AZD2171 and Pemetrexed Disodium in Treating Patients With Relapsed Non-Small Cell Lung Cancer

PRIMARY OBJECTIVES:

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

SECONDARY OBJECTIVES:

I. 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.

Inclusion criteria

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

• 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
• ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
• 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
• 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
• Fertile patients must use effective contraception
• 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
• 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 inability or unwillingness to take folic acid, cyanocobalamin (vitamin B12), or dexamethasone
• No prior pemetrexed disodium
• At least 5 half-lives since prior and no concurrent drugs or biologics with proarrythmic potential including:

• 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
• Not pregnant or nursing
• 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 combination antiretroviral therapy for HIV-positive patients
• No other concurrent anticancer agents or therapies
• No other concurrent investigational agents
• Life expectancy > 12 weeks
• No concurrent medications that can markedly affect renal function (e.g., vancomycin or amphotericin)
• Negative pregnancy test
• Relapsed disease