Docetaxel & Oxaliplatin in Combination With Bevacizumab as First-Line Treatment in Subjects With Non-Small Cell Lung Cancer (NSCLC)

A Phase II Multicenter Study of Docetaxel and Oxaliplatin in Combination With Bevacizumab as First-Line Treatment in Chemotherapy-Naïve Subjects With Unresectable Locally Advanced and/or Recurrent (Stage IIIB) or Metastatic (Stage IV) Non-Squamous Cell Histology Non-Small Cell Lung Cancer (NSCLC)

The purpose of this study was to see how well three investigational drugs worked together in preventing progression of the disease. This study provided a new combination of chemotherapy drugs - docetaxel and oxaliplatin - as first line therapy in the treatment of lung cancer. The therapy included bevacizumab that may prevent or slow down the blood supply to the tumor and may also prevent tumor growth. The three investigational drugs are United States Food and Drug Administration (FDA) approved.

The planned treatment duration for each participant is six 21-day treatment cycles of combination therapy; non-progressing participants will continue on bevacizumab monotherapy until progression. After discontinuation or after completion of all study treatments, all participants will be contacted every 3 months for a maximum of 2 years from first treatment to document overall survival and record new anticancer treatment (chemotherapy or biologic).

Inclusion Criteria

Participants who met all of the following criteria during screening were considered for enrollment into the study:

1. Had the informed consent in writing for all prior to registration into the study

2. Had histologic or cytologic confirmation of locally advanced or metastatic (stage IIIb/IV) NSCLC (non-squamous histology). Participants with mixed tumor types could have been enrolled, unless small cell elements were discovered

3. Had measurable disease, defined as at least 1 lesion that could be accurately measured in at least 1 dimension (longest diameter) as ≥ 2.0 cm with conventional computerized tomography (CT) or magnetic resonance imaging (MRI) scans, or as ≥ 1.0 cm with spiral CT scan

4. Had no prior systemic chemotherapy

5. Was male or female ≥ 18 years old

6. Had an estimated life expectance of ≥ 12 weeks

7. Had an ECOG performance status (PS) of 0, 1, or 2

8. Was a nonpregnant, nonlactating female Was a male or female of childbearing potential who was willing to use an effective form of contraception while on therapy and for 90 days thereafter.

9. Had adequate renal function as determined by the following within 2 weeks prior to study registration.

   • A calculated creatinine clearance greater than 45 mL/min using the Cockcroft-Gault formula
   • A urine dipstick or urinalysis for protein <2+ (Participants discovered to have ≥ 2+ proteinuria on dipstick or urinalysis at baseline had to undergo a 24 hour urine collection and had to have ≤ 1 gm of protein over 24 hours to be eligible).

10. Had a hematologic evaluation within 2 weeks prior to study registration (and met the minimum values):

    • Had absolute neutrophil count (ANC) ≥ 1,500 cells/microL
    • Had platelet count ≥ 100,000 cells/microL
    • Had hemoglobin ≥ 9.9 gm/deciL (erythropoietin [e.g., Epogen®] could have been used to maintain or exceed this level)
    • Had a partial thromboplastin time (PTT) ≤ upper limit of normal (ULN)

11. Had a hepatic function evaluation within 2 weeks prior to study registration met the eligibility criteria for bilirubin, Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase.

Exclusion criteria

Participants with any of the following were not included in the study:

1. Had received prior systemic chemotherapy or vascular endothelial growth factor (VEGF) or epidermal growth factor receptor (EGFR) inhibitor therapy at any time; or had received recent or current radiation therapy

2. Had intrathoracic lung carcinoma of squamous cell histology. (Participants with extrathoracic-only squamous cell NSCLC were eligible. Participants with only peripheral lung lesions (of any NSCLC histology) were also eligible

3. Had cardiovascular diseases and related treatment, including the following:

   • New York Heart Association Class ≥ 2 congestive heart failure; participants with a history of serious cardiac disease not adequately controlled; or a history of myocardial infarction or unstable angina pectoris within 6 months prior to study registration
   • History of stroke or transient ischemic attack within 6 months of study registration
   • History of hypertensive crisis or hypertensive encephalopathy
   • History of thrombotic or hemorrhagic disease
   • Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation)
   • Clinically meaningful peripheral vascular disease, or arrhythmia
   • Inadequately controlled blood pressure (defined as systolic blood pressure >150 mm Hg and/or diastolic blood pressure >100 mm Hg)
   • Significant vascular disease (e.g., aortic aneurysm, aortic dissection) within 6 months prior to study registration
   • Therapeutic anticoagulation (Participants receiving prophylactic anticoagulation for venous access devices were allowed providing they met certain criteria)
   • Chronic daily treatment with aspirin (≥ 325 mg/day) or nonsteroidal anti-inflammatory agents known to inhibit platelet function; treatment with dipyridamole, ticlopidine, clopidogrel, or cilostazol was not allowed.

4. Had a surgical procedure in anamnesis (medical history):

   • Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks prior to study registration, or anticipation of need for major surgical procedure during the course of the study
   • In the case of high-risk procedures, such as liver resection, thoracotomy, or neurosurgery, within 8 weeks prior to study registration
   • Minor surgical procedures (e.g., fine needle aspirations, core biopsies) within 7 days prior to registration

5. Had a serious nonhealing wound, active ulcer, or untreated bone fracture

6. Had a history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study registration

7. Had a history of gross hemoptysis (defined as bright red blood of ≥ 0.5 teaspoon) within 4 weeks prior to study registration

8. Had a history of hypersensitivity reaction to drugs formulated with polysorbate 80 or platinum containing compounds

9. Had peripheral neuropathy ≥ Grade 2 (based on CTCAE v3.0)

10. Had known central nervous system (CNS) disease, except for treated brain metastasis. However, participants with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to study registration were excluded.

11. Had a history of a malignancy other than NSCLC; exceptions to this included:

    • Curatively treated basal cell carcinoma, cervical intraepithelial neoplasia, or localized prostate cancer with a current prostate-specific antigen (PSA) of less than 1.0 ng/dL on 2 successive evaluations at least 3 months apart, and the most recent evaluation being within 4 weeks of study registration
    • History of another malignancy that was curatively treated and no evidence of disease for a minimum of 5 years

12. Had symptoms of a clinically meaningful illness in the 90 days before study registration, or had history of other disease, (such as human immunodeficiency virus [HIV] positive, chronic infection [e.g., pulmonary tuberculosis], or hepatitis A, B, or C [active or previously treated]), had an active infection with fever, had metabolic dysfunction, had physical examination finding, or had clinical a laboratory finding giving reasonable suspicion of a disease or condition that contraindicated the use of an investigational drug, that might affect the interpretation of the results of the study, or render the participant at high risk from treatment complications; (testing for these conditions was at investigator discretion)

13. Had a mental condition rendering the participant unable to understand the nature, scope, and possible consequences of the study

The above information is not intended to contain all considerations relevant to a patients potential participation in a clinical trial.