Negative sorafenib results from ESCAPE trial and safety concerns of regimen

Sorafenib has demonstrated in vivo anti-tumor efficacy. This trial will evaluate the safety and preliminary efficacy of sorafenib following chemoradiation in locally advanced NSCLC.

Outline: This is a multi-center study.

Chemotherapy/radiation therapy (2 cycles)

• Cisplatin 50 mg/m2 IV days 1 and 8 of 28 day cycle
• Etoposide 50 mg/m2 IV days 1-5 of 28 day cycle
• Concurrent chest radiation (planned dose is 5940 cGy with an additional, optional boost of 1080 cGy to a total allowed dose of 7020 cGy) with the following:

Maintenance therapy of Sorafenib 400 mg PO BID of 28 day cycle, to begin a minimum of 6 and maximum of 9 weeks from completion of chemo-radiotherapy until PD, intolerable toxicity, or up to 1 year.

Patients with progressive disease will discontinue treatment.

ECOG performance status 0 or 1

Hematopoietic:

• Absolute neutrophil count (ANC) ≥ 1500 mm3
• Platelet count ≥ 100,000 mm3
• Hemoglobin ≥ 9 g/dL
• PT or INR < 1.5 x ULN unless on anti-coagulant therapy
• PTT < 1.5 x ULN unless on anti-coagulant therapy

Hepatic:

• Bilirubin ≤ 1.5 x ULN
• ALT ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver involvement)
• AST ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver involvement)

Renal:

• Creatinine < 1.5 X upper limit of normal (ULN)

Cardiovascular:

• No significant history of cardiac disease: Congestive heart failure > class II NYHA.
• Patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within 90 days prior to registration for initial therapy) or myocardial infarction within 6 months prior to registration for initial therapy.

Respiratory:

• FEV1 ≥ 1 liter by spirometry within 60 days prior to registration for initial therapy.

Inclusion Criteria:

• Histological or cytological proof of non-small cell lung cancer (NSCLC).
• Measurable or non-measurable disease per RECIST.
• Unresectable Stage IIIA or IIIB disease as evaluated by imaging.
• Must be age ≥ 18 years at the time of consent.
• Written informed consent and HIPAA authorization for release of personal health information.
• Females of childbearing potential and males must be willing to use an effective method of contraception.
• Females of childbearing potential must have a negative pregnancy test within 7 days prior to being registered for initial therapy.

Exclusion Criteria:

• No prior chemotherapy or radiotherapy for lung cancer.
• No positive supraclavicular or scalene lymph nodes extending up into the cervical region.
• No superior sulcus (pancoast tumors).
• No malignant pleural effusions. The only exception is a patient with a pleural effusion visible only on CT scan (and not visible on CXR) OR deemed too small to tap.
• No clinically significant or malignant pericardial effusions.
• No CNS metastases.
• No unintended weight loss (> 5% body weight) in the preceding 90 days prior to registration for initial therapy.
• No treatment with any investigational agent within 30 days prior to being registered for initial therapy.
• No prior therapy with a Ras pathway inhibitor or anti-angiogenic agent.
• No other active cancers.
• Females must not be breastfeeding.
• No active clinically serious infections as judged by the treating investigator (> CTC v3, Grade 2) including known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C.
• No major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to registration for initial therapy.
• No anticipation of need for major surgical procedure during the course of the study.
• No minor surgical procedures such as fine needle aspirations or cone biopsies within 7 days prior to registration for initial therapy.
• No history of allergic reactions to drugs utilizing the vehicle polysorbate 80 + polyethylene glycol (etoposide).
• No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to registration for initial therapy.
• No use inhibitors or inducers of the cytochrome p450 system CYP3A4 enzyme or other medications such as aprepitant, ketoconazole, itraconazole, quinidine, digoxin, cyclosporine, ritonavir, grapefruit products, St. John's Wort, rifampin (rifampicin), carbamazepine, phenytoin, dexamethasone, and phenobarbital.
• No evidence or history of bleeding diathesis or coagulopathy.
• No serious non-healing wound, ulcer, or bone fracture.
• No known or suspected allergy to sorafenib.
• No uncontrolled hypertension defined as systolic blood pressure > 150 mm Hg or diastolic pressure > 90 mm Hg, despite optimal medical management.
• No thrombolic or embolic events such as a cerebrovascular accident including transient ischemic attacks within 6 months prior to registration for initial therapy.
• No pulmonary hemorrhage/bleeding event ≥ CTCAE Grade 2 within 4 weeks prior to registration for initial therapy.
• No hemorrhage/bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to registration for initial therapy.
• No condition that impairs patient's ability to swallow whole pills or any malabsorption problem.