• Response rate (complete and partial) [ Designated as safety issue: No ]
  

• Progression-free survival [ Designated as safety issue: No ]
  
• Overall survival [ Designated as safety issue: No ]
  

OBJECTIVES:

Primary

• Evaluate the response rate in patients with relapsed non-small cell lung cancer treated with AZD2171 and pemetrexed disodium.

Secondary

• Assess the progression-free and overall survival of patients treated with this regimen.

OUTLINE: This is a multicenter study. Patients are stratified according to prior bevacizumab treatment (yes vs no).

Patients receive oral AZD2171 once daily on days 1-28 in course 1 and on days 1-21 in course 2 and all subsequent courses. Patients also receive pemetrexed disodium IV over 10 minutes on day 8 in course 1 and on day 1 in course 2 and all subsequent courses. Treatment repeats every 3 weeks* in the absence of disease progression or unacceptable toxicity.

NOTE: * The first course is 4 weeks in duration; all subsequent courses are 3 weeks in duration.

After completion of study treatment, patients are followed at 4 weeks and then periodically thereafter.

PROJECTED ACCRUAL: A total of 74 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed non-small cell lung cancer

• Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan

  • Lesions in a previously irradiated area are considered measurable provided there has been an increase of ≥ 10 mm since completion of radiotherapy

• Relapsed disease

  • Received 1-2 prior regimens*, including 1 doublet chemotherapy regimen, AND meets 1 of the following criteria:

    • No prior bevacizumab (cohort A)

      • Patients with squamous cell carcinoma, treated and controlled brain metastases, or history of hemoptysis allowed

    • Previously treated with bevacizumab (cohort B)

      • No discontinuation of bevacizumab for uncontrollable hypertension and/or life-threatening bleeding
      • Must have disease progression after prior bevacizumab NOTE: *Prior adjuvant therapy is considered 1 regimen if disease progression occurred within 1 year of completion of therapy; if a regimen was discontinued within 2 courses for allergic reaction or unacceptable drug-specific toxicity, that regimen dose not count
• No large pleural effusion or ascites unless drained

• No active brain metastases by brain MRI or CT scan within the past 4 weeks

  • Patients with treated, controlled brain metastasis allowed provided they are neurologically stable without seizures within the past 3 weeks

PATIENT CHARACTERISTICS:

• ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
• Life expectancy > 12 weeks
• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• WBC ≥ 3,000/mm^3
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST and ALT ≤ 2.5 times ULN (< 5 times ULN if liver metastases present)
• Creatinine normal OR creatinine clearance ≥ 60 mL/min
• Urine protein ≤ 1+ on 2 consecutive dipsticks taken ≥ 1 week apart
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No significant hemorrhage (i.e., > 30 mL in 1 episode) within the past 3 months
• No significant hemoptysis (i.e., > 5 mL fresh blood in 1 episode) within the past 4 weeks
• No active gastrointestinal disease that may affect the ability of the patient to absorb AZD2171
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD2171 or pemetrexed disodium
• No other malignancies within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ

• No uncontrolled intercurrent illness including, but not limited to, any of the following:

  • Ongoing or active infection
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Psychiatric illness or social situation that would preclude study compliance
• No New York Heart Association class III or IV heart disease
• Mean QTc < 470 msec by ECG
• No history of familial long QT syndrome

• No resting blood pressure (BP) consistently > 140/90 mm Hg

  • Patients whose BP is controlled after starting, adjusting, or increasing medication allowed

• LVEF normal by MUGA or echocardiogram for patients at increased risk for left ventricular dysfunction, as evidenced by any of the following:

  • Prior treatment with anthracyclines
  • New York Heart Association class III or IV heart disease or controlled class II disease
  • Prior central thoracic radiotherapy, including radiotherapy to the heart
  • Myocardial infarction within the past 12 months
• No inability or unwillingness to take folic acid, cyanocobalamin (vitamin B12), or dexamethasone

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• At least 4 weeks since prior definitive chest radiotherapy (> 60 Gy) and recovered
• At least 3 months since prior craniotomy for resection of brain metastasis
• At least 3 weeks since prior radiotherapy for brain metastases
• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered
• At least 2 weeks since prior palliative radiotherapy
• At least 2 weeks since prior surgery (excluding the placement of vascular access or drainage of pleural effusion or ascites) and recovered
• No prior pemetrexed disodium

• At least 5 half-lives since prior and no concurrent drugs or biologics with proarrythmic potential, including any of the following:

  • Amiodarone hydrochloride
  • Arsenic trioxide
  • Bepridil
  • Chloroquine
  • Chlorpromazine
  • Cisapride
  • Clarithromycin
  • Disopyramide
  • Dofetilide
  • Domperidone
  • Droperidol
  • Erythromycin
  • Halofantrine
  • Haloperidol
  • Ibutilide
  • Mesoridazine
  • Methadone
  • Pentamidine
  • Pimozide
  • Procainamide
  • Sotalol
  • Sparfloxacin
  • Thioridazine
• More than 30 days since prior investigational agents and recovered

• No aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) for 2 days before, during, and for 2 days after pemetrexed disodium administration

  • Low-dose aspirin (≤ 325 mg/day) for vascular disorders allowed
• No long-acting NSAIDs (e.g., naproxen, piroxicam, diflunisal, nabumetone, or celecoxib) for 5 days before, during, and for 2 days after pemetrexed disodium
• No concurrent medications that can markedly affect renal function (e.g., vancomycin or amphotericin)
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent anticancer agents or therapies
• No other concurrent investigational agents