A Study of Biomarker-Driven Therapy in Metastatic Colorectal Cancer (mCRC)

Colorectal Cancer Clinical Trial

— MODUL  

Official title:

A Multi-Centre Randomised Clinical Trial of Biomarker-Driven Maintenance Treatment for First-Line Metastatic Colorectal Cancer (MODUL)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02291289
• Other study ID #: MO29112
• Secondary ID: 2014-001017-61
• Status: Completed
• Phase: Phase 2
• Start date: April 17, 2015
• Est. completion date: March 24, 2021

Study information

• Verified date: October 2023
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This randomized, multi-center, active-controlled, open-label, parallel-group study will investigate the efficacy and safety of biomarker-driven maintenance treatment for first-line mCRC. Participants with mCRC are eligible for entry and cannot have received any prior chemotherapy in the metastatic setting. The entire study duration is anticipated to be approximately 7.5 years.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1044
• Est. completion date: March 24, 2021
• Est. primary completion date: May 31, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• ECOG PS of less than or equal to (<=) 2

• At least 16 weeks of life expectancy at time of entry into the study

• Histologically confirmed colorectal cancer (CRC) with mCRC confirmed radiologically

• Measureable, unresectable disease according to RECIST 1.1

• No prior chemotherapy for CRC in the metastatic setting

• Archival tumor formalin-fixed paraffin-embedded tissue block from the primary tumor obtained at the time of the initial diagnosis is available

• Adequate hematological, liver and renal function

• Agreement to use highly effective measures of contraception

Exclusion Criteria for All Participants:

• Less than 6 months from completion of any prior neoadjuvant or adjuvant chemotherapy, radiotherapy

• Prior or current treatment with bevacizumab or any other anti-angiogenic drug (vascular endothelial growth factor or vascular endothelial growth factor receptor therapies or tyrosine kinase inhibitors)

• Current or recent (within 10 days of study enrollment) use of aspirin (more than [>] 325 milligrams per day [mg/day]), clopidogrel (> 75 mg/day), or current or recent (within 10 days prior to the start of study induction treatment) use of therapeutic oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes (prophylactic uses allowed)

• Active infection requiring intravenous antibiotics at the start of study induction treatment

• Previous or concurrent malignancy, except for adequately treated basal or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the participant has been disease-free for 5 years prior to study entry

• Inadequately controlled hypertension; prior history of hypertensive crisis or hypertensive encephalopathy

• Clinically significant (active) cardiovascular disease, for example cerebrovascular accidents <= 6 months prior to start of study induction treatment, myocardial infarction <= 6 months prior to study enrollment, unstable angina, New York Heart Association (NYHA) Functional Classification Grade II or greater congestive heart failure, or serious cardiac arrhythmia uncontrolled by medication or potentially interfering with protocol treatment

• Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months of start of study induction treatment

• Active symptomatic or untreated central nervous system (CNS) metastases; CNS disease other than supratentorial or cerebellar metastases (in other words, patients with metastases to midbrain, pons, medulla or spinal cord are excluded); history of or known carcinomatous meningitis

• Known hypersensitivity to any component of any of the study induction or maintenance treatment medications

• Pregnancy or lactation

Exclusion Criteria for Participants in Cohort 1 (MP):

• Inability to swallow pills

• Refractory nausea and vomiting, malabsorption, external biliary shunt or significant bowel resection that would preclude adequate absorption

• History or presence of clinically significant ventricular or atrial dysrhythmias

• Corrected QT (QTc) interval >= 450 millisecond assessed within 3 weeks prior to randomization, long QT syndrome or, uncorrectable electrolyte abnormalities (including magnesium) or requirement for medicinal products known to prolong the QT interval

• ECOG PS > 2

Exclusion Criteria for Participants in Cohort 2 (MP):

• History of autoimmune disease including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis

• Prior allogeneic bone marrow transplantation or prior solid organ transplantation

• History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis at most recent chest imaging (computed tomography [CT] scan or magnetic resonance imaging [MRI])

• Positive test for human immunodeficiency virus (HIV)

• Active hepatitis B virus (HBV) or hepatitis C virus (HCV) at Screening

• Active tuberculosis

• Severe infection within 4 weeks prior to start of maintenance treatment including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia; has signs or symptoms of significant infection or has received oral or IV antibiotics within 2 weeks prior to start of maintenance treatment

• Administration of a live, attenuated vaccine within 4 weeks prior to start of maintenance treatment or anticipation that such a live attenuated vaccine will be required during the remainder of the study

• Prior treatment with cluster of differentiation (CD) 137 agonists, anti-cytotoxic T-lymphocyte-associated antigen (CTLA) 4, anti-programmed death-1 (PD-1), or anti-programmed death-ligand 1 (PD-L1) therapeutic antibody or pathway-targeting agents

• Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin-2) within 4 weeks or five half-lives of the drug, whichever is longer, prior to start of maintenance treatment

• Treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to start of maintenance treatment, or anticipated requirement for systemic immunosuppressive medications during the remainder of the study

• If receiving receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor (for example, denosumab) and unwilling to adopt alternative treatment such as bisphosphonates while receiving atezolizumab

Exclusion Criteria for Participants in Cohort 3 (MP):

• Inability to swallow pills

• Left ventricular ejection fraction (LVEF) less than (<) 50 percent (%) as assessed after completion of induction treatment by either 2-dimensional echocardiogram or multiple-gated acquisition

• Clinically significant cardiovascular disease, including unstable angina, history of or active congestive heart failure of = NYHA Grade 2, history of or ongoing serious cardiac arrhythmia requiring treatment (except for controlled atrial fibrillation and/or paroxysmal supraventricular tachycardia).

• Current uncontrolled hypertension with or without medication

• Current dyspnea at rest due to complications of advanced malignancy or other disease requiring continuous oxygen therapy

• Insulin-dependent diabetes

• Current known infection with HIV, HBV, or HCV (active infection or carriers)

• Requirement for concurrent use of the antiviral agent sorivudine (antiviral) or chemically related analogues, such as brivudine

• Malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach or small bowel, or ulcerative colitis

• Known hypersensitivity to murine proteins

Exclusion Criteria for Participants in Cohort 4 (MP):

• Inability to swallow medications

• History of autoimmune disease including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis

• History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on most recent chest imaging (CT scan or MRI)

• Malabsorption condition that would alter the absorption of orally administered medications

• Amylase or lipase = 1.5 times the upper limit of normal within 14 days prior to maintenance treatment initiation

• Serum albumin less than (<) 2.5 grams per deciliter (g/dL)

• LVEF < institutional lower limit of normal or < 50%, whichever is lower

• Poorly controlled hypertension

• Uncontrolled pleural effusion, pericardial effusion or ascites requiring repeated drainage more than once every 28 days. Indwelling drainage catheters are allowed

• Unstable angina, new onset angina within last 3 months, myocardial infarction within last 6 months and current congestive heart failure = NYHA Grade 2

• History of stroke, reversible ischemic neurological defect, or transient ischemic attack within 6 months prior to initiation of maintenance treatment

• History or evidence of intracranial hemorrhage or spinal cord hemorrhage

• Evidence of clinically significant vasogenic edema

• Any hemorrhage or bleeding event = National Cancer Institute Common Terminology Criteria for Adverse Events Grade 3 within 28 days prior to initiation of maintenance treatment

• History or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for central serous retinopathy, retinal vein occlusion, or neovascular macular degeneration

• Positive HIV test

• Active HBV or HCV

• Active tuberculosis

• Severe infection within 4 weeks prior to start of maintenance treatment including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia; has signs or symptoms of significant infection or has received oral or IV antibiotics within 2 weeks prior to start of maintenance treatment.

• Prior allogeneic bone marrow transplantation or prior solid organ transplantation

• Administration of a live, attenuated vaccine within 4 weeks prior to start of study maintenance treatment or anticipation that such a live attenuated vaccine will be required during the study

• Prior treatment with CD137 agonists, anti-CTLA4, anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway-targeting agents

• Prior treatment with a mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) or ERK inhibitor

• Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin-2) within 4 weeks or five half-lives of the drug, whichever is longer, prior to start of study maintenance treatment

• Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 2 weeks prior to start of study maintenance treatment, or requirement for systemic immunosuppressive medications during the trial.

• If receiving a RANKL inhibitor (for example, denosumab), unwilling to adopt alternative treatment such as (but not limited to) bisphosphonates, while receiving atezolizumab.

• Consumption of foods, supplements or drugs that are potent cytochrome P450 3A4 (CYP3A4) enzyme inducers or inhibitors = 7 days before initiation of study maintenance treatment or expected concomitant use during maintenance treatment. These include St. John's wort or hyperforin (potent CYP3A4 enzyme inducer) and grapefruit juice (potent CYP3A4 enzyme inhibitor)

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms

Intervention

Drug:
• Cetuximab
500 mg/m^2 via IV infusion on Day 1 of every 2-week cycle
• FOLFOX induction regimen
Administered per the Investigator's discretion in accordance with locally approved prescribing information.
• Fluoropyrimidine (5-FU/LV or capecitabine)
Per Investigator's discretion: 5-FU 1600-2400 mg/m^2 administered via 46-hour IV infusion on Day 1 of every 2-week cycle and LV 400 mg/m^2 administered via a 2-hour infusion on Day 1 every 2 weeks or 1000 mg/m^2 twice-daily capecitabine (BID) by mouth given days 1-14 every 2 weeks. The chosen fluoropyrimidine should be administered in accordance with local prescribing information.
• Atezolizumab
800 mg atezolizumab via 60-minute IV infusion on Day 1 of every 2-week cycle, or a fixed dose of 840 mg
• Vemurafenib
960 mg vermurafenib BID by mouth
• Bevacizumab
5 mg/kg bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle per local prescribing information
• Trastuzumab
Initial loading dose of 8 mg/kg followed by 6 mg/kg for subsequent doses by IV infusion on Day 1 of every 3-week treatment cycle
• Pertuzumab
Initial fixed loading dose of 840 mg followed by 420 mg for subsequent doses by IV infusion on Day 1 of each 3-week treatment cycle
• Cobimetinib
60 mg orally once daily for 3 weeks followed by a 1-week treatment break
• 5-FU/LV
1600-2400 mg/m^2 5-FU via 46-hour IV infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle until disease progression per the Investigator's assessment using modified Response Evaluation Criteria in Solid Tumors or death from any cause, whichever occurs first. The fluoropyrimidine should be administered in accordance with local prescribing information.
• Capecitabine
1000 mg/m^2 twice-daily capecitabine (BID) by mouth given days 1-14 every 2 weeks. The fluoropyrimidine should be administered in accordance with local prescribing information.

Locations

Country	Name	City	State
Argentina	Hospital de Gastroenterologia Dr. Bonorino Udaondo ; Servicio de Oncología	Buenos Aires
Argentina	Centro Oncologico Riojano Integral (CORI)	La Rioja
Argentina	Clínica Viedma	Viedma Rio Negro
Belgium	Institut Jules Bordet X	Brussels
Belgium	Hospital Erasme	Bruxelles
Belgium	UZ Leuven Gasthuisberg	Leuven
Belgium	CHC MontLégia	Liege
Belgium	AZ Delta (Campus Rumbeke)	Roeselare
Bosnia and Herzegovina	University Clinical Center of the Republic of Srpska	Banja Luka
Brazil	Hospital de Cancer de Barretos	Barretos	SP
Brazil	Hospital Amaral Carvalho	Jau	SP
Brazil	Hospital da Cidade de Passo Fundo; Centro de Pesquisa em Oncologia	Passo Fundo	RS
Brazil	Hospital das Clinicas - UFRGS	Porto Alegre	RS
Brazil	Hospital Nossa Senhora da Conceicao	Porto Alegre	RS
Brazil	Faculdade de Medicina de Sao Jose do Rio Preto - FAMERP*X*	Sao Jose do Rio Preto	SP
Brazil	Instituto de Ensino e Pesquisa Sao Lucas - IEP	Sao Paulo	SP
Denmark	Herlev Hospital; Afdeling for Kræftbehandling	Herlev
Denmark	Regionshospitalet Gødstrup; Kræftafdelingen	Herning
Denmark	Rigshospitalet; Onkologisk Klinik	København Ø
Denmark	Odense Universitetshospital, Onkologisk Afdeling R	Odense C
Denmark	Sygehus Syd Roskilde; Onkologisk/haematologisk ambulatorium	Roskilde
Egypt	Ain Shams University Hospital; Oncology	Cairo
Egypt	National Cancer Institute	Cairo
France	Clinique Sainte Catherine	Avignon
France	HOPITAL JEAN MINJOZ; Oncologie	Besancon
France	Hopital Augustin Morvan; Federation De Cancerologie	Brest
France	Chu Estaing; Chir Generale Digestive A Et B	Clermont Ferrand
France	Hôpital Franco-Britannique- Fondation Cognacq-Jay; Cancerologie	Levallois-Perret
France	Hopital Claude Huriez; Medecine Interne Oncologie	Lille
France	Ch De Montbeliard;Chir Generale Digestive	Montbeliard
France	Hopital Caremeau; Gastro Enterologie	Nimes
France	Hopital Saint Antoine; Oncologie Medicale	Paris
France	Hopital Haut Leveque	Pessac
France	Chu La Miletrie; Gastro Enterologie Endoscopies	Poitiers
France	ICANS	Strasbourg
France	Hopital Rangueil; Gastro Enterologie Et Nutrition	Toulouse
France	Institut Gustave Roussy; Departement Oncologie Medicale	Villejuif
Germany	Hämatologie Onkologie im Zentrum MVZ GmbH	Augsburg
Germany	DRK Kliniken Berlin Köpenick Darmzentrum	Berlin
Germany	Onkologische Schwerpunktpraxis Kurfürstendamm	Berlin
Germany	BAG Freiberg-Richter, Jacobasch, Illmer, Wolf; Gemeinschaftspraxis Hämatologie-Onkologie	Dresden
Germany	Krankenhaus Nordwest; Klinik f. Onkologie und Hämatologie	Frankfurt
Germany	PIOH PD Dr. R. Schnell ? Dr. H. Schulz ? Dr. M. Hellmann	Frechen
Germany	Klinik Fulda, Medizinisches Versorgungszentrum Osthessen GmbH	Fulda
Germany	Universitätsklinikum Hamburg-Eppendorf, Onkologisches Zentrum, Studienzentrale der II. Med. Klinik	Hamburg
Germany	Medizinische Hochschule Hannover; Zentrum Innere Medizin; Abt. Hämatologie u. Onkologie	Hannover
Germany	SLK-Kliniken Heilbronn GmbH; Klinik für Innere Medizin III; Schwerpunkt Häma./Onko./Palliativm.	Heilbronn
Germany	Klinik der Ruhr-Uni Bochum; Marien-Hospital Herne	Herne
Germany	Gemeinschaftspraxis für Hämatologie und Onkologie, PD Dr. Bauer, Dr. Thiel	Lebach
Germany	Klinikum Magdeburg gGmbH Klinik für Allgemein- und Viszeralchirurgie	Magdeburg
Germany	Onkologische Gemeinschaftspraxis	Magdeburg
Germany	Universitätsklinikum Magdeburg Klinik für Gastroenterologie und Hepatologie	Mageburg
Germany	Kliniken Maria Hilf GmbH, Krankenhaus St. Franziskus	Mönchengladbach
Germany	Städt. Klinikum München GmbH Klinikum Neuperlach Klinik f.Hämatologie u.Onkologie	München
Germany	Gemeinschaftspraxis für Hämatologie und Onkologie	Münster
Germany	Brüderkrankenhaus St. Josef	Paderborn
Germany	Studienzentrum Onkologie Ravensburg GbR; Onkologie Ravensburg	Ravensburg
Germany	Prosper-Hospital, Medizinische Klinik I	Recklinghausen
Germany	Krankenhaus Barmherziger Brüder; Klinik für Internistische Onkologie / Hämatologie	Regensburg
Germany	Klinikum am Steinenberg / Ermstalklinik	Reutlingen
Germany	Praxis für Hämatologie & Onkologie	Saarbruecken
Germany	MVZ für Hämatologie, Onkologie, Strahlentherapie und Palliativmedizin -; Klinik Dr. Hancken	Stade
Germany	Klinikum Mutterhaus der Borromaeerinnen gGmbH; Haematologie/Onkologie	Trier
Germany	Klinikum Wetzlar-Braunfels, Klinik für Hämatologie/Onkologie und Palliativmedizin	Wetzlar
Greece	Agioi Anargyroi; 3Rd Dept. of Medical Oncology	Athens
Greece	Univ General Hosp Heraklion; Medical Oncology	Heraklion
Greece	Uni Hospital of Ioannina; Oncology Dept.	Ioannina
Greece	University Hospital of Patras Medical Oncology	Patras
Greece	Thermi Clinic; Oncology Clinic	Thermi Thessalonikis
Greece	Bioclinic Thessaloniki	Thessaloniki
Greece	Euromedical General Clinic of Thessaloniki; Oncology Department	Thessaloniki
Italy	Humanitas Gavazzeni;U.O. Oncologia Medica	Bergamo	Lombardia
Italy	Azienda Ospedaliero-Universitaria Careggi;S.C. Oncologia Medica 1	Firenze	Toscana
Italy	IRST Istituto Scientifico Romagnolo Per Lo Studio E Cura Dei Tumori, Sede Meldola; Oncologia Medica	Meldola	Emilia-Romagna
Italy	Asst Grande Ospedale Metropolitano Niguarda; Dipartimento Di Ematologia Ed Oncologia	Milano	Lombardia
Italy	Irccs Istituto Europeo Di Oncologia (IEO); Oncologia Medica	Milano	Lombardia
Italy	Irccs Istituto Nazionale Dei Tumori (Int);S.C. Medicina Oncologica 1	Milano	Lombardia
Italy	IRCCS Istituto Nazionale Tumori Fondazione Pascale; Oncologia Medica A	Napoli	Campania
Italy	IRCCS Istituto Oncologico Veneto (IOV); Oncologia Medica Prima	Padova	Veneto
Italy	A.O. Universitaria Di Parma; Oncologia Medica	Parma	Emilia-Romagna
Italy	Istituto Regina Elena; Oncologia Medica A	Roma	Lazio
Italy	Policlinico Universitario "Agostino Gemelli"; U.O.C. Oncologia Medica	Roma	Lazio
Italy	IRCCS Ospedale Casa Sollievo Della Sofferenza; Oncologia	San Giovanni Rotondo	Puglia
Italy	A.O.U.I. VERONA-OSPEDALE POLICLINICO G.B. ROSSI BORGO ROMA;ONCOLOGIA MEDICA-d.U.	Verona	Veneto
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Mexico	Fundacion Rodolfo Padilla Padilla A.C.	León	Guanajuato
Mexico	Instituto Nacional de Cancerologia; Oncology	Mexico City
Mexico	Oaxaca Site Management Organization	Oaxaca de Juárez	Oaxaca
Mexico	Cancerologia de Queretaro; Oncologia	Queretaro, Queretaro	Queretaro
Netherlands	Antoni van Leeuwenhoek Ziekenhuis	Amsterdam
Netherlands	Ijsselland Ziekenhuis; Inwendige Geneeskunde	Capelle A/d IJssel
Netherlands	Deventer Ziekenhuis; Interne Geneeskunde	Deventer
Netherlands	Albert Schweitzer Ziekenhuis - loc Dordrecht	Dordrecht
Netherlands	Catharina ZKHS; Inwendige Geneeskunde Afd.	Eindhoven
Netherlands	St. Antonius locatie Leidsche Rijn	Utrecht
Netherlands	Isala Klinieken	Zwolle
Poland	Szpital Uniwersytecki w Krakowie, Oddzia? Kliniczny Kliniki Onkologii	Kraków
Poland	Narodowy Instytut Onkologii im. M. Sklodowskiej-Curie; Klinika Onkologii i Radioterapii,	Warszawa
Portugal	HUC; Servico de Oncologia Medica	Coimbra
Portugal	Hospital de Santa Maria; Servico de Oncologia Medica	Lisboa
Russian Federation	Russian Oncology Research Center n.a. N.N. Blokhin Dpt of Clinical Pharmacology and Chemotherapy	Moscow	Moskovskaja Oblast
Russian Federation	Bashkirian Republican Clinical Oncology Dispensary	UFA	Baskortostan
Serbia	Institute for Oncology and Radiology of Serbia; Clinic for Medical Oncology	Belgrade
Slovakia	Narodny Onkologicky Ustav; Oddelenie klinickej onkologie E	Bratislava
Slovakia	POKO Poprad; Department of Oncology	Poprad
Slovenia	Institute of Oncology Ljubljana	Ljubljana
Spain	Hospital General Univ. de Alicante; Servicio de Oncologia	Alicante
Spain	Hospital Universitari Germans Trias i Pujol; Servicio de Oncologia	Badalona	Barcelona
Spain	Hospital Universitario Reina Sofia; Servicio de Oncologia	Córdoba	Cordoba
Spain	Hospital General Universitario de Elche; Servicio de Oncologia	Elche	Alicante
Spain	Complejo Hospitalario de Jaen-Hospital Universitario Medico Quirurgico; Servicio de Oncologia	Jaen
Spain	Hospital Universitari Arnau de Vilanova de Lleida; Servicio de Oncologia	Lerida
Spain	Hospital General Universitario Gregorio Marañon; Servicio de Oncologia	Madrid
Spain	Hospital Ramon y Cajal; Servicio de Oncologia	Madrid
Spain	Hospital Universitario 12 de Octubre; Servicio de Oncologia	Madrid
Spain	Hospital Universitario La Paz; Servicio de Oncologia	Madrid
Spain	Hospital Universitario Puerta de Hierro; Servicio de Oncologia	Majadahonda	Madrid
Spain	Hospital Regional Universitario Carlos Haya; Servicio de Oncologia	Malaga
Spain	Hospital de Navarra; Servicio de Oncologia	Navarra
Spain	Complejo Hospitalario de Orense; Servicio de Oncologia	Orense
Spain	Hospital Univ. Central de Asturias; Servicio de Oncologia	Oviedo	Asturias
Spain	Hospital Universitario Son Espases	Palma De Mallorca	Islas Baleares
Spain	Hospital de Donostia; Servicio de Oncologia Medica	San Sebastian	Guipuzcoa
Spain	Hospital Univ Vall d'Hebron; Servicio de Oncologia	Sant Andreu de La Barca	Barcelona
Spain	Complejo Hospitalario Nuestra Señora de la Candelaria; Servicio de Oncologia	Santa Cruz de Tenerife	Tenerife
Spain	Hospital Universitario Marques de Valdecilla; Servicio de Oncologia	Santander	Cantabria
Spain	Complejo Hospitalario Universitario de Santiago (CHUS) ; Servicio de Oncologia	Santiago de Compostela	LA Coruña
Spain	Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia	Valencia
Spain	Hospital General Universitario de Valencia; Servicio de oncologia	Valencia
Spain	Hospital Universitario la Fe; Servicio de Oncologia	Valencia
Spain	Hospital Clinico Universitario Lozano Blesa; Servicio de Oncologia	Zaragoza
Spain	Hospital Universitario Miguel Servet; Servicio Oncologia	Zaragoza
Sweden	Skånes University Hospital, Skånes Department of Onclology	Lund
Sweden	Karolinska Hospital; Oncology - Radiumhemmet	Stockholm
Turkey	Acibadem University School of Medicine, Adana Hospital; General Surgery	Adana
Turkey	Trakya University Medical Faculty Research And Practice Hospital Medical Oncology Department	Edirne
Turkey	Istanbul Uni Capa Medical Faculty; Inst. of Oncology	Istanbul
Turkey	Marmara Uni Faculty of Medicine; Medical Oncology	Istanbul
Turkey	Ege Uni Medical Faculty Hospital; Oncology Dept	Izmir
Turkey	Hacettepe Uni Medical Faculty Hospital; Oncology Dept	Sihhiye/Ankara
United Kingdom	Aberdeen Royal Infirmary; Medical Oncology Dept	Aberdeen
United Kingdom	Birmingham Heartlands Hospital	Birmingham
United Kingdom	Broomfield Hospital; Oncology	Chelsmford
United Kingdom	Castle Hill Hospital; The Queens Centre for Oncology and Haematology	Cottingham
United Kingdom	Guys and St Thomas NHS Foundation Trust, Guys Hospital	London
United Kingdom	Royal Marsden Hospital; Dept of Med-Onc	London
United Kingdom	Christie Hospital Nhs Trust; Medical Oncology	Manchester
United Kingdom	Mount Vernon Hospital	Middlesex
United Kingdom	Queen's Hospital	Romford
United Kingdom	Southampton General Hospital; Medical Oncology	Southampton
United Kingdom	Royal Marsden Hospital; Dept. of Medicine	Sutton

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

Argentina,  Belgium,  Bosnia and Herzegovina,  Brazil,  Denmark,  Egypt,  France,  Germany,  Greece,  Italy,  Korea, Republic of,  Mexico,  Netherlands,  Poland,  Portugal,  Russian Federation,  Serbia,  Slovakia,  Slovenia,  Spain,  Sweden,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-Free Survival (PFS)	PFS is defined as the time from randomization to the first occurrence of disease progression according to RECIST v1.1, or death from any cause, whichever occurs first. Progressive disease (PD) for target lesion: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/=5 mm. PD for non-target lesion: Unequivocal progression of existing non-target lesions.	From randomization until disease progression or death from any cause, up to 5 years
Secondary	Overall Survival (OS)	OS is defined as the time from randomization into the MTP to time of death from any cause.	From randomization until death from any cause, up to 5 years
Secondary	Percentage of Participants With Adverse Events		From baseline until end of study (up to 5 years)
Secondary	Overall Response	Calculated as the number of participants with a best overall response of CR or PR according to RECIST 1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR= CR + PR.	From randomization until disease progression, up to 5 years
Secondary	Disease Control Rate (DCR)	DCR is defined as the percentage of participants with CR, PR, or stable disease (SD) at 16 weeks. Per RECIST v1.1, CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression, taking as reference the smallest sum on study. Disease progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including baseline, or the appearance of one or more new lesions.	From randomization until disease progression, up to 5 years
Secondary	Time to Treatment Response	Calculated as the time from randomization to the first Occurrence of a documented Objective Response (CR or PR) determined according to RECIST 1.1. CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.	From randomization until disease progression or death from any cause, up to 5 years
Secondary	Duration of Response	Defined as the time from the first assessment of CR or PR until disease progression or death from any cause, whichever occurs first. CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.	From first objective response until disease progression or death from any cause, up to 5 years
Secondary	Percentage of Participants With Improvement and/or Stayed the Same on the Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score		From baseline until end of study (up to 5 years)