| 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 | 21.1 |
| 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 compare PFS of LY2875358 plus erlotinib therapy with erlotinib monotherapy as first-line treatment in metastatic NSCLC patients with activating EGFRmt who have disease control after an 8-week lead-in treatment with erlotinib monotherapy. |
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| E.2.2 | Secondary objectives of the trial |
• To compare the following efficacy variables between the 2 arms:
• Change in tumor size (CTS)
• Overall response rate (ORR)
• Duration of response (DoR)
• Time to progressive disease (TTPD)
• Disease control rate (DCR)
• Overall survival (OS)
• To compare patient-reported symptoms and quality of life (QoL)
• To characterize the safety and tolerability of LY2875358 plus erlotinib compared with erlotinib monotherapy
• To evaluate the pharmacokinetics of LY2875358 and erlotinib when administered in combination and compare them with erlotinib monotherapy
• To evaluate incidence and serum levels of antitherapeutic antibodies (ATAs) 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, Seventh Edition; Edge et al. 2009).
[2] Have at least 1 measurable lesion whose presence is assessable using standard techniques by RECIST version 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 molecular evidence of an EGFRmt known to be associated with 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). This determination should be made from a NSCLC tumor sample based on testing with an EGFRmt assay (either a regulatory approved assay or by a local assay validated in a local laboratory according to institutional guidelines and local standard of care).
[4] Availability of adequate tumor-derived material from a biopsy or surgery (tumor blocks or slides) for analysis of MET expression status (needed for stratification) and exploratory biomarkers analysis.
[5] Have a performance status of 2 on the Eastern Cooperative Oncology Group (ECOG) scale.
[6] Have not received previous systemic chemotherapy, systemic therapy with biologics, or molecular-targeted therapy for Stage IV NSCLC. Patients who received chemotherapy as neoadjuvant or adjuvant therapy for early-stage NSCLC disease and completed therapy at least 6 months prior to enrollment are eligible.
[7] Have adequate organ function, as demonstrated by the following parameters:
• Hematologic: Absolute neutrophil count (ANC) 1.5 × 109/L, platelets 100 × 109/L, and hemoglobin 8 g/dL
• Hepatic: Bilirubin ≤1.5 × upper limits of normal (ULN); albumin ≥25 g/L; alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤2.5 × ULN or ≤5 × ULN in patients with hepatic metastases. NOTE: Patients with bone metastases and isolated elevation of ALP and patients with a documented Gilbert syndrome and isolated elevation of bilirubin are eligible.
• Renal: Serum creatinine level ≤1.5 × ULN; or calculated serum creatinine clearance ≥50 mL/min according to the method of Cockcroft and Gault
[8] Patients who require oral anticoagulants (eg, warfarin) are eligible provided there is increased vigilance with respect to the monitoring of the patient’s international normalized ratio (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 or oral factor Xa inhibitors, with which an interaction with LY2875358 or erlotinib is not expected.
[9] Are men or women at least 18 years of age at the time of screening (or older, if required based on local laws and regulations).
[10] 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.
[11] Are able to swallow tablets.
[12] Have an estimated life expectancy of at least 12 weeks in the judgment of the investigator.
[13] Patients must have given written informed consent prior to any study-specific procedures and be willing to make themselves available for the duration of the study and follow study procedures.
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| E.4 | Principal exclusion criteria |
[14] 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.
[15] Have previously completed or withdrawn from this study or any other study investigating LY2875358. (This exclusion criterion does not apply to patients who are rescreened prior to enrollment.)
[16] Have a serious concomitant systemic disorder (eg, active infection including human immunodeficiency virus [HIV], or significant cardiac disease (eg, history of New York Heart Association class ≥3 disease, unstable angina, or 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.
[17] Have interstitial pneumonia or interstitial fibrosis of the lung that, in the opinion of the investigator, could compromise the patient or the study treatment with erlotinib.
[18] Have pleural effusion, pericardial fluid, or ascites requiring drainage every other week or more frequently.
NOTE: Patients with a permanently implanted catheter system in place for repeated draining of pleural effusions or ascites (eg, “PleurX” system) are eligible.
[19] Have a history of another malignancy except for basal or squamous cell skin cancer, in situ carcinoma of the cervix, other non-invasive cancers that in the judgment of the investigator and sponsor may not affect the interpretation of the study results or other solid tumors treated curatively and without evidence of recurrence for at least 3 years prior to the study.
[20] Have any major surgery less than 2 weeks prior to initiation of study treatment.
[21] Have any condition (eg, psychological, geographical.) that does not permit compliance with study and follow-up procedures or suggests that the patient is, in the investigator’s opinion, not an appropriate candidate for the study.
[22] Are pregnant or lactating women.
The following Exclusion Criteria [23]–[24] will be assessed at the end of the 8-week lead-in study period with erlotinib monotherapy:
[23] Have radiographic or clinical progression of disease (according to RECIST version 1.1) at the end of the 8-week erlotinib lead-in study period.
[24] Have CNS metastasis (screening not required) except:
Patients with CNS metastases treated with surgery and/or radiation are eligible for randomization if they are, at the end of the 8-week erlotinib lead-in study period, either or both of the following:
• Clinically stable with regard to neurologic function and off corticosteroids after cranial irradiation (ie, whole-brain radiation therapy, focal radiation therapy, or stereotactic radiosurgery) at least 3 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 magnetic resonance imaging (MRI) or IV contrast–enhanced computed tomography (CT) performed within 3 weeks prior to randomization
• asymptomatic with regard to neurologic function and, if taking corticosteroids, must be on a stable dose for ≥2 weeks prior to randomization.
Patients with CNS metastases not treated with surgery and/or radiation are eligible for randomization if they are at the end of the 8-week erlotinib lead-in study period asymptomatic and clinically stable with regard to neurologic function and not requiring steroids or anticonvulsants to control CNS metastases-related symptoms.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of the study is progression-free survival (PFS). PFS is defined as the time from the date of study randomization to the date of first observation of objective radiographic progression or death from any cause as defined by RECIST 1.1 (Eisenhauer et al. 2009). If a patient is event-free at analysis, the patient will be censored at the last progression-free tumor assessment. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary analysis will be performed after 90 PFS events for approximately 129 patients with determinable MET expression status have been reported. |
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| E.5.2 | Secondary end point(s) |
The following secondary endpoints will be assessed:
- Change in tumor Size: from baseline to the measurement with the smallest tumor size during the study
- Disease control rate: 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)
- Overall response rate: The proportion of patients who exhibits a confirmed CR or PR relative to baseline as defined by RECIST 1.1 (Eisenhauer et al. 2009)
- Duration of response: 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.
- Time to progressive disease: The time from the date of randomization to the date of first observation of objective progression.
- Overall survival: The time from the date of randomization to the date of death from any cause
- Patient-reported outcome: using European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-LC13 questionnaires
- 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
-PK: Serum concentrations of LY2875358 and plasma concentrations of erlotinib will be assayed using validated methods
- 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 |
| After at least 90 OS events or 3 years after the last patient entered treatment for patients with determinable MET expression status, 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 |
| Patient-reported outcomes |
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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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Patients on erlotinib monotherapy are allowed to cross over to LY2875358 + erlotinib, upon progressi |
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| 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.8.2.4 | 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 36 |
| 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 |
| Korea, Republic of |
| Taiwan |
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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 | 9 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 9 |
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