Trial to Assess Safety and Efficacy of Lenvatinib (18 mg vs. 14 mg) in Combination With Everolimus in Participants With Renal Cell Carcinoma

Phase 2

Completed

Conditions: Renal Cell Carcinoma

Interventions: Drug: lenvatinib
Drug: everolimus

Registration Number: NCT03173560

Lead Sponsor: Eisai Inc.

Brief Summary: Study E7080-G000-218 is a Randomized, open-label (formerly Double-blind), Phase 2 Trial conducted to assess whether a starting dose of lenvatinib 14 milligrams (mg) in combination with everolimus 5 mg once daily (QD) will provide comparable efficacy (based on objective response rate \[ORR\] at 24 weeks \[ORR24W\]) with an improved safety profile compared to lenvatinib 18 mg in combination with everolimus 5 mg (based on treatment-emergent intolerable Grade 2, or any greater than or equal to (\>=) Grade 3 adverse events (AEs) in the first 24 weeks after randomization).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 343

Inclusion Criteria

Histological or cytological confirmation of predominant clear cell renal cell carcinoma (RCC) (original tissue diagnosis of RCC is acceptable)
Documented evidence of advanced RCC
One prior disease progression episode on or after vascular endothelial growth factor (VEGF)-targeted treatment (for example, but not limited to, sunitinib, sorafenib, pazopanib, cabozantinib, bevacizumab, axitinib, vatalanib, AV951/tivozanib) administered for the treatment of RCC. Prior programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) treatment in addition to 1 prior VEGF-targeted treatment is allowed.
At least 1 measurable target lesion according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) meeting the following criteria:
- Lymph node (LN) lesion that measures at least 1 dimension as >=1.5 centimeter (cm) in the short axis;
- Non-nodal lesion that measures >=1.0 cm in the longest diameter;
- The lesion is suitable for repeat measurement using computerized tomography/magnetic resonance imaging (CT/MRI). Lesions that have had external beam radiotherapy (EBRT) or locoregional therapy must show radiographic evidence of disease progression based on RECIST 1.1 to be deemed a target lesion.
Male or female participants age >=18 years (or any age >=18 years if that age is considered to be an adult per the local jurisdiction) at the time of informed consent
Karnofsky Performance Status (KPS) of >=70
Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP less than or equal to (<=) 150/90 millimeters of mercury (mmHg) at Screening and no change in antihypertensive medications within 1 week before Cycle 1/Day 1
Adequate renal function defined as calculated creatinine clearance >=30 milliliters per minute (mL/min) per the Cockcroft and Gault formula
Adequate bone marrow function defined by:
- Absolute neutrophil count (ANC) >=1500/millimeters cubed (mm^3) (>=1.5*10^9/Liters [L]);
- Platelets >=100,000/mm^3 (>=100*10^9/L);
- Hemoglobin >=9 grams per deciliter (g/dL)
Adequate blood coagulation function defined by International Normalized Ratio (INR) <=1.5 (except for participants on warfarin therapy where INR must be <=3.0 prior to randomization)
Adequate liver function defined by:
- Total bilirubin <=1.5 times the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert's syndrome;
- Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) <=3* the ULN (in the case of liver metastases <=5* the ULN). Participants with bone metastases with ALP values greater than 3 times can be included.
Participant must voluntarily agree to provide written informed consent
Participant must be willing and able to comply with all aspects of the protocol

Exclusion Criteria

More than 1 prior VEGF-targeted treatment for advanced RCC
Participants with Central Nervous System (CNS) metastases are not eligible, unless they have completed local therapy for at least 4 weeks and have discontinued the use of corticosteroids for this indication or are on a tapering regimen of corticosteroids (defined as <=10 mg prednisolone equivalent) before starting treatment in this study. Any signs (example, radiologic) or symptoms of brain metastases must be stable for at least 4 weeks before starting study treatment.
Active malignancy (except for RCC or definitively treated basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix or bladder) within the past 24 months
Any anti-cancer treatment (except for radiation therapy) within 21 days, or any investigational agent within 30 days prior to the first dose of study drug; participants should have recovered from any toxicity related to previous anti-cancer treatment to Common Toxicity Criteria (CTC) grade 0 or 1.
Prior radiation therapy within 21 days prior to the start of study treatment with the exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks prior to study treatment start
Known intolerance to study drug (or any of the excipients) and/or known hypersensitivity to rapamycins (example, sirolimus, everolimus, temsirolimus) or any of the excipients
Participants with proteinuria greater than (>) 1+ on urinalysis will undergo 24-hour urine collection for quantitative assessment of proteinuria. Participants with urine protein >=1 g/24 hour will be ineligible.
Fasting total cholesterol ˃300 mg/dL (or ˃7.75 millimoles [mmol]/L) and/or fasting triglycerides level ˃2.5* the ULN. Note: these participants can be included after initiation or adjustment of lipid-lowering medication.
Uncontrolled diabetes as defined by fasting glucose >1.5 times the ULN. Note: these participants can be included after initiation or adjustment of glucose-lowering medication.
Prolongation of QT corrected (QTc) interval to >480 milliseconds (ms)
Participants who have not recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy
Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib or everolimus
Bleeding or thrombotic disorders or participants at risk for severe hemorrhage. The degree of tumor invasion/infiltration of major blood vessels (example, carotid artery) should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy.
Clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study drug
Significant cardiovascular impairment within 6 months prior to the first dose of study drug; history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke, or cardiac arrhythmia associated with significant cardiovascular impairment or left ventricular ejection fraction (LVEF) below the institutional normal range as determined by screening multigated acquisition (MUGA) scan or echocardiogram.
Active infection (any infection requiring systemic treatment)
Any medical or other condition that in the opinion of the investigator(s) would preclude the participant's participation in a clinical study
Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [β-hCG] (or human chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 International Units per Liter [IU/L] or equivalent units of β-hCG [or hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
Females of childbearing potential who (Note: all females will be considered to be of childbearing potential unless they are postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause] or have been sterilized surgically [that is, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing].):
- do not agree to use a highly effective method of contraception for the entire study period and for up to 8 weeks after study drug discontinuation, that is:
  - total abstinence (if it is their preferred and usual lifestyle)
  - an intrauterine device (IUD) or hormone releasing system (IUS)
  - a contraceptive implant
  - an oral contraceptive (with additional barrier method) (Note: Participants must be on a stable dose of the same oral hormonal contraceptive product for at least 4 weeks before dosing with study drug and for the duration of the study.) OR
- do not have a vasectomized partner with confirmed azoospermia

For sites outside of the European Union, it is permissible that if a highly effective method of contraception is not appropriate or acceptable to the participant, then the participant must agree to use a medically acceptable method of contraception, that is, double barrier methods of contraception, such as condom plus diaphragm or cervical/vault cap with spermicide.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Lenvatinib 18 mg plus everolimus 5 mg	everolimus	Participants will receive oral lenvatinib 18 mg QD plus oral everolimus 5 mg QD as the starting dose in Cycle 1 or later (cycle length =28 days) during randomization phase. After the data cutoff for the primary analysis, participants will receive study treatment as continuous 56-day cycles.
Lenvatinib 18 mg plus everolimus 5 mg	lenvatinib	Participants will receive oral lenvatinib 18 mg QD plus oral everolimus 5 mg QD as the starting dose in Cycle 1 or later (cycle length =28 days) during randomization phase. After the data cutoff for the primary analysis, participants will receive study treatment as continuous 56-day cycles.
Lenvatinib 14 mg plus everolimus 5 mg	everolimus	Participants will receive oral lenvatinib 14 mg once daily (QD) plus oral everolimus 5 mg QD as the starting dose for Cycle 1. If there are no intolerable Grade 2 or any \>= Grade 3 treatment-emergent adverse events (TEAEs) that require dose reduction in the first 28-day cycle (that is, the first 4 weeks of treatment), the lenvatinib dose will be escalated to 18 mg QD (plus everolimus 5 mg) beginning in Cycle 2 or later (cycle length equal to \[=\] 28 days) during randomization phase. After the data cutoff for the primary analysis, participants will receive study treatment as continuous 56-day cycles.
Lenvatinib 14 mg plus everolimus 5 mg	lenvatinib	Participants will receive oral lenvatinib 14 mg once daily (QD) plus oral everolimus 5 mg QD as the starting dose for Cycle 1. If there are no intolerable Grade 2 or any \>= Grade 3 treatment-emergent adverse events (TEAEs) that require dose reduction in the first 28-day cycle (that is, the first 4 weeks of treatment), the lenvatinib dose will be escalated to 18 mg QD (plus everolimus 5 mg) beginning in Cycle 2 or later (cycle length equal to \[=\] 28 days) during randomization phase. After the data cutoff for the primary analysis, participants will receive study treatment as continuous 56-day cycles.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Intolerable Grade 2 or Any Grade >=Grade 3 TEAEs Within 24 Weeks	Up to Week 24	TEAE was defined as an adverse event (AE) with an onset that had occurred after receiving study drug. A severity grade was defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03. As per NCI-CTCAE, Grade 1 scales as Mild; Grade 2 scales as Moderate; Grade 3 scales as severe or medically significant but not immediately life threatening; Grade 4 scales as life-threatening consequences; and Grade 5 scales as death related to AE.
Objective Response Rate at Week 24 (ORR24W)	At Week 24	ORR24W was defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) at the Week 24 (after randomization) time point, during treatment or within 28 days after the last dose date but on or prior to the start of new anticancer therapy based on investigator assessment according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR: defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to less than (\<) 10 millimeters (mm). PR: defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. To be considered a BOR, all responses had to be confirmed no less than 4 weeks after the initial assessment of response.

Secondary Outcome Measures

Name	Time	Method
Progression-free Survival (PFS)	From the date of randomization to the date of the first documentation of PD or date of death, whichever occurred first or up to date of data cutoff for the primary analysis (up to 29 months)	PFS was defined as the time from the date of randomization to the date of the first documentation of PD by investigator assessment or date of death, whichever occurred first according to RECIST v1.1. PD: at least 20% increase (including an absolute increase of at least 5 millimeter \[mm\]) in the sum of diameter (SOD) of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. Median PFS was analyzed using the Kaplan-Meier product-limit estimates for each treatment group and presented with 2-sided 95% confidence interval (CI). As pre-specified in the protocol, data for this secondary outcome measure was collected and analyzed till the primary analysis only.
Objective Response Rate (ORR)	From date of randomization up to first documentation of PD or date of death, whichever occurred first or up to the date of data cut off for the primary analysis (up to 29 months)	ORR was defined as the percentage of participants with a BOR of CR or PR at the at the end of treatment based on investigator assessment according to RECIST v1.1. CR: defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to \<10 mm. PR: defined as at least a 30 % decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. To be considered a BOR, all responses had to be confirmed no less than 4 weeks after the initial assessment of response. As pre-specified in the protocol, data for this secondary outcome measure was collected and analyzed till the primary analysis only.
Number of Participants With TEAEs and Serious TEAEs	From date of first dose of study drug up to 28 days after last dose of study drug (up to 71 months)	TEAEs were defined as those adverse events (AEs) that occurred (or worsened, if present at Baseline) after the first dose of study drug through 28 days after the last dose of study drug. An AE was defined as any untoward medical occurrence in a participants or clinical investigation participant administered an investigational product. An AE does not necessarily have a causal relationship with medicinal product. A serious adverse event (SAE) was defined as any AE if it resulted in death or life-threatening AE or required inpatient hospitalization or prolongation of existing hospitalization or resulted in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions or was a congenital anomaly/birth defect.
Percentage of Participants Who Discontinued Treatment Due to Toxicity	From date of first dose of study drug up to 28 days after last dose of study drug (up to 71 months)	Percentage of participants who discontinued treatment due to toxicity, defined as the percentage of participants who discontinued study treatment due to TEAEs. Toxicity (except hypertension and non-infectious pneumonitis) was assessed according to NCI-CTCAE v4.03.
Time to Treatment Failure Due to Toxicity	From the date of randomization to the date of discontinuation of study treatment due to TEAEs, or date of data cut off for the primary analysis (up to 29 months)	Time to treatment failure due to toxicity was defined as the time from the date of randomization to the date that a participant discontinued study treatment due to TEAEs. Toxicity (except hypertension and non-infectious pneumonitis) was assessed according to CTCAE v4.03. As planned, data for this secondary outcome measure was collected and analyzed till the primary analysis only.
Plasma Concentration of Lenvatinib	Cycle 1 Day 1: 0.5-4 hours and 6-10 hours post-dose; Cycle 1 Day 15: pre-dose, 0.5-4 hours and 6-10 hours post-dose; Cycle 2 Day 1: pre-dose and 2-12 hours post-dose (each cycle length =28 days)	PK sparse sampling was performed. As planned, the post-dose plasma sample was collected anytime between 0.5 to 4 hours at Cycle 1 Days 1 and 15, between 6 to 10 hours at Cycle 1 Days 1 and 15, and between 2 to 12 hours at Cycle 2 Day 1. Only one sample was collected for each post-dose category between specified timepoints.
Whole Blood Concentration of Everolimus	Cycle 1 Day 1: 0.5-4 hours and 6-10 hours post-dose; Cycle 1 Day 15: pre-dose, 0.5-4 hours and 6-10 hours post-dose; Cycle 2 Day 1: pre-dose and 2-12 hours post-dose (each cycle length =28 days)	PK sparse sampling was performed. As planned, the post-dose whole blood sample was collected anytime between 0.5 to 4 hours at Cycle 1 Days 1 and 15, between 6 to 10 hours at Cycle 1 Days 1 and 15, and between 2 to 12 hours at Cycle 2 Day 1. Only one sample was collected for each post-dose category between specified timepoints.
Model Predicted Apparent Total Clearance (CL/F) for Lenvatinib Alone and When Coadministration With Everolimus in Renal Cell Carcinoma (RCC) Participants to Assess Drug-Drug Interaction	Cycle 1 Day 1: 0.5-4 hours and 6-10 hours post-dose; Cycle 1 Day 15: pre-dose, 0.5-4 hours and 6-10 hours post-dose; Cycle 2 Day 1: pre-dose and 2-12 hours post-dose (each cycle length =28 days)	Sparse PK samples were collected and analyzed using a population PK approach to estimate PK parameters. The lenvatinib concentration data was pooled from studies E7080 -G000-205 (NCT01136733), E7080-M001-221 (NCT02915783), E7080-J081-112 (NCT02454478) and from current study E7080-G000-218 (NCT03173560). A previously developed 3-compartment PK model for lenvatinib was fitted to the pooled dataset. Individual lenvatinib CL/F value was derived from the final PK model. The outcome measure was assessed for lenvatinib 18 mg dose only.
Model Predicted Dose Normalized AUC for Everolimus Alone and When Coadministration With Lenvatinib in RCC Participants to Assess Drug-Drug Interaction	Cycle 1 Day 1: 0.5-4 hours and 6-10 hours post-dose; Cycle 1 Day 15: pre-dose, 0.5-4 hours and 6-10 hours post-dose; Cycle 2 Day 1: pre-dose and 2-12 hours post-dose (each cycle length =28 days)	Sparse PK samples were collected and analyzed using a population PK approach to estimate PK parameters. The everolimus concentration data was pooled from studies E7080-G000-205 (NCT01136733), E7080-M001-221 (NCT02915783), E7080-J081-112 (NCT02454478) or from current study E7080-G000-218 (NCT03173560). A previously developed 3-compartment PK model for everolimus was fitted to the pooled dataset. Individual everolimus AUC at steady state based on the starting dose was derived as a function of starting dose from the final PK model.
Model Predicted Dose Normalized Area Under the Plasma Concentration-time Curve (AUC) for Lenvatinib Alone and When Coadministration With Everolimus in RCC Participants to Assess Drug-Drug Interaction	Cycle 1 Day 1: 0.5-4 hours and 6-10 hours post-dose; Cycle 1 Day 15: pre-dose, 0.5-4 hours and 6-10 hours post-dose; Cycle 2 Day 1: pre-dose and 2-12 hours post-dose (each cycle length =28 days)	Sparse PK samples were collected and analyzed using a population PK approach to estimate PK parameters. The lenvatinib concentration data was pooled from studies E7080 -G000-205 (NCT01136733), E7080-M001-221 (NCT02915783), E7080-J081-112 (NCT02454478) and from current study E7080-G000-218 (NCT03173560). A previously developed 3-compartment PK model for lenvatinib was fitted to the pooled dataset. Individual lenvatinib AUC at steady state based on the starting dose was derived as a function of starting dose from the final PK model. The outcome measure was assessed for lenvatinib 18 mg dose only.
Model Predicted CL/F for Everolimus Alone and When Coadministration With Lenvatinib in RCC Participants to Assess Drug-Drug Interaction	Cycle 1 Day 1: 0.5-4 hours and 6-10 hours post-dose; Cycle 1 Day 15: pre-dose, 0.5-4 hours and 6-10 hours post-dose; Cycle 2 Day 1: pre-dose and 2-12 hours post-dose (each cycle length =28 days)	Sparse PK samples were collected and analyzed using a population PK approach to estimate PK parameters. The everolimus concentration data was pooled from studies E7080-G000-205 (NCT01136733), E7080-M001-221 (NCT02915783), E7080-J081-112 (NCT02454478) or from current study E7080-G000-218 (NCT03173560). A previously developed 3-compartment PK model for everolimus was fitted to the pooled dataset. Individual everolimus CL/F value was derived from the final PK model.
Overall Survival (OS)	From the date of randomization until the date of death from any cause, or up to date of data cut off for the primary analysis (up to 29 months)	OS was defined as the time from the date of randomization until the date of death from any cause. In the absence of confirmation of death, participants will be censored either at the date that the participant was last known to be alive or the date of data cutoff for the primary analysis, whichever comes earlier. Median OS was to be calculated using Kaplan-Meier estimate and presented with 2-sided 95% confidence interval. As pre-specified in the protocol, data for this secondary outcome measure was collected and analyzed till the primary analysis only.
Health-Related Quality of Life (HRQoL) Assessed by Functional Assessment of Cancer Therapy Kidney Syndrome Index-Disease-Related Symptoms (FKSI-DRS) Scores	At baseline (prior to first dose of study drug), on Day 1 of each subsequent cycle (cycle length =28 days), and at the Off-treatment visit (up to 29 months)	The FKSI-DRS consisted of 9 items that experts and participants had indicated are important targets for the treatment of advanced kidney cancer, and that clinical experts had indicated are primarily disease-related, as opposed to treatment-related. Symptoms assessed on the FKSI-DRS included lack of energy, fatigue, weight loss, pain, bone pain, shortness of breath, cough, fever, or hematuria. Each item was scored on a 5-point Likert-type scale (0 = not at all; 4 = very much) where total score ranged from 0 (worst) to 36 (best), where higher scores correspond to better outcomes. As pre-specified in the protocol, data for this secondary outcome measure was collected and analyzed till the primary analysis only.
HRQoL Assessed by European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 Scores	At baseline (prior to first dose of study drug), on Day 1 of each subsequent cycle (cycle length =28 days), and at the Off-treatment visit (up to 29 months)	The EORT QLQ-C30 consisted of 30 questions comprising 9 multiple-item scales and 6 single items. Multiple-item scales of QLQ-C30 consisted of 5 functional scales (physical, role, emotional, cognitive, and social) and 3 symptom scales (fatigue, nausea and vomiting, pain) and a global health status/QOL score. Six single-item scales of QLQ-C30 involved dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties. First 28 questions used a 4-point scale (1 = Not at all to 4 = Very much); and last 2 questions used a 7-point scale (1 = Very poor to 7 = Excellent). Scores for all scales range from 0 to 100. For the overall HRQoL and functioning scales, a higher score was correlated with better HRQoL, whereas a higher score for symptom scales represented worse HRQoL. As pre-specified in protocol, data for secondary outcome measure was collected and analyzed till primary analysis only.
HRQoL Assessed by European Quality of Life (EuroQol) Five-Dimensional, 3-Level (EQ-5D-3L) Index Score and Visual Analogue Scale (VAS)	At baseline (prior to first dose of study drug), on Day 1 of each subsequent cycle (cycle length =28 days), and at the Off-treatment visit (up to 29 months)	The EQ-5D-3L is a health profile questionnaire assessing quality of life along 5 dimensions. Participants rate 5 dimensions of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) by choosing from 3 answering options (1=no problems; 2=some problems; 3=extreme problems). The summed score ranges from 5-15 with "5" corresponding to no problems and "15" corresponding to severe problems in the 5 dimensions. The EQ-5D index was calculated by applying preference-based weights (tariffs) to the scores of the five health state dimensions. Index values can range from -1 to 1, with 0 representing a health state equivalent to death and 1 representing perfect health. EQ-5D-3L also included an EQ visual analogue scale (VAS) that ranges between 100 (best imaginable health) and 0 (worst imaginable health). Decrease from baseline in EQ-5D-3L signifies improvement. Total index EQ-5D-3L summary score was weighted with a range of -0.594 (worst) to 1.0 (best).
Progression-free Survival After Next Line of Therapy (PFS2)	From the time of randomization to the date of PD after next line of therapy or death from any cause or the date of data cutoff for the primary analysis, whichever occurs first (up to 29 months)	PFS2, defined as the time from randomization to the date of PD after next line of therapy or death from any cause, whichever occurred first based on investigator assessment according to RECIST v1.1. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. Median PFS2 was analyzed using the Kaplan-Meier product-limit estimates for each treatment group and presented with 2-sided 95% CI. As pre-specified in protocol, data for this secondary outcome measure was collected and analyzed till the primary analysis only.

Trial Locations

Locations (93): Northern Cancer Institute, Saint Leonards
🇦🇺
Saint Leonards, New South Wales, Australia
Nemocnice Na Bulovce
🇨🇿
Prague, Czechia
Optimal Research
🇺🇸
Honolulu, Hawaii, United States
City of Hope National Medical Center
🇺🇸
Duarte, California, United States
Szpital Specjalistyczny w Brzozowie
🇵🇱
Brzozow, Poland
Taichung Veterans General Hospital
🇨🇳
Taichung, Taiwan
Alberta Health Service - Tom Baker Cancer Centre
🇨🇦
Calgary, Alberta, Canada
Helsingin Yliopistollinen Keskussairaala
🇫🇮
Helsinki, Finland
Alexandra Hospital
🇬🇷
Athens, Greece
Centro Hospitalar do Porto - Hospital de Santo António
🇵🇹
Porto, Portugal
Chelyabinsk Regional Clinical Oncology Dispensary
🇷🇺
Chelyabinsk, Russian Federation
Federal State Institution Medical Radiology Research Center
🇷🇺
Obninsk, Russian Federation
British Columbia Cancer Agency
🇨🇦
Kelowna, British Columbia, Canada
Turun Yliopistollinen Keskussairaala
🇫🇮
Turku, Finland
Copernicus PL Sp. z o.o. Wojewodzkie Centrum Onkologii
🇵🇱
Gdansk, Poland
Centro Hospitalar Lisboa Norte, E.P.E. - Hospital de Santa Maria
🇵🇹
Lisbon, Portugal
Instituto Portugues de Oncologia Do Porto Francisco Gentil Epe
🇵🇹
Porto, Portugal
Oncology Center Sfantul Nectarie
🇷🇴
Craiova, Romania
China Medical University Hospital
🇨🇳
Taichung, Taiwan
Central Clinical Hospital With Polyclinic of President Administration of RF
🇷🇺
Moscow, Russian Federation
Papageorgiou General Hospital of Thessaloniki
🇬🇷
Thessaloniki, Greece
Hagaziekenhuis
🇳🇱
Den Haag, Netherlands
Prof Dr I Chiricuta Institute of Oncology
🇷🇴
Cluj-Napoca, Romania
Altay Regional Oncology Center
🇷🇺
Barnaul, Russian Federation
Moscow City Oncology Hospital #62
🇷🇺
Moscow, Russian Federation
Juravinski Cancer Centre
🇨🇦
Hamilton, Ontario, Canada
London Health Sciences Centre
🇨🇦
London, Ontario, Canada
University of Pittsburgh Medical Center
🇺🇸
Pittsburgh, Pennsylvania, United States
Fakultni nemocnice v Motole
🇨🇿
Prague, Czechia
Azienda Ospedaliera San Camillo Forlanini
🇮🇹
Roma, Italy
EUROMEDICA General Clinic of Thessaloniki
🇬🇷
Thessaloniki, Greece
SP ZOZ Szpital Uniwersytecki w Krakowie
🇵🇱
Krakow, Poland
Centrum Onkologii Ziemi Lubelskiej
🇵🇱
Lublin, Poland
Samodzielny Publiczny Zaklad Opieki Zdrowotnej Opolskie Centrum Onkologii
🇵🇱
Opole, Poland
Mrukmed. Lekarz Beata Madej-Mruk i Partner. Spolka Partnerska
🇵🇱
Rzeszow, Poland
Presidio Ospedaliero San Donato
🇮🇹
Arezzo, Italy
AORN A Cardarelli
🇮🇹
Napoli, Italy
Fiona Stanley Hospital
🇦🇺
Murdoch, Western Australia, Australia
Oklahoma Cancer Specialist and Research Institute , LLC
🇺🇸
Tulsa, Oklahoma, United States
Fakultni nemocnice Olomouc
🇨🇿
Olomouc, Czechia
Masarykuv onkologicky ustav
🇨🇿
Brno, Czechia
Adelaide Cancer Center
🇦🇺
Kurralta Park, South Australia, Australia
University of Tennessee Medical Center
🇺🇸
Knoxville, Tennessee, United States
Sir Mortimer B Davis Jewish General Hospital
🇨🇦
Montreal, Quebec, Canada
Sunshine Hospital
🇦🇺
Saint Albans, Victoria, Australia
Tampereen yliopistollinen sairaala
🇫🇮
Tampere, Finland
University General Hospital of Patras
🇬🇷
Patras, Greece
Interbalkan Medical Center of Thessaloniki
🇬🇷
Pylaia, Greece
MC Haaglanden
🇳🇱
Den Haag, Netherlands
NZOZ Vesalius
🇵🇱
Krakow, Poland
National Cancer Center
🇰🇷
Goyang-si, Gyeonggido, Korea, Republic of
Centro Hospitalar E Universitário de Coimbra EPE
🇵🇹
Coimbra, Portugal
Champalimaud Cancer Center
🇵🇹
Lisboa, Portugal
Christie Hospital
🇬🇧
Manchester, United Kingdom
Beatson West of Scotland Cancer Centre
🇬🇧
Glasgow, United Kingdom
Clinica Universidad Navarra
🇪🇸
Pamplona, Spain
Hospital Universitario 12 de Octubre
🇪🇸
Madrid, Spain
Hospital Universitario Son Espases
🇪🇸
Palma de Mallorca, Spain
Oncocenter Clinical Oncology
🇷🇴
Timisoara, Romania
Regional Clinical Oncology Hospital
🇷🇺
Yaroslavl, Russian Federation
Hospital de la Santa Creu I Sant Pau
🇪🇸
Barcelona, Spain
Hospital Universitario A Coruna
🇪🇸
A Coruna, Spain
Hospital Clinic de Barcelona
🇪🇸
Barcelona, Spain
Hospital Universitario Germans Trias i Pujol
🇪🇸
Badalona, Spain
Fundacion Instituto Valenciano de Oncologia
🇪🇸
Valencia, Spain
Hospital Universitario Ramon y Cajal
🇪🇸
Madrid, Spain
Mount Vernon Hospital
🇬🇧
Northwood, United Kingdom
Singleton Hospital
🇬🇧
Swansea, United Kingdom
Severance Hospital - Yonsei University Health System
🇰🇷
Seoul, Korea, Republic of
C.H. Regional Reina Sofia
🇪🇸
Cordoba, Spain
Baptist Health Medical Group Oncology, LLC - US Oncology
🇺🇸
Miami, Florida, United States
Innovative Clinical Research Institute, LLC
🇺🇸
Whittier, California, United States
Texas Oncology PA - US Oncology
🇺🇸
Fort Worth, Texas, United States
Metropolitan hospital
🇬🇷
Athens, Greece
Macquarie University
🇦🇺
Macquarie Park, New South Wales, Australia
Ottawa Hospital Cancer Centre
🇨🇦
Ottawa, Ontario, Canada
Sunnybrook Research Institute- University of Toronto
🇨🇦
Toronto, Ontario, Canada
Vaasan Keskussairaala
🇫🇮
Vaasa, Finland
Chonnam National University Hwasun Hospital
🇰🇷
Chŏnam, Korea, Republic of
IRCCS Istituto Nazionale dei Tumori
🇮🇹
Milano, Lombardia, Italy
Samsung Medical Center
🇰🇷
Seoul, Korea, Republic of
Leids Universitair Medisch Centrum
🇳🇱
Leiden, Netherlands
MAGODENT Sp. z o.o. Szpital Elblaska
🇵🇱
Warszawa, Poland
Medisprof SRL
🇷🇴
Cluj-Napoca, Romania
Clinical Oncology Dispensary
🇷🇺
Omsk, Russian Federation
Moscow Scientific Research Oncology Institute P.A. Herzen
🇷🇺
Moscow, Russian Federation
ICO l'Hospitalet - Hospital Duran i Reynals
🇪🇸
Hospitalet de Llobregat, Spain
MD Anderson Cancer Center Madrid
🇪🇸
Madrid, Spain
Hospital Clinico San Carlos
🇪🇸
Madrid, Spain
Asan Medical Center
🇰🇷
Seoul, Korea, Republic of
The Catholic University of Korea, Seoul Saint Mary's Hospital
🇰🇷
Seoul, Korea, Republic of
National Taiwan University Hospital
🇨🇳
Taipei, Taiwan
Taipei Veterans General Hospital
🇨🇳
Taipei, Taiwan