Pemetrexed Disodium With or Without Sorafenib as Second-Line Therapy in Treating Patients With Stage IIIB or Stage IV Non-Small Cell Lung Cancer

OBJECTIVES:

Primary

- Compare the progression-free survival of patients with stage IIIB or IV non-small cell
lung cancer treated with pemetrexed disodium with or without sorafenib tosylate as
second-line therapy.

Secondary

- Compare the overall survival of patients treated with these regimens.

- Compare the tumor response rate and duration of response in patients treated with these
regimens.

- Compare the toxicity profile of these regimens in these patients.

Tertiary

- Assess polymorphisms and gene expression in circulating peripheral mononuclear cells
and circulating tumor cells of pemetrexed disodium target genes and genes encoding
enzymes involved in the transport, activation, and inactivation of pemetrexed disodium.

- Correlate haplotype-tagged single nucleotide polymorphisms or gene expression levels
with intracellular levels of pemetrexed disodium polyglutamates, toxicity, and/or
efficacy of pemetrexed disodium.

- Assess the expression and polymorphisms in the target genes (i.e., TS, DHFR, GARFT) and
methylthioadenosine phosphorylase (as antibodies become available) in paraffin-embedded
tissue and compare results to those obtained in circulating tumor tissue, correlating
results with response.

- Correlate predictive markers of hypertension (e.g. pharmacogenetics, vascular
endothelial growth factor [VEGF]-A, sVEGF receptor-1, and ADMA) with clinical toxicity
and outcomes.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to ECOG
performance status (0 vs 1) and North Central Cancer Treatment Group membership. Patients
are randomized to 1 of 2 treatment arms.

- Arm I: Patients receive oral sorafenib tosylate twice daily on days 1-21 and pemetrexed
disodium IV over 10 minutes on day 1.

- Arm II: Patients receive pemetrexed disodium IV over 10 minutes on day 1. In both arms,
courses repeat every 21 days in the absence of disease progression or unacceptable
toxicity.

Blood and tissue samples are collected for pharmacokinetic analysis and research studies.
Gene expression assays and polymorphism studies (e.g., using polymerase chain reaction) of
circulating peripheral blood mononuclear cells are conducted for reduced folate carrier,
multidrug resistance-associated protein, folate receptor, BCRP, folylpolyglutamate synthase,
MTHFR, methionine synthase, methylthioadenosine phosphorylase, TS, dihydrofolate reductase,
GARFT, endothelial nitric oxide synthase, angiotensinogen, dimethylarginine
dimethylaminohydrolase, vascular endothelial growth factor (VEGF), and VEGF receptor.
Enzyme-linked immunosorbent assays and immunohistochemistry are also conducted.

After completion of study treatment, patients are followed periodically for up to 5 years.

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