Phase II Randomized Study of Pemetrexed With Sorafenib Versus Pemetrexed Alone as Second-Line Therapy in Patients With Advanced Non-Small Cell Lung Cancer

Inclusion Criteria

DISEASE CHARACTERISTICS:

- Histologically or cytologically confirmed non-squamous cell non-small cell lung
cancer (NSCLC)

- Stage IIIB or IV disease

- Squamous cell carcinomas are not allowed

- Adenosquamous histology allowed

- Measurable disease, defined as ≥ 1 lesion with longest diameter ≥ 2.0 cm by
conventional techniques or ≥ 1.0 cm by spiral CT scan

- No nonmeasurable disease only, including small lesions and truly nonmeasurable
lesions, including any of the following:

- Bone lesions

- Leptomeningeal disease

- Ascites

- Pleural/pericardial effusion

- Inflammatory breast disease

- Lymphangitis cutis/pulmonis

- Abdominal masses that are not confirmed and followed by imaging techniques

- Cystic lesions

- Previously treated with 1 chemotherapy regimen, including adjuvant treatment

- Prior treatment with adjuvant chemotherapy is allowed and not counted as a
regimen

- Symptomatic pleural effusions should be drained prior to study entry

- No symptomatic serosal effusion (≥ CTCAE v3.0 grade 2 dyspnea) that is not
amenable to drainage prior to study entry

- Stable brain metastasis allowed provided the following criteria are met:

- Treated with either whole brain radiotherapy or gamma knife surgery

- More than 4 weeks since prior steroids

PATIENT CHARACTERISTICS:

- ECOG performance status 0-1

- Life expectancy ≥ 12 weeks

- Absolute neutrophil count ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- Hemoglobin ≥ 9 g/dL

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN) OR direct bilirubin normal

- Creatinine clearance ≥ 45 mL/min

- AST and ALT ≤ 3 times ULN (5 times ULN if liver has tumor involvement)

- INR < 1.5 OR PT/PTT normal

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 2 weeks after
completion of study treatment

- Able to take folic acid, cyanocobalamin, and dexamethasone

- No clinically significant infection

- No known HIV positivity

- No evidence or history of bleeding diathesis or coagulopathy

- No serious nonhealing wound, ulcer, or bone fracture

- No significant traumatic injury within the past 4 weeks

- No bleeding ≥ grade 2 (except grade 2 petechiae) within the past 4 weeks

- No second primary malignancy except carcinoma in situ of the cervix or
nonmelanomatous skin cancer, unless malignancy was diagnosed and definitively treated
≥ 5 years ago with no subsequent evidence of recurrence

- History of low-grade (Gleason score ≤ 6) localized prostate cancer allowed

- Patients with a history of DCIS that has been definitively treated will be
eligible even if diagnosed < 5 years prior to registration

- No other severe underlying disease or condition that, in the opinion of the
investigator, would preclude study compliance or increase risk for serious adverse
events

- Able to swallow pills

- No concurrent severe and/or uncontrolled medical conditions, including any of the
following:

- Uncontrolled blood pressure, defined as systolic blood pressure (BP) > 150 mm Hg
and/or diastolic BP > 100 mm Hg, in spite of adequate antihypertensive therapy

- Angina pectoris

- Congestive heart failure within the past 3 months, unless LVEF > 40%

- Myocardial infarction within the past 6 months

- Cardiac arrhythmia

- Diabetes mellitus

- Active hemoptysis

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- Recovered from all prior therapy, except for alopecia

- No prior sorafenib tosylate or pemetrexed disodium

- No prior therapy with agents that target VEGF, VEGF receptor, or VEGF receptor
tyrosine kinase inhibitor (prior bevacizumab is allowed)

- Prior radiotherapy allowed if all the following criteria are met:

- No more than 25% of bone marrow was irradiated

- Measurable disease, whether there is in-field disease progression/recurrence or
disease outside the treatment fields of radiation port, is present

- No acetylsalicylic acid dose of ≥ 1.3 grams/day for ≥ 10 days before and after
completion of study treatment

- At least 4 weeks since prior full-field radiotherapy

- At least 2 weeks since prior limited-field radiotherapy

- At least 4 weeks since prior major surgery (i.e., laparotomy) or open biopsy

- At least 2 weeks since prior minor surgery

- At least 3 weeks since prior chemotherapy (6 weeks for mitomycin C and nitrosoureas)

- At least 2 weeks since prior immunotherapy, biologic therapy, or gene therapy

- At least 4 weeks prior hormonal therapy

- At least 4 weeks since other prior investigational agents

- No concurrent antiretroviral therapy

- No concurrent major surgery

- No concurrent steroids

- No concurrent therapeutic anticoagulation

- Concurrent prophylactic anticoagulation (i.e., low-dose warfarin) of venous or
arterial access devices allowed provided requirements for PT, INR, or PTT are
met

- No concurrent Hypericum perforatum (St. John's wort)

- No concurrent grapefruit or grapefruit juice

- No concurrent prophylactic use of colony-stimulating factors

- No other concurrent anticancer agents or therapies