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

NCT04737187 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: CL3-95005-0072020-001976-14
• Study Type: interventional
• Target: 492
• Locations: 14 countries
• Sites: 99

Brief 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.

Conditions

Refractory Metastatic Colorectal Cancer

Keywords

trifluridine/tipiracil/lonsurf; TAS102; bevacizumab; avastin; RAS status (wild type, mutant)

Outcome Measures

Primary Outcomes (4)

• 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-off date, whichever comes first (maximum duration: up to 20 months)

• 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

• 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

• 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 Outcomes (9)

• Progression Free Survival (PFS)

  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)

• Probability of Participants With Progression Free Survival at 3, 6, 9 and 12 Months

  From randomization until 3, 6, 9, and 12 months post treatment

• Overall Response Rate (ORR)

  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)

• Percentage of Participants With Disease Control

  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)

• Number of Participants With Treatment-emergent Adverse Events (TEAE) and Treatment-emergent Serious Adverse Events (TESAEs)

  From baseline (Cycle 1 Day 1) up to 30 days after the last dose of study drug (i.e., up to 30.7 months)

Study Arms (2)

Trifluridine/Tipiracil + Bevacizumab

EXPERIMENTAL

Participants were administered 35 milligrams per square meter per dose (mg/m²/dose) trifluridine/tipiracil (FTD/TPI) orally twice a day (BID), within 1 hour after completion of morning and evening meals, 5 days on (Day 1 to 5 and Day 8 to 12) with 2 days off (Day 6 to 7 an Day 13 to 14), over 2 weeks, followed by a 14-day rest; with bevacizumab (5 milligrams per kilogram \[mg/kg\], intravenous \[IV\] infusion administered every 2 weeks (Day 1 and Day 15). This treatment cycle was repeated every 4 weeks.

Drug: Trifluridine/Tipiracil; Drug: Bevacizumab

Trifluridine/Tipiracil

ACTIVE COMPARATOR

Participants were administered 35 mg/m²/dose of FTD/TPI orally BID, within 1 hour after completion of morning and evening meals, 5 days on (Day 1 to 5 and Day 8 to 12) with 2 days off (Day 6 to 7 and Day 13 to 14), over 2 weeks, followed by a 14-day rest. This treatment cycle was repeated every 4 weeks.

Drug: Trifluridine/Tipiracil

Interventions

Trifluridine/Tipiracil DRUG

Taken by mouth two times a day, 5 days on/2 days off, over 2 weeks, followed by a 14-day rest

Also known as: TAS102, S 95005, Lonsurf

Trifluridine/Tipiracil; Trifluridine/Tipiracil + Bevacizumab

Bevacizumab DRUG

administered every 2 weeks (Day 1 and Day 15)

Also known as: Avastin

Trifluridine/Tipiracil + Bevacizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Has histologically confirmed unresectable adenocarcinoma of the colon or rectum (all other histological types are excluded).
• RAS status must have been previously determined (mutant or wild-type) based on local assessment of tumor biopsy.
• 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.
• Has measurable or non-measurable disease as defined by RECIST version 1.1
• Is able to swallow oral tablets.
• Estimated life expectancy ≥12 weeks.
• Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1

You may not qualify if:

• More than 2 prior chemotherapy regimens for the treatment of advanced colorectal cancer.
• Pregnancy, lactating female or possibility of becoming pregnant during the study.
• Patients currently receiving or having received anticancer therapies within 4 weeks prior to randomization.
• Has not recovered from clinically relevant non-hematologic CTCAE grade ≥ 3 toxicity of previous anticancer therapy prior to randomization (excluding alopecia, and skin pigmentation).
• Has symptomatic central nervous system metastases that are neurologically unstable or requiring increasing doses of steroids to control CNS disease.
• Has severe or uncontrolled active acute or chronic infection.
• Has active or history of interstitial lung disease and/or pneumonitis, or pulmonary hypertension.
• Known Hepatitis B or Hepatitis C Virus infection.
• Known carriers of HIV antibodies.
• 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.
• Deep arterial thromboembolic events including cerebrovascular accident or myocardial infarction within the last 6 months prior to randomization.
• 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

Sponsors & Collaborators

• Taiho Oncology, Inc.: lead
• Institut de Recherches Internationales Servier: collaborator

Study Sites (99)

Mayo Clinic Hospital

Phoenix, Arizona, 85054, United States

Location

City of Hope

Duarte, California, 91010, United States

Location

City of Hope - South Pasedena

South Pasadena, California, 91030, United States

Location

City of Hope - Upland

Upland, California, 91786, United States

Location

Mayo Clinic - FL

Jacksonville, Florida, 32224, United States

Location

Mount Sinai Comprehensive Cancer Center

Miami Beach, Florida, 33140, United States

Location

Comprehensive Hematology Oncology

St. Petersburg, Florida, 33709, United States

Location

DuPage Medical Group - Joliet Oncology-Hematology Associates

Joliet, Illinois, 60435, United States

Location

Investigative Clinical Research of Indiana LLC

Noblesville, Indiana, 46062, United States

Location

Oncology Hematology West, PC dba Nebraska Cancer Specialists

Omaha, Nebraska, 68130, United States

Location

Mayo Clinic - Rochester

Rochester, New York, 55905, United States

Location

Renovatio Clinical - El Paso

El Paso, Texas, 79915, United States

Location

"Medizinische Universität Graz "

Graz, 8036, Austria

Location

"Medizinische Universität Innsbruck Univ.-Klinik für Innere Medizin V"

Innsbruck, 6020, Austria

Location

"Ordensklinikum Linz Barmherzige Schwestern Interne I"

Linz, 4010, Austria

Location

"Landeskrankenhaus Feldkirch Interne E"

Rankweil, 6830, Austria

Location

"Landeskrankenhaus (SALK) Universitätsklinik für Innere Medizin III (SALK)"

Salzburg, 5020, Austria

Location

"Allgemeines Krankenhaus - Universitätskliniken Klinische Abteilung für Onkologie"

Vienna, 1090, Austria

Location

"Landesklinikum Wiener Neustadt "

Wiener Neustadt, 2700, Austria

Location

"OLV Ziekenhuis Oncology"

Aalst, 9300, Belgium

Location

"Universitair Ziekenhuis Antwerpen Oncologie"

Edegem, 2650, Belgium

Location

"UZ Leuven Campus Gasthuisberg Digestieve Oncologie"

Leuven, 3000, Belgium

Location

"CHC Montlégia Oncologie"

Liège, 4000, Belgium

Location

"AZ NIKOLAAS Oncology"

Sint-Niklaas, 9100, Belgium

Location

"Hospital do Câncer de Barretos - Fundação Pio XII Unidade de Pesquisa Clínica"

Barretos, 14784-400, Brazil

Location

"Hospital de Base Centro Integrado de Pesquisa"

São José do Rio Preto, 15090-000, Brazil

Location

"ICESP - Instituto do Câncer do Estado de São Paulo Centro Integrado de Pesquisa"

São Paulo, 01246-000, Brazil

Location

Hospital A C Camargo Unidade de Pesquisa Clinica Rua Antonio Prudente

São Paulo, 01509-900, Brazil

Location

Hospital Sao Camilo Nucleo de Pesquisa Av Alcantara Machado

São Paulo, 03102-002, Brazil

Location

Hospital Albert Einstein Instituto de Ensino e Pesquisa Av Albert Einstein

São Paulo, 05652- 900, Brazil

Location

"Aalborg Universitetshospital, Syd Onkologisk Afdeling"

Aalborg, 9000, Denmark

Location

Rigshospitalet Dpt of Oncology

Copenhagen, 2100, Denmark

Location

"Regionshospitalet Herning, Hospitalsenheden Vest Onkologisk Afdeling"

Herning, 7400, Denmark

Location

"Odense Universitetshospital Department of Oncology"

Odense, 5000, Denmark

Location

"CHU Jean Minjoz Service d'oncologie médicale"

Besançon, 25030, France

Location

"CHU Morvan Institut de Cancérologie et d'Hématologie"

Brest, 29200, France

Location

"Centre de lutte contre le cancer Francois Baclesse UCP Digestif"

Caen, 14076, France

Location

Hôpital Saint-Antoine Service d'Oncologie Médicale

Paris, 75012, France

Location

"Hôpital Européen Georges Pompidou Oncologie Hépatogastroenterologie-oncologie digestive"

Paris, 75015, France

Location

CHU de Poitiers Pole Régional de Cancérologie

Poitiers, 86021, France

Location

Onkologische Schwerpunktpraxis Kurfuerstendamm

Berlin, 10707, Germany

Location

Charite Universitätsmedizin Medizinische Klinik m.S. Haemat., Onko., Tumorimmunologie

Berlin, 13353, Germany

Location

Lübecker Onkologische Schwerpunktpraxis im Hochschulstadttei

Lübeck, 23562, Germany

Location

Klinikum der Universität München Campus Großhadern, Medizinische Klinik und Poliklinik III

München, 81377, Germany

Location

Magyar Honvedseg Egeszsegugyi Kozpont Onkologiai Osztaly

Budapest, 1062, Hungary

Location

Szent Imre Egyetemi Oktatokorhaz Klinikai Onkologiai Osztaly

Budapest, 1115, Hungary

Location

Debreceni Egyetem Orvos es Egeszsegtudomanyi Centrum Onkologiai Intezet

Debrecen, 4032, Hungary

Location

Petz Aladar Megyei Oktato Korhaz Onkoradiologiai Osztaly

Győr, 9024, Hungary

Location

Bacs-Kiskun Megyei Korhaz Onkoradiologiai Kozpont

Kecskemét, 6000, Hungary

Location

Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kp. Onkoterápiás Klinika

Szeged, 6720, Hungary

Location

JNSZ Megyei Hetenyi Geza Korhaz es Rendelointezet Megyei Onkologiai Centrum

Szolnok, 5004, Hungary

Location

Markusovszky Egyetemi Oktatokorhaz Onkoradiologiai Osztaly

Szombathely, 9700, Hungary

Location

Azienda Policlinico Universitaria - Presidio Monserrato Oncologia Medica Strada Statale 554 Sestu-Monserrato

Cagliari, Italiy, 9100, Italy

Location

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, 80131, Italy

Location

Istituto Nazionale Tumori, I.R.C.C.S "Fondazione G Pascale" Struttura Complessa di Oncologia Medica Addominale

Napoli, 80131, Italy

Location

Istituto Oncologico Veneto IOV - IRCCS Unita Operativa Complessa Oncologia Medica 1 Via Gattamelata 64

Padua, 35128, Italy

Location

A.O.U. Pisana-Ospedale Santa Chiara U.O. di Oncologia Medica 2

Pisa, 56126, Italy

Location

Ospedale San Carlo U.O. Oncologia Medica Via Potito Petrone, Ctr Macchia Romana

Potenza, 85100, Italy

Location

Arcispedale Santa Maria Nuova Unità di Oncologia

Reggio Emilia, 42123, Italy

Location

Istituto Clinico Humanita IRCCS Dipartimento di Oncologia Medica ed Ematologia Via Manzoni,

Rozzano (MI), 20089, Italy

Location

IRCSS Casa Sollievo della Sofferenza Dipartimento Onco-Ematologia Vale Cappuccini 1

San Giovanni Rotondo, 71013, Italy

Location

Przychodnia Lekarska "KOMED"

Konin, 62-500, Poland

Location

SP ZOZ Szpital Uniwersytecki w Krakowie Oddzial Kliniczny Onkologii

Krakow, 31-531, Poland

Location

Opolskie Centrum Onkologii im. Tadeusza Koszarowskiego Oddzial Onkologii Klinicznej

Opole, 45-061, Poland

Location

Wojewodzki Szpital Specjalistyczny im. Janusza Korczaka w Slupsku Sp. z o.o.

Słupsk, 76-200, Poland

Location

Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie Państwowy Instytut Badawczy Klinika Onkologii i Radioterapii

Warsaw, 02-034, Poland

Location

Wojskowy Instytut Medyczny Klinika Onkologii

Warsaw, 04-141, Poland

Location

Centralny Szpital Kliniczny MSWiA Oddział Radioterapii i Onkologii

Warzszawa, 02-507, Poland

Location

Pan American Center for Oncology Trials, LLC

Río Piedras, Porto RICO, 00935, Puerto Rico

Location

Arkhangelsk Clinical Oncology Dispensary chemotherapy department

Arkhangelsk, 163045, Russia

Location

Clinical Oncology Dispensary No.1 Chemotherapy Department

Krasnodar, 350040, Russia

Location

Russian Cancer Research Center n.a. NN Blokhin Clinical Pharmacology and Chemotherapy

Moscow, 115478, Russia

Location

University Headache Clinic Outpatient oncology clinic

Moscow, 121467, Russia

Location

Moscow City Oncology Hospital # 62 chemotherapy department

Moscow Region, 143423, Russia

Location

Omsk Clinical Oncologic Dispensary Chemotherapy

Omsk, 644046, Russia

Location

Scientific Centre for Specialized Medical Care (oncological) Chemotherapy

Saint Petersburg, 115478, Russia

Location

National Medical Research Center of Oncology N.N. Petrova

Saint Petersburg, 197758, Russia

Location

Saint Petersburg City Oncology Clilnic

Saint Petersburg, 198255, Russia

Location

Multidisciplinary clinic "Reaviz

Samara, 443011, Russia

Location

Oncology dispensary No.2 Oncology department

Sochi, 354057, Russia

Location

SBIH of YR "Clinical oncology hospital chemotherapy department"

Yaroslavl, 150054, Russia

Location

"H. Valle de Hebrón Servicio de Oncología - (VHIR)"

Barcelona, 08035, Spain

Location

"Hospital de la Santa Creu I Sant Pau Oncología Medica"

Barcelona, 08041, Spain

Location

"Hospital Uni. Reina Sofía - Hospital Provincial Departamento de Oncología Médica"

Córdoba, 14004, Spain

Location

"INSTITUTO CATALAN DE ONCOLOGÍA - ICO Oncología Médica"

L'Hospitalet de Llobregat, 08908, Spain

Location

"Hospital Universitario Ramón y Cajal Servicio de Oncologia Médica"

Madrid, 28034, Spain

Location

"HOSPITAL 12 DE OCTUBRE Servicio Oncología Médica"

Madrid, 28041, Spain

Location

"Hospital Universitario Marqués de Valdecilla oncología medica"

Santander, 39008, Spain

Location

H.VIRGEN DEL ROCIO Servicio de Oncología Médica

Seville, 41013, Spain

Location

H. GENERAL DE VALENCIA Servicio de Oncología Médica

Valencia, 46014, Spain

Location

Hospital Universitario Miguel Servet Edif. de maternidad planta 8. Servicio de Oncología Médical

Zaragoza, 50009, Spain

Location

Kyiv City Clinical Oncological Centre

Kiev, Ukrain, 03115, Ukraine

Location

Cherkasy Regional Oncological Dispensary Regional Clinical Oncological Centre

Cherkassy, 18009, Ukraine

Location

"MI ""Dnipropetrovsk City Multi-field Clinical Hospital #4"" Department of Oncology"

Dnipro, 49102, Ukraine

Location

LLC Ukrainian Center of Tomotherapy "Tomoclinic", Chemoteraphy Department

Kropyvnytskyi, 25011, Ukraine

Location

National Institute of Cancer Abdominal Oncology Department

Kyiv, 03022, Ukraine

Location

Medical Center n.a. Acad. Spizhenko "Syber Clinic Spizhenko"" Department of Oncology

Kyiv, 08112, Ukraine

Location

"Clinical and diagnostic Centre of Medics-rey Inter. Group LLC Hospital of Israeli Oncology "LISOD"

Kyiv, 08720, Ukraine

Location

Podillia Regional Oncology Centre Chemotherapy Department

Vinnitsya, 21029, Ukraine

Location

Related Publications (2)

• 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. Trifluridine-Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer. N Engl J Med. 2023 May 4;388(18):1657-1667. doi: 10.1056/NEJMoa2214963.

  PMID: 37133585 RESULT

• Prager GW, Taieb J, Fakih M, Ciardiello F, Van Cutsem E, Elez E, Wyrwicz L, Stroyakovskiy D, Liposits G, Bondarenko I, Modest DP, Amellal N, Tabernero J; SUNLIGHT Investigators. Plain language summary of SUNLIGHT: trifluridine/tipiracil and bevacizumab for refractory metastatic colorectal cancer. Future Oncol. 2024;20(36):2823-2832. doi: 10.1080/14796694.2024.2366100. Epub 2024 Jul 2.

  PMID: 38953855 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

trifluridine tipiracil drug combination; Bevacizumab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Taiho
• Organization: Taiho Oncology, Inc.

medicalinformation@taihooncology.com

+1-844-878-2446

Study Officials

• Josep Tabernero, Prof

  Vall d'Hebron Institute of Oncology

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 29, 2021
• First Posted: February 3, 2021
• Study Start: November 25, 2020
• Primary Completion: July 19, 2022
• Study Completion: September 12, 2023
• Last Updated: September 24, 2024
• Results First Posted: December 26, 2023

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

HU (8); BR (6); AU (7); US (12); PR (1); UA (8); IT (9); DK (4); BE (5); ES (10); DE (4); RU (12); FR (6); PL (7)