A Randomized, Double-Blind, Phase 3 Study of Docetaxel and Ramucirumab versus Docetaxel and Placebo in the Treatment of Stage IV Non-Small Cell Lung Cancer Following Disease Progression after One Prior Platinum-Based Therapy

Eligible male and female patients are required to: (1) have histologically or cytologically confirmed NSCLC, Stage IV based on the AJCC 7th edition; (2) have had disease progression during or after 1and only 1 prior first-line platinum based chemotherapy which may include bevacizumab with or without maintenance therapy for advanced/metastatic disease; (3) be at least 18 years of age; (4) have a life expectancy >=3 months; and (5) have adequate organ function.

[15] The patient has had disease progression on more than 1 prior chemotherapy regimens (with or without maintenance therapy) for advanced and/or metastatic disease.
[16] Patients whose only prior treatment for advanced disease was a tyrosine kinase inhibitor (for example, erlotinib).
[17] The patient's tumor wholly or partially contains small cell lung cancer.
[18] The patient has undergone major surgery within 28 days prior to randomization, or subcutaneous venous access device placement within 7 days prior to randomization. Furthermore, any patient with postoperative bleeding complications or wound complications from a surgical procedure performed in the last 2 months will be excluded.
[19] The patient has an elective or a planned major surgery during the course of the trial.
[20] The patient is receiving concurrent treatment with other anticancer therapy, including other chemotherapy, immunotherapy, hormonal therapy, chemoembolization, or targeted therapy.
• The last dose of bevacizumab must be at least 28 days from the time of randomization.
• The last dose of cytotoxic chemotherapy must be at least 14 days from the time of randomization.
[21] The patient has untreated CNS metastases. Patients with treated brain metastases are eligible if they are clinically stable with regard to neurologic function, off steroids after cranial irradiation (whole brain radiation therapy, focal radiation therapy, and stereotactic radiosurgery) ending at least 2 weeks prior to randomization, or after surgical resection performed at least 28 days prior to randomization. The patient may have no evidence of Grade >=1 CNS hemorrhage based on pretreatment MRI or IV contrast CT scan (performed within 21 days before randomization).
[22] The patient has radiologically documented evidence of major blood vessel invasion or encasement by cancer.
[23] The patient has radiographic evidence of intratumor cavitation, regardless of tumor histology.
[24] The patient has a history of uncontrolled hereditary or acquired thrombotic disorder.
[25] The patient is receiving therapeutic anticoagulation with warfarin, low-molecular weight heparin, or similar agents. Patients receiving prophylactic, low-dose anticoagulation therapy are eligible provided that the coagulation parameters defined in the inclusion criteria (INR <=1.5, or PT <=1.5 x ULN and PTT/aPTT <=1.5 x ULN) are met.
[26] The patient is receiving chronic therapy with nonsteroidal anti-inflammatory drugs (NSAIDs; for example, indomethacin, ibuprofen, naproxen, or similar agents) or other antiplatelet agents (for example, clopidogrel, ticlopidine, dipyridamole, and anagrelide). Aspirin use at doses up to 325 mg/day is permitted.
[27] Patients with a history of gross hemoptysis (defined as bright red blood or >=1/2 teaspoon) within 2 months prior to randomization.
[28] The patient has clinically relevant congestive heart failure (NYHA II-IV) or symptomatic or poorly controlled cardiac arrhythmia.
[29] The patient has experienced any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to randomization.
[30] The patient has uncontrolled arterial hypertension >=150 / >=90 mm Hg despite standard medical management.
[31] The patient has had a serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to randomization.
[32] The patient has significant bleeding disorders, vasculitis, or experienced Grade 3/4 gastrointestinal (GI) bleeding within 3 months prior to randomization.
[33] History of GI perforation and / or fistulae within 6 months prior to randomization.
[34] The patient has a bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection (hemicolectomy or extensive small intestine resection with chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic diarrhea.
[35] The patient has peripheral neuropathy >=Grade 2 (NCI-CTCAE v 4.02).
[36] The patient has a serious illness or medical condition(s) including, but not limited to, the following:
• Known human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness.
• Active or uncontrolled clinically serious infection.
• Previous or concurrent malignancy except for basal or squamous cell skin cancer and/or in situ carcinoma of the cervix, or other solid tumors treated curatively and without evidence of recurrence for at least 3 years prior to randomization.
• Uncontrolled metabolic disorders or other nonmalignant organ or systemic diseases or secondary effects of cancer that induce a high medical risk and/or make assessment of survival uncertain.
• Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient ineligible for entry into this study.
• The patient has significant third-space fluid retention (e.g., ascites or pleural effusion), and is not amenable for required repeated drainage.
• Known allergy or hypersensitivity reaction to any of the treatment components.
• The patient has a known history of drug abuse.
[37] The patient is pregnant (confirmed by urine or serum beta human chorionic gonadotropin [β-HCG] test within 7 days prior to randomization), or breastfeeding.
[38] Patient is currently enrolled in or discontinued within 28 days prior to randomization from a clinical trial involving an investigational product or nonapproved use of a drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study. Patients participating in surveys or observational studies are eligible to participate in this study.
[39] Prior therapy with docetaxel.