Phase 2 Study of Maintenance OSI-906 Plus Erlotinib (Tarceva®), or Placebo Plus Erlotinib in Patients With Nonprogression Following 4 Cycles of Platinum-based Chemotherapy

Adult patients with advanced Non-small Cell Lung Cancer (NSCLC) and nonprogression after platinum-based chemotherapy will be randomized 1:1 to receive either OSI-906 plus erlotinib or placebo plus erlotinib.

Inclusion criteria

• Histologically confirmed locally advanced or metastatic stage IIIB or IV NSCLC
• Have experienced Complete Response (CR), Partial Response (PR) or Stable Disease (SD) following completion of 4 cycles of first-line platinum-based chemotherapy and are not progressing at time of entry into study (prior completed first-line combination bevacizumab therapy is permitted; however, current use of maintenance bevacizumab is not permitted. A maximum interval of 28 days between the last day of the treatment cycle and randomization
• Patient has recovered from prior chemotherapy-related toxicity to ≤ grade 2
• EGFR mutation status must be confirmed for participation in the study. EGFR analysis can be performed either by central or local laboratory. If analysis is done locally, verifiable documentation confirming the EGFR mutation status must be submitted for review and approval by APGD prior to randomization. If no local result is available, formalin-fixed, paraffin-embedded archival tissue representative of the tumor or in the absence of archival tissue, a fresh tumor tissue sample of sufficient size to perform EGFR mutation analysis must be submitted centrally. Results of the central analysis must be available prior to randomization. Additionally, subjects should provide tissue blocks centrally for biomarker analysis whenever possible. Ideal tissue requirement: block with ≥5 mm2 tumor area sufficient to provide four 4-micron, and five 10-micron sections)
• Measurable disease (for those patients with PR or SD after first-line platinum-based chemotherapy) according to Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1)
• Eastern Cooperative Oncology Group (ECOG) Performance Status(PS) 0 - 1
• Previous adjuvant or neo-adjuvant treatment is permitted
• Must be able to take oral medication
• Fasting glucose ≤ 150 mg/dL (8.3 mmol/L). Concurrent use of non-insulinotropic antihyperglycemic therapy is permitted if the dose has been stable for ≥ 4 weeks at the time of randomization
• Adequate hematopoietic, hepatic, and renal function defined as follows:

• Neutrophil count ≥ 1.5 x 109/L
• Platelet count ≥ 100 x 109/L
• Bilirubin ≤ 1.5 x Upper Limit of Normal (ULN)
• AST and ALT ≤ 2.5 x ULN, or ≤ 5 x ULN if patient has documented liver metastases
• Serum creatinine ≤ 1.5 x ULN
• Potassium, magnesium and calcium within normal limits (supplementation and retesting is permitted)

Female patient must be either:

• Of non child bearing potential:

• post-menopausal (defined as at least 1 year without any menses) prior to

Screening, or

• documented surgically sterile or status post hysterectomy (at least 1 month prior to Screening)

• Or, if of childbearing potential:
• must have a negative urine pregnancy test at Screening, and
• must use two forms of birth control (one of which must be a barrier method) starting at Screening and throughout the study period and for 30 days after final study drug administration

• Female patient must not be breastfeeding at Screening or during the study period and for 30 days after final study drug administration
• Female patient must not donate ova starting at Screening and throughout the study period and for 30 days after final study drug administration
• Male patient and their female spouse/partners who are of childbearing potential must be using highly effective contraception consisting of two forms of birth control (one of which must be a barrier method) starting at Screening and continue throughout the study period and for 30 days after final study drug administration
• Male patient must not donate sperm starting at Screening and throughout the study period and for at least 30 days after final study drug administration
• Prior radiation therapy is permitted provided patients have recovered from acute toxic effects of radiotherapy prior to randomization. A minimum of 28 days must have elapsed between the end of radiotherapy and randomization
• Prior surgery is permitted provided that the surgery was performed 21 days prior to randomization and adequate wound healing has occurred prior to randomization
• Patients must provide written (signed) informed consent to participate in the study and for use of tumor tissues

Exclusion criteria

• Prior exposure to agents directed at the Human Epidermal Receptor (HER) axis (eg, erlotinib, gefitinib, cetuximab, and trastuzumab)
• Malignancies other than NSCLC within past 3 years (exceptions if curatively treated: basal or squamous cell carcinoma of skin; locally advanced prostate cancer; ductal carcinoma in situ of breast; in situ cervical carcinoma; and superficial bladder cancer)
• Type 1 diabetes mellitus or Type 2 diabetes mellitus currently requiring insulinotropic or insulin therapy
• Prior insulin-like growth factor receptor (IGF-1R)
• Prior investigational agent within 21 days prior to randomization
• Concurrent use of maintenance bevacizumab
• History of poorly controlled gastrointestinal disorders that could affect the absorption of study drug (eg, Crohn's disease, ulcerative colitis, etc)
• History (within last 180 days) of significant cardiovascular disease unless the disease is well-controlled. Significant cardiac disease includes second/third degree heart block; clinically significant ischemic heart disease; superior vena cava (SVC) syndrome; poorly controlled hypertension; congestive heart failure of New York Heart Association (NYHA) Class II or worse (slight limitation of physical activity; comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea)
• History of arrhythmia (multifocal premature ventricular contractions [PVCs], bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) that is symptomatic or requires treatment (≥ grade 3), left bundle branch block (LBBB), or asymptomatic sustained ventricular tachycardia are not allowed. Patients with atrial fibrillation controlled by medication are not excluded
• Mean QTcF interval > 450 msec based on independent central reviewer analysis of screening visit ECGs
• Use of drugs that have a known risk of causing Torsades de Pointes (TdP) are prohibited within 14 days prior to randomization
• Use of the potent CYP1A2 inhibitors ciprofloxacin and fluvoxamine. Other less potent CYP1A2 inhibitors/inducers are not excluded
• Use of potent CYP3A4 inhibitor such as ketoconazole, clarithromycin, atazanavir, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO), or voriconazole
• Use of proton pump inhibitors such as omeprazole. Use of H2-receptor antagonists such as ranitidine are not excluded
• History of cerebrovascular accident (CVA) within 180 days prior to randomization or that resulted in ongoing neurologic instability
• Active infection, serious underlying medical condition (including any type of active seizure disorder within 12 months prior to randomization), or serious chronic illness that would impair the ability of the patient to receive study drug
• History of any psychiatric or neurologic condition that might impair the patient's ability to understand or to comply with the requirements of the study or to provide informed consent
• Pregnant or breast-feeding females
• Symptomatic brain metastases that are not stable, require steroids, or that have required radiation and/or other related treatment (e.g., anti-epileptic medication) within 21 days prior to randomization
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to study drug
• Participated in any interventional clinical study or has been treated with any investigational drugs within 30 days or 5 half lives whichever is longer, prior to the initiation of Screening or during the course of the study