A Study Of Avelumab Alone Or In Combination With Pegylated Liposomal Doxorubicin Versus Pegylated Liposomal Doxorubicin Alone In Patients With Platinum Resistant/Refractory Ovarian Cancer (JAVELIN Ovarian 200)
Summary
A Phase 3 global study comparing avelumab alone to avelumab plus PLD and to PLD alone to demonstrate that avelumab given alone or in combination with PLD is superior to PLD alone in prolonging Overall Survival in patients with platinum resistant/platinum refractory ovarian cancer.
Key Facts
Lead Sponsor
Pfizer
Enrollment
566
Start Date
2015-12-21
Completion Date
2018-09-19
Study Type
INTERVENTIONAL
Official Title
A PHASE 3, MULTICENTER, RANDOMIZED, OPEN-LABEL STUDY OF AVELUMAB (MSB0010718C) ALONE OR IN COMBINATION WITH PEGYLATED LIPOSOMAL DOXORUBICIN VERSUS PEGYLATED LIPOSOMAL DOXORUBICIN ALONE IN PATIENTS WITH PLATINUM-RESISTANT/REFRACTORY OVARIAN CANCER
Interventions
Conditions
Eligibility
Age Range
18 Years+
Sex
FEMALE
Inclusion Criteria: * Histologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer, including malignant mixed Müllerian tumors with high grade serous component. * Platinum resistant/refractory disease, defined as disease progression within 180 days following the last administered dose of platinum therapy (resistant), or lack of response or disease progression while receiving the most recent platinum based therapy (refractory), respectively. * Received up to 3 lines of systemic anticancer therapy for platinum sensitive disease, most recently platinum containing, and no prior systemic therapy for platinum resistant disease * Measurable disease by investigator assessment with at least 1 unidimensional measurable lesion by RECIST v.1.1 that has not previously been irradiated * Active autoimmune disease that might deteriorate when receiving an immunostimulatory agents. Patients with diabetes type I, vitiligo, psoriasis, hypo or hyperthyroid disease not requiring immunosuppressive treatment are eligible. Mandatory tumor biopsy must be performed prior to enrollment for all patients (unless there is a documented clinical contraindication). In addition, availability of archived FFPE tumor tissue should be confirmed. If a patient underwent tumor tissue collection within 3 months prior to enrollment with no intervening treatment, and the sample is provided, then a new de novo tumor biopsy is not required. Exclusion Criteria: * Non epithelial tumor or ovarian tumors with low malignant potential (ie, borderline tumors). * Prior therapy with an anti PD 1, anti PD L1, anti PD L2, anti CD137, or anti cytotoxic T lymphocyte associated antigen 4 (CTLA 4) antibody (including ipilimumab, tremelimumab or any other antibody or drug specifically targeting T cell co stimulation or immune checkpoint pathways). * Known symptomatic brain metastases requiring steroids. Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry, have discontinued corticosteroid treatment for these metastases for at least 4 weeks prior to study entry and are neurologically stable. * Diagnosis of any other malignancy within 5 years prior to registration, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or of the cervix. * Severe gastrointestinal conditions such as clinical or radiological evidence of bowel obstruction within 4 weeks prior to study entry, uncontrolled diarrhea in the last 4 weeks prior to enrollment, or history of inflammatory bowel disease.
Outcome Measures
Primary Outcomes
Overall Survival (OS)
OS is defined as the time from the date of randomization to the date of death due to any cause. OS time was summarized by treatment arm using the Kaplan-Meier method.
Time frame: From randomization until the date of first documented progression or date of deaths from any cause, whichever came first, assessed up to 30 months (based on cutoff date: 19 September 2018).
Progression Free Survival (PFS) Based on Blinded Independent Central Review (BICR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
PFS is defined as the time from date of randomization to the date of the first documentation of progression of disease (PD) or death due to any cause, whichever occurs first. PFS time was summarized by treatment arm using the Kaplan-Meier method. PFS based on BICR assessment was evaluated for this endpoint.
Time frame: From randomization to date of first documentation of PD or death due to any cause whichever was first (up to 30 months); based on cutoff date: 19 September 2018.
Secondary Outcomes
Objective Response Rate (ORR) Based on BICR Assessment
Percentage of participants achieved objective response (OR) based on BICR assessment is presented for this endpoint. OR is defined as a complete response (CR, disappearance of all target lesions) or partial response (PR, \>=30% decrease under the baseline of the sum of diameters of all target measurable lesions) according to the RECIST (version 1.1) recorded from randomization until disease progression or death due to any cause. Both CR and PR must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met and before the first documentation of disease progression. Only tumor assessments performed on or before the start date of any further anti-cancer therapies are considered in the assessment of best overall response.
Time frame: Tumor assessments as assessed by BICR were conducted at every 8 weeks from screening until documented disease progression (approximately up to 30 months); based on cutoff date: 19 September 2018.
ORR Based on Investigator Assessment
Percentage of participants achieved OR based on investigator assessment is presented for this endpoint. OR is defined as a CR (disappearance of all target lesions) or PR (\>=30% decrease under the baseline of the sum of diameters of all target measurable lesions) according to the RECIST (version 1.1) recorded from randomization until disease progression or death due to any cause. The ORR on each randomized treatment arm were estimated by dividing the number of participants with OR (CR or PR) by number of participants randomized to the respective treatment arm.
Time frame: Tumor assessments as assessed by investigator were conducted at every 8 weeks from screening until documented disease progression, up to 30 months; based on cutoff date: 19 September 2018.
PFS Based on Investigator Assessment According to RECIST Version 1.1
PFS is defined as the time from date of randomization to the date of the first documentation of PD or death due to any cause, whichever occurs first. PFS time was summarized by treatment arm using the Kaplan-Meier method.
Time frame: From randomization to date of first documentation of PD or death due to any cause whichever was first (up to 30 months); based on cutoff date: 19 September 2018.
Duration of Response (DR) Based on BICR Assessment
DR is defined, for participants with an OR per RECIST version 1.1, as the time from the first documentation of objective tumor response (CR \[disappearance of all target lesions\] or PR \[\>=30% decrease under the baseline of the sum of diameters of all target measurable lesions\]) to the first documentation of objective tumor progression or death due to any cause, whichever occurs first.
Time frame: Tumor assessments as assessed by investigator were conducted at every 8 weeks from screening until documented disease progression, up to 30 months; based on cutoff date: 19 September 2018.
DR Based on Investigator Assessment
DR is defined, for participants with an OR per RECIST version 1.1, as the time from the first documentation of objective tumor response (CR \[disappearance of all target lesions\] or PR \[\>=30% decrease under the baseline of the sum of diameters of all target measurable lesions\]) to the first documentation of objective tumor progression or death due to any cause, whichever occurs first.
Time frame: Tumor assessments as assessed by investigator were conducted at every 8 weeks from screening until documented disease progression, up to 30 months; based on cutoff date: 19 September 2018.
Disease Control (DC) Rate Based on BICR Assessment
Percentage of participants achieving DC based on BICR assessment is presented in this endpoint. DC is a best overall response of CR (disappearance of all target lesions), PR (\>=30% decrease under the baseline of the sum of diameters of all target measurable lesions), non-complete response/non-progressive disease or stable disease (SD) according to the RECIST version 1.1.
Time frame: Tumor assessments as assessed by investigator were conducted at every 8 weeks from screening until documented disease progression, up to 30 months; based on cutoff date: 19 September 2018.
DC Rate Based on Investigator Assessment
Percentage of participants achieving DC based on investigator assessment is presented in this endpoint. DC is a best overall response of CR (disappearance of all target lesions), PR (\>=30% decrease under the baseline of the sum of diameters of all target measurable lesions), non-complete response/non-progressive disease or SD according to the RECIST version 1.1.
Time frame: Tumor assessments as assessed by investigator were conducted at every 8 weeks from screening until documented disease progression, up to 30 months; based on cutoff date: 19 September 2018.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
An adverse event (AE) is any untoward medical occurrence in a clinical investigation patient administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; life-threatening; initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; progression of the malignancy under study. Treatment emergent AEs are those events with onset dates occurring during the on-treatment period for the first time, or if the worsening of an event is during the on-treatment period.
Time frame: From the time of the first dose of study treatment through a minimum of 30 days + last dose of study treatment, start day of new anti-cancer therapy -1 day (up to 70 months); based on cutoff date: 13 July 2022.
Number of Participants With Laboratory Abnormalities
The number of participants with following laboratory abnormalities meeting any of the Grades 1 to 4 classified according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) toxicity grading version 4.03 were summarized: hematology (anemia, lymphocyte count decreased, neutrophil count decreased; and platelet count decreased) and chemistry laboratory tests (creatinine increased; serum amylase increased and lipase increased).
Time frame: From screening to the end of treatment/withdrawal visit, up to 2.7 years, based on cutoff date: 19 September 2018.
Change From Baseline in Vital Signs - Blood Pressure
Vital signs included blood pressure and pulse rate. Changes from baseline in sitting diastolic blood pressure (DBP) and systolic blood pressure (SBP) were summarized.
Time frame: From screening to the end of treatment/withdrawal visit, up to 2.7 years, based on cutoff date: 19 September 2018.
Change From Baseline in Vital Signs - Pulse Rate
Vital signs included blood pressure and pulse rate. Changes from baseline in sitting pulse rate were summarized.
Time frame: From screening to the end of treatment/withdrawal visit, up to 2.7 years, based on cutoff date: 19 September 2018.
Number of Participants With Electrocardiogram (ECG) Abnormalities
Categorical summarization ECG criteria were as follows: 1) QT interval, QTcB, QTcF and QTcP: increase from baseline \>30 ms or 60 ms; absolute value \> 450 ms, \>480 ms and \> 500 ms; 2) heart rate (HR): change from baseline \>=20 bpm and absolute value \<=50 bpm or \>=120 bpm; 3) PR interval: absolute value \>=220 ms and increase from baseline \>=20 ms; 4) QRS: \>= 120 ms.
Time frame: From screening to the end of treatment/withdrawal visit, up to 2.7 years, based on cutoff date: 19 September 2018.
Number of Participants With % Left Ventricular Ejection Fraction (LVEF) Decrease From Baseline
LVEF decrease was summarized by multiple-gated acquisition (MUGA)/ echocardiogram (ECHO) parameter. Participants with a LVEF% \>=10 points and \>= 15 points decrease from baseline during the on-treatment period were summarized.
Time frame: Screening, Cycle 3 Day 1 (repeated every 2 cycles) to the end of treatment/withdrawal visit, based on cutoff date: 19 September 2018.
Number of Participants With PD-L1 Expression for PFS (Based on BICR Assessment) and for OS
PD-L1 expression was assessed by immunohistochemistry. Participants were considered positive for PD-L1 if their baseline tissue sample demonstrated PD-L1 expression on \>=1% of tumor cells or \>=5% of immune cells.
Time frame: Biomarkers are measured only at screening.
Number of Participants With CD8 Expression for PFS (Based on BICR Assessment) and for OS
Tumor infiltrating CD8 positive (CD8+) T lymphocytes was assessed by immunohistochemistry. Participants were considered positive for CD8 T cells if their baseline tissue sample demonstrated presence of \>=1% CD8+ cells across the area of the tumor.
Time frame: Biomarkers are measured only at screening.
Number of Participants With Improved, Stable and Deterioration Based on 10-Point Change for EORTC QLQ-C30 Global QoL
The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30) is a 30 question survey and includes 5 functional domain subscales, global health status/quality of life, disease/treatment related symptoms, and the perceived financial impact of disease. Higher scores are reflective of a greater presence of symptoms.
Time frame: Day 1 of Cycle 1, Day 1 of each subsequent cycle, end of treatment/withdrawal visit and the 30, 60 and 90 days safety follow up visits, based on cutoff date: 19 September 2018.
Time to Deterioration in Abdominal/GI Symptom Subscale of EORTC QLQ-OV28
The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Ovarian Cancer 28 (EORTC QLQ-OV28) is a 28 item instrument with 7 functional domain subscales. Time to deterioration was defined as the time from randomization to the first time the participant's score showed a 15-point or higher increase in the score of the abdominal/GI symptom subscale of the EORTC QLQ-OV28.
Time frame: From Day 1 of Cycle 1 to prior to end of treatment/withdrawal visit, based on cutoff date: 19 September 2018.
Change From Baseline in EQ-VAS Score at End of Treatment
The EuroQol- 5 Dimensions- 5 Levels (EQ-5D-5L) questionnaire consists of the EQ-5D-5L descriptive system and a visual analogue scale (the EuroQol-visual analogue scale \[EQ-VAS\]). The respondent's self-rated health is assessed on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state) by the EQ-VAS.
Time frame: Baseline and end of treatment/withdrawal visit
Serum Trough Concentration (Ctrough) For Avelumab Following Cycle 2 Day 1 Pegylated Liposomal Doxorubicin (PLD) Dose
Ctrough was defined as predose concentration during multiple dosing, and can be observed directly from data.
Time frame: At predose (0 H) on Cycle 2 Day 1
Serum Maximum Concentration (Cmax) For Avelumab Following Cycle 2 Day 1 PLD Dose
Cmax was defined as maximum observed serum concentration, and can be observed directly from data.
Time frame: At postdose (end of infusion, 1H) on Cycle 2 Day 1
Cmax For Doxorubicin Following Cycle 2 Day 1 PLD Dose
Cmax was defined as maximum observed serum concentration, and can be observed directly from data.
Time frame: From predose (0 H) of Cycle 2 Day 1 through 336 hours postdose
Area Under The Concentration Time Profile From Time Zero to 24 Hours (AUC24) For Doxorubicin Following Cycle 2 Day 1 PLD Dose
AUC24 was defined as area under the concentration time profile from time zero to 24 hours.
Time frame: From 0 through 24 hours postdose
Area Under The Concentration Time Profile From Time Zero to 336 Hours (AUC336) For Doxorubicin Following Cycle 2 Day 1 PLD Dose
AUC336 was defined as area under the concentration time profile from time zero to 336 hours.
Time frame: From predose (0 H) of Cycle 2 Day 1 through 336 hours postdose
Area Under The Concentration Time Profile From Time Zero to The Last Quantifiable Concentration (AUClast) For Doxorubicin Following Cycle 2 Day 1 PLD Dose
AUClast was defined as area under the concentration time profile from time zero to the time of the last quantifiable concentration (Clast).
Time frame: From predose (0 H) of Cycle 2 Day 1 through 336 hours postdose
Number of Participants With Treatment-Boosted Anti-Drug Antibody (ADA)
Treatment-boosted ADA was defined as a positive ADA result at baseline and the titer ≥ 8×baseline titer at least once after treatment with avelumab.
Time frame: At predose (0 H) of select cycles starting from Cycle 1 through Cycle 24, at end of treatment and 30 days after the last dose of avelumab
Number of Participants With Treatment-Induced ADA
Treatment-induced ADA was defined as participant who was ADA-negative at baseline and has at least one positive post-baseline ADA result; or if participant did not have a baseline sample, the participant had at least one positive past-baseline ADA result.
Time frame: At predose (0 H) of select cycles starting from Cycle 1 through Cycle 24, at end of treatment and 30 days after the last dose of avelumab
Number of Participants With Treatment-Induced Neutralizing Antibody (nAb)
Treatment-induced nAb was defined as participant who was not nAb positive at baseline and had at least one positive post-baseline nAb result; or if participant did not have a baseline sample, the participant had at least one positive past-baseline ADA result.
Time frame: At predose (0 H) of select cycles starting from Cycle 1 through Cycle 24, at end of treatment and 30 days after the last dose of avelumab
Locations
Arizona Oncology Associates, PC - HAL, Chandler, United States
Arizona Oncology Associates, PC - HAL, Phoenix, United States
Arizona Oncology Associates, PC - HAL, Phoenix, United States
Arizona Oncology Associates, PC - HAL, Scottsdale, United States
Arizona Oncology Associates, PC-HAL, Tempe, United States
Arizona Oncology Associates, PC - HOPE, Tucson, United States
Arizona Oncology Associates, PC - HOPE, Tucson, United States
Highlands Oncology Group, Fayetteville, United States
Highlands Oncology Group, Rogers, United States
University of California, Irvine/UC Irvine Health, Orange, United States
Sansum Clinic, Santa Barbara, United States
Sansum Clinic, Solvang, United States
Rocky Mountain Cancer Centers, Aurora, United States
Rocky Mountain Cancer Centers, Boulder, United States
Rocky Mountain Cancer Centers, Lakewood, United States
Florida Cancer Specialists, Daytona Beach, United States
Florida Cancer Specialists, Wellington, United States
Florida Cancer Specialists, West Palm Beach, United States
Atlanta Gynecologic Oncology, Atlanta, United States
Northside Hospital - Pharmacy, Atlanta, United States
University Gynecologic Oncology, Atlanta, United States
Northwest Georgia Oncology Centers, P.C., Austell, United States
Northwest Georgia Oncology Centers, P.C., Carrollton, United States
Northwest Georgia Oncology Centers, P.C., Cartersville, United States
Northwest Georgia Oncology Centers, P.C., Douglasville, United States
Northwest Georgia Oncology Centers, P.C., Marietta, United States
The University of Kansas Clinical Research Center, Fairway, United States
The University of Kansas Cancer Center and Medical Pavilion, Westwood, United States
Norton Cancer Institute, Norton Healthcare Pavilion, Louisville, United States
Norton Healthcare Pharmacy, Attn: Marlon Baranda, Pharm D, Louisville, United States
Norton Hospital, Louisville, United States
Norton Cancer Institute, St. Matthews Campus, Louisville, United States
Norton Women's and Children's Hospital, Louisville, United States
Norton Brownsboro Hospital, Louisville, United States
Norton Cancer Institute, Brownsboro Hospital Campus, Louisville, United States
Maryland Oncology Hematology, P.A., Bethesda, United States
Maryland Oncology Hematology, P.A., Columbia, United States
Maryland Oncology Hematology P.A., Silver Spring, United States
Maryland Oncology Hematology P.A., Silver Spring, United States
Massachusetts General Hospital, Boston, United States
Brigham Women's Hospital, Boston, United States
Dana Farber Cancer Institute, Boston, United States
The University of Kansas Cancer Center, CCP - North, Kansas City, United States
Center of Hope at Renown Regional Medical Center, Reno, United States
Southwest GYN Oncology Associates, Inc., Albuquerque, United States
University of New Mexico Comprehensive Cancer Center, Albuquerque, United States
Hope Women's Cancer Centers, Asheville, United States
Mission Hospital, Inc., Asheville, United States
Novant Health Oncology Specialists, Kernersville, United States
Novant Health Oncology Specialists, Winston-Salem, United States
Cleveland Clinic Taussig Cancer Center, Cleveland, United States
Fairview Hospital Moll Pavilion Cancer Center, Cleveland, United States
Fairview Hospital Moll Pavilion Pharmacy, Cleveland, United States
Cleveland Clinic Taussig Cancer Center, Cleveland, United States
Cleveland Clinic, Cleveland, United States
Hillcrest Hospital Hirsch Cancer Center Pharmacy, Mayfield Heights, United States
Hillcrest Hospital, Mayfield Heights, United States
Willamette Valley Cancer Institute and Research Center, Eugene, United States
Investigational Drug Services, University of Pennsylvania, Philadelphia, United States
The University of Pennsylvania Health System, Philadelphia, United States
Fox Chase Cancer Center, Philadelphia, United States
Tennessee Oncology, PLLC, Dickson, United States
Tennessee Oncology, PLLC, Franklin, United States
Tennessee Oncology, PLLC, Gallatin, United States
Tennessee Oncology, PLLC, Hermitage, United States
Tennessee Oncology, PLLC, Lebanon, United States
Tennessee Oncology, PLLC, Murfreesboro, United States
Tennessee Oncology, PLLC, Nashville, United States
The Sarah Cannon Research Institute, Nashville, United States
Tennessee Oncology, PLLC, Nashville, United States
Tennessee Oncology, PLLC, Nashville, United States
Tennessee Oncology, PLLC, Nashville, United States
Tennessee Oncology, PLLC, Shelbyville, United States
Tennessee Oncology, PLLC, Smyrna, United States
Texas Oncology-Austin Central, Austin, United States
Texas Oncology-South Austin, Austin, United States
Texas Oncology - Bedford, Bedford, United States
Texas Oncology -Fort Worth Cancer Center, Fort Worth, United States
US Oncology Investigational Products Center (IPC), Irving, United States
US Oncology Investigational Products Center, Irving, United States
Texas Oncology - San Antonio Medical Center, San Antonio, United States
Texas Oncology - The Woodlands, Gynecologic Oncology, The Woodlands, United States
Utah Cancer Specialists, Salt Lake City, United States
Carilion Clinic Gynecologic Oncology, Roanoke, United States
Carilion Clinic, Roanoke, United States
Froedtert and The Medical College of Wisconsin, Milwaukee, United States
Froedtert Hospital, Milwaukee, United States
Epic Pharmacy,Newcastle Private Hospital, New Lambton Heights, Australia
Newcastle Private Hospital Pty Limited, Newcastle, Australia
Icon Cancer Care Wesley, Auchenflower, Australia
Rivercity Pharmacy, Auchenflower, Australia
Mater Pharmacy Services, Brisbane, Australia
Icon Cancer Care Chermside, Chermside, Australia
Clinical Research Unit, Herston, Australia
Metro North Hospital and Health Service, Herston, Australia
Oncology Pharmacy, Herston, Australia
Icon Cancer Care, South Brisbane, Australia
Icon Cancer Foundation, South Brisbane, Australia
Mater Cancer Care Centre, South Brisbane, Australia
Icon Cancer Care Southport, Southport, Australia
Cabrini Health Limited, Brighton, Australia
Cabrini Health Limited, Malvern, Australia
Peter MacCallum Cancer Centre, Melbourne, Australia
Royal Melbourne Hospital, Parkville, Australia
Pharmacy Department, Parkville, Australia
The Royal Women's Hospital, Parkville, Australia
Medizinische Universitat Graz, LKH-Univ. Klinikum Graz, Graz, Austria
Medizinische Universitat Innsbruck, Innsbruck, Austria
University Hospital Gent, Ghent, Belgium
Institut Jules Bordet, Brussels, Belgium
AZ Groeninge Hospital, Kortrijk, Belgium
Universitaire Ziekenhuizen Leuven, Leuven, Belgium
CHU de Liege - Sart Tilman, Liège, Belgium
Clinique et Maternite Sainte Elisabeth, Namur, Belgium
Tom Baker Cancer Centre, Calgary, Canada
Cross Cancer Institute, Edmonton, Canada
British Columbia Cancer Agency - Sindi Ahluwalia Hawkins Centre for the Southern Interior, Kelowna, Canada
British Columbia Cancer Agency-Vancouver Centre, Vancouver, Canada
St. Boniface General Hospital, Winnipeg, Canada
Health Sciences Centre, Winnipeg, Canada
CancerCare Manitoba, Winnipeg, Canada
Nova Scotia Health Authority, QEII Health Sciences Centre, Nova Scotia Cancer Centre, Halifax, Canada
Nova Scotia Health Authority, QEII Health Sciences Centre, Halifax, Canada
The Ottawa Hospital, Ottawa, Canada
Sunnybrook Research Institute, Toronto, Canada
Princess Margaret Cancer Centre, Toronto, Canada
Jewish General Hospital, Montreal, Canada
McGill University Health Centre - Glen Site, Montreal, Canada
Oncology Pharmacy McGill University Health Centre, Montreal, Canada
Vseobecna fakultni nemocnice v Praze, Fakultni poliklinika, Prague, Czechia
Fakultni nemocnice Olomouc, Olomouc, Czechia
Fakultni nemocnice Ostrava, Ostrava-Poruba, Czechia
Vseobecna fakultni nemocnice v Praze, Nemocnicni lekarna,, Prague, Czechia
Vseobecna fakultni nemocnice v Praze, Neurologicka klinika, Prague, Czechia
Vseobecna fakultni nemocnice v Praze, Prague, Czechia
Fakultni nemocnice v Motole, Prague, Czechia
Krajska zdravotni a.s., Masarykova nemocnice v Usti nad Labem, o.z, Ústí nad Labem, Czechia
Aalborg University Hospital, Aalborg, Denmark
Rigshospitalet, Copenhagen, Denmark
Centre Francois Baclesse, Caen, France
Centre Leon Berard, Lyon, France
Service de Radiologie, Lyon, France
Centre Antoine Lacassagne, Nice, France
Hôpital Européen Georges Pompidou, Paris, France
Hôpital Européen Georges Pompidou, Paris, France
Centre Hospitalier Lyon Sud, Pierre-Bénite, France
Institut de Cancérologie de Lorraine, Vandœuvre-lès-Nancy, France
Gustave Roussy Cancer Campus, Villejuif, France
General Hospital of Athens Alexandra, Athens, Greece
General Oncology Hospital of Kifissia "Agioi Anargiroi", 2nd Department of Medical Oncology, Athens/New Kifissia, Greece
Princess Margaret Hospital, Hong Kong, Hong Kong
University of Hong Kong, Hong Kong, Hong Kong
Orszagos Onkologiai Intezet, Gyogyszertar, Budapest, Hungary
Orszagos Onkologiai Intezet, Nogyogyaszati Osztaly, Budapest, Hungary
Debreceni Egyetem Klinikai Gyogyszertar, Debrecen, Hungary
Debreceni Egyetem Klinikai Kozpont, Debrecen, Hungary
Jasz-Nagykun-Szolnok Megyei Hetenyi Geza Korhaz-Rendelointezet, Onkologiai Kozpont, Szolnok, Hungary
Mater Misericordiae University Hospital, Dublin, Ireland
Mater Private Hospital, Dublin, Ireland
St James's Hospital, Dublin, Ireland
Mater Misericoridae University Hospital, Dublin, Ireland
Mater Private Hospital, Dublin, Ireland
Pharmacy Department, Dublin, Ireland
St Vincent's University Hospital, Dublin, Ireland
University Hospital Waterford, Waterford, Ireland
Shaare Zedek Medical Center, Jerusalem, Israel
Poliambulatorio Specialistico Villa Salute, Manerbio, Italy
Congregazione delle Suore Infermiere dell'Addolorata, Costa Masnaga, Italy
ASST Fatebenefratelli Sacco, Miano, Italy
Servizio Sanitario Regionale Emilia-Romagna, Lugo, Italy
Fondazione del Piemonte per l'Oncologia, Candiolo, Italy
Habilita, San Marco Bergamo, Bergamo, Italy
Humanitas Cliniche Gavazzeni, Bergamo, Italy
Humanitas, Unita Operativa di Cardiologia 2, Bergamo, Italy
Fondazione Poliambulanza Istituto Ospedelario, Brescia, Italy
Congregazione delle Suore Infermiere dell'Addolorata, Como, Italy
Fondazione Teresa Camplani, Cremona, Italy
Regione Lombardia, A O Istituti Ospitalieri di Cremona, Cremona, Italy
Regione Lombardia, ASST Cremona, Cremona, Italy
Istituto Europeo di Oncologia, Milan, Italy
Ambulatorio dott. Francesco Cavanna, Medico Chirurgo, Piacenza, Italy
Azienda Unita Sanitaria Locale di Piacenza, Piacenza, Italy
Azienda USL 4 Prato, Prato, Italy
Azienda USL 4 Toscana Centro, Prato, Italy
Servizio Sanitario Regionale Emilia-Romagna, Rimini, Italy
C D C, Sede di Torino Centro, Torino, Italy
Shikoku Cancer Center, Matsuyama, Japan
Ehime University Hospital, Tōon, Japan
Hokkaido University Hospital, Sapporo, Japan
Hyogo Cancer Center, Akashi, Japan
University of Tsukuba Hospital, Tsukuba, Japan
Tokai University Hospital, Isehara, Japan
Nippon Medical School Musashikosugi Hospital, Kawasaki, Japan
Yokohama City University Hospital, Yokohama, Japan
Tohoku University Hospital, Sendai, Japan
Saitama Medical University International Medical Center, Hidaka, Japan
Saitama Cancer Center, Kita-adachi-gun, Japan
National Defense Medical College Hospital, Tokorozawa, Japan
Seirei Hamamatsu General Hospital, Hamamatsu, Japan
Jichi Medical University Hospital, Shimotsuke, Japan
The University of Tokyo Hospital, Bunkyo-ku, Japan
National Cancer Center Hospital, Chuo-ku, Japan
Kagoshima University Hospital, Kagoshima, Japan
Kagoshima City Hospital, Kagoshima, Japan
Niigata Cancer Center Hospital, Niigata, Japan
Universitair Medisch Centrum Groningen, Groningen, Netherlands
Universitair Medisch Centrum Groningen, Groningen, Netherlands
LUMC, Leiden, Netherlands
Maastricht Universitair Medisch Centrum, Maastricht, Netherlands
Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway
Sykehusapoteket i Bergen, Bergen, Norway
Oslo Universitetssykehus, Oslo, Norway
Sykehusapoteket Oslo, Oslo, Norway
Centrum Onkologii, Instytut im. M. Sklodowskiej-Curie, Oddzial w Krakowie, Apteka Szpitalna, Krakow, Poland
Centrum Onkologii, Instytut im. M. Sklodowskiej-Curie, Oddzial w Krakowie, Krakow, Poland
Wojewodzki Szpital Specjalistyczny w Olsztynie, Apteka Szpitalna, Olsztyn, Poland
Wojewodzki Szpital Specjalistyczny w Olsztynie, Olsztyn, Poland
Szpital Kliniczny Przemienienia Panskiego Uniwersytetu Medycznego im. Karola Marcinkowskiego w, Poznan, Poland
Szpital Kliniczny Przemienienia Panskiego Uniwersytetu Medycznego, Poznan, Poland
SPZOZ Wojewodzki Szpital Specjalistyczny nr 3 w Rybniku, Apteka Szpitalna, Rybnik, Poland
SPZOZ Wojewodzki Szpital Specjalistyczny nr 3 w Rybniku, Rybnik, Poland
State Budgetary Healthcare Institution "Oncology Center #2" of the Ministry of Healthcare, Sochi, Russia
State Budgetary Healthcare Institution Pyatigorsk Oncology Dispensary, Pyatigorsk, Russia
Evimed Llc, Chelyabinsk, Russia
State Budgetary Healthcare Institution, Chelyabinsk, Russia
State Budgetary Healthcare Institution "Clinical oncology dispensary #1", Krasnodar, Russia
Federal State Budgetary Institution "Russian Cancer Research Center n.a. N.N. Blokhin", Moscow, Russia
State Budgetary Healthcare Institution of Nizhegorogsky region, Nizhny Novgorod, Russia
State Budgetary Healthcare Institution "Orenburg Regional Clinical Oncological Dispensary", Orenburg, Russia
State Budget Institution of Healthcare Saint Petersburg Clinical Scientific - Practice Center, Saint Petersburg, Russia
State Regional Budgetary Healthcare Institution "Regional clinical oncology dispensary", Veliky Novgorod, Russia
National University Hospital, Singapore, Singapore
National University Hospital, Singapore, Singapore
National Cancer Centre Singapore Pharmacy, Singapore, Singapore
National Cancer Centre Singapore, Singapore, Singapore
Raffles Hospital, Singapore, Singapore
National Cancer Center, Goyang-si, South Korea
Clinical Trial Pharmacy, Keimyung University Dongsan Medical Center, Daegu, South Korea
Keimyung University Dongsan Medical Center, Daegu, South Korea
Korea University Anam Hospital, Seoul, South Korea
Seoul National University Hospital, Seoul, South Korea
Severance Hospital, Yonsei University Health System, Clinical Trial Pharmacy, Seoul, South Korea
Severance Hospital, Yonsei University Health System, Seoul, South Korea
Asan Medical Center, Seoul, South Korea
Samsung Medical Center Clinical Trial Pharmacy, Seoul, South Korea
Samsung Medical Center, Seoul, South Korea
Department of Pharamacy, The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul, South Korea
The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul, South Korea
The Catholic University of Korea, Seoul, South Korea
Institut Catala d'Oncologia - Hospital Duran y Reynalds, L'Hospitalet de Llobregat, Spain
Hospital Universitario Reina Sofia, Córdoba, Spain
lnstitut Catala d Oncologia de Girona. Hospital Universitario Dr. Josep Trueta, Girona, Spain
Hospital MD Anderson, Madrid, Spain
Hospital Universitario La Paz, Madrid, Spain
Centro Integral Oncologico Clara Campal, Madrid, Spain
Hospital Universitario Virgen de Valme, Seville, Spain
Universitatsspital Basel, Frauenklinik, Basel, Switzerland
Universitatsspital Basel, Basel, Switzerland
Luzerner Kantonsspital, Medizinische Onkologie, Studienzentrale Onkologie, Lucerne, Switzerland
Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland
Kantonsapotheke Zurich, Zurich, Switzerland
Universitaetsspital Zurich, Klinik fuer Gynakologie, Zurich, Switzerland
Universitatsspital Zurich, Clinical Trials Center, Zurich, Switzerland
Universitatsspital Zurich, Institut fur diagnostische und interventionelle Radiologie, Zurich, Switzerland
Universitatsspital Zurich, Universitares Herzzentrum Zurich, Zurich, Switzerland
Clinical Trial Pharmacy, National Cheng Kung University Hospital, Tainan, Taiwan
National Cheng Kung University Hospital, Tainan, Taiwan
National Taiwan University Hospital, Taipei, Taiwan
Clinical Trial Pharmacy, Mackay Memorial Hospital, Taipei, Taiwan
Mackay Memorial Hospital, Taipei, Taiwan
Clinical Trial Pharmacy, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan
Clinical Trial Pharmacy, Taipei Veterans General Hospital, Taipei, Taiwan
Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan
Taipei Veterans General Hospital, Taipei, Taiwan
Chang Gung Memorial Hospital - Linkou Branch, Taoyuan, Taiwan
Chemotherapy Pharmacy, Chang Gung Memorial Hospital - Linkou Branch, Taoyuan, Taiwan
Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
Ross Hall Hospital, Glasgow, United Kingdom
The Clatterbridge Cancer Centre NHS Foundation Trust, Bebington, Wirral, United Kingdom
The Clatterbridge Cancer Centre, Bebington, Wirral, United Kingdom
East and North Hertfordshire NHS Trust, Northwood, United Kingdom
Northampton General Hospital NHS Trust, Northampton, United Kingdom
Oxford University Hospitals NHS Foundation Trust, Headington, United Kingdom
The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom
Spire Healthcare Limited (St. Anthony's Hospital), Sutton, United Kingdom
NHS Greater Glasgow and Clyde, Glasgow, United Kingdom
University College London Hospital NHS Foundation Trust, London, United Kingdom
Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom
Guy's & St. Thomas' NHS Foundation Trust, London, United Kingdom
The Royal Marsden NHS Foundation Trust, London, United Kingdom
Imperial College Healthcare NHS Trust, London, United Kingdom
University College London Hospital NHS Foundation Trust, London, United Kingdom
The Christie Hospital NHS Foundation Trust, Manchester, United Kingdom
Nottingham University Hospital NHS Trust, Nottingham, United Kingdom
Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom