A Safety and Efficacy Study of Carboplatin, Paclitaxel, Bevacizumab and CA4P in 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 the safety, tolerability and efficacy of combretastatin A4 phosphate (CA4P), also known as fosbretabulin, in combination with bevacizumab (Avastin), carboplatin and paclitaxel in patients with chemotherapy naïve non-small cell lung cancer (NSCLC). This is a randomized parallel arm study. All participants will receive carboplatin, paclitaxel and bevacizumab, and half will additionally receive CA4P. Patients who complete the first 6 cycles of therapy and have not experienced disease progression will receive maintenance therapy with bevacizumab alone or with bevacizumab plus CA4P. The rationale for this study is the potential additive or synergistic actions of vascular disrupting agents like CA4P with anti-angiogenic agents like bevacizumab.

Detailed Description
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Lung cancer has become the leading cause of cancer death in both men and women in the US and Europe, accounting for 29% of all cancer deaths. Non-Small Cell Lung cancer (NSCLC) accounts for approximately 80% of all lung cancer cases. Currently, no curative treatment is available for advanced stages of the disease (stages III and IV), which comprise the majority of cases. Treatment with the combination of carboplatin and paclitaxel has been shown to be effective and well tolerated in advanced stage NSCLC. Targeted therapies, such as bevacizumab, often act synergistically with chemotherapy. Bevacizumab inhibits vascular endothelial growth factor (VEGF), necessary for endothelial cell proliferation and new blood vessel formation. CA4P targets existing abnormal vasculature of tumors, impeding tumor blood flow and leading to extensive tumor cell death as a consequence of oxygen and nutrient deprivation. This study will compare the effect of CA4P when combined with chemotherapy and bevacizumab on progression free survival (PFS) to PFS after chemotherapy and bevacizumab alone.

Official Title
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A Phase II Study to Assess the Safety and Efficacy of the Combination of Carboplatin, Paclitaxel, and Bevacizumab ± Combretastatin A4 Phosphate (CA4P) Followed by Bevacizumab ± CA4P in Subjects With Chemotherapy Naïve Stage IIIB/IV Non-Squamous Cell Histology Non-Small Cell Lung Cancer (NSCLC)

Conditions
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Tumors

Intervention / Treatment
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* Drug: Fosbretabulin
* Drug: Carboplatin
* Drug: Paclitaxel
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically confirmed Stage IIIB NSCLC with malignant pleural effusion, or Stage IV disease Measurable disease on CT scan (by the Response Evaluation Criteria in Solid Tumors [RECIST] criteria) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 (which means able to independently care for self and to perform light work) . Adequate blood counts Adequate liver and kidney function Subjects or their legal representatives must be able to read, understand and provide written informed consent to participate in the trial. Exclusion Criteria: Predominant Squamous Cell NSCLC histology. History of treatment for NSCLC with chemotherapy, biological therapy, immunotherapy (surgery or radiation therapy are accepted) Brain (CNS) metastasis by head CT scan or MRI Subjects with history of prior malignancy except for curatively treated basal cell carcinoma of the skin; cervical intra-epithelial neoplasia; or localized prostate cancer with a current prostate specific antigen (PSA) of < 4.0 mg/dL. Subjects with other curatively treated malignancies who have no evidence of metastatic disease and >2 year disease free interval may be entered after discussion with the Medical Monitor. History of bleeding disorders, particularly coughing up ≥ ½ teaspoon bright red blood during the last 3 months Certain cardiac disorders such as recent myocardial infarction (MI), severe congestive heart failure, certain types of abnormal cardiac rhythm Uncontrolled high blood pressure despite medications Uncontrolled, clinically significant active infection. Known HIV Known hypersensitivity to any of the components of CA4P, paclitaxel, carboplatin, bevacizumab, or radiologic contrast dyes. Details of the above and additional inclusion and exclusion criteria can be discussed with an investigator.

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 |
| --- | --- |
| Active Comparator: Arm 1: Chemotherapy+Bevacizumab<br>Carboplatin (AUC 6), paclitaxel (200 mg/m2), and bevacizumab (15 mg/kg)administered intravenously on Day 1 of a 21-day cycle for up to six treatment cycles. After 6 cycles, subjects who have not progressed may continue to receive bevacizumab (15 mg/kg) alone on Day 1 every 3 weeks until progression or until 12 months from randomization. | Drug: Carboplatin<br>* Chemotherapy: Carboplatin (AUC 6) on Day 1 of each 21 day cycle for 6 cycles.<br>* Other names: Paraplatin;Drug: Paclitaxel<br>* Chemotherapy: Paclitaxel (20 mg/m2) on Day 1 of each 21-day cycle for 6 cycles.<br>* Other names: Taxol;Drug: Bevacizumab<br>* Bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle for 6 cycles.<br>* Other names: Avastin;|
| Experimental: Arm 2: Active Comparator+Fosbretabulin<br>Carboplatin (AUC 6), paclitaxel (200 mg/m2), and bevacizumab (15 mg/kg), administered intravenously Day 1 of a 21-day cycle and fosbretabulin (60 mg/m2) on Days 7, 14, and 21 for up to six treatment cycles. After 6 cycles, subjects who have not progressed may continue to receive bevacizumab (15 mg/kg) on Day 1 and fosbretabulin on Days 1, 7 and 14 every 3 weeks until progression or until 12 months from randomization. | Drug: Fosbretabulin<br>* Arm 2 only: Fosbretabulin (60 mg/m2) on Days 7,14 and 21 for 6 cycles.<br>* Other names: CA4P;Drug: Carboplatin<br>* Chemotherapy: Carboplatin (AUC 6) on Day 1 of each 21 day cycle for 6 cycles.<br>* Other names: Paraplatin;Drug: Paclitaxel<br>* Chemotherapy: Paclitaxel (20 mg/m2) on Day 1 of each 21-day cycle for 6 cycles.<br>* Other names: Taxol;Drug: Bevacizumab<br>* Bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle for 6 cycles.<br>* Other names: Avastin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) in the Intent-to-Treat Population | Progression was defined using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0. Based on 20% increase of the longest diameter of target lesions or appearance of one or more new non-target lesions or/and progression of non-target lesions since the treatment started. | Six 21-day cycles | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Tumor Response Rate (RR) in the Intent-to-Treat Population | Based on Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0 for target lesions (assessed by MRI or CT scan): Complete Response (CR) is defined as the disappearance of all target lesions, Partial Response (PR) is defined as at least a 30% decrease in the sum of the longest diameter of target lesions, Progressive Disease is defined as at least 20% increase in the sum of the longest diameter of target lesions, Stable Disease (SD) is defined as neither shrinkage to qualify for a PR or increase to qualify for a PD. | Six 21-day cycles | 
| Overall Survival (OS) Using a Multivariate Cox Regression Model in the Intent-to-Treat Population |  | Until death or lost to follow-up, up to 12 months since randomization | 
| Chemistry NCI-CTCAE Toxicity Grade of 3 or 4 (Safety Population) |  | Days 1 (pretreatment) per 21-day Cycle (6 Cycles) | 
| Hematology NCI-CTCAE Grade 3 or 4 (Safety Population) |  | Days 1 (pretreatment), 7, 14, and 21 per 21-day Cycle (6 Cycles) | 
| Coagulation NCI-CTCAE Grade 3 or 4 (Safety Population) |  | Day 1 (pretreatment) per 21-day Cycle (6 Cycles) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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non-small cell lung cancer, non-small cell lung carcinoma, neoplasms, lung, lung cancer, tumors, NSCLC