A Randomized, Open-Label Phase 2 Study Evaluating LY2875358 Plus Erlotinib and LY2875358 Monotherapy in MET Diagnostic Positive NSCLC Patients with Acquired Resistance to Erlotinib

[1] Have a histologically or cytologically confirmed diagnosis of metastatic Stage IV NSCLC at the time of study entry (American Joint Committee on Cancer Staging Criteria for NSCLC, 7th edition; Edge et al. 2009) and must be, in the judgment of the investigator, an appropriate candidate for experimental therapy.;[2] Have at least 1 measurable extra-CNS lesion whose presence is assessable using standard techniques by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) (Eisenhauer et al. 2009). For patients with prior radiation therapy, measurable lesions must be outside a previous radiotherapy field if they are the sole site of disease, unless disease progression has been documented at that site since radiation. ;[3] Have documented radiographic progression of disease (use RECIST version 1.1 as guidance for definition of progression) while on continuous treatment with erlotinib monotherapy within at least the last 28 days (minimum >=100 mg erlotinib/d). Patients may not have received any other intervening systemic therapy since most recent radiographic progression on erlotinib except erlotinib which is allowed to be continued at the investigator*s discretion until initiation of study treatment. Patients who stopped erlotinib treatment upon progression will need to initiate JTBC study treatment no later than 28 days after discontinuing erlotinib. ;NOTE: Patients whose disease progresses only in the central nervous system (CNS) are not eligible.;[4] Have either one or both of the following:;• Molecular evidence of an activating EGFRmt known to be associated with EGFR TKI drug sensitivity (G719X, exon 19 deletion, L858R, L861Q; further activating EGFRmt may be included in the future if supported by scientific evidence after discussion with the sponsor) from a tumor sample based on testing with a validated EGFRmt assay. ;• Objective clinical benefit from most recent erlotinib treatment as defined by either documented partial or complete response or stable disease >=6 months as defined by RECIST version 1.1 in absence of radiographic progression after initiation of erlotinib. Patients with only symptomatic improvement while on erlotinib but no corresponding evidence of radiographic stability of disease are not eligible.;[5] Determined to be MET diagnostic (+) as determined by the Study JTBC central laboratory based upon testing of a NSCLC tumor sample obtained at any time (ie. time of diagnosis of NSCLC or any time beyond). ;[6] Availability of a tumor sample taken from an extra-CNS lesion, or patient willingness to undergo a tumor biopsy of an extra-CNS lesion, post-erlotinib progression. The tumor sample should be taken from a progressing lesion on erlotinib whenever possible. ;[7] Performance status of <=2 on the Eastern Cooperative Oncology Group (ECOG) scale.;[8] Have adequate organ function, as demonstrated by: ;• Hematologic: Absolute neutrophil count (ANC) *1.5 × 109/L, platelets *100 × 109/L, and hemoglobin *8 g/dL. Patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin until 14 days after the erythrocyte transfusion.;• Hepatic: bilirubin <=1.5 times upper limits of normal (ULN), albumin >=25 g/L alkaline phosphatase (ALP), and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <=2.5 times ULN or <=5 times ULN in patients with hepatic metastases.;• Renal: Serum creatinine level <=1.5 × ULN or calculated serum creatinine clearance >=50 mL/min, according to the method of Cockcroft and Gault.;[9] Patients who require oral anticoagulants (eg. warfarin) are eligible provided there is increased vigilance with respect to the monitoring of INR, according to investigator judgment. If medically appropriate and the treatment is available, the investigator may also consider switching these patients to low-molecular-weight heparin, with which an interaction with LY2875358 or erlotinib is not expected.;[10] Are male or female and at least 18 years old (or older if required by local law or regulations) at the time of screening.;[11] Eligible patients of reproductive potential (both sexes) must agree to use adequate contraceptive methods (hormonal or barrier methods) during the study period and at least 12 weeks after the last dose of study therapy, or longer if required by local regulations.;Women of child-bearing potential must test negative for pregnancy within 7 days prior to enrollment based on a serum pregnancy test and must also not be breastfeeding. ;[12] Are able to swallow tablets.;[13] Have an estimated life expectancy of at least 12 weeks in the judgment of the investigator.;[14] Have given written informed consent/assent prior to any study-specific procedures and are willing to make themselves available for the duration of the study and are willing to follow study procedures.

[15] Are currently enrolled in, or discontinued within the last 30 days 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.;[16] Have previously completed or withdrawn from this study (exclusive patients who are rescreened prior to enrollment) or have been treated previously with LY2875358 or any other MET-targeting experimental therapeutic (including but not limited to: XL184, ARQ197, MetMab, crizotinib). There are no limitations to systemic therapies regimens (including any EGFR-directed therapies) prior to the most recent progression on erlotinib monotherapy.;[17] Have a serious concomitant systemic disorder (eg, active infection including human immunodeficiency virus), or significant cardiac disease (eg, history of New York Heart Association class >=3, unstable angina, myocardial infarction) in 6 months prior to study drug administration that, in the opinion of the investigator, would compromise the patient*s ability to adhere to the protocol.;[18] Have interstitial pneumonia or interstitial fibrosis of the lung, which, in the opinion of the investigator, could compromise the patient or the study treatment with erlotinib.;[19] Have pleural effusion, pericardial fluid, or ascites requiring drainage every other week or more frequently.;[20] have a history of another 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 the study.;[21] Have major surgery less than 2 weeks prior initiation of study treatment therapy. ;[22] Have any condition (eg, psychological, geographical) that does not permit compliance with study and follow-up procedures, or patient is, in the investigator*s opinion, not an appropriate candidate for the study.;[23] Pregnant or lactating women.;[24] Have symptomatic CNS metastasis (baseline computer tomography [CT] or magnetic resonance imaging [MRI] of the brain required in all patients. For those patients with known CNS metastases ongoing CNS surveillance using the same modality is required at half the frequency as extra-CNS imaging).;Patients with asymptomatic CNS metastases are eligible if they are clinically stable with regard to neurologic function and either untreated and not requiring steroids or anticonvulsants to control CNS metastases related symptoms or are off steroids after cranial irradiation (whole-brain radiation therapy, focal radiation therapy, and stereotactic radiosurgery) 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 or IV contrast-enhanced CT (performed within 2 weeks prior to randomization).