Carboplatin and Gemcitabine With Bevacizumab Every 2 Weeks for Stage IIIb/IV Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine whether treatment with carboplatin and gemcitabine combined with bevacizumab every two weeks will provide increased survival.

Detailed Description
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Treatment with Carboplatin and gemcitabine is one of the most active combination therapies used for first-line therapy of NSCLC. The optimum schedule for administration of carboplatin and gemcitabine is currently unknown. The addition of bevacizumab to another comparable platinum combination showed an overall survival advantage and a significantly greater response rate and progression-free survival.

Official Title
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Phase II Study of Biweekly Carboplatin and Gemcitabine With Bevacizumab as 1st Line Treatment in Patients With Advanced, Inoperable Stage IIIb/IV NSCLC

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: Gemcitabine, Carboplatin, Bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed non-small cell lung cancer (NSCLC) EXCEPT squamous cell carcinoma or predominantly squamous. Mixed tumors will be categorized by the predominant cell type unless small cell elements are present in which case the patient is ineligible. (Sputum cytology alone is not acceptable) Must have disease that is not curative by standard methods. Prior adjuvant systemic chemotherapy, immunotherapy, or biological therapy is allowed, except for prior use of bevacizumab. If gemcitabine was used, more than six months must have elapsed between completion of adjuvant therapy and disease progression. Patient must be at least 14 days from previous systemic therapy (at least 30 days for investigational agents) and have recovered from the acute toxic effects of the treatment as determined by the treating physician prior to study registration. Prior therapy other than adjuvant therapy is not allowed. Prior radiation therapy must be completed at least 14 days of study registration and subjects must fully recover from acute toxicities as determined by the treating physician. Prior radiation to > 25% of bone marrow is not allowed. Prior radiation therapy to the whole pelvis is not allowed. Disease status must be measurable or non-measurable as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. ECOG Performance status of 0 or 1 Age 18 years or greater Adequate organ function within 14 days of study registration including the following: Adequate bone marrow reserve: absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L, platelets ≥ 100 x 10^9/L, hemoglobin ≥ 9 g/dL Hepatic: bilirubin ≤ 1.5 times the upper limit of normal (× ULN), alkaline phosphatase (ALP), aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 × ULN (ALP, AST, and ALT ≤ 5 × ULN is acceptable if liver has tumor involvement) Renal: Adequate renal function as evidenced by creatinine clearance of > 50ml/min, estimated by the Cockcroft-Gault equation or urine dipstick for proteinuria < 2+ (patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible) Coagulation: INR < 1.5, PTT < the upper limits of normal (ULN) unless stable on therapeutic anticoagulation at study entry. The addition of anticoagulants after study start is not allowed. Women of childbearing potential and sexually active males are required to use an effective method of contraception (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicidal, condom with spermicidal, or abstinence) during the study and for 3 months after the last dose of study drug. Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care. Exclusion Criteria: Intrathoracic lung carcinoma of squamous cell histology. Mixed tumors will be categorized by the predominant cell type unless small cell elements are present, in which case the patient is ineligible; sputum cytology alone is acceptable for inclusion. Subjects with extrathoracic-only squamous cell NSCLC are eligible. Subjects with only peripheral lung lesions of any NSCLC histology will also be eligible. A peripheral lesion is defined as a lesion in which the epicenter of the tumor is < 2 cm from the costal or diaphragmatic pleura in a three-dimensional orientation based on each lobe of the lung and is > 2 cm from the trachea, main and lobar bronchi. Pregnant (positive pregnancy test within 14 days of study enrollment) or breast-feeding. Gemcitabine and carboplatin are pregnancy category D - clear evidence of risk in pregnancy; bevacizumab is pregnancy category C - risk in pregnancy cannot be ruled out. Pregnancy testing is not required for post-menopausal (defined as absence of menses for the preceding 24 consecutive months) or surgically sterilized women. Inadequately controlled hypertension (defined as systolic blood pressure >150 and/or diastolic blood pressure > 100 mmHg on antihypertensive medications) Any prior history of hypertensive crisis or hypertensive encephalopathy New York Heart Association (NYHA) Grade II or greater congestive heart failure History of stroke or transient ischemic attack within 6 months prior to study enrollment Clinically significant peripheral vascular disease (e.g., aortic aneurysm, aortic dissection) Symptomatic peripheral vascular disease Evidence of bleeding diathesis or coagulopathy in the absence of therapeutic anticoagulation Current or recent (within 10 days of enrollment) use of aspirin (>325 mg/day) or chronic use of other NSAIDs known to inhibit platelet function Treatment with dipyridamole (Persantine), ticlopidine (Ticlid), clopidogrel (Plavix) and/or cilostazol (Pletal) Requiring therapeutic anticoagulation Current, ongoing treatment with full-dose warfarin or its equivalent (i.e., unfractionated and/or low molecular weight heparin) History of thrombotic or hemorrhagic disorders T4 tumors with invasion of the heart or great vessels Presence or history of central nervous system or brain metastases, except for treated brain metastases. Treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI/CT) during the screening period. Anticonvulsants are allowed, providing the subject is on a stable dose. Treatment for brain metastases may include whole brain radiotherapy, radiosurgery (RS; Gamma Knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating physician. Subjects with CNS metastases treated by radiotherapy within 28 days of Day 1 will be excluded. Subjects treated by neurosurgical resection or brain biopsy performed within 3 months prior to Day 1 will be excluded. History of another malignancy other than NSCLC except in situ carcinoma of the cervix; adequately treated nonmelanomatous carcinoma of the skin; low grade (Gleason score ≤ 6) localized prostate cancer or other prior malignancy treated at least 2 years previously with no evidence of recurrence Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to treatment start, anticipation of need for major surgical procedure during the course of the study Minor surgical procedures such as fine needle aspirations or core biopsies within 7 days prior to treatment start History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to treatment start Serious, non-healing wound, ulcer, or bone fracture, or the presence of a serious active infection History of hemoptysis defined as bright red blood of 1/2 teaspoon or more in the previous 1 month before enrollment Patients with known hypersensitivity to any of the components of carboplatin, gemcitabine or bevacizumab. Known HIV or Hepatitis B or C (active, previously treated or both) Inability to comply with study and/or follow-up procedures Life expectancy < 12 weeks.

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients with Stage IIIb/IV Non-Small Cell Lung Cancer<br>Patients treated with Gemcitabine 2000mg/m^2 intravenously (IV) over 30 minutes, followed by Carboplatin AUC= 3 IV over 30 minutes and Bevacizumab 10 mg/kg IV over 90 minutes 1st infusion, 60 minutes 2nd infusion and 30 minutes for the following infusions. Cycles will be repeated every 2 weeks for a maximum of 6 cycles of therapy. Bevacizumab will continue to be given until disease progression. | Drug: Gemcitabine, Carboplatin, Bevacizumab<br>* Patients will be treated with Gemcitabine 2000mg/m^2 intravenously (IV) over 30 minutes, followed by Carboplatin AUC= 3 IV over 30 minutes and Bevacizumab 10 mg/kg IV over 90 minutes 1st infusion, 60 minutes 2nd infusion and 30 minutes for the following infusions. Cycles will be repeated every 2 weeks for a maximum of 6 cycles of therapy. Bevacizumab will continue to be given until disease progression.<br>* Other names: Gemzar, Carboplatin, Avastin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression | Time to progression (progression free survival)is defined as the time from the start of treatment until first documented sign of disease progression or death due to any cause. For subjects who do not progress, time to progression will be censored at the time of last tumor assessment. | From Enrollment Through 2 Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response by Cycle | Number of patients and their best response recorded from the state of treatment until disease progression. Response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST): Complete Response-disappearance of all target lesions; Partial Response=30% decrease in sum of longest diameter of target lesions; Progressive Disease=20% increase in sum of longest diameter of target lesions; Stable Disease=small changes that did not meet above criteria. | After Cycle 4, Cycle 6 and Cycle 7 of Therapy | 
| Duration of Response | For subjects who show a response, duration of response is defined to be the time from first documented evidence of response(30% decrease or complete disappearance of tumor) until the first documented sign of disease progression or death due to any cause. For subjects who do not progress or die, duration of response will be censored at the time of last tumor assessment. | From Enrollment through Date of First Documented Disease Progression or Date of Death From Any Cause, Whichever Came First, Up to 100 Months | 
| Overall Survival Time | Overall survival is defined as the time from the start of treatment until death due to whatever cause. For subjects alive at study completion, time to death will be censored at the time of last contact. | Baseline to Death | 
| Time to Best Response | Time to best response is defined as the time from the start of treatment until first documented evidence of tumor response (30% decrease or complete disappearance of tumor). For subjects who do not show a tumor response, the time will be censored at the time of last contact. | From Enrollment to First Tumor Response | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Carcinoma, Non-Small-Cell Lung, Gemcitabine, Carboplatin, Bevacizumab, Biological therapy, Drug therapy