Gemcitabine and Carboplatin With or Without AZD2171 as First-Line Therapy in Treating Patients With Stage IIIB 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 gemcitabine and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. AZD2171 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 gemcitabine and carboplatin together with AZD2171 may kill more tumor cells. PURPOSE: This randomized phase II trial is studying how well giving gemcitabine and carboplatin together with AZD2171 works compared to giving gemcitabine and carboplatin without AZD2171 as first-line therapy in treating patients with stage IIIB or stage IV non-small cell lung cancer.

Detailed Description
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OBJECTIVES: Primary Assess the objective tumor response rate in patients with stage IIIB or IV non-small cell lung cancer treated with gemcitabine hydrochloride, carboplatin, and AZD2171 as first-line therapy. Secondary Compare the proportion of patients who are progression-free at 6 months after treatment with gemcitabine hydrochloride and carboplatin with vs without AZD2171. Compare the duration of response for responding patients treated with these regimens. Compare the time-to-progression and time-to-treatment failure. Compare the 1-year overall survival. Compare the clinical toxicities. Assess the safety and tolerability of these regimens in these patients. Tertiary Collect blood and tumor specimens for future evaluation of pharmacogenetic and proteomic markers of tumor response and toxicity to therapy with these agents. Bank paraffin-embedded tissue blocks/slides and blood samples for future histochemistry evaluation and DNA extraction. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to prior adjuvant therapy (yes vs no) and ECOG performance status (0 vs 1). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8, carboplatin IV over 30 minutes on day 1, and oral AZD2171 once daily on days 1-21. Treatment repeats every 21 days for up to 6 courses. Patients achieving stable disease, partial response, or complete response after 6 courses of therapy receive AZD2171 alone as above. Treatment with AZD2171 repeats every 21 days in the absence of disease progression or unacceptable toxicity. Arm II: Patients receive gemcitabine and carboplatin as in arm I. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients undergo blood collection periodically during study for pharmacologic correlative studies. After completion of study treatment, patients are followed periodically for 5 years. PROJECTED ACCRUAL: A total of 102 patients will be accrued for this study.

Official Title
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A Randomized Phase II Study of Gemcitabine and Carboplatin With or Without AZD2171 as First-Line Therapy in Advanced Non-Small Cell Lung Cancer

Conditions
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Lung Cancer

Intervention / Treatment
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* Drug: carboplatin
* Drug: cediranib maleate
* Drug: gemcitabine hydrochloride


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed non-small cell lung cancer (NSCLC) Squamous cell histology allowed No mixed histology with small cell component Stage IIIB (with pleural effusion) or stage IV disease Presence of peritoneal or pericardial effusion alone in the absence of cytologic evidence is not allowed Measurable disease, defined as ≥ 1 lesion with longest diameter ≥ 2.0 cm by conventional techniques OR ≥ 1.0 cm by spiral CT scan If the only site of measurable disease was previously irradiated, progressive disease must be evident Ineligible for bevacizumab therapy No symptomatic, untreated, or uncontrolled CNS metastases CNS metastases treated with whole-brain radiation (WBRT) allowed 4 weeks after completion of WBRT PATIENT CHARACTERISTICS: ECOG performance status 0-1 Life expectancy ≥ 12 weeks Absolute neutrophil count ≥ 1,500/mm^3 Hemoglobin ≥ 9 g/dL Platelet count ≥ 100,000/mm^3 Bilirubin ≤ 3 times upper limit of normal (ULN) ALT and AST ≤ 3 times ULN (5 times ULN if liver involvement) Alkaline phosphatase ≤ 5 times ULN Not pregnant or nursing Negative pregnancy test Fertile patients must use effective nonhormonal contraception No proteinuria ≥ 1+ No uncontrolled blood pressure (BP), defined as systolic BP > 150 mm Hg and/or diastolic BP > 100 mm Hg in spite of adequate antihypertensive therapy No impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of AZD2171 (e.g., ulcerative disease, uncontrolled nausea, vomiting, or diarrhea, malabsorption syndrome, or small bowel resection) No seizure disorder No significant traumatic injury within 4 weeks prior to study entry No second primary malignancy except any of the following: Carcinoma in situ of the cervix Nonmelanoma skin cancer Prior malignancy diagnosed and definitively treated ≥ 5 years ago with no subsequent evidence of recurrence History of low-grade (Gleason score ≤ 6) localized prostate cancer even if diagnosed < 5 years prior to registration Treated stage I breast cancer ≤ 5 years prior to registration No uncontrolled intercurrent illness, including, but not limited to, any of the following: Ongoing or active infection Significant pulmonary symptoms at baseline due to disease Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia Psychiatric illness or social situation that would limit compliance with study requirements Baseline hemoptysis Cavitating lesions No QTc prolongation > 500 msec or other significant ECG abnormality within the past 14 days No New York Heart Association class III or IV disease PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior chemotherapy for advanced lung cancer Neoadjuvant or adjuvant therapy for lung cancer within the past 12 months allowed More than 12 months since prior immunotherapy and biologic therapy More than 4 weeks since prior radiotherapy (2 weeks for palliative radiotherapy to skeletal metastases) At least 2 weeks since prior WBRT No radiotherapy to ≥ 25% of bone marrow No major surgery (i.e., laparotomy) or open biopsy within 4 weeks prior to study entry (2 weeks for minor surgery) Insertion of a vascular access device not considered major or minor surgery No concurrent combination antiretroviral therapy for HIV-positive patients No concurrent grapefruit or grapefruit juice during AZD2171 treatment No concurrent drugs or biologics with proarrhythmic potential Concurrent palliative radiotherapy to nontarget sites (i.e., painful pre-existing bony metastasis) allowed with AZD2171 (chemotherapy is held until completion of radiotherapy)

Ages Eligible for Study
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Minimum Age: 18 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8, carboplatin IV over 30 minutes on day 1, and oral AZD2171 once daily on days 1-21. Treatment repeats every 21 days for up to 6 courses. Patients achieving stable disease, partial response, or complete response after 6 courses of therapy receive AZD2171 alone as above. Treatment with AZD2171 repeats every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: carboplatin<br>* Given IV<br>Drug: cediranib maleate<br>* Given orally<br>Drug: gemcitabine hydrochloride<br>* Given IV<br>|
| Active Comparator: Arm II<br>Patients receive gemcitabine and carboplatin as in arm I. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. | Drug: carboplatin<br>* Given IV<br>Drug: gemcitabine hydrochloride<br>* Given IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Response Rate (Complete Response and Partial Response) as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) (Phase II Patients Only) | A confirmed tumor response was defined as a complete response (CR) or partial response (PR) noted as the objective status on 2 consecutive evaluations at least 6 weeks apart. Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria: Complete Response (CR): disappearance of all target lesions; Partial Response (PR) 30% decrease in sum of longest diameter of target lesions | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival Rate at 6 Months After Randomization (Phase II Patients Only) | Estimated using the Binomial point estimator (number of successes divided by the total number of evaluable patients). A patient is classified as a success if alive and progression-free at 6 months. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | 6 months | 
| Progression-free Survival (Phase II Patients Only) | Progression-free survival was defined as the time from study enrollment to the first date of disease progression or death as a result of any cause, whichever occurs first. Progression-free survival will be censored at the date of the last contact for patients who are still alive and who have not had disease progression. | Up to 5 years | 
| Time to Treatment Failure (Phase II Patients Only) | Time to treatment failure was defined to be the time from date of registration to the date at which the patient was removed from the treatment due to progression, toxicity, refusal or death from any cause. | Up to 15 months | 
| Overall Survival at 1 Year After Randomization (Phase II Patients Only) | Overall survival was defined as the time from study enrollment to the time of death from any cause. A patient is classified as a success if alive at 1 year. | 1 year | 
| Overall Survival (Phase II Patients Only) | Overall survival was defined as the time from study enrollment to the time of death from any cause. Overall survival will be censored at the date of the last follow-up visit for patients who are still alive or lost to follow-up. | Up to 5 years | 
| Dose Limiting Toxicity (DLT) (Lead-in Phase Arm I Patients Only) | DLT was defined as an adverse event occurring in cycle 1 only, at least possibly attributed to the study treatment and meeting the following criteria: 1) Grade 4 absolute neutrophil count (ANC) >5 days or of any duration with fever >38.5 degree Celsius; 2) Grade 4 platelet count; 3) Grade 3 or higher non-hematologic toxicities (for nausea, vomiting or diarrhea, grade 3 toxicities will be DLT if they occur despite maximal use of anti-emetic support or anti-diarrhea agents, respectively); 4) Cediranib dose interruption of >14 days for drug-related toxicities. | Cycle 1 (up to 3 weeks) | 

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