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
Overview
- Phase
- Phase 3
- Intervention
- Ramucirumab
- Conditions
- Metastatic Non-Small Cell Lung Cancer
- Sponsor
- Eli Lilly and Company
- Enrollment
- 545
- Locations
- 106
- Primary Endpoint
- Part B: Progression Free Survival (PFS)
- Status
- Active, not recruiting
- Last Updated
- 3 months ago
Overview
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.
Investigators
Eligibility 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.
Arms & Interventions
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.
Intervention: Ramucirumab
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.
Intervention: Erlotinib
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.
Intervention: Placebo
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.
Intervention: Erlotinib
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.
Intervention: Ramucirumab
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.
Intervention: Gefitinib
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.
Intervention: Osimertinib
Outcomes
Primary Outcomes
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.
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 Outcomes
- Part B: Overall Survival (OS)(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])(Randomization to Progressive Disease (Up To 37 Months))
- Part B: Percentage of Participants With CR, PR, or Stable Disease (SD) (Disease Control Rate [DCR])(Randomization to Progressive Disease (Up To 37 Months))
- Part B: Duration of Response (DoR)(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(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(Cycle 1 Predose through Follow-up (Up To 37 Months))
- Part B: Best Change From Baseline on the Lung Cancer Symptom Scale (LCSS)(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(Baseline, Cycle 40 (each cycle is 2 weeks))
- Part B: Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score(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(Baseline, Cycle 28 (each cycle is 2 weeks))