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

Study Overview
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Brief Summary
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RATIONALE: Pemetrexed disodium and sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Sorafenib may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving pemetrexed disodium together with sorafenib may kill more tumor cells. PURPOSE: This randomized phase II trial is studying pemetrexed disodium and sorafenib to see how well they work compared with pemetrexed disodium alone as second-line therapy in treating patients with stage IIIB or stage IV non-small cell lung cancer.

Detailed Description
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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.

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

Conditions
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Lung Cancer

Intervention / Treatment
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* Drug: pemetrexed disodium
* Drug: sorafenib tosylate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive oral sorafenib tosylate twice daily on days 1-21 and pemetrexed disodium IV over 10 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: pemetrexed disodium<br>* given IV<br>Drug: sorafenib tosylate<br>* given orally<br>|
| Active Comparator: Arm II<br>Patients receive pemetrexed disodium IV over 10 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: pemetrexed disodium<br>* given IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | The progression-free survival (PFS) was defined as the time from date of randomization to the documentation of disease progression or death as a result of any cause, whichever comes first. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST), 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. | Time from randomization to the disease progression or death (up to 5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival was defined as the time from study enrollment (randomization) to the time of death from any cause or last follow-up. | Time from randomization to death or last follow-up (up to 5 years) | 
| Time to Treatment Failure | Time to treatment failure was defined as the time from date of randomization to the date at which the patient was removed from the treatment due to progression, toxicity, refusal or other medical problems. | Up to 5 years | 
| Duration of Response | Duration of response was defined as the time from the date at which the patient's earliest best objective status was first noted to be either a complete response (CR) or partial response (PR) to the earliest date progression was documented. Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria: Complete Response (CR): disappearance of all target lesions; Partial Response (PR) 30% decrease in sum of longest diameter of target lesions; | Up to 5 years | 
| Number of Participants With at Least One Grade 3 or Above Adverse Events Assessed by NCI CTCAE v4.0 | Adverse events were assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grading: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening, Grade 5=Death. The maximum grade for each type of adverse events were recorded for each patient. | Up to 3 years | 
| Confirmed Response Rate (Complete Response and Partial Response) as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) | A confirmed tumor response was defined as a complete response (CR) or partial response (PR) noted as the objective status on 2 consecutive evaluations at least 6 weeks apart. Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria: Complete Response (CR): disappearance of all target lesions; Partial Response (PR) 30% decrease in sum of longest diameter of target lesions; Progressive Disease (PD): 20% increase in sum of longest diameter of target lesions; Stable Disease (SD): small changes that do not meet above criteria. | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent non-small cell lung cancer, stage IIIB non-small cell lung cancer, stage IV non-small cell lung cancer, adenosquamous cell lung cancer, adenocarcinoma of the lung