Paclitaxel + Carboplatin With/Out Cediranib Maleate in Stage III or Stage IV Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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RATIONALE: 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. Cediranib maleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving paclitaxel and carboplatin together with AZD2171 may kill more tumor cells. It is not yet known whether giving paclitaxel and carboplatin together with AZD2171 is more effective than giving paclitaxel and carboplatin together with a placebo in treating non-small cell lung cancer. PURPOSE: This randomized phase II/III trial is studying how well giving paclitaxel and carboplatin together with cediranib maleate works and compares it to giving paclitaxel and carboplatin together with placebo in treating patients with stage III 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 paclitaxel and carboplatin in combination with either cediranib maleate or a placebo. Determine the pharmacogenomics and pharmacodynamic aspects of these regimens in these patients. (Phase II) Compare the overall survival of patients treated with these regimens. (Phase III) Secondary Compare objective tumor response rates in patients treated with these regimens. Determine the time to response and response duration in patients treated with these regimens. (Phase III) Determine the nature, severity, and frequency of the toxic effects of these regimens, including hemorrhage and hemoptysis, in these patients. Correlate the expression of tissue markers (at diagnosis) with outcomes and response in patients treated with these regimens. (Phase III) Compare quality of life of patients treated with these regimens. (Phase III) OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to gender, participating center, disease stage (IIIB vs IV), weight loss (≥ 5% vs < 5%), and prior adjuvant chemotherapy (yes vs no). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive oral cediranib maleate once daily in the absence of disease progression or unacceptable toxicity. Patients also receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on day 1. Treatment with paclitaxel and carboplatin repeats every 21 days for 6-8 courses in the absence of disease progression or unacceptable toxicity. Arm II: Patients receive oral placebo once daily in the absence of disease progression or unacceptable toxicity. Patients also receive paclitaxel and carboplatin as in arm I. Quality of life is assessed at baseline, before each treatment course, after completion of study treatment, and every 3 months thereafter. After completion of study treatment, patients are followed every 3 months. PROJECTED ACCRUAL: A total of 750 patients will be accrued for this study.

Official Title
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A Phase II/III Double Blind Randomized Trial of AZD2171 Versus Placebo in Patients Receiving Paclitaxel/Carboplatin Chemotherapy for the Treatment of Advanced or Metastatic Non-Small Cell Lung Cancer

Conditions
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Lung Cancer

Intervention / Treatment
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* Drug: carboplatin
* Drug: cediranib maleate
* Drug: paclitaxel
* Other: placebo


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed non-small cell lung cancer (NSCLC), meeting 1 of the following stage criteria: Stage IIIB disease Patients without pleural effusion who are not candidates for combined modality treatment OR who were treated at centers where combined modality treatment is not considered standard treatment are eligible Stage IV disease Measurable disease (phase II) Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by x-ray, ultrasound, physical exam, or conventional CT scan OR ≥ 10 mm by spiral CT scan Measurable lesions must be outside a previous radiotherapy field if they are the sole site of disease, unless disease progression has been documented No significant central thoracic lesion with any appreciable cavitation Measurable or nonmeasurable disease (phase III) No necrotic or hemorrhagic tumor or metastases No untreated brain or meningeal metastases CT scans are not required to rule out disease unless there is clinical suspicion of CNS disease Patients with previously treated stable brain metastases (by radiography or clinical exam) are eligible provided they are asymptomatic and do not require corticosteroids PATIENT CHARACTERISTICS: Performance status ECOG 0-1 Life expectancy Not specified Hematopoietic Absolute granulocyte count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 No overt bleeding (i.e., ≥ 30 mL/episode) within the past 3 months Hepatic Bilirubin ≤ 1.5 times upper limit of normal (ULN) ALT ≤ 2 times ULN (< 5 times ULN if liver metastases are present) Renal Creatinine clearance ≥ 50 mL/min Proteinuria ≤ grade 1 Cardiovascular Mean QTc ≤ 470 msec (with Bazett's correction) by ECG No unstable angina No congestive heart failure No myocardial infarction within the past year No cardiac ventricular arrhythmias requiring medication No history of 2nd- or 3rd-degree atrioventricular conduction defects No untreated or uncontrolled cardiovascular condition No symptomatic cardiac dysfunction No uncontrolled hypertension (i.e., resting blood pressure ≥ 150/100 mm Hg despite antihypertensive therapy) No history of labile hypertension No history of poor compliance with antihypertensive medication No history of familial long-QT syndrome Pulmonary No clinically relevant hemoptysis (i.e., ≥ 5 mL fresh blood) within the past 4 weeks Flecks of blood only in sputum allowed Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective (double method for females; barrier method for males) contraception Able and willing to participate in the quality of life assessment No peripheral neuropathy > grade 1 No prior allergic reaction to drugs containing Cremophor EL® No active or uncontrolled infection No serious illness or medical condition which would preclude study compliance No inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis) No other malignancy within the past 5 years except basal cell or squamous cell skin cancer or in situ cancer PRIOR CONCURRENT THERAPY: Biologic therapy At least 14 days since prior epidermal growth factor receptor-inhibitor therapy (e.g., tyrosine kinase inhibitor, monoclonal antibodies, vaccines, or other agents) No prior antiangiogenesis therapy, including any of the following: Bevacizumab Cediranib maleate AZD6474 PTK787/ZK222584 (PTK/ZK) Sunitinib malate Concurrent epoetin alfa allowed Chemotherapy At least 12 months since prior adjuvant chemotherapy Combined chemotherapy and radiotherapy regimens for locally advanced stage IIIB disease is not considered adjuvant therapy and is not allowed No prior chemotherapy for metastatic or recurrent NSCLC Endocrine therapy See Disease Characteristics At least 1 week since prior steroids Radiotherapy See Disease Characteristics At least 21 days since prior radiotherapy except for low-dose non-myelosuppressive radiotherapy with approval Concurrent palliative radiotherapy allowed with approval Surgery At least 14 days since prior major surgery Other Recovered from prior therapy Prior treatment with cyclooxygenase-2 inhibitors allowed Concurrent prophylactic anticoagulation (e.g., warfarin) allowed provided requirements for INR are met No potent inhibitors of CYP3A4 and 2C8, including any of the following drugs: Amiodarone hydrochloride Clarithromycin Citalopram hydrobromide Erythromycin Omeprazole Simvastatin Atorvastatin Lovastatin Montelukast sodium Verapamil hydrochloride Ketoconazole Miconazole Indinovir and other antivrails Diltiazem No other concurrent experimental drug or anticancer therapy

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive oral cediranib maleate once daily in the absence of disease progression or unacceptable toxicity. Patients also receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on day 1. Treatment with paclitaxel and carboplatin repeats every 21 days for 6-8 courses in the absence of disease progression or unacceptable toxicity. | Drug: carboplatin<br>* Given IV<br>Drug: cediranib maleate<br>* Given orally<br>Drug: paclitaxel<br>* Given IV<br>|
| Active Comparator: Arm II<br>Patients receive oral placebo once daily in the absence of disease progression or unacceptable toxicity. Patients also receive paclitaxel and carboplatin as in arm I. | Drug: carboplatin<br>* Given IV<br>Drug: paclitaxel<br>* Given IV<br>Other: placebo<br>* Given orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival |  | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity |  | 3 years | 
| Quality of Life |  | 3 years | 
| Overall survival |  | 3 years | 
| Correlative Studies |  | 3 years | 

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