Peter R Galle, MD Study Chair University Medical Center, Mainz, Germany Richard S Finn, MD Study Chair UCLA Department of Medicine, Division of Hematology-Oncology
University Hospital Bonn 53127 Bonn (Nordrhein-Westfalen) GermanyNoch nicht rekrutierend» Google-MapsUniversity Hospital Carl Gustav Carus Dresden 1307 Dresden (Sachsen) GermanyNoch nicht rekrutierend» Google-MapsUniversitäts-Brustzentrum am Universitätsklinikum des Saarlandes Kirrberger Straße 100 66424 Homburg DeutschlandNoch nicht rekrutierend» Google-Maps
Universitätsklinikum Schleswig-Holstein -Kiel 24105 Kiel (Schleswig-Holstein) GermanyNoch nicht rekrutierend» Google-MapsUniversitätsmedizin: Medizinische Klinik und Poliklinik I D-55131 Mainz (Rheinland-Pfalz) GermanyRekrutierend» Google-MapsUCLA Santa Monica Hematology Oncology 90404 Santa Monica United StatesRekrutierend» Google-MapsMiami Cancer Institute 33176 Miami United StatesNoch nicht rekrutierend» Google-MapsIcahn School of Medicine at Mount Sinai 10029 New York United StatesNoch nicht rekrutierend» Google-MapsUniversity Hospitals Cleveland Medical Center 44106 Cleveland United StatesNoch nicht rekrutierend» Google-MapsHôpital Erasme 1070 Brussels BelgiumNoch nicht rekrutierend» Google-MapsUCL SAINT LUC - UC Louvain 1200 Brussels BelgiumRekrutierend» Google-MapsCHU Amiens-Picardie 80054 Amiens FranceNoch nicht rekrutierend» Google-MapsCHU Jean Minjoz 25000 Besançon FranceNoch nicht rekrutierend» Google-MapsHôpital Avicenne - APHP 93000 Bobigny FranceNoch nicht rekrutierend» Google-MapsHôpital Beaujon - APHP 92110 Clichy FranceNoch nicht rekrutierend» Google-MapsHôpital Henri Mondor 94010 Créteil FranceRekrutierend» Google-MapsCHU Grenoble Alpes - Site Nord 38700 La Tronche FranceNoch nicht rekrutierend» Google-MapsCHU de Nantes - Hôtel-Dieu 44093 Nantes FranceNoch nicht rekrutierend» Google-MapsJSC VIANI Batumi Referral Hospital 6010 Batumi GeorgiaRekrutierend» Google-MapsIsrael-Georgian Medical Research Clinic Healthycore 0112 Tbilisi GeorgiaRekrutierend» Google-MapsNew Hospitals 0114 Tbilisi GeorgiaRekrutierend» Google-MapsDepartment Of Clinical Oncology, Queen Mary Hospital, University of Hong Kong 999077 Hong Kong Hong KongNoch nicht rekrutierend» Google-MapsHumanity and Health Clinical Trial Center 999077 Hong Kong Hong KongNoch nicht rekrutierend» Google-MapsQueen Mary Hospital, University of Hong Kong Department of Medicine, Medical Oncology 999077 Hong Kong Hong KongNoch nicht rekrutierend» Google-MapsASST Papa Giovanni XXIII Hospital 24127 Bergamo ItalyNoch nicht rekrutierend» Google-MapsOspedale Garibaldi Nesima 95122 Catania ItalyNoch nicht rekrutierend» Google-MapsSan Raffaele Hospital 20132 Milan ItalyNoch nicht rekrutierend» Google-MapsASST Grande Ospedale Metropolitano Niguarda 20162 Milan ItalyNoch nicht rekrutierend» Google-MapsAzienda Ospedaliera Universitaria Federico II di Napoli 80131 Napoli ItalyNoch nicht rekrutierend» Google-MapsEhime University Hospital 791-0295 Tōon JapanNoch nicht rekrutierend» Google-MapsFujita Health University Hospital Department of Gastroenterology and Hepatology 470-1101 Kutsukake JapanNoch nicht rekrutierend» Google-MapsChiba University Hospital 260-8677 Chiba JapanNoch nicht rekrutierend» Google-MapsKurume University Hospital 830-0011 Fukuoka JapanNoch nicht rekrutierend» Google-MapsNagoya University Hospital 466-8560 Nagoya JapanNoch nicht rekrutierend» Google-MapsKindai University Hospital 589-8511 Osaka sayama-shi, Osaka JapanNoch nicht rekrutierend» Google-MapsToyama University Hospital 930-0194 Toyama JapanNoch nicht rekrutierend» Google-MapsKanagawa Cancer Center 241-8515 Yokohama JapanNoch nicht rekrutierend» Google-MapsInje University Haeundae Paik Hospital Busan Korea, Republic ofRekrutierend» Google-MapsCha Bundang Medical Center Seongnam-si Korea, Republic ofRekrutierend» Google-MapsAsan Medical Center Seoul Korea, Republic ofRekrutierend» Google-MapsSeoul National University Hospital Seoul Korea, Republic ofNoch nicht rekrutierend» Google-MapsSeverance Hospital, Yonsei University Health System Seoul Korea, Republic ofRekrutierend» Google-MapsClinic for Digestive Surgery, University Clinical Center of Serbia Belgrade SerbiaRekrutierend» Google-MapsMilitary Medical Academy Belgrade SerbiaNoch nicht rekrutierend» Google-MapsClinical Center Nis Niš SerbiaNoch nicht rekrutierend» Google-MapsInstitue of Oncology Vojvodine Sremska Kamenica (Oncology Institute of Volvodina) 21204 Sremska Kamenica SerbiaNoch nicht rekrutierend» Google-MapsHospital Universitario Vall d'Hebron 8035 Barcelona SpainNoch nicht rekrutierend» Google-MapsHospital Reina Sofía 14004 Córdoba SpainNoch nicht rekrutierend» Google-MapsInstituto Catalán de Oncología L'Hospitalet 08908 L'Hospitalet De Llobregat SpainNoch nicht rekrutierend» Google-MapsHospital Ramón y Cajal 28034 Madrid SpainNoch nicht rekrutierend» Google-MapsHospital Universitario La Paz 28046 Madrid SpainNoch nicht rekrutierend» Google-MapsHospital Puerta de Hierro 28222 Majadahonda SpainNoch nicht rekrutierend» Google-MapsHospital Universitario Virgen del Rocío 41013 Sevilla SpainNoch nicht rekrutierend» Google-MapsHospital Universitario Miguel Servet 50009 Zaragoza SpainNoch nicht rekrutierend» Google-MapsKaohsiung Chang Gung Memorial Hospital 800-852 Kaohsiung TaiwanNoch nicht rekrutierend» Google-MapsChina Medical University Hospital 404332 Taichung TaiwanRekrutierend» Google-MapsTaichung Veterans General Hospital 40705 Taichung TaiwanNoch nicht rekrutierend» Google-MapsNational Cheng Kung University Hospital 704 Tainan TaiwanRekrutierend» Google-MapsChi Mei Medical Center-Liuying 73657 Tainan TaiwanRekrutierend» Google-MapsNational Taiwan University Hospital 10041 Taipei TaiwanRekrutierend» Google-MapsChang Gung Memorial Hospital - Linkou 333 Taoyuan TaiwanNoch nicht rekrutierend» Google-MapsTaipei Veterans General Hospital 11217 Tapei TaiwanNoch nicht rekrutierend» Google-MapsGülhane Eğitim ve Araştırma Hastanesi 6010 Ankara TurkeyRekrutierend» Google-MapsGazi University MF 6560 Ankara TurkeyRekrutierend» Google-MapsAnkara City Hospital 6800 Ankara TurkeyRekrutierend» Google-MapsDicle University MF 21280 Diyarbakır TurkeyRekrutierend» Google-MapsKoc University Hospital 34010 Istanbul TurkeyNoch nicht rekrutierend» Google-Maps
1. Progression-free Survival (PFS) Assessed by the Investigator as per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) for HCC (Time Frame - up to 3.5 years): PFS, defined as the time (in months) from the date of randomization until the date of progressive disease (PD) or death due to any cause, whichever occurs first. PD will be assessed locally by the Investigator using mRECIST.
Secondary outcome:
1. Progression-free Survival (PFS) Assessed by the Investigator as per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (Time Frame - up to 3.5 years): PFS, defined as the time (in months) from the date of randomization until the date of progressive disease (PD) or death due to any cause, whichever occurs first. PD will be assessed locally by the Investigator using RECIST 1.1.
2. Progression-free Survival (PFS) Assessed by Blinded Independent Central Review (BICR) as per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) and RECIST Version 1.1 (Time Frame - up to 3.5 years): PFS, defined as the time (in months) from the date of randomization until the date of PD or death due to any cause, whichever occurs first. PD will be assessed by BICR using, independently, mRECIST and RECIST 1.1.
3. Overall Survival (OS) of Intermediate-Stage HCC (Rego-Pembro versus Loco-regional Therapy) (Time Frame - up to 3.5 years): OS, defined as the time (in months) from the date of randomization until the date of death due to any cause.
4. Overall Response Rate (ORR) Assessed by Investigator and Blinded Independent Central Review (BICR) as per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) and RECIST Version 1.1 (Time Frame - up to 3.5 years): ORR, defined as the proportion of patients who have a complete response (CR) or partial response (PR) according to RECIST v.1.1 and mRECIST, based on the Investigator's and BICR assessment.
5. Time to unTACEable Progression (TTUP) (Time Frame - up to 3.5 years): To evaluate the two treatment arms (rego-pembro versus loco-regional therapy) with respect to TTUP. TTUP, defined as the time (in months) from the date of randomization until any of the following criteria are met:
Factors related to liver function:
Decompensated cirrhosis (Child-Pugh class B score > 8), including jaundice, clinical hepatic encephalopathy, and refractory ascites and/or hepatorenal syndrome
Impaired portal-vein blood flow (portal-vein thrombus, hepatofugal blood flow)
ECOG PS ≥ 2 Note: transient post-TACE/TARE impairment of liver function of Child-Pugh class B score > 8, that return to pre-TACE/TARE values within 4 weeks of the TACE/TARE session will not qualify as TTUP.
Factors related to HCC:
Failure of the treated nodule to achieve Stable Disease (SD), PR or CR by mRECIST
Malignant portal vein thrombosis
Marcovascular invasion (MVI) or Extra-hepatic Spread (EHS)
6. Duration of Response (DOR) of Rego-Pembro Versus Loco-regional Therapy (Time Frame - up to 3.5 years): To evaluate the two treatment arms with respect to DOR. DOR, defined as the time (in months) from first documentation of response (PR or CR) to PD or death, based on Investigator's assessment or death from any cause, in patients who had a best overall response of CR or PR.
7. Number of Patients with Adverse Events as Assessed by the National Cancer Institute Common Terminology Criteria of Adverse Events (NCI-CTCAE) Version 5 (Time Frame - up to 3.5 years): The NCI-CTCAE is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading scale is provided for each AE term with unique clinical descriptions of severity based on this general guideline: Grade 1 (mild) to 5 (death). AEs will be tabulated by treatment arm, system organ class, preferred term, severity, and relationship to treatment.
8. Change from Baseline in the Physical Functioning Sub-scale Score and Global Health Status/Quality of Life Scale Score as assessed by European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC QLQ-C30) (Time Frame - up to 3.5 years): To evaluate the patient reported outcomes in the two treatment arms (rego-pembro versus loco-regional therapy) as assessed by EORTC QLQ C30. EORTC QLQ C30 is a quality-of-life questionnaire to assess patients' physical, psychological and social functions. The questionnaire is composed of functional scales (physical, role, cognitive, emotional, social), symptom scales (fatigue, pain, and nausea and vomiting), global health status and quality of life scale, also several single-item symptom measures (scaling of items: 1 = Not at all to 4 = Very much; 1 = Very poor to 7 = Excellent). Scores range from 0 to 100, with a high score representing a better health-related quality of life.
9. Change from Baseline in Health-related Quality of Life in Hepatocellular Carcinoma as Assessed by European Organization for Research and Treatment of Cancer's Quality of Life Questionnaire for HCC (EORTC QLQ-HCC18) (Time Frame - up to 3.5 years): To evaluate patient reported outcomes in the two treatment arms (rego-pembro versus loco-regional therapy) as assessed by EORTC QLQ-HCC18. EORTC QLQ-HCC18 is an 18-question module specifically to assess symptom burden and impact on health-related quality of life measuring HCC-specific symptoms. The instrument is an 18-item scale, and scores are based on a 4-point Likert scale (with 1 = 'not at all' to 4 = 'very much'); scaled scores range from 0-100 with a higher score indicating worse symptoms.
10. Change from Baseline in Health-Related Quality of Life as Assessed by the EuroQol's 5-level EQ-5D Health Questionnaire (EQ-5D-5L) (Time Frame - up to 3.5 years): To evaluate patient reported outcomes for health-related quality of life in the two treatment arms (rego-pembro versus loco-regional therapy) as assessed by health questionnaire EQ-5D-5L. Each dimension (Mobility, Self-care, Usual activities, Pain & discomfort, Anxiety & depression) in the EQ-5D-5L has five response levels: no problems (Level 1); slight; moderate; severe; and extreme problems (Level 5). There are 3,125 possible health states defined by combining one level from each dimension, ranging from 11111 (full health) to 55555 (worst health).
Experimental: Regorafenib + Pembrolizumab Investigational arm: regorafenib at a dose of 90 mg orally once per day (on days 1 to 21 of a 28-day cycle), in combination with pembrolizumab 400 mg using a 30-minute intravenous infusion, on day 1 of a 6-week cycle.
Active Comparator: Loco-regional therapy Control arm: Patients will be treated with TACE or TARE "on-demand" according to site's standard of practice.
Regorafenib in combination with pembrolizumab (Stivarga® (regorafenib) / Keytruda® (pembrolizumab) / ): Randomized patients will receive regorafenib at a dose of 90 mg per day by mouth on days 1 to 21 of a 28-day cycle, in combination with pembrolizumab 400 mg using a 30-minute intravenous infusion, on day 1 (D1) of a 6-week cycle.
Loco-regional therapy (Convention transarterial chemoembolization (cTACE) / Drug-eluting bead transarterial chemoembolization (DEB-TACE) / Transarterial Chemoembolization (TACE) / Transarterial radioembolization (TARE) / ): Patients will be treated with TACE or TARE "on-demand" according to site's standard of practice.
Quelle: ClinicalTrials.gov
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"Regorafenib-pembrolizumab vs. TACE/TARE in Intermediate Stage HCC Beyond Up-to-7"
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