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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02411448
Recruitment Status : Active, not recruiting
First Posted : April 8, 2015
Results First Posted : March 4, 2020
Last Update Posted : June 2, 2023
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company

Study Description
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Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Metastatic Non-Small Cell Lung Cancer Drug: Ramucirumab Drug: Placebo Drug: Erlotinib Drug: Gefitinib Drug: Osimertinib Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 545 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : May 6, 2015
Actual Primary Completion Date : January 23, 2019
Estimated Study Completion Date : December 16, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer

Arms and Interventions
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Arm Intervention/treatment
Experimental: Ramucirumab + Erlotinib

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
Administered IV.
Other Name: LY3009806

Drug: Erlotinib
Administered orally.
Placebo Comparator: Placebo + Erlotinib

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
Administered IV.

Drug: Erlotinib
Administered orally.
Experimental: Ramucirumab + Gefitinib or Osimertinib

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
Administered IV.
Other Name: LY3009806

Drug: Gefitinib
Administered orally.

Drug: Osimertinib
Administered orally.


Outcome Measures
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Primary Outcome Measures :
  1. Part B: Progression Free Survival (PFS) [ Time Frame: Randomization to Measured Progressive Disease or Death from Any Cause (Up To 37 Months) ]
    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.

  2. Number of Participants With Treatment-Emergent Adverse Events [ Time Frame: Cycle 1 Day 1 through End of Study (Up To 3 Years) ]
    A summary of other non-serious adverse events and all serious adverse events, regardless of causality, is located in the Reported Adverse Events Section.


Secondary Outcome Measures :
  1. Part B: Overall Survival (OS) [ Time Frame: Randomization to Date of Death from Any Cause (Up To 37 Months) ]
    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).

  2. Part B: Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate [ORR]) [ Time Frame: Randomization to Progressive Disease (Up To 37 Months) ]
    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.

  3. Part B: Percentage of Participants With CR, PR, or Stable Disease (SD) (Disease Control Rate [DCR]) [ Time Frame: Randomization to Progressive Disease (Up To 37 Months) ]
    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.

  4. Part B: Duration of Response (DoR) [ Time Frame: 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) ]
    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.

  5. Part B: Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab [ Time Frame: Cycle 2 Day 1: Predose; Cycle 4 Day 1: Predose; Cycle 7 Day 1: Predose; Cycle 14 Day 1 ]
    Part B: Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab

  6. Part B: Number of Participants With Anti-Ramucirumab Antibodies [ Time Frame: Cycle 1 Predose through Follow-up (Up To 37 Months) ]
    Part B: Number of Participants With Anti-Ramucirumab Antibodies.

  7. Part B: Best Change From Baseline on the Lung Cancer Symptom Scale (LCSS) [ Time Frame: Baseline, End of Study (Up To 37 Months) ]
    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).

  8. Part B: Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score [ Time Frame: Baseline, Cycle 10 (each cycle is 2 weeks) ]
    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.

  9. Part B: Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score [ Time Frame: Baseline, Cycle 28 (each cycle is 2 weeks) ]
    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.

  10. Part B: Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score [ Time Frame: Baseline, Cycle 40 (each cycle is 2 weeks) ]
    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.


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02411448


Locations
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Sponsors and Collaborators
Eli Lilly and Company
Investigators
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Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST) Eli Lilly and Company
  Study Documents (Full-Text)

Documents provided by Eli Lilly and Company:
Study Protocol: Protocol I4T-MC-JVCY(f)  [PDF] April 23, 2018
Study Protocol: Protocol Addendum I4T-MC-JVCY(9)  [PDF] August 15, 2017
Statistical Analysis Plan  [PDF] December 13, 2018

More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT02411448    
Other Study ID Numbers: 15540
I4T-MC-JVCY ( Other Identifier: Eli Lilly and Company )
2014-004824-22 ( EudraCT Number )
First Posted: April 8, 2015    Key Record Dates
Results First Posted: March 4, 2020
Last Update Posted: June 2, 2023
Last Verified: May 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: Data are available 6 months after the primary publication and approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting.
Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
URL: https://vivli.org/
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
 Bronchial Neoplasms
Erlotinib Hydrochloride
Gefitinib
Osimertinib
Ramucirumab
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action