Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Objectives

Primary

1. 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

1. Compare the overall survival of patients treated with these regimens.
2. Compare the tumor response rate and duration of response in patients treated with these regimens.
3. Compare the toxicity profile of these regimens in these patients.

Tertiary

1. 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.
2. Correlate haplotype-tagged single nucleotide polymorphisms or gene expression levels with intracellular levels of pemetrexed disodium polyglutamates, toxicity, and/or efficacy of pemetrexed disodium.
3. 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.
4. Correlate predictive markers of hypertension (e.g. pharmacogenetics, vascular endothelial growth factor [VEGF]-A, sVEGF receptor-1, and ADMA) with clinical toxicity and outcomes.

Entry 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

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

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

Expected Enrollment

A total of 104 patients will be accrued for this study.

Outcomes

Progression-free survival

Time to disease progression
Overall survival
Toxicity
Time to treatment failure
Duration of response
Correlation of polymorphisms (including SNPs) of pemetrexed disodium target genes (TS, DHFR, GARFT), vascular endothelial growth factor (VEGF)-A, and sVEGF receptor-1 with toxicity, confirmed response, overall survival, and time to progression
Correlation of level and ratios of pemetrexed disodium target genes (TS, DHFR, GARFT), VEGF-A, and sVEGFR-1 with toxicity, confirmed response, overall survival, and time to progression

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.

Trial Contact Information

Trial Lead Organizations

North Central Cancer Treatment Group

Alex Adjei, MD, PhD, Protocol chair		Ph: 507-538-0268; 800-685-6825 Email: alex.adjei@roswellpark.org
Grace Dy, MD, Protocol co-chair		Ph: 507-538-7623 Email: cancerclinicals@mayo.edu

Registry Information
Official Title		Phase II Randomized Study of Pemetrexed With Sorafenib Versus Pemetrexed Alone as Second-Line Therapy in Patients With Advanced Non-Small Cell Lung Cancer
Trial Start Date		2007-09-07
Trial Completion Date		2008-07-14 (estimated)
Registered in ClinicalTrials.gov		NCT00454194
Date Submitted to PDQ		2007-02-12
Information Last Verified		2010-04-09
NCI Grant/Contract Number		CA25224

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