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

Phase 3

Completed

• Conditions: Refractory Metastatic Colorectal Cancer
• Interventions: Drug: Trifluridine/Tipiracil; Drug: Bevacizumab

• Registration Number: NCT04737187
• Lead Sponsor: Taiho Oncology, Inc.

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.

Detailed 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).

Study Timeline

• Study Start: 2020-11-25
• Study First Submitted: 2021-01-29
• Study First Submitted QC: 2021-02-02
• Study First Posted: 2021-02-03
• Primary Completion: 2022-07-19
• Disposition First Submitted: 2023-07-12
• Study Completion: 2023-09-12
• Results First Submitted: 2023-10-17
• Results First Submitted QC: 2023-12-05
• Results First Posted: 2023-12-26
• Disposition First Posted: 2023-12-26
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-25
• Last Update Posted: 2024-08-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 492

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Trifluridine/Tipiracil + Bevacizumab	Bevacizumab	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.
Trifluridine/Tipiracil + Bevacizumab	Trifluridine/Tipiracil	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.
Trifluridine/Tipiracil	Trifluridine/Tipiracil	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.

Primary Outcome Measures

Name	Time	Method
Overall Survival (OS)	From date of randomization to the death due to any cause or cut-off date, whichever comes first (maximum duration: up to 20 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.
Survival Probability at 6 Months	From date of randomization until 6 months post treatment	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.
Survival Probability at 12 Months	From date of randomization until 12 months post treatment	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.
Survival Probability at 18 Months	From date of randomization until 18 months post treatment	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.

Secondary Outcome Measures

Name	Time	Method
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)	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.
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	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.
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)	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.
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)	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.
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)	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.
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30): Time to Definitive Deterioration of >=10 Points in Sub-scale Scores - Kaplan-Meier Analysis	Date of randomization to first deterioration in QoL score >=10 points or death due to any cause, which ever occurred first (i.e., up to 20 months)	EORTC QLQ-C30: 30 item questionnaires with 5 multi-item functional subscales (physical, role, cognitive, emotional, social functioning), 3 multi-item symptom scales (fatigue, nausea/vomiting, and pain), global health/quality of life (QOL) subscale and 6 single items assessing other cancer related symptoms (dyspnea, sleep disturbance, appetite, diarrhea, constipation and financial impact of cancer). It employed twenty-eight 4-point Likert scales with responses from "not at all" to "very much" and GHS/QoL, scored on scale of 1 (very poor) to 7 (excellent). All scales are transformed from raw scores to linear scales ranging 0 to 100. Higher score for functional \& GHS/QoL = higher level of functioning, \& higher score for symptoms scales = higher symptom burden. Time to definitive \>=10 points deterioration: time from date of randomization to first deterioration in QoL score \>=10 points compared to baseline with no later improvement or death due to any cause. Kaplan-Meier method was used.
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30): Time to Definitive Deterioration of >=10 Points in the Global Health Status Score - Kaplan-Meier Analysis	Date of randomization to first deterioration in QoL score >=10 points or death due to any cause, which ever occurred first (i.e., up to 20 months)	EORTC QLQ-C30: 30 item questionnaires composed of 5 multi-item functional subscales (physical, role, cognitive, emotional, social functioning), 3 multi-item symptom scales (fatigue, nausea/vomiting, and pain), global health/QOL subscale and 6 single items assessing other cancer related symptoms (dyspnea, sleep disturbance, appetite, diarrhea, constipation and financial impact of cancer). It employed twenty-eight 4-point Likert scales with responses from "not at all" to "very much" and GHS/QoL, scored on scale of 1 (very poor) to 7 (excellent). All scales are transformed from raw scores to linear scales ranging 0 to 100. Higher score for functional \& GHS/QoL = higher level of functioning, \& higher score for symptoms scales = higher symptom burden. Time to definitive \>=10 points deterioration: time from date of randomization to the first deterioration in QoL score \>=10 points compared to baseline with no later improvement or death due to any cause. Kaplan-Meier method was used.
Change From Baseline in European Quality of Life Group Questionnaire With 5 Dimensions and 5 Levels Per Dimension (EQ-5D-5L): Health State Utility Index Value at Specified Timepoints	Baseline, Cycle 1, Cycle 2, Cycle 3, Cycle 4, Cycle 5, Cycle 6, Cycle 7, Cycle 8, Cycle 9, Cycle 10, Cycle 11, Cycle 12, Cycle 13 and Cycle 14	The EQ-5D-5L is a standardized measure of health status that provides a general assessment of health utility and consist in 2 sections a descriptive system comprising 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) and Visual Analog Scale (VAS). Each dimension has a 5-level response: no problems, slight problems, moderate problems, severe problems, and extreme problems. Response options are measured with a 5-point Likert scale. The 5D-5L systems are converted into a single index utility score between 0 to 1, where higher score indicates a better health state and lower score indicate worse health state.
Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 Levels (EQ-5D-5L) Score: Visual Analogic Scale (VAS) at Specified Timepoints	Baseline, Cycle 1, Cycle 2, Cycle 3, Cycle 4, Cycle 5, Cycle 6, Cycle 7, Cycle 8, Cycle 9, Cycle 10, Cycle 11, Cycle 12, Cycle 13 and Cycle 14	The EQ-5D-5L is a standardized measure of health status that provides a general assessment of health utility and consist of 2 sections; descriptive system comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) and a VAS. The VAS records the respondent's self-rated health on a 20 centimeter (cm) vertical VAS; the scale went from 0 (worst imaginable health state) to 100 (best imaginable health state). This information can be used as a quantitative measure of health as judged by the individual respondents.

Trial Locations

Locations (99)

Investigative Clinical Research of Indiana LLC; 🇺🇸 Noblesville, Indiana, United States

"Landeskrankenhaus Feldkirch Interne E"; 🇦🇹 Rankweil, Austria

Mayo Clinic - FL; 🇺🇸 Jacksonville, Florida, United States

Mayo Clinic - Rochester; 🇺🇸 Rochester, New York, United States

Comprehensive Hematology Oncology; 🇺🇸 Saint Petersburg, Florida, United States

"CHU Jean Minjoz Service d'oncologie médicale"; 🇫🇷 Besancon, France

Magyar Honvedseg Egeszsegugyi Kozpont Onkologiai Osztaly; 🇭🇺 Budapest, Hungary

Rigshospitalet Dpt of Oncology; 🇩🇰 Copenhagen, Denmark

Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kp. Onkoterápiás Klinika; 🇭🇺 Szeged, Hungary

City of Hope - Upland; 🇺🇸 Upland, California, United States

"Aalborg Universitetshospital, Syd Onkologisk Afdeling"; 🇩🇰 Aalborg, Denmark

Lübecker Onkologische Schwerpunktpraxis im Hochschulstadttei; 🇩🇪 Luebeck, Germany

City of Hope; 🇺🇸 Duarte, California, United States

SP ZOZ Szpital Uniwersytecki w Krakowie Oddzial Kliniczny Onkologii; 🇵🇱 Krakow, Poland

"OLV Ziekenhuis Oncology"; 🇧🇪 Aalst, Belgium

A.O.U. Pisana-Ospedale Santa Chiara U.O. di Oncologia Medica 2; 🇮🇹 Pisa, Italy

"ICESP - Instituto do Câncer do Estado de São Paulo Centro Integrado de Pesquisa"; 🇧🇷 Sao Paulo, Brazil

Renovatio Clinical - El Paso; 🇺🇸 El Paso, Texas, United States

Bacs-Kiskun Megyei Korhaz Onkoradiologiai Kozpont; 🇭🇺 Kecskemét, Hungary

"H. Valle de Hebrón Servicio de Oncología - (VHIR)"; 🇪🇸 Barcelona, Spain

"Hospital de la Santa Creu I Sant Pau Oncología Medica"; 🇪🇸 Barcelona, Spain

Azienda Policlinico Universitaria - Presidio Monserrato Oncologia Medica Strada Statale 554 Sestu-Monserrato; 🇮🇹 Cagliari, Italiy, Italy

Przychodnia Lekarska "KOMED"; 🇵🇱 Konin, Poland

Wojewodzki Szpital Specjalistyczny im. Janusza Korczaka w Slupsku Sp. z o.o.; 🇵🇱 Słupsk, Poland

"HOSPITAL 12 DE OCTUBRE Servicio Oncología Médica"; 🇪🇸 Madrid, Spain

"Centre de lutte contre le cancer Francois Baclesse UCP Digestif"; 🇫🇷 Caen, France

CHU de Poitiers Pole Régional de Cancérologie; 🇫🇷 Poitiers, France

Arkhangelsk Clinical Oncology Dispensary chemotherapy department; 🇷🇺 Arkhangelsk, Russian Federation

Clinical Oncology Dispensary No.1 Chemotherapy Department; 🇷🇺 Krasnodar, Russian Federation

"Hospital Universitario Marqués de Valdecilla oncología medica"; 🇪🇸 Santander, Spain

Szent Imre Egyetemi Oktatokorhaz Klinikai Onkologiai Osztaly; 🇭🇺 Budapest, Hungary

University Headache Clinic Outpatient oncology clinic; 🇷🇺 Moscow, Russian Federation

Pan American Center for Oncology Trials, LLC; 🇵🇷 Río Piedras, Puerto Rico

"Clinical and diagnostic Centre of Medics-rey Inter. Group LLC Hospital of Israeli Oncology "LISOD"; 🇺🇦 Kyiv, Ukraine

Istituto Clinico Humanita IRCCS Dipartimento di Oncologia Medica ed Ematologia Via Manzoni,; 🇮🇹 Rozzano (MI), Italy

Petz Aladar Megyei Oktato Korhaz Onkoradiologiai Osztaly; 🇭🇺 Győr, Hungary

Oncology dispensary No.2 Oncology department; 🇷🇺 Sochi, Russian Federation

Wojskowy Instytut Medyczny Klinika Onkologii; 🇵🇱 Warszawa, Poland

"Hospital Uni. Reina Sofía - Hospital Provincial Departamento de Oncología Médica"; 🇪🇸 Cordoba, Spain

Hospital Universitario Miguel Servet Edif. de maternidad planta 8. Servicio de Oncología Médical; 🇪🇸 Zaragoza, Spain

Centralny Szpital Kliniczny MSWiA Oddział Radioterapii i Onkologii; 🇵🇱 Warzszawa, Poland

Moscow City Oncology Hospital # 62 chemotherapy department; 🇷🇺 Moscow Region, Russian Federation

"INSTITUTO CATALAN DE ONCOLOGÍA - ICO Oncología Médica"; 🇪🇸 Hospitalet de Llobregat, Spain

"Hospital Universitario Ramón y Cajal Servicio de Oncologia Médica"; 🇪🇸 Madrid, Spain

Kyiv City Clinical Oncological Centre; 🇺🇦 Kiev, Ukrain, Ukraine

Cherkasy Regional Oncological Dispensary Regional Clinical Oncological Centre; 🇺🇦 Cherkassy, Ukraine

National Institute of Cancer Abdominal Oncology Department; 🇺🇦 Kyiv, Ukraine

Medical Center n.a. Acad. Spizhenko "Syber Clinic Spizhenko"" Department of Oncology; 🇺🇦 Kyiv, Ukraine

H. GENERAL DE VALENCIA Servicio de Oncología Médica; 🇪🇸 Valencia, Spain

"Universitair Ziekenhuis Antwerpen Oncologie"; 🇧🇪 Edegem, Belgium

"UZ Leuven Campus Gasthuisberg Digestieve Oncologie"; 🇧🇪 Leuven, Belgium

"Regionshospitalet Herning, Hospitalsenheden Vest Onkologisk Afdeling"; 🇩🇰 Herning, Denmark

"Odense Universitetshospital Department of Oncology"; 🇩🇰 Odense, Denmark

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 Oncologico Veneto IOV - IRCCS Unita Operativa Complessa Oncologia Medica 1 Via Gattamelata 64; 🇮🇹 Padova, Italy

Arcispedale Santa Maria Nuova Unità di Oncologia; 🇮🇹 Reggio Emilia, Italy

Hôpital Saint-Antoine Service d'Oncologie Médicale; 🇫🇷 Paris, France

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, Brazil

H.VIRGEN DEL ROCIO Servicio de Oncología Médica; 🇪🇸 Sevilla, Spain

Saint Petersburg City Oncology Clilnic; 🇷🇺 St Petersburg, Russian Federation

Russian Cancer Research Center n.a. NN Blokhin Clinical Pharmacology and Chemotherapy; 🇷🇺 Moscow, 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

SBIH of YR "Clinical oncology hospital chemotherapy department"; 🇷🇺 Yaroslavl, Russian Federation

Onkologische Schwerpunktpraxis Kurfuerstendamm; 🇩🇪 Berlin, Germany

Charite Universitätsmedizin Medizinische Klinik m.S. Haemat., Onko., Tumorimmunologie; 🇩🇪 Berlin, Germany

Mayo Clinic Hospital; 🇺🇸 Phoenix, Arizona, United States

Oncology Hematology West, PC dba Nebraska Cancer Specialists; 🇺🇸 Omaha, Nebraska, United States

Markusovszky Egyetemi Oktatokorhaz Onkoradiologiai Osztaly; 🇭🇺 Szombathely, Hungary

"Landesklinikum Wiener Neustadt "; 🇦🇹 Wiener Neustadt, Austria

"Landeskrankenhaus (SALK) Universitätsklinik für Innere Medizin III (SALK)"; 🇦🇹 Salzburg, Austria

"Allgemeines Krankenhaus - Universitätskliniken Klinische Abteilung für Onkologie"; 🇦🇹 Wien, Austria

"Hospital de Base Centro Integrado de Pesquisa"; 🇧🇷 Sao Jose Do Rio Preto, Brazil

"Hôpital Européen Georges Pompidou Oncologie Hépatogastroenterologie-oncologie digestive"; 🇫🇷 Paris, France

Istituto Nazionale Tumori, I.R.C.C.S "Fondazione G Pascale" Struttura Complessa di Oncologia Medica Addominale; 🇮🇹 Napoli, Italy

Ospedale San Carlo U.O. Oncologia Medica Via Potito Petrone, Ctr Macchia Romana; 🇮🇹 Potenza, Italy

IRCSS Casa Sollievo della Sofferenza Dipartimento Onco-Ematologia Vale Cappuccini 1; 🇮🇹 San Giovanni Rotondo, Italy

Scientific Centre for Specialized Medical Care (oncological) Chemotherapy; 🇷🇺 St Petersburg, Russian Federation

Mount Sinai Comprehensive Cancer Center; 🇺🇸 Miami Beach, Florida, United States

DuPage Medical Group - Joliet Oncology-Hematology Associates; 🇺🇸 Joliet, Illinois, United States

"Hospital do Câncer de Barretos - Fundação Pio XII Unidade de Pesquisa Clínica"; 🇧🇷 Barretos, Brazil

City of Hope - South Pasedena; 🇺🇸 South Pasadena, California, United States

Debreceni Egyetem Orvos es Egeszsegtudomanyi Centrum Onkologiai Intezet; 🇭🇺 Debrecen, Hungary

JNSZ Megyei Hetenyi Geza Korhaz es Rendelointezet Megyei Onkologiai Centrum; 🇭🇺 Szolnok, Hungary

"CHU Morvan Institut de Cancérologie et d'Hématologie"; 🇫🇷 Brest, France

Klinikum der Universität München Campus Großhadern, Medizinische Klinik und Poliklinik III; 🇩🇪 Muenchen, Germany

"Medizinische Universität Graz "; 🇦🇹 Graz, Austria

"Medizinische Universität Innsbruck Univ.-Klinik für Innere Medizin V"; 🇦🇹 Innsbruck, Austria

"Ordensklinikum Linz Barmherzige Schwestern Interne I"; 🇦🇹 Linz, Austria

Opolskie Centrum Onkologii im. Tadeusza Koszarowskiego Oddzial Onkologii Klinicznej; 🇵🇱 Opole, Poland

Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie Państwowy Instytut Badawczy Klinika Onkologii i Radioterapii; 🇵🇱 Warszawa, Poland

"MI ""Dnipropetrovsk City Multi-field Clinical Hospital #4"" Department of Oncology"; 🇺🇦 Dnipro, Ukraine

LLC Ukrainian Center of Tomotherapy "Tomoclinic", Chemoteraphy Department; 🇺🇦 Kropyvnytskyi, Ukraine

Podillia Regional Oncology Centre Chemotherapy Department; 🇺🇦 Vinnitsya, Ukraine

"CHC Montlégia Oncologie"; 🇧🇪 Liege, Belgium

"AZ NIKOLAAS Oncology"; 🇧🇪 Sint Niklaas, Belgium