A Study of Ramucirumab (LY3009806) in Combination With Erlotinib in Previously Untreated Participants With EGFR Mutation-Positive Metastatic NSCLC (RELAY)

Study Overview
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Brief Summary
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The main purpose of this study is to evaluate the efficacy and safety of ramucirumab in combination with erlotinib as compared to placebo in combination with erlotinib in previously untreated participants with stage IV non-small cell lung cancer (NSCLC) harboring an activating epidermal growth factor receptor (EGFR) mutation (Exon 19-Del and Exon 21 L858R). Safety and tolerability of ramucirumab in combination with erlotinib will be assessed in Part A before proceeding to Part B. The purpose of Part C is to determine the efficacy and safety of ramucirumab in combination with gefitinib in previously untreated East Asian participants with EGFR mutation-positive metastatic NSCLC and of ramucirumab in combination with osimertinib in those participants whose disease progressed on ramucirumab and gefitinib and that have T790M - positive metastatic NSCLC.

Official Title
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A Multicenter, Randomized, Double-Blind Study of Erlotinib in Combination With Ramucirumab or Placebo in Previously Untreated Patients With EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer

Conditions
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Metastatic Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Ramucirumab
* Drug: Placebo
* Drug: Erlotinib
* Drug: Gefitinib
* Drug: Osimertinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cytologically or histologically confirmed diagnosis of Stage IV NSCLC as defined by the American Joint Committee on Cancer Staging Criteria for Lung Cancer (AJCC 7th edition 2009). Eligible for first-line treatment with erlotinib based on documented evidence of tumor harboring an activating EGFR mutation [exon 19 deletion or exon 21 (L858R) substitution mutation]. Mandatory provision of adequate archived stage IV NSCLC tissue samples or tissue samples other than stage IV NSCLC may be acceptable (optional for part C). At least one measurable lesion. Life expectancy of at least 3 months. Exclusion Criteria: Known T790M EGFR mutation (not applicable for Part C Period 2). Known leptomeningeal carcinomatosis, uncontrolled/unstable spinal cord compression, or brain metastases. Serious illness or medical condition. Ongoing treatment with CYP3A4 inducers or strong inhibitors. Ongoing therapy with nonsteroidal anti-inflammatory drugs for more than 2 months. History of gross hemoptysis. Significant bleeding disorders. Radiologically documented evidence of major blood vessel invasion or encasement by cancer. Radiographic evidence of intratumor cavitation. History of gastrointestinal perforation within last 6 months. History of bowel obstruction, inflammatory enteropathy or extensive intestinal resection. History of any arterial thrombotic event within 6 months prior to enrollment. The participant has any known significant ophthalmologic abnormalities of the surface of the eye.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ramucirumab + Erlotinib<br>Part A: 10 milligrams per kilogram (mg/kg) ramucirumab administered every 2 weeks intravenously (IV) in combination with 150 mg erlotinib daily orally. Participants may continue to receive treatment until discontinuation criteria are met. Part B: 10 mg/kg ramucirumab administered every 2 weeks IV in combination with 150 mg erlotinib daily orally. Participants may continue to receive treatment until discontinuation criteria are met. | Drug: Ramucirumab<br>* Administered IV.<br>* Other names: LY3009806;Drug: Erlotinib<br>* Administered orally.<br>|
| Placebo Comparator: Placebo + Erlotinib<br>Part B: Placebo administered every 2 weeks IV in combination with 150 mg erlotinib daily orally. Participants may continue to receive treatment until discontinuation criteria are met. | Drug: Placebo<br>* Administered IV.<br>Drug: Erlotinib<br>* Administered orally.<br>|
| Experimental: Ramucirumab + Gefitinib or Osimertinib<br>Part C: 10 mg/kg ramucirumab administered every 2 weeks intravenously (IV) + 250 mg Gefitinib or 80 mg Osimertinib daily orally. Ramucirumab and gefitinib administered during period 1. Ramucirumab and osimertinib administered during period 2. | Drug: Ramucirumab<br>* Administered IV.<br>* Other names: LY3009806;Drug: Gefitinib<br>* Administered orally.<br>Drug: Osimertinib<br>* Administered orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part B: Progression Free Survival (PFS) | PFS is defined as the time from the date of randomization to the date of radiographically documented progressive disease (PD) based on investigator assessment, or the date of death due to any cause, whichever is first assessed via Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1 or more new lesions is also considered progression. | Randomization to Measured Progressive Disease or Death from Any Cause (Up To 37 Months) | 
| Number of Participants With Treatment-Emergent Adverse Events | A summary of other non-serious adverse events and all serious adverse events, regardless of causality, is located in the Reported Adverse Events Section. | Cycle 1 Day 1 through End of Study (Up To 3 Years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part B: Overall Survival (OS) | OS was defined as the time from the date of randomization to the date of death from any cause. For each participant who was not known to have died as of the data-inclusion cutoff date for a particular analysis,OS was censored for that analysis at the date of last contact prior to the data-inclusion cutoff date (contacts considered in the determination of last contact date include adverse event (AE) date, lesion assessment date, visit date, and last known alive date). | Randomization to Date of Death from Any Cause (Up To 37 Months) | 
| Part B: Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate [ORR]) | ORR was defined as the percentage of randomized participants achieving a best overall response of partial response (PR) or complete response (CR) assessed via Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR was defined as the disappearance of all lesions, pathological lymph node reduction in short axis to <10 mm, and normalization of tumor marker levels of non-target lesions. PR was at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1 or more new lesions is also considered progression. | Randomization to Progressive Disease (Up To 37 Months) | 
| Part B: Percentage of Participants With CR, PR, or Stable Disease (SD) (Disease Control Rate [DCR]) | DCR was defined as the percentage of randomized participants achieving a best overall response of CR,PR, or stable disease(SD) assessed via Response Evaluation Criteria in Solid Tumors(RECIST) version 1.1. CR was defined as the disappearance of all lesions,pathological lymph node reduction in short axis to <10 mm, and normalization of tumor marker levels of non-target lesions.PR was at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters.SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease(PD) was at least a 20% increase in the sum of the diameters of target lesions,taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.The appearance of 1 or more new lesions is also considered progression. | Randomization to Progressive Disease (Up To 37 Months) | 
| Part B: Duration of Response (DoR) | DoR was defined as the date of first documented CR or PR (responder) to the date of progressive disease or the date of death due to any cause, whichever was earlier. If a responder was not known to have died or have progressive disease, then the participant was censored at the date of last evaluable tumor assessment.CR was defined as the disappearance of all lesions, pathological lymph node reduction in short axis to <10 mm, and normalization of tumor marker levels of non-target lesions. PR was at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1 or more new lesions is also considered progression. | Date of Complete Response (CR) or Partial Response (PR) to Date of Objective Disease Progression or Death Due to Any Cause (Up To 37 Months) | 
| Part B: Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | Part B: Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | Cycle 2 Day 1: Predose; Cycle 4 Day 1: Predose; Cycle 7 Day 1: Predose; Cycle 14 Day 1 | 
| Part B: Number of Participants With Anti-Ramucirumab Antibodies | Part B: Number of Participants With Anti-Ramucirumab Antibodies. | Cycle 1 Predose through Follow-up (Up To 37 Months) | 
| Part B: Best Change From Baseline on the Lung Cancer Symptom Scale (LCSS) | The LCSS consisted of 9 items: 6 items focused on lung cancer symptoms [loss of appetite, fatigue, cough, dyspnea (shortness of breath), hemoptysis (blood in sputum), and pain] and 3 global items (symptom distress, interference with activity level, and global quality of life). Participant responses to each item were measured using visual analogue scales (VAS) with 100-millimeter (mm) lines. A higher score for any item represented a higher level of symptoms/problems. The LCSS total score was defined as the mean of all 9 items. Average symptom burden index (ASBI) was calculated as the mean of the six symptom-specific questions from the LCSS. Potential scores range from 0 (for best outcome) to 100 (for worst outcome). | Baseline, End of Study (Up To 37 Months) | 
| Part B: Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score | The EQ-5D-5L is a standardized instrument used to measure self-reported health status of the participants. It consists of 5 health dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). There are 5 response levels (no problems, slight problems, moderate problems, severe problems, and extreme problems/unable to), ranging from 1 to 5 (good to bad). Dimension responses were converted to an index score using UK weights. The index scores were anchored on full health (1.0) to dead (0) with negative values assigned to health states considered worse than death. | Baseline, Cycle 10 (each cycle is 2 weeks) | 
| Part B: Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score | The EQ-5D-5L is a standardized instrument used to measure self-reported health status of the participants. It consists of 5 health dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). There are 5 response levels (no problems, slight problems, moderate problems, severe problems, and extreme problems/unable to), ranging from 1 to 5 (good to bad). Dimension responses were converted to an index score using UK weights. The index scores were anchored on full health (1.0) to dead (0) with negative values assigned to health states considered worse than death. | Baseline, Cycle 28 (each cycle is 2 weeks) | 
| Part B: Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score | The EQ-5D-5L is a standardized instrument used to measure self-reported health status of the participants. It consists of 5 health dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). There are 5 response levels (no problems, slight problems, moderate problems, severe problems, and extreme problems/unable to), ranging from 1 to 5 (good to bad). Dimension responses were converted to an index score using UK weights. The index scores were anchored on full health (1.0) to dead (0) with negative values assigned to health states considered worse than death. | Baseline, Cycle 40 (each cycle is 2 weeks) |