Study of Erlotinib (Tarceva®) in Combination With OSI-906 in Patients With Advanced Non-small Cell Lung Cancer (NSCLC) With Activating Mutations of the Epidermal Growth Factor Receptor (EGFR) Gene

• Overall Survival (OS) [ Time Frame: 33 months ] [ Designated as safety issue: No ]
  Time from the date of randomization until the documented date of death.
• Disease Control Rate (DCR) [ Time Frame: 33 months ] [ Designated as safety issue: No ]
  Proportion of patients with a best overall response of complete response (CR), partial response (PR), or stable disease based on RECIST version 1.1 criteria.
• Best Overall Response Rate [ Time Frame: 33 months ] [ Designated as safety issue: No ]
• Duration of Response (CR/PR) [ Time Frame: 33 months ] [ Designated as safety issue: No ]

  Time from the date of the first documented response (CR/PR) to documented progression or death due to underlying cancer.

  Defined for patients whose best overall response was CR or PR.

• Safety assessed through evaluation of adverse events, laboratory, physical examination, and Electrocardiogram (ECG) data [ Time Frame: 33 months ] [ Designated as safety issue: No ]

• Overall Survival [ Time Frame: 15 months ] [ Designated as safety issue: No ]
• Disease Control Rate [ Time Frame: 15 months ] [ Designated as safety issue: No ]
• Duration of Response [ Time Frame: 15 months ] [ Designated as safety issue: No ]
• Safety Profile of OSI-906/erlotinib combination [ Time Frame: 15 months ] [ Designated as safety issue: Yes ]
  The safety evaluation will be based mainly on adverse events, laboratory, physical examination, and ECG data.
• Pharmacokinetics (PK) profile of OSI-906/erlotinib combination [ Time Frame: 15 months ] [ Designated as safety issue: No ]
  Plasma concentrations of OSI-906 and erlotinib/OSI-420 (a metabolite of erlotinib) will be obtained from analysis of plasma samples.
• Exploratory Biomarkers and correlations with treatment outcome [ Time Frame: 15 months ] [ Designated as safety issue: No ]
  Exploratory biomarker analysis will include relationships between biomarkers, including proteins and nucleic acids, and the effects of OSI-906/erlotinib on clinical outcome.
• Overall Response Rate [ Time Frame: 15 months ] [ Designated as safety issue: No ]

A multicenter, randomized, double-blind, placebo-controlled, phase 2 study of Erlotinib (Tarceva®) in combination with OSI-906 in Patients with Advanced non-small cell lung cancer (NSCLC) with Activating Mutations of the Epidermal Growth Factor Receptor (EGFR) Gene who are Chemonaive.

Based on the recommendation of the Data Monitoring Committee, OSI-906 and matching placebo are no longer being administered as of 01 March 2013.

This is a multi-center, randomized (1:1), double-blind, placebo-controlled, phase 2 study. Patients will be stratified according to the following 2 parameters: (1) EGFR activating mutation type (exon 19 deletion versus exon 21 single point mutation); and (2) Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. 1).

• Non Small Cell Lung Cancer
• NSCLC

• Drug: OSI-906
  As of 01 March 2013, OSI-906 is no longer being administered
• Drug: Erlotinib
  Erlotinib administered orally
  Other Names:

  • Tarceva
  • OSI-774
• Drug: Placebo
  As of 01 March 2013, the matching placebo is no longer being administered

• Experimental: Arm A: Erolitinib plus OSI-906
  As of 01 March 2013, OSI-906 is no longer being administered
  Interventions:

  • Drug: OSI-906
  • Drug: Erlotinib
• Placebo Comparator: Arm B: Eroltinib plus Placebo
  As of 01 March 2013, the matching placebo is no longer being administered
  Interventions:

  • Drug: Erlotinib
  • Drug: Placebo

Inclusion Criteria:

• Historically confirmed advanced NSCLC stages IIIB or IV
• Exon 19 deletion or exon 21 activating mutation in EGFR
• EGFR mutation status must be confirmed for participation in the study. EGFR 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 sponsor 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 for biomarker central 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 according to RECIST (version 1.1)
• ECOG performance status 0-1
• Must be able to take oral medication
• Fasting glucose <= 150 mg/dL (8.3 mmol/L). Concurrent use of non-insulinotropic anti hyperglycemic therapy is permitted if the dose has been stable for >= 4 weeks at the time of randomization

• Adequate hematopoietic, hepatic, and renal function as follows:

  • Neutrophil count >= 1500/uL
  • Platelet count >= 100,000/uL
  • Serum creatinine <= 1.5 x Upper Limit of Normal (ULN)
  • Potassium, magnesium, and calcium within normal limits (supplementation and re-testing is permitted)
  • Total bilirubin <= 1.5 x ULN
  • AST and ALT <= 2.5 x ULN, or <= 5 x ULN if patient has documented liver metastases
• Patients - both male and female - with reproductive potential (ie, menopausal for less than 1 year and not surgically sterilized) must agree to practice effective contraceptive measure throughout the study. Women of childbearing potential must provide a negative pregnancy test (serum or urine) within 14 days prior to randomization. Men must agree not to donate sperm while on study drug and up to 90 days following the last dose of study drug
• Patients must provide written informed consent to participate in the study
• Patients may not have received chemotherapy for advanced NSCLC. Previous adjuvant and/or neoadjuvant treatment for NSCLC is permitted
• Prior radiation therapy is permitted provided patients have recovered from the 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 done >= 28 days prior to randomization and adequate wound healing has occurred prior to randomization

Exclusion Criteria:

• Prior exposure to agents directed at the Human Epidermal Receptor (HER) axis (eg, erlotinib, gefitinib, and cetuximab)
• Prior insulin-like growth factor -1 receptor (IGF-1R) inhibitor therapy
• Malignancies other than NSCLC within the 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)
• Diabetes mellitus currently requiring insulinotropic or insulin therapy
• Use of proton pump inhibitors such as omeprazole within 14 days prior to randomization. H2-receptor antagonists such as ranitidine are not excluded
• Symptomatic brain metastases that are not stable, require steroids, or have required radiation and/or other related treatment (i.e., anti-epileptic medication) within 21 days prior to randomization
• Prior investigational agent within 21 days prior to randomization
• History of poorly controlled gastrointestinal disorders that could affect the absorption of study drug (eg, Crohn's disease or ulcerative colitis)
• History (within last 6 months) 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 no 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 at screening
• Use of drugs that have a known risk of causing Torsades de Pointes (TdP) ('Torsades List' on www.azcert.org/medical-pros/drug-lists/bycategory.cfm) are prohibited within 14 days prior to randomization
• Use of strong/moderate CYP1A2 inhibitors such as ciprofloxacin and fluvoxamine. Other less potent CYP1A2 inhibitors/inducers are not excluded
• Use of strong/moderate CYP3A4 inhibitors and inducers
• History of cerebrovascular accident (CVA) within 6 months prior to randomization or that resulted in ongoing neurologic instability
• 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
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to the study drug
• Active infection, serious underlying medical condition (including any type of active seizure disorder within 12 months prior to randomization), symptomatic brain metastases, or serious chronic illness that would impair the ability of the patient to receive study drug