Clinical trial NCT02411448: A Study of Ramucirumab (LY3009806) in Combination With Erlotinib in Previously Untreated Participants With EGFR Mutation-Positive Metastatic NSCLC (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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Metastatic Non-Small Cell Lung Cancer
Lead sponsor: Eli Lilly and Company
Sponsor class: INDUSTRY
First posted: 2015-04-08
Enrollment: 545
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.
* 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.

Primary outcomes:
measure: Part B: Progression Free Survival (PFS)
timeFrame: Randomization to Measured Progressive Disease or Death from Any Cause (Up To 37 Months)
measure: Number of Participants With Treatment-Emergent Adverse Events
timeFrame: Cycle 1 Day 1 through End of Study (Up To 3 Years)
Secondary outcomes:
measure: Part B: Overall Survival (OS)
timeFrame: Randomization to Date of Death from Any Cause (Up To 37 Months)
measure: Part B: Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate [ORR])
timeFrame: Randomization to Progressive Disease (Up To 37 Months)
measure: Part B: Percentage of Participants With CR, PR, or Stable Disease (SD) (Disease Control Rate [DCR])
timeFrame: Randomization to Progressive Disease (Up To 37 Months)
measure: Part B: Duration of Response (DoR)
timeFrame: 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)
measure: Part B: Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab
timeFrame: Cycle 2 Day 1: Predose; Cycle 4 Day 1: Predose; Cycle 7 Day 1: Predose; Cycle 14 Day 1
measure: Part B: Number of Participants With Anti-Ramucirumab Antibodies
timeFrame: Cycle 1 Predose through Follow-up (Up To 37 Months)
measure: Part B: Best Change From Baseline on the Lung Cancer Symptom Scale (LCSS)
timeFrame: Baseline, End of Study (Up To 37 Months)
measure: Part B: Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score
timeFrame: Baseline, Cycle 10 (each cycle is 2 weeks)
measure: Part B: Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score
timeFrame: Baseline, Cycle 28 (each cycle is 2 weeks)
measure: Part B: Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score
timeFrame: Baseline, Cycle 40 (each cycle is 2 weeks)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA Hematology/Oncology - Santa Monica
state: California
city: Denver
country: United States
facility: St. Charles Health System
state: Colorado
city: Honolulu
country: United States
facility: The Gastroenterology Group, P.C.
state: Hawaii
city: Wichita
country: United States
facility: Cancer Center of Kansas
state: Kansas
city: Fresh Meadows
country: United States
facility: Queens Medical Associates
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Pittsburgh
country: United States
facility: AHN Allegheny General Hospital
state: Pennsylvania
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Montpellier
country: France
facility: Hôpital Arnaud de Villeneuve - CHU Montpellier
state: Hérault
city: La Tronche
country: France
facility: Chu Grenoble Alpes
state: Isère
city: Lille
country: France
facility: Hopital Claude Huriez - CHU de Lille
state: Nord
city: Poitiers
country: France
facility: Centre Hospitalier Universitaire de Poitiers
state: Vienne
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou
city: Gerlingen
country: Germany
facility: Robert-Bosch-Krankenhaus
state: Baden-Württemberg
city: Heidelberg
country: Germany
facility: Thoraxklinik Heidelberg gGmbH
state: Baden-Württemberg
city: Köln
country: Germany
facility: Klinikum Köln-Merheim
state: Nordrhein-Westfalen
city: Halle (Saale)
country: Germany
facility: Städtisches Krankenhaus Martha-Maria Halle-Dölau gGmbH
state: Sachsen-Anhalt
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz GmbH
state: Sachsen
city: Großhansdorf
country: Germany
facility: LungenClinic Grosshansdorf
state: Schleswig-Holstein
city: Berlin
country: Germany
facility: Helios Klinikum Emil von Behring Berlin-Zehlendorf
city: Athens
country: Greece
facility: Sotiria Thoracic Diseases Hospital of Athens
state: Attikí
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Yau Ma Tei
country: Hong Kong
facility: Queen Elizabeth Hospital
city: Aviano
country: Italy
facility: Cro-Irccs
state: Friuli-Venezia Giulia
city: Bari
country: Italy
facility: Instituto Tumori Giovanni Paolo II
state: Puglia
city: Orbassano
country: Italy
facility: Azienda Sanitaria Ospedaliera S Luigi Gonzaga
state: Torino
city: Bologna
country: Italy
facility: IRCCS - AOU di Bologna
city: Milano
country: Italy
facility: Ospedale San Raffaele
city: Padova
country: Italy
facility: Istituto Oncologico Veneto IRCCS
city: Nagoya
country: Japan
facility: Aichi Cancer Center Hospital
state: Aichi
city: Kashiwa
country: Japan
facility: National Cancer Center Hospital East
state: Chiba
city: Toon
country: Japan
facility: Ehime University Hospital
state: Ehime
city: Kurume
country: Japan
facility: Kurume University Hospital
state: Fukuoka
city: Asahikawa
country: Japan
facility: National Hospital Organization Asahikawa Medical Center
state: Hokkaido
city: Akashi
country: Japan
facility: Hyogo Cancer Center
state: Hyogo
city: Amagashiki
country: Japan
facility: Hyogo Prefectual Amagasaki General Medical Center
state: Hyogo
city: Himeji
country: Japan
facility: Himeji Medical Center
state: Hyogo
city: Kobe
country: Japan
facility: Foundation for Biomedical Research and innovation
state: Hyogo
city: Kobe
country: Japan
facility: Kobe City Medical Center General Hospital
state: Hyogo
city: Kanazawa
country: Japan
facility: Kanazawa University Hospital
state: Ishikawa
city: Yokohama
country: Japan
facility: Kanagawa Cardiovascular and Respiratory Center
state: Kanagawa
city: Yokohama
country: Japan
facility: Kanagawa Cancer Center
state: Kanagawa
city: Sendai
country: Japan
facility: Sendai Kousei Hospital
state: Miyagi
city: Niigata-shi
country: Japan
facility: Niigata Cancer Center Hospital
state: Niigata
city: Habikino
country: Japan
facility: Osaka Habikino Medical Center
state: Osaka
city: Hirakata
country: Japan
facility: Kansai Medical University Hospital
state: Osaka
city: Kishiwada
country: Japan
facility: Kishiwada City Hospital
state: Osaka
city: Osaka-Sayama
country: Japan
facility: Kindai University Hospital- Osakasayama Campus
state: Osaka
city: Sakai
country: Japan
facility: National Hospital Organization Kinki-Chuo Chest Medical Center
state: Osaka
city: Ina-machi
country: Japan
facility: Saitama Prefectural Cancer Center
state: Saitama
city: Nagaizumi
country: Japan
facility: Shizuoka Cancer Center
state: Shizuoka
city: Bunkyo-ku
country: Japan
facility: Tokyo Met Cancer & Infectious Diseases Center Komagome Hp
state: Tokyo
city: Chuo-Ku
country: Japan
facility: National Cancer Center Hospital
state: Tokyo
city: Koto
country: Japan
facility: Japanese Foundation for Cancer Research
state: Tokyo
city: Ube
country: Japan
facility: National Hospital Organization Yamaguchi Ube Medical Center
state: Yamaguchi
city: Chiba
country: Japan
facility: Chiba University Hospital
city: Fukuoka
country: Japan
facility: National Hospital Organization Kyushu Medical Center
city: Fukuoka
country: Japan
facility: National Hospital Organization Kyushu Cancer Center
city: Fukuoka
country: Japan
facility: Kyushu University Hospital
city: Kyoto
country: Japan
facility: Kyoto University Hospital
city: Nagasaki
country: Japan
facility: Nagasaki University Hospital
city: Niigata
country: Japan
facility: Niigata University Medical & Dental Hospital
city: Okayama
country: Japan
facility: Okayama University Hospital
city: Osaka
country: Japan
facility: Osaka City General Hospital
city: Osaka
country: Japan
facility: Osaka Medical Center for Cancer and Cardiovascular Diseases
city: Osaka
country: Japan
facility: Osaka City University Hospital
city: Tokyo
country: Japan
facility: St. Lukes International Hospital
city: Tokyo
country: Japan
facility: Juntendo University Hospital
city: Tokyo
country: Japan
facility: Nippon Medical School Hospital
city: Wakayama
country: Japan
facility: Wakayama MedicaL University Hospital
city: Cheongju-si
country: Korea, Republic of
facility: Chungbuk National University Hospital
state: Chungcheongbuk-do [Chungbuk]
city: Seongnam
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
state: Kyǒnggi-do
city: Suwon-si
country: Korea, Republic of
facility: The Catholic University Of Korea St. Vincent's Hospital
state: Kyǒnggi-do
city: Suwon-si
country: Korea, Republic of
facility: Ajou University Hospital
state: Kyǒnggi-do
city: Jin-ju-si
country: Korea, Republic of
facility: Gyeongsang National University Hospital
state: Kyǒngsangnam-do
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
state: Seoul-teukbyeolsi [Seoul]
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
state: Seoul-teukbyeolsi [Seoul]
city: Seoul
country: Korea, Republic of
facility: The Catholic Univ. of Korea Seoul St. Mary's Hospital
state: Seoul-teukbyeolsi [Seoul]
city: Seoul
country: Korea, Republic of
facility: Korea University Guro Hospital
state: Seoul-teukbyeolsi [Seoul]
city: Ulsan
country: Korea, Republic of
facility: Ulsan University Hospital
state: Ulsan-Kwangyǒkshi
city: Bucuresti
country: Romania
facility: Institutul Oncologic
state: București
city: Cluj-Napoca
country: Romania
facility: S.C. MedisProf SRL
state: Cluj
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
state: Barcelona [Barcelona]
city: Hospitalet
country: Spain
facility: Instituto Catalan de Oncologia - Hospital Duran i Reynals
state: Barcelona [Barcelona]
city: Palma
country: Spain
facility: Hospital Son Llatzer
state: Illes Balears [Islas Baleares]
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
state: Madrid, Comunidad De
city: Pozuelo de Alarcon
country: Spain
facility: Hospital Universitario Quironsalud Madrid
state: Madrid
city: Pamplona
country: Spain
facility: Clinica Universitaria De Navarra
state: Navarra
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen de Valme
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe
city: Kaohsiung Niao Sung Dist
country: Taiwan
facility: Chang Gung Memorial Hospital at Kaohsiung
state: Kaohsiung
city: Kaohsiung
country: Taiwan
facility: E-DA Hospital
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Tainan
country: Taiwan
facility: National Cheng-Kung University Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: MacKay Memorial Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Bornova
country: Turkey
facility: Ege Universitesi Hastanesi
state: İzmir
city: Adana
country: Turkey
facility: Baskent University Dr. Turgut Noyan Research and Training Center
city: Edirne
country: Turkey
facility: Trakya University
city: Malatya
country: Turkey
facility: İnönü Üniversitesi Turgut Özal Tıp Merkezi Eğitim ve Araştırma Hastanesi
city: London
country: United Kingdom
facility: Royal Marsden Hospital (Chelsea)
state: Kensington And Chelsea
city: Chelsea
country: United Kingdom
facility: Charing Cross Hospital
state: London
city: Nottingham
country: United Kingdom
facility: City Hospital, Nottingham University Hospitals
state: Nottinghamshire
Study officials:
affiliation: Eli Lilly and Company
name: 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)
role: STUDY_DIRECTOR
References:
citation: Nakagawa K, Garon EB, Gao L, Callies S, Zimmermann A, Walgren R, Visseren-Grul C, Reck M. RELAY, ramucirumab plus erlotinib versus placebo plus erlotinib in untreated EGFR-mutated metastatic non-small cell lung cancer: exposure-response relationship. Cancer Chemother Pharmacol. 2022 Aug;90(2):137-148. doi: 10.1007/s00280-022-04447-x. Epub 2022 Jul 16.
citation: Nishio M, Nishio K, Reck M, Garon EB, Imamura F, Kawaguchi T, Yamaguchi H, Ikeda S, Hirano K, Visseren-Grul C, Ceccarelli M, Wijayawardana SR, Zimmermann A, Matsui T, Enatsu S, Nakagawa K. RELAY+: Exploratory Study of Ramucirumab Plus Gefitinib in Untreated Patients With EGFR-Mutated Metastatic NSCLC. JTO Clin Res Rep. 2022 Feb 26;3(4):100303. doi: 10.1016/j.jtocrr.2022.100303. eCollection 2022 Apr.
citation: Nadal E, Horinouchi H, Shih JY, Nakagawa K, Reck M, Garon EB, Wei YF, Kollmeier J, Frimodt-Moller B, Barrett E, Lipkovich O, Visseren-Grul C, Novello S. RELAY, Ramucirumab Plus Erlotinib Versus Placebo Plus Erlotinib in Patients with Untreated, Epidermal Growth Factor Receptor Mutation-Positive, Metastatic Non-Small-Cell Lung Cancer: Safety Profile and Manageability. Drug Saf. 2022 Jan;45(1):45-64. doi: 10.1007/s40264-021-01127-2. Epub 2021 Dec 20.
citation: Mitani S, Chen Y, Inoue K, Mori J, Gao L, Long A, Wakabayashi S. Clinical Impact of a Shortened Infusion Duration of Ramucirumab in Japanese Patients -A Model-Based Approach. Gan To Kagaku Ryoho. 2021 Nov;48(11):1381-1387.
citation: Nakagawa K, Garon EB, Seto T, Nishio M, Ponce Aix S, Paz-Ares L, Chiu CH, Park K, Novello S, Nadal E, Imamura F, Yoh K, Shih JY, Au KH, Moro-Sibilot D, Enatsu S, Zimmermann A, Frimodt-Moller B, Visseren-Grul C, Reck M; RELAY Study Investigators. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Dec;20(12):1655-1669. doi: 10.1016/S1470-2045(19)30634-5. Epub 2019 Oct 4.
citation: Reck M, Garon EB, Paz-Ares L, Ponce S, Jaime JC, Juan O, Nadal E, Kiura K, Widau RC, He S, Dalal R, Lee P, Nakagawa K. Randomized, Double-Blind Phase Ib/III Study of Erlotinib With Ramucirumab or Placebo in Previously Untreated EGFR-Mutant Metastatic Non-Small-Cell Lung Cancer (RELAY): Phase Ib Results. Clin Lung Cancer. 2018 May;19(3):213-220.e4. doi: 10.1016/j.cllc.2017.11.003. Epub 2017 Nov 21.
citation: Garon EB, Reck M, Paz-Ares L, Ponce S, Jaime JC, Juan O, Nadal E, Lee P, Dalal R, Liu J, He S, Treat J, Nakagawa K. Treatment Rationale and Study Design for the RELAY Study: A Multicenter, Randomized, Double-Blind Study of Erlotinib With Ramucirumab or Placebo in Patients With Epidermal Growth Factor Receptor Mutation-Positive Metastatic Non-Small-Cell Lung Cancer. Clin Lung Cancer. 2017 Jan;18(1):96-99. doi: 10.1016/j.cllc.2016.05.023. Epub 2016 Jun 8.