Phase III Study of Trifluridine/Tipiracil With and Without Bevacizumab in Refractory Metastatic Colorectal Cancer Patients

Refractory Metastatic Colorectal Cancer Clinical Trial

— SUNLIGHT  

Official title:

An Open-label, Randomized, Phase III Study Comparing Trifluridine/Tipiracil in Combination With Bevacizumab to Trifluridine/Tipiracil Monotherapy in Patients With Refractory Metastatic Colorectal Cancer (SUNLIGHT Study)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04737187
• Other study ID #: CL3-95005-007
• Secondary ID: 2020-001976-14
• Status: Completed
• Phase: Phase 3
• Start date: November 25, 2020
• Est. completion date: September 12, 2023

Study information

• Verified date: December 2023
• Source: Taiho Oncology, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is designed as an international, open-label, controlled two-arm, randomized phase III comparison study evaluating the efficacy and safety of trifluridine/tipiracil in combination with bevacizumab versus trifluridine/tipiracil monotherapy in patients with refractory mCRC.

Description:

This is an international, open-label, controlled two-arm, randomised phase III study evaluating the efficacy and safety of trifluridine/tipiracil in combination with bevacizumab versus trifluridine/tipiracil monotherapy in patients with refractory mCRC. The analysis will be done after 331 events are reported. In order to observe this number of events, 490 patients will be randomised (1:1) to receive trifluridine/tipiracil in combination with bevacizumab (experimental arm) or trifluridine/tipiracil monotherapy (control arm).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 492
• Est. completion date: September 12, 2023
• Est. primary completion date: July 19, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Has histologically confirmed unresectable adenocarcinoma of the colon or rectum (all other histological types are excluded).

2. RAS status must have been previously determined (mutant or wild-type) based on local assessment of tumor biopsy.

3. Has received a maximum of 2 prior chemotherapy regimens for the treatment of advanced colorectal cancer and had demonstrated progressive disease or intolerance to their last regimen.

4. Has measurable or non-measurable disease as defined by RECIST version 1.1

5. Is able to swallow oral tablets.

6. Estimated life expectancy =12 weeks.

7. Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1

Exclusion Criteria:

1. More than 2 prior chemotherapy regimens for the treatment of advanced colorectal cancer.

2. Pregnancy, lactating female or possibility of becoming pregnant during the study.

3. Patients currently receiving or having received anticancer therapies within 4 weeks prior to randomization.

4. Has not recovered from clinically relevant non-hematologic CTCAE grade = 3 toxicity of previous anticancer therapy prior to randomization (excluding alopecia, and skin pigmentation).

5. Has symptomatic central nervous system metastases that are neurologically unstable or requiring increasing doses of steroids to control CNS disease.

6. Has severe or uncontrolled active acute or chronic infection.

7. Has active or history of interstitial lung disease and/or pneumonitis, or pulmonary hypertension.

8. Known Hepatitis B or Hepatitis C Virus infection.

9. Known carriers of HIV antibodies.

10. Confirmed uncontrolled arterial hypertension (defined as systolic blood pressure = 150 mm Hg and/or diastolic blood pressure = 100 mm Hg) or uncontrolled or symptomatic arrhythmia.

11. Deep arterial thromboembolic events including cerebrovascular accident or myocardial infarction within the last 6 months prior to randomization.

12. Treatment with any of the following within the specified time frame prior to

randomization:

• major surgery within 4 weeks prior to randomisation (the surgical incision should be fully healed prior to study drug administration), or has not recovered from side effects of previous surgery, or patient that may require major surgery during the study
• Prior radiotherapy if completed less than 4 weeks before randomisation, except if provided as a short course for symptoms palliation only.
• Drainage for ascites, pleural effusion or pericardial fluid within 4 weeks prior to randomization

13. Other clinically significant medical conditions.

14. Other malignancies.

Related Conditions & MeSH terms

• Colorectal Neoplasms
• Refractory Metastatic Colorectal Cancer

Intervention

Drug:
• Trifluridine/Tipiracil
Taken by mouth two times a day, 5 days on/2 days off, over 2 weeks, followed by a 14-day rest
• Bevacizumab
administered every 2 weeks (Day 1 and Day 15)

Locations

Country	Name	City	State
Austria	"Medizinische Universität Graz "	Graz
Austria	"Medizinische Universität Innsbruck Univ.-Klinik für Innere Medizin V"	Innsbruck
Austria	"Ordensklinikum Linz Barmherzige Schwestern Interne I"	Linz
Austria	"Landeskrankenhaus Feldkirch Interne E"	Rankweil
Austria	"Landeskrankenhaus (SALK) Universitätsklinik für Innere Medizin III (SALK)"	Salzburg
Austria	"Allgemeines Krankenhaus - Universitätskliniken Klinische Abteilung für Onkologie"	Wien
Austria	"Landesklinikum Wiener Neustadt "	Wiener Neustadt
Belgium	"OLV Ziekenhuis Oncology"	Aalst
Belgium	"Universitair Ziekenhuis Antwerpen Oncologie"	Edegem
Belgium	"UZ Leuven Campus Gasthuisberg Digestieve Oncologie"	Leuven
Belgium	"CHC Montlégia Oncologie"	Liege
Belgium	"AZ NIKOLAAS Oncology"	Sint Niklaas
Brazil	"Hospital do Câncer de Barretos - Fundação Pio XII Unidade de Pesquisa Clínica"	Barretos
Brazil	"Hospital de Base Centro Integrado de Pesquisa"	Sao Jose Do Rio Preto
Brazil	"ICESP - Instituto do Câncer do Estado de São Paulo Centro Integrado de Pesquisa"	Sao Paulo
Brazil	Hospital A C Camargo Unidade de Pesquisa Clinica Rua Antonio Prudente	Sao Paulo
Brazil	Hospital Albert Einstein Instituto de Ensino e Pesquisa Av Albert Einstein	Sao Paulo
Brazil	Hospital Sao Camilo Nucleo de Pesquisa Av Alcantara Machado	São Paulo
Denmark	"Aalborg Universitetshospital, Syd Onkologisk Afdeling"	Aalborg
Denmark	Rigshospitalet Dpt of Oncology	Copenhagen
Denmark	"Regionshospitalet Herning, Hospitalsenheden Vest Onkologisk Afdeling"	Herning
Denmark	"Odense Universitetshospital Department of Oncology"	Odense
France	"CHU Jean Minjoz Service d'oncologie médicale"	Besancon
France	"CHU Morvan Institut de Cancérologie et d'Hématologie"	Brest
France	"Centre de lutte contre le cancer Francois Baclesse UCP Digestif"	Caen
France	"Hôpital Européen Georges Pompidou Oncologie Hépatogastroenterologie-oncologie digestive"	Paris
France	Hôpital Saint-Antoine Service d'Oncologie Médicale	Paris
France	CHU de Poitiers Pole Régional de Cancérologie	Poitiers
Germany	Charite Universitätsmedizin Medizinische Klinik m.S. Haemat., Onko., Tumorimmunologie	Berlin
Germany	Onkologische Schwerpunktpraxis Kurfuerstendamm	Berlin
Germany	Lübecker Onkologische Schwerpunktpraxis im Hochschulstadttei	Luebeck
Germany	Klinikum der Universität München Campus Großhadern, Medizinische Klinik und Poliklinik III	Muenchen
Hungary	Magyar Honvedseg Egeszsegugyi Kozpont Onkologiai Osztaly	Budapest
Hungary	Szent Imre Egyetemi Oktatokorhaz Klinikai Onkologiai Osztaly	Budapest
Hungary	Debreceni Egyetem Orvos es Egeszsegtudomanyi Centrum Onkologiai Intezet	Debrecen
Hungary	Petz Aladar Megyei Oktato Korhaz Onkoradiologiai Osztaly	Gyor
Hungary	Bacs-Kiskun Megyei Korhaz Onkoradiologiai Kozpont	Kecskemét
Hungary	Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kp. Onkoterápiás Klinika	Szeged
Hungary	JNSZ Megyei Hetenyi Geza Korhaz es Rendelointezet Megyei Onkologiai Centrum	Szolnok
Hungary	Markusovszky Egyetemi Oktatokorhaz Onkoradiologiai Osztaly	Szombathely
Italy	Azienda Policlinico Universitaria - Presidio Monserrato Oncologia Medica Strada Statale 554 Sestu-Monserrato	Cagliari	Italiy
Italy	A.O.U. Seconda Universita degli Studi di Napoli U.O.C di Oncologia Medica e di Ematologia Dipartimento Medico di Internistica clinca e sperimentale " F Magrassi - A. Lanzara" Via Sergio Pansisni ,	Napoli
Italy	Istituto Nazionale Tumori, I.R.C.C.S "Fondazione G Pascale" Struttura Complessa di Oncologia Medica Addominale	Napoli
Italy	Istituto Oncologico Veneto IOV - IRCCS Unita Operativa Complessa Oncologia Medica 1 Via Gattamelata 64	Padova
Italy	A.O.U. Pisana-Ospedale Santa Chiara U.O. di Oncologia Medica 2	Pisa
Italy	Ospedale San Carlo U.O. Oncologia Medica Via Potito Petrone, Ctr Macchia Romana	Potenza
Italy	Arcispedale Santa Maria Nuova Unità di Oncologia	Reggio Emilia
Italy	Istituto Clinico Humanita IRCCS Dipartimento di Oncologia Medica ed Ematologia Via Manzoni,	Rozzano (MI)
Italy	IRCSS Casa Sollievo della Sofferenza Dipartimento Onco-Ematologia Vale Cappuccini 1	San Giovanni Rotondo
Poland	Przychodnia Lekarska "KOMED"	Konin
Poland	SP ZOZ Szpital Uniwersytecki w Krakowie Oddzial Kliniczny Onkologii	Krakow
Poland	Opolskie Centrum Onkologii im. Tadeusza Koszarowskiego Oddzial Onkologii Klinicznej	Opole
Poland	Wojewodzki Szpital Specjalistyczny im. Janusza Korczaka w Slupsku Sp. z o.o.	Slupsk
Poland	Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie Panstwowy Instytut Badawczy Klinika Onkologii i Radioterapii	Warszawa
Poland	Wojskowy Instytut Medyczny Klinika Onkologii	Warszawa
Poland	Centralny Szpital Kliniczny MSWiA Oddzial Radioterapii i Onkologii	Warzszawa
Puerto Rico	Pan American Center for Oncology Trials, LLC	Río Piedras
Russian Federation	Arkhangelsk Clinical Oncology Dispensary chemotherapy department	Arkhangelsk
Russian Federation	Clinical Oncology Dispensary No.1 Chemotherapy Department	Krasnodar
Russian Federation	Russian Cancer Research Center n.a. NN Blokhin Clinical Pharmacology and Chemotherapy	Moscow
Russian Federation	University Headache Clinic Outpatient oncology clinic	Moscow
Russian Federation	Moscow City Oncology Hospital # 62 chemotherapy department	Moscow Region
Russian Federation	Omsk Clinical Oncologic Dispensary Chemotherapy	Omsk
Russian Federation	National Medical Research Center of Oncology N.N. Petrova	Saint-petersburg
Russian Federation	Multidisciplinary clinic "Reaviz	Samara
Russian Federation	Oncology dispensary No.2 Oncology department	Sochi
Russian Federation	Saint Petersburg City Oncology Clilnic	St Petersburg
Russian Federation	Scientific Centre for Specialized Medical Care (oncological) Chemotherapy	St Petersburg
Russian Federation	SBIH of YR "Clinical oncology hospital chemotherapy department"	Yaroslavl
Spain	"H. Valle de Hebrón Servicio de Oncología - (VHIR)"	Barcelona
Spain	"Hospital de la Santa Creu I Sant Pau Oncología Medica"	Barcelona
Spain	"Hospital Uni. Reina Sofía - Hospital Provincial Departamento de Oncología Médica"	Cordoba
Spain	"INSTITUTO CATALAN DE ONCOLOGÍA - ICO Oncología Médica"	Hospitalet de Llobregat
Spain	"HOSPITAL 12 DE OCTUBRE Servicio Oncología Médica"	Madrid
Spain	"Hospital Universitario Ramón y Cajal Servicio de Oncologia Médica"	Madrid
Spain	"Hospital Universitario Marqués de Valdecilla oncología medica"	Santander
Spain	H.VIRGEN DEL ROCIO Servicio de Oncología Médica	Sevilla
Spain	H. GENERAL DE VALENCIA Servicio de Oncología Médica	Valencia
Spain	Hospital Universitario Miguel Servet Edif. de maternidad planta 8. Servicio de Oncología Médical	Zaragoza
Ukraine	Cherkasy Regional Oncological Dispensary Regional Clinical Oncological Centre	Cherkassy
Ukraine	"MI ""Dnipropetrovsk City Multi-field Clinical Hospital #4"" Department of Oncology"	Dnipro
Ukraine	Kyiv City Clinical Oncological Centre	Kiev	Ukrain
Ukraine	LLC Ukrainian Center of Tomotherapy "Tomoclinic", Chemoteraphy Department	Kropyvnytskyi
Ukraine	"Clinical and diagnostic Centre of Medics-rey Inter. Group LLC Hospital of Israeli Oncology "LISOD"	Kyiv
Ukraine	Medical Center n.a. Acad. Spizhenko "Syber Clinic Spizhenko"" Department of Oncology	Kyiv
Ukraine	National Institute of Cancer Abdominal Oncology Department	Kyiv
Ukraine	Podillia Regional Oncology Centre Chemotherapy Department	Vinnitsya
United States	City of Hope	Duarte	California
United States	Renovatio Clinical - El Paso	El Paso	Texas
United States	Mayo Clinic - FL	Jacksonville	Florida
United States	DuPage Medical Group - Joliet Oncology-Hematology Associates	Joliet	Illinois
United States	Mount Sinai Comprehensive Cancer Center	Miami Beach	Florida
United States	Investigative Clinical Research of Indiana LLC	Noblesville	Indiana
United States	Oncology Hematology West, PC dba Nebraska Cancer Specialists	Omaha	Nebraska
United States	Mayo Clinic Hospital	Phoenix	Arizona
United States	Mayo Clinic - Rochester	Rochester	New York
United States	Comprehensive Hematology Oncology	Saint Petersburg	Florida
United States	City of Hope - South Pasedena	South Pasadena	California
United States	City of Hope - Upland	Upland	California

Sponsors (2)

Lead Sponsor	Collaborator
Taiho Oncology, Inc.	Institut de Recherches Internationales Servier

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  Brazil,  Denmark,  France,  Germany,  Hungary,  Italy,  Poland,  Puerto Rico,  Russian Federation,  Spain,  Ukraine, 

References & Publications (1)

Prager GW, Taieb J, Fakih M, Ciardiello F, Van Cutsem E, Elez E, Cruz FM, Wyrwicz L, Stroyakovskiy D, Papai Z, Poureau PG, Liposits G, Cremolini C, Bondarenko I, Modest DP, Benhadji KA, Amellal N, Leger C, Vidot L, Tabernero J; SUNLIGHT Investigators. Tri — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival (OS)	Overall survival defined as the observed time elapsed between the date of randomization and the date of death due to any cause. The primary estimand of interest was defined to assess the effect of the randomized treatments on the survival duration in all participants regardless of whether or not intercurrent events had occurred (treatment policy strategy). Analysis was performed using Kaplan- Meier method.	From date of randomization to the death due to any cause or cut-ff date, whichever comes first (maximum duration: up to 20 months)
Primary	Survival Probability at 6 Months	Overall survival defined as the observed time elapsed between the date of randomization and the date of death due to any cause. The primary estimand of interest was defined to assess the effect of the randomized treatments on the survival duration in all participants regardless of whether or not intercurrent events had occurred (treatment policy strategy). Analysis was performed using Kaplan- Meier method. In this outcome measure, data of survival probability at 6 months was reported.	From date of randomization until 6 months post treatment
Primary	Survival Probability at 12 Months	Overall survival defined as the observed time elapsed between the date of randomization and the date of death due to any cause. The primary estimand of interest was defined to assess the effect of the randomized treatments on the survival duration in all participants regardless of whether or not intercurrent events had occurred (treatment policy strategy). Analysis was performed using Kaplan- Meier method. In this outcome measure, data of survival probability at 12 months was reported.	From date of randomization until 12 months post treatment
Primary	Survival Probability at 18 Months	Overall survival defined as the observed time elapsed between the date of randomization and the date of death due to any cause. The primary estimand of interest was defined to assess the effect of the randomized treatments on the survival duration in all participants regardless of whether or not intercurrent events had occurred (treatment policy strategy). Analysis was performed using Kaplan- Meier method. In this outcome measure, data of survival probability at 18 months was reported.	From date of randomization until 18 months post treatment
Secondary	Progression Free Survival (PFS)	PFS was defined as the time elapsed between the date of randomisation and the date of radiological tumour progression as per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) assessed by investigator, or death (from any cause), whichever comes first. Progressive Disease (PD) as per RECIST 1.1: at least a 20 percent (%) increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. Analysis was performed by Kaplan-Meier method.	From randomization to the date of radiological tumour progression or death due to any cause or data cut-off date whichever comes first (i.e., up to 20 months)
Secondary	Probability of Participants With Progression Free Survival at 3, 6, 9 and 12 Months	PFS was defined as the time elapsed between the date of randomisation and the date of radiological tumour progression as per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) assessed by investigator, or death (from any cause), whichever comes first. Progressive Disease (PD) as per RECIST 1.1: at least a 20 percent (%) increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. Analysis was performed by Kaplan-Meier method. In this outcome measure, data of PFS at 3 months was reported.	From randomization until 3, 6, 9, and 12 months post treatment
Secondary	Overall Response Rate (ORR)	Objective response was defined as percentage of participants who achieved complete response (CR) or partial response (PR) according to the RECIST version 1.1 and using investigator's tumour assessment. As per RECIST 1.1, CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the Baseline sum diameters.	From the date of randomization to the date of documentation of progression or death due to any cause or data cut-off, whichever occurred first (i.e., up to 20 months)
Secondary	Percentage of Participants With Disease Control	Disease control is defined as percentage of participants who achieved CR or PR, or stable disease (SD) as per RECIST 1.1 and using investigator's tumour assessment from the date of randomization to until disease progression or death due to any cause. As per RECIST 1.1, CR: disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: at least a 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters. PD: at least 20% increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions.	From randomization to the date of first documented tumor progression, death due to any cause or data cut-off date whichever comes first (i.e., up to 20 months)
Secondary	Number of Participants With Treatment-emergent Adverse Events (TEAE) and Treatment-emergent Serious Adverse Events (TESAEs)	An AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily have to have a causal relationship with the treatment. Serious adverse events (SAEs) was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were defined as AEs that developed, worsened or became serious during the TEAE period (time from the first dose of study treatment up to 30 days after the last dose of study treatment). TEAEs included both SAEs and non-SAEs.	From Baseline up to 30 days after the last dose of study treatments (i.e., up to 19.5 months)