This is a phase II, single institution trial for patients with clinical Stage IB-IIIA NSCLC (T1-3N0-2M0) who have resectable lung tumors. The primary goal of this study is to show that the addition of bevacizumab to a cisplatin-based chemotherapy in the neoadjuvant setting for non-squamous cell carcinomas improves the rate of pathologic downstaging, which correlates with survival. Downstaging is defined as any decrease in the final pathologic stage compared with the clinical stage before induction therapy.

Condition	Intervention	Phase
Carcinoma, Non-Small-Cell Lung Carcinoma, Squamous Cell	Drug: Bevacizumab  Drug: Docetaxel  Drug: Cisplatin	Phase II

Further Study Details: 

Primary Outcomes: The primary goal of this study is to show that the addition of bevacizumab to cisplatin-based chemotherapy in the neoadjuvant setting for non-squamous cell carcinomas improves the rate of pathologic downstaging.
Secondary Outcomes: To determine the 3-year overall survival and median survival for stage IB-IIIA NSCLC patients treated with cisplatin-based chemotherapy ± bevacizumab (groups A and B combined).
Expected Total Enrollment:  70

Primary Objective:

*To determine the rate of downstaging for Stage IB-IIIA NSCLC patients treated with neoadjuvant chemotherapy + bevacizumab (group A only; non-squamous cell). Downstaging is defined as any decrease in the final pathologic stage compared with the clinical stage before induction therapy.

Secondary Objectives:

• To determine the 3-year overall survival and median survival for stage IB-IIIA NSCLC patients treated with cisplatin-based chemotherapy ± bevacizumab (groups A and B combined).
• For patients with stage IB-IIIA NSCLC, to determine the safety profiles of preoperative bevacizumab + chemotherapy and postoperative bevacizumab monotherapy.
• To explore potential surrogate markers of bevacizumab activity, including levels of VEGF-A (in plasma and in platelets), endothelial progenitor cells (EPCs), and hematopoietic progenitor cells (HPCs).
• In pre and post-treatment tumor samples, to evaluate expression of VEGF receptors 1, 2, 3 and cognate ligands and explore the relationships with downstaging, objective response rate, and survival.
• To explore if radiologic response to bevacizumab can be detected by 3-D volumetric CT scan.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria:

• Pathologic confirmation of NSCLC at MSKCC
• Stages IB, IIA, IIB or IIIA (T1-3N0-2M 0) NSCLC
• Patients must be candidates for resection with curative intent.
• Measurable disease, defined as at least one lesion that can be accurately measured in at least two dimensions
• Age >= 18 years
• Karnofsky performance status >= 70%
• Normal marrow function: leukocytes >=3,000/ul, absolute neutrophil count >=1,500ul, platelets >=100,000ul, hemoglobin >=9gm/dl
• Adequate renal function, with creatinine <= 1.3 mg/dl or calculated creatinine clearance >=60ml/min by Cockcroft and Gault equation using parameters of age, weight (kg), and baseline serum creatinine (mg/dl)
• Adequate hepatic function: Total bilirubin within normal limits, AST <= 1.5 x UNL, ALT <= 1.5 x UNL, alkaline phosphatase <= 1.5 x UNL
• Women of childbearing age must have a negative urine or blood pregnancy test
• Men and women of childbearing potential must be willing to consent to using effective contraception while on treatment and for at least 3 months thereafter.
• Patients must have ability to understand and the willingness to sign a written informed consent document.
• For group B: Patients with SQUAMOUS CELL carcinoma or NON-SQUAMOUS CELL large central tumor in proximity blood vessels will be assigned to group B (preoperative chemotherapy).

Exclusion Criteria:

• Prior chemotherapy or radiation therapy, with the exception of chemotherapy for non-oncologic conditions (ie, methotrexate for the treatment of rheumatoid arthritis)
• Prior treatment with bevacizumab or other agents specifically targeting VEGF
• Patients with a history of severe hypersensitivity reaction to docetaxel (Taxotere) or other drugs formulated with polysorbate 80
• Patients with known hypersensitivity to other recombinant human antibodies
• Patients must not be receiving any other investigational agents
• Prior malignancy in the past 5 years, other than non-melanoma skin cancer and in situ carcinoma of the cervix
• Patients who report a hearing deficit at baseline, even if it does not require a hearing aid or intervention, or interfere with activities of daily life (CTCAE grade 2 or higher)
• Peripheral neuropathy > grade 1.
• Uncontrolled hypertension
• History of arterial thromboembolic events, including transient ischemic attack (TIA), cerebrovascular accident (CVA), unstable angina, or myocardial infarction (MI) within the last 3 years.
• Patients with clinically significant peripheral arterial disease
• Urine protein:creatinine ratio >=1.0 at screening
• History of thrombotic disorders or coagulopathy
• History of bleeding diathesis or hemorrhagic disorders.
• Patients must have INR <=1.5 and a PTT <=1.5 x upper limits of normal (UNL).
• Current use of warfarin.
• Current use of heparin or low-molecular weight heparin. -Chronic daily treatment with aspirin (>81mg/day) or nonsteroidal anti- inflammatory medications known to inhibit platelet function. Treatment with dipyramidole (Persantine), ticlopidine (Ticlid), clopidogrel (Plavix) and or cilostazol (Pletal) is also not allowed.
• Esophageal varices, non-healing ulcer, wound, or bone fracture
• Patients with gross hemoptysis (defined as bright red blood of ½ teaspoon of more) within 28 days prior to Day 0 protocol treatment will be excluded from this trial.
• Significant traumatic injury or major surgery within 28 days prior to Day 0 of protocol treatment

Please refer to this study by ClinicalTrials.gov identifier  NCT00130780

Naiyer Rizvi, M.D.      212-639-3204    rizvin@mskcc.org

New York
      Memorial Sloan Kettering Cancer Center, New York,  New York,  10021,  United States

Study chairs or principal investigators

Naiyer Rizvi, M.D.,  Principal Investigator,  Memorial Sloan-Kettering Cancer Center   

Study ID Numbers:  05-052
Last Updated:  August 15, 2005
Record first received:  August 12, 2005
ClinicalTrials.gov Identifier:  NCT00130780
Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2005-08-23