradiotherapy in stage III NSCLC. To determine clinical efficacy, as defined by metabolic response, sites of recurrence (e.g., local, regional, distant) and progression-free and overall survival.

Official Title
-----------------
Phase I Dose Escalation Trial of Proton Beam Radiotherapy With Concurrent Chemotherapy and Nelfinavir for Inoperable Stage III NSCLC

Conditions
-----------------
Non Small Cell Lung Cancer

Intervention / Treatment
-----------------
* Drug: Nelfinavir


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed diagnosis of NSCLC. Stage IIIA or IIIB NSCLC. Patients must have no evidence of metastatic disease based on routine imaging. Patients must have a Karnofsky Performance Status of 60. Age 18 and older. Patients must be able to provide informed consent. Adequate bone marrow function (i.e. WBC larger than or equal to 4000/mm3, platelets larger than or equal to 100,000 mm3). Adequate renal function for cisplatin or carboplatin as determined by the medical oncologist: Usually Calculated creatinine clearance (CrCl) larger than or equal to 45 mL/min or serum creatinine level smaller than or equal to1.5 x institutional ULN. Patients must have bilirubin 1.5 mg/dl. Women of child-bearing potential as long as she agrees to use a recognized method of birth control (e.g. oral contraceptive, IUD, condoms or other barrier methods etc). Hysterectomy or menopause must be clinically documented. Exclusion Criteria: Prior or simultaneous malignancies within the past two years (other than cutaneous squamous or basal cell carcinoma or melanoma in situ). Pregnant women, women planning to become pregnant and women that are nursing. Actively being treated on any other research study. For the Nelfinavir phase of the trial only: Patients who are taking Antiarrhythmics (amiodarone, quinidine), Antimycobacterial (rifampin), Ergot Derivatives (dihydroergotamine, ergonovine, ergotamine, ethylergonovine), Herbal Products (St. John's wort/ hypericum perforatum), HMG-CoA Reductase Inhibitors (lovastatin, simvastatin), Neuroleptic (pimozide), Proton Pump Inhibitors, or Sedative/ Hypnotics (midazolam, triazolam). Note: Patients with the following conditions are deemed unsuitable for cisplatin-based chemotherapy (and will be treated with carboplatin): (a) Hearing impairment/ peripheral neuropathy Grade 1 or less at baseline (b) Symptomatic/uncontrolled congestive heart failure (unable to tolerate volume load with pre- and post-cisplatin hydration)

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Proton RT and Nelfinavir<br> | Drug: Nelfinavir<br>* Two dose levels of Nelfinavir will be evaluated in each concurrent chemotherapy group (carboplatin/paclitaxel and cisplatin/etoposide) at the RPTD does of proton beam radiotherapy: 625 and 1250 mg PO bid.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of Proton Radiation | Ability to successfully plan proton plans | 10 days | 
| Acute Toxicity (or Dose Limiting Toxicity) | Dose limiting toxicities of grade 3 or higher per CTCAE 4.0 | 14 days | 
| Late Toxicity | Late toxicities graded according to the RTOG/EORTC late morbidity scale | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Efficacy | Defined as metabolic response (complete, partial or less than partial) based on PET/CT imaging. Patients are followed for disease recurrence and site (local, regional, distant). Progression-free and overall survival are defined as from start of treatment to first documented recurrence (for PFS), date of death or last patient contact alive. | One year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Stage IIIA or IIIB NSCLC