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

Metastatic Non-Small Cell Lung Cancer Clinical Trial

— RELAY  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02411448
• Other study ID #: 15540
• Secondary ID: I4T-MC-JVCY2014-
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: May 6, 2015
• Est. completion date: December 16, 2024

Study information

• Verified date: March 2024
• Source: Eli Lilly and Company
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 545
• Est. completion date: December 16, 2024
• Est. primary completion date: January 23, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Metastatic Non-Small Cell Lung Cancer

Intervention

Drug:
• Ramucirumab
Administered IV.
• Placebo
Administered IV.
• Erlotinib
Administered orally.
• Gefitinib
Administered orally.
• Osimertinib
Administered orally.

Locations

Country	Name	City	State
Canada	Cross Cancer Institute	Edmonton	Alberta
France	Chu Grenoble Alpes	La Tronche	Isère
France	Hopital Claude Huriez - CHU de Lille	Lille	Nord
France	Hôpital Arnaud de Villeneuve - CHU Montpellier	Montpellier	Hérault
France	Hôpital Européen Georges Pompidou	Paris
France	Centre Hospitalier Universitaire de Poitiers	Poitiers	Vienne
Germany	Helios Klinikum Emil von Behring Berlin-Zehlendorf	Berlin
Germany	Klinikum Chemnitz GmbH	Chemnitz	Sachsen
Germany	Robert-Bosch-Krankenhaus	Gerlingen	Baden-Württemberg
Germany	LungenClinic Grosshansdorf	Großhansdorf	Schleswig-Holstein
Germany	Städtisches Krankenhaus Martha-Maria Halle-Dölau gGmbH	Halle (Saale)	Sachsen-Anhalt
Germany	Thoraxklinik Heidelberg gGmbH	Heidelberg	Baden-Württemberg
Germany	Klinikum Köln-Merheim	Köln	Nordrhein-Westfalen
Greece	Sotiria Thoracic Diseases Hospital of Athens	Athens	Attikí
Hong Kong	Queen Mary Hospital	Hong Kong
Hong Kong	Queen Elizabeth Hospital	Yau Ma Tei
Italy	Cro-Irccs	Aviano	Friuli-Venezia Giulia
Italy	Instituto Tumori Giovanni Paolo II	Bari	Puglia
Italy	IRCCS - AOU di Bologna	Bologna
Italy	Ospedale San Raffaele	Milano
Italy	Azienda Sanitaria Ospedaliera S Luigi Gonzaga	Orbassano	Torino
Italy	Istituto Oncologico Veneto IRCCS	Padova
Japan	Hyogo Cancer Center	Akashi	Hyogo
Japan	Hyogo Prefectual Amagasaki General Medical Center	Amagashiki	Hyogo
Japan	National Hospital Organization Asahikawa Medical Center	Asahikawa	Hokkaido
Japan	Tokyo Met Cancer & Infectious Diseases Center Komagome Hp	Bunkyo-ku	Tokyo
Japan	Chiba University Hospital	Chiba
Japan	National Cancer Center Hospital	Chuo-Ku	Tokyo
Japan	Kyushu University Hospital	Fukuoka
Japan	National Hospital Organization Kyushu Cancer Center	Fukuoka
Japan	National Hospital Organization Kyushu Medical Center	Fukuoka
Japan	Osaka Habikino Medical Center	Habikino	Osaka
Japan	Himeji Medical Center	Himeji	Hyogo
Japan	Kansai Medical University Hospital	Hirakata	Osaka
Japan	Saitama Prefectural Cancer Center	Ina-machi	Saitama
Japan	Kanazawa University Hospital	Kanazawa	Ishikawa
Japan	National Cancer Center Hospital East	Kashiwa	Chiba
Japan	Kishiwada City Hospital	Kishiwada	Osaka
Japan	Foundation for Biomedical Research and innovation	Kobe	Hyogo
Japan	Kobe City Medical Center General Hospital	Kobe	Hyogo
Japan	Japanese Foundation for Cancer Research	Koto	Tokyo
Japan	Kurume University Hospital	Kurume	Fukuoka
Japan	Kyoto University Hospital	Kyoto
Japan	Tominaga Hospital	Nagaizumi	Shizuoka
Japan	Nagasaki University Hospital	Nagasaki
Japan	Aichi Cancer Center Hospital	Nagoya	Aichi
Japan	Niigata University Medical & Dental Hospital	Niigata
Japan	Niigata Cancer Center Hospital	Niigata-shi	Niigata
Japan	Okayama University Hospital	Okayama
Japan	Osaka City General Hospital	Osaka
Japan	Osaka City University Hospital	Osaka
Japan	Osaka Medical Center for Cancer and Cardiovascular Diseases	Osaka
Japan	Kindai University Hospital	Osaka-Sayama	Osaka
Japan	National Hospital Organization Kinki-Chuo Chest Medical Center	Sakai	Osaka
Japan	Sendai Kousei Hospital	Sendai	Miyagi
Japan	Juntendo University Hospital	Tokyo
Japan	Nippon Medical School Hospital	Tokyo
Japan	St. Lukes International Hospital	Tokyo
Japan	Ehime University Hospital	Toon	Ehime
Japan	National Hospital Organization Yamaguchi Ube Medical Center	Ube	Yamaguchi
Japan	Wakayama MedicaL University Hospital	Wakayama
Japan	Kanagawa Cancer Center	Yokohama	Kanagawa
Japan	Kanagawa Cardiovascular and Respiratory Center	Yokohama	Kanagawa
Korea, Republic of	Chungbuk National University Hospital	Cheongju-si	Chungcheongbuk-do [Chungbuk]
Korea, Republic of	Gyeongsang National University Hospital	Jin-ju-si	Kyongsangnam-do
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam	Kyonggi-do
Korea, Republic of	Asan Medical Center	Seoul	Seoul-teukbyeolsi [Seoul]
Korea, Republic of	Korea University Guro Hospital	Seoul	Seoul-teukbyeolsi [Seoul]
Korea, Republic of	Samsung Medical Center	Seoul	Seoul-teukbyeolsi [Seoul]
Korea, Republic of	The Catholic Univ. of Korea Seoul St. Mary's Hospital	Seoul	Seoul-teukbyeolsi [Seoul]
Korea, Republic of	Ajou University Hospital	Suwon-si	Kyonggi-do
Korea, Republic of	The Catholic University Of Korea St. Vincent's Hospital	Suwon-si	Kyonggi-do
Korea, Republic of	Ulsan University Hospital	Ulsan	Ulsan-Kwangyokshi
Romania	Institutul Oncologic	Bucuresti	Bucure?ti
Romania	S.C. MedisProf SRL	Cluj-Napoca	Cluj
Spain	Hospital Universitari Vall d'Hebron	Barcelona	Barcelona [Barcelona]
Spain	Instituto Catalan de Oncologia - Hospital Duran i Reynals	Hospitalet	Barcelona [Barcelona]
Spain	Hospital Universitario 12 de Octubre	Madrid	Madrid, Comunidad De
Spain	Hospital Son Llatzer	Palma	Illes Balears [Islas Baleares]
Spain	Clinica Universitaria De Navarra	Pamplona	Navarra
Spain	Hospital Universitario Quironsalud Madrid	Pozuelo de Alarcon	Madrid
Spain	Hospital Universitario Nuestra Señora de Valme	Sevilla
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Spain	Hospital Universitari i Politecnic La Fe	Valencia
Taiwan	E-DA Hospital	Kaohsiung
Taiwan	Chang Gung Memorial Hospital at Kaohsiung	Kaohsiung Niao Sung Dist	Kaohsiung
Taiwan	China Medical University Hospital	Taichung
Taiwan	Taichung Veterans General Hospital	Taichung
Taiwan	National Cheng-Kung University Hospital	Tainan
Taiwan	MacKay Memorial Hospital	Taipei
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei
Turkey	Baskent University Dr. Turgut Noyan Research and Training Center	Adana
Turkey	Ege Universitesi Hastanesi	Bornova	Izmir
Turkey	Trakya University	Edirne
Turkey	Inönü Üniversitesi Turgut Özal Tip Merkezi Egitim ve Arastirma Hastanesi	Malatya
United Kingdom	Charing Cross Hospital	Chelsea	London
United Kingdom	Royal Marsden Hospital (Chelsea)	London	Kensington And Chelsea
United Kingdom	City Hospital, Nottingham University Hospitals	Nottingham	Nottinghamshire
United States	Levine Cancer Institute	Charlotte	North Carolina
United States	St. Charles Health System	Denver	Colorado
United States	Queens Medical Associates	Fresh Meadows	New York
United States	The Gastroenterology Group, P.C.	Honolulu	Hawaii
United States	TRIO-US (Translational Research in Oncology-US)	Los Angeles	California
United States	UCLA Hematology/Oncology - Santa Monica	Los Angeles	California
United States	AHN Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	Cancer Center of Kansas	Wichita	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Eli Lilly and Company

Countries where clinical trial is conducted

United States,  Canada,  France,  Germany,  Greece,  Hong Kong,  Italy,  Japan,  Korea, Republic of,  Romania,  Spain,  Taiwan,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)

External Links

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