Study of Osimertinib With and Without Ramucirumab in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC)

Exclusion Criteria

• •Subjects unable to stop use of medications that are potent inducers of CYP3A4 or known to prolong QT interval. See Appendix B for additional details.
• •Any prior history of other cancer within the prior 2 years with the exception of: adequately treated basal cell carcinoma, cervical intraepithelial neoplasia \[CIN\]/cervical carcinoma in situ, melanoma in situ or ductal carcinoma in situ \[DCIS\], localized Gleason 6 prostate cancer, papillary thyroid cancer or other non-melanoma skin cancers.
• •Previous treatment with any EGFR TKIs, including erlotinib, gefitinib, afatinib, avitinib, dacomitinib, rociletinib, or osimertinib.
• •Previous treatment with any anti-VEGF medications, including vandetinib, nintedanib, bevacizumab, or ramucirumab.
• •Spinal cord compression unless asymptomatic or stable for at least 2 weeks prior to start of study treatment.
• •Any unresolved toxicities from prior therapy greater than CTCAE grade 1 (with the exception of alopecia grade 2) at the time of starting study treatment.
• •Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator's opinion makes it undesirable for the subject to participate in the trial or which would jeopardize compliance with the protocol, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
• •Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of osimertinib.
• •Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.
• •Patients with uncharacterized eye disorders.
• •History of hypersensitivity of osimertinib or ramucirumab (or active or inactive excipients of osimertinib or ramucirumab).
• •Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirement.
• •Any of the following cardiac criteria:
• •* Mean resting corrected QT interval (QTc using Fridericia's formula) \> 470 msec.
• •* Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval \>250msec.
• •* Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval.
• •* The patient has experienced any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to first dose of protocol therapy.
• •* The patient has uncontrolled or poorly-controlled hypertension (\>160 mmHg systolic or \> 100 mmHg diastolic for \>4 weeks) despite standard medical management.
• •The patient has experienced any Grade 3-4 GI bleeding within 3 months prior to first dose of protocol therapy.
• •The patient has a history of deep vein thrombosis (DVT), pulmonary embolism (PE), or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered "significant") during the 3 months prior to first dose of protocol therapy.
• •The patient has cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis.
• •Any hemoptysis (defined as bright red blood or ≥ 1/2 teaspoon) within 2 months prior to first dose of protocol therapy or with radiographic evidence of intratumor cavitation or has radiologically documented evidence of major blood vessel invasion or encasement by cancer.
• •The patient has a prior history of GI perforation/fistula (within 6 months of first dose of protocol therapy) or risk factors for perforation.
• •The patient has a serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to first dose of protocol therapy.
• •The patient has undergone major surgery within 28 days prior to first dose of protocol therapy, or minor surgery/subcutaneous venous access device placement within 7 days prior to the first dose of protocol therapy. The patient has elective or planned major surgery to be performed during the course of the clinical trial.