Cediranib, Paclitaxel, and Carboplatin in Treating Patients With Stage IIIB or Stage IV Non-Small Cell Lung Cancer

A Double Blind Randomized Trial of Cediranib Versus Placebo in Patients Receiving Paclitaxel/Carboplatin Chemotherapy for the Treatment of Advanced or Metastatic Non-Small Cell Lung Cancer

RATIONALE: Cediranib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether cediranib is more effective than a placebo when given together with paclitaxel and carboplatin in treating patients with non-small cell lung cancer.

PURPOSE: This randomized phase III trial is studying how well cediranib works when given together with paclitaxel and carboplatin in treating patients with stage IIIB or stage IV non-small cell lung cancer.

OBJECTIVES:

Primary

• To compare overall survival of patients with stage IIIB-IV non-small cell lung cancer treated with cediranib vs placebo administered in combination with paclitaxel and carboplatin.

Secondary

• To compare the progression-free survival of patients treated with these regimens.
• To compare the objective response rates in patients treated with these regimens.
• To estimate time to response and response duration in patients treated with these regimens.
• To evaluate the nature, severity, and frequency of toxicities, including hemorrhage and hemoptysis, in patients treated with these regimens.
• To compare the pharmacokinetics of paclitaxel between the two arms in a subset of enrolled patients
• To compare the quality of life of patients treated with these regimens.
• To determine the incremental cost effectiveness and cost utility ratios for these regimens.
• To correlate the expression of tissue markers (at diagnosis) with outcomes and response in an exploratory fashion OUTLINE: This is a multicenter study. Patients are stratified by gender, center, disease stage (IIIB vs IV), weight loss (< 5% vs 5-10% vs unknown), and prior adjuvant chemotherapy (yes vs no). Patients are randomized to 1 of 2 treatment arms.
• Arm I: Patients receive oral cediranib once daily on days 1-21 and paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on day 1.
• Arm II: Patients receive oral placebo once daily on days 1-21 and paclitaxel and carboplatin as in arm I.

Treatment in both arms repeats every 21 days for 4 to 6 courses in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline, on day 1 of each course, and periodically thereafter.

After completion of study therapy, patients are followed every 12 weeks.

DISEASE CHARACTERISTICS:

• Histologically or cytologically* confirmed non-small cell carcinoma of the lung

  • Stage IIIB or IV disease NOTE: *Diagnosis by sputum cytology alone allowed provided it is confirmed by a second sputum specimen

• Measurable disease, defined as at least 1 measurable lesion > 20 mm by x-ray, ultrasound, or physical exam or ≥ 10 mm (lymph nodes must be ≥ 15 mm in the short axis) by spiral CT scan or physical exam (in the first 260 patients randomized**)

  • Measurable lesions that are sole sites of disease must be outside a previous radiotherapy field unless disease progression has been documented NOTE: **Measurable or nonmeasurable disease allowed after the first 260 patients

• No appreciable cavitation in central thoracic lesions

• No untreated brain or meningeal metastases

  • Patients with treated and radiologic or clinical evidence of stable brain metastases, with no evidence of cavitation or hemorrhage in the brain lesion, are eligible provided the metastases are asymptomatic and do not require corticosteroids

• No pleural effusion

PATIENT CHARACTERISTICS:

• ECOG performance status 0-1

• Absolute granulocyte count ≥ 1,500/mm^3

• Platelet count ≥ 100,000/mm^3

• Creatinine clearance > 50 mL/min

• Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

• ALT ≤ 2 times ULN (< 5 times ULN if due to liver metastasis)

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective double-method contraception (barrier method for men)

• No other malignancy within the past 5 years, except in situ cancer, basal cell or squamous cell skin cancer, or malignancy cured by definitive prior therapy alone (e.g., surgery) and continuously disease-free for at least 5 years

• Mean QTc with Bazett correction ≤ 480 msec in screening ECG (at least one value must be ≤ 480 msec when measured automatically or manually corrected using Bazett's or Fridericia's correction)

• No history of familial long QT syndrome

• No untreated and/or uncontrolled cardiovascular conditions and/or symptomatic cardiac dysfunction including any of the following:

  • Unstable angina
  • Congestive heart failure
  • Myocardial infarction within the past year
  • Cardiac ventricular arrhythmias requiring medication
  • History of second or third degree atrioventricular conduction defects

• LVEF > 50% in patients with significant cardiac history, even if controlled

• No resting BP consistently > 150 mm Hg systolic and/or > 100 mm Hg diastolic

• No poorly controlled hypertension

• No history of labile hypertension or poor compliance with anti-hypertensive medication

• No overt bleeding (> 30 mL bleeding/episode) from any site within the past 3 months

• No clinically relevant hemoptysis (> 5 mL fresh blood) within the past 4 weeks

  • Flecks of blood in sputum allowed

• No active or uncontrolled infections, or serious illnesses or medical conditions which would not permit the patient to be treated according to the study

• No prior allergic reactions to drugs containing Cremophor EL®

• No inflammatory bowel disease (e.g., Crohn disease or ulcerative colitis)

• No documented weight loss > 10% within the past 3 months

  • Patients with weight loss 5-10% or whose weight loss status is unknown are eligible provided serum albumin levels are ≥ 30 g/L

• No peripheral neuropathy > grade 1

• Must be fit for combined modality treatment

• Sufficiently fluent and willing to complete quality-of-life questionnaires

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• Recovered from all prior therapy

• No prior chemotherapy for metastatic or recurrent disease

• No prior anti-angiogenic therapy (e.g., bevacizumab, cediranib, AZD6474, PTK/ZK, sunitinib malate, or other agents considered angiogenesis inhibitors by NCIC Clinical Trials Group for any indication)

  • Prior cox-2 inhibitors in standard doses allowed

• At least 12 months since prior adjuvant chemotherapy for completely resected disease

  • Combined chemotherapy/radiotherapy regimens for locally advanced stage IIIB disease not allowed

• At least 21 days since prior radiotherapy

• At least 21 days since prior cetuximab or other monoclonal antibodies

• At least 14 days since prior EGFR inhibitor therapy for adjuvant therapy or metastatic disease (e.g., tyrosine kinase inhibitors, vaccines, or other agents considered by NCIC CTG as acting on the EGFR pathway)

• At least 14 days since prior major surgery

• At least 1 week since prior corticosteroids

• No other concurrent experimental drugs, anticancer treatment, or investigational therapy