| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non Small Cell Lung Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10059515 |
| E.1.2 | Term | Non-small cell lung cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of this study is to evaluate the overall response rate (ORR) of LY2875358 plus erlotinib therapy and LY2875358 monotherapy in patients with MET diagnostic positive (MET diagnostic [+]) NSCLC and acquired resistance to erlotinib.
As a co-primary objective, this study will evaluate the ORR of LY2875358 plus erlotinib therapy
and LY2875358 monotherapy in the subpopulation of patients with MET-high expression status
based on their post-erlotinib progression NSCLC tumor sample.
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are as follows:
• To evaluate efficacy variables:
o Progression-free survival (PFS)
o Time to progressive disease (TTPD)
o Change in tumor size (CTS)
o Disease control rate (DCR)
o Duration of response (DoR)
o Overall survival (OS)
• To evaluate patient-reported outcome (PRO) measures and quality of life
• To characterize the safety and tolerability of LY2875358 when administered in combination with erlotinib or as monotherapy
• To evaluate pharmacokinetics of LY2875358 when administered in combination with erlotinib and as monotherapy
• To evaluate incidence and serum levels of antitherapeutic antibodies against LY2875358
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
[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.
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| E.4 | Principal exclusion criteria |
[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).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of the study is the Overall Response Rate (ORR). A responder is defined as any patient who exhibits a confirmed complete response (CR) or partial response (PR) relative to baseline as defined by RECIST 1.1 (Eisenhauer et al. 2009). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Database lock for the final analysis of the primary endpoint of ORR will occur after last patient enrolled has been followed for at least five months and investigator-assessed best response assessments have been completed for all patients. |
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| E.5.2 | Secondary end point(s) |
Secondary endpoints:
- Progression-free survival (PFS): The time from the date of study enrollment (randomization) to the date of first observation of objective progression or death from any cause as defined by RECIST 1.1 (Eisenhauer et al. 2009).
- Time to progressive disease (TTPD): The time from the date of study enrollment (randomization) to the date of first observation of objective progression
- Change in tumor size (CTS): The change in tumor size from baseline measurement to the measurement with the smallest tumor size during the study
- Disease control rate (DCR): The proportion of patients in the analysis population who exhibit a SD or confirmed CR or PR relative to baseline during the study; response is defined by RECIST 1.1 (Eisenhauer et al. 2009)
- Duration of response (DoR): The time from the date of first evidence of a CR or PR to the first date of objective recurrent or progressive disease or the date of death due to any cause, whichever is earlier.
- Overall survival (OS): The time from the date of study enrollment to the date of death from any cause
Health Outcomes:
Patient symptoms, QoL, and health status will be assessed using the European Organisation for the Research and
Treatment of Cancer (EORTC) questionnaires QLQ-C30, QLQ-LC13, and EuroQol EQ-5D.
Safety and tolerability:
The NCI-CTCAE version 4.0 will serve as the reference document for choosing appropriate terminology for, and grading the severity of, all AEs and other symptoms.
Pharmacokinetic:
The parameters for erlotinib will include steady-state maximum and minimum concentrations (Css,max and
Css,min) and area under the concentration-time curve during the dosing interval at steady state (AUCτ,ss). The parameters for LY2875358 may include systemic clearance (CL), volume of distribution (V), Css, min, and target mediated drug disposition (TMDD) model parameters, such as receptor-mediated clearance, non–receptor mediated
clearance, volume of the central compartment, and volume of the peripheral compartment.
Immunogenicity
Immunogenicity will be assessed by a validated assay designed to detect ATAs in the presence of the investigational product.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Database lock for an updated safety and efficacy analysis is estimated to occur after at least 75 OS events or 2 years after LPET, whichever occurs first. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Health outcome/quality of life |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.3.1 | Comparator description |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Israel |
| Korea, Republic of |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 21 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 21 |
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