A Study of Alectinib (RO5424802) in Participants With Non-Small Cell Lung Cancer Who Have Anaplastic Lymphoma Kinase (ALK) Mutation and Failed Crizotinib Treatment
- Registration Number
- NCT01801111
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
This open-label, non-randomized, multicenter, Phase 1/2 study will evaluate the safety and efficacy of alectinib in participants with non-small cell lung cancer who have ALK mutation and failed crizotinib treatment. In Part 1, cohorts of participants will receive escalating doses of alectinib orally twice daily. In Part 2, participants will receive the recommended phase 2 dose (RP2D) of alectinib as determined in Part 1. Treatment will continue in Part 1 and Part 2 on the same dose until disease progression. In Part 3, following disease progression, participants without epidermal growth factor receptor (EGFR) mutation will be offered continued treatment with alectinib, participants with EGFR mutations will be offered a combination of alectinib and erlotinib.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 138
- Locally advanced or metastatic non-small cell lung cancer (stage IIIB or IV by American Joint Committee on Cancer [AJCC])
- Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- Documented ALK rearrangement based on Food and Drug Administration (FDA)-approved test
- Prior treatment with crizotinib and progression according to response evaluation criteria in solid tumors version 1.1 (RECIST v1.1) criteria. Participants had to have a minimum 1-week wash-out period between the last dose of crizotinib and the first dose of study treatment. Participants can either be chemotherapy-naïve or have received at least one line of platinum-based chemotherapy
- Adequate hematologic, hepatic, and renal function
- Participants with brain or leptomeningeal metastases are allowed if protocol defined criteria are met
- Measurable disease according to RECIST v1.1 prior to administration of first dose of study drug
- Receipt of any other ALK inhibitors in addition to crizotinib
- Receipt of any prior cytotoxic chemotherapy for ALK-positive NSCLC within 4 weeks prior to the first dose of study drug
- Participants who received crizotinib or any other tyrosine kinase inhibitors need to have a minimum 1-week washout period before the first dose of study drug
- Active or uncontrolled infectious diseases requiring treatment
- National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03) Grade 3 or higher toxicities due to prior therapy that have not shown improvement and are considered to interfere with current study medication
- History of organ transplant
- Co-administration of anti-cancer therapies other than those administered in this study
- Baseline corrected Q-T interval (QTc) greater than (>) 470 milliseconds, or baseline symptomatic bradycardia (less than 45 heart beats per minute)
- Pregnant or breastfeeding women
- Known Human Immunodeficiency Virus (HIV) positivity or Acquired Immunodeficiency Syndrome (AIDS)-related illness
- History of hypersensitivity to any of the additives in the alectinib formulation
- Any clinically significant concomitant disease or condition that could interfere with, or for which treatment might interfere with, the conduct of the study, or absorption of oral medications, or that would, in the opinion of the principal investigator, pose an unacceptable risk to the participant in the study
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Alectinib Alectinib Participants will receive alectinib treatment continuously starting from Day 1 Cycle 1 (in 28-day cycles) until disease progression, death, or withdrawal for any other reasons, whichever occurs first. After PD, participants without EGFR mutation will continue treatment with alectinib alone and participants with EGFR mutation will receive alectinib in combination with erlotinib as per discretion of the treating physician. Alectinib Erlotinib Participants will receive alectinib treatment continuously starting from Day 1 Cycle 1 (in 28-day cycles) until disease progression, death, or withdrawal for any other reasons, whichever occurs first. After PD, participants without EGFR mutation will continue treatment with alectinib alone and participants with EGFR mutation will receive alectinib in combination with erlotinib as per discretion of the treating physician.
- Primary Outcome Measures
Name Time Method Recommended Phase 2 Dose (RP2D) of Alectinib Cycle 1 (up to 28 days) RP2D was to be determined based on the safety and tolerability profile of the study treatment.
Percentage of Participants With Dose Limiting Toxicities (DLTs) Cycle 1 (up to 28 days) DLTs were to be assessed based on the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.3 (NCI-CTCAE v 4.3). DLTs: drug-related toxicities that meet any one of the following criteria: Grade 4 thrombocytopenia; Grade 3 thrombocytopenia with bleeding; Grade 4 neutropenia continuing for greater than or equal to (\>/=) 7 consecutive days or neutropenic fever; Non-hematological toxicity of Grade 3 or higher; Adverse events that require interruption of treatment for a total of \>/=7 days.
Percentage of Participants Achieving Objective Response (Complete Response [CR] or Partial Response [PR]) as Assessed by Independent Radiological Review Committee (IRC) in Response Evaluable (RE) Population Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years) Tumor response was assessed by IRC according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Objective response was defined as percentage of participants with a CR or PR that was confirmed by repeat assessments \>/=4 weeks after initial documentation. CR was defined as disappearance of all target, non-target lesions; normalization of tumor marker level; and reduction in all lymph nodes size to less than (\<) 10 millimeters (mm). PR was defined as \>/=30 percent (%) decrease in the sum of diameters (SoD) of target lesions (taking as reference the baseline SoD). The 95% confidence interval (CI) was computed using Clopper-Pearson method.
Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by IRC in Chemotherapy-Pretreated Participants Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years) Tumor response was assessed by IRC according to RECIST v1.1. Objective response was defined as percentage of participants with a CR or PR that was confirmed by repeat assessments \>/=4 weeks after initial documentation. CR was defined as disappearance of all target, non-target lesions; normalization of tumor marker level; and reduction in all lymph nodes size to \<10 mm. PR was defined as \>/=30% decrease in the SoD of target lesions (taking as reference the baseline SoD). The 95% CI was computed using Clopper-Pearson method.
- Secondary Outcome Measures
Name Time Method Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by Investigator in RE Population Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years) Tumor response was assessed by the investigator according to RECIST v1.1. Objective response was defined as percentage of participants with a CR or PR that was confirmed by repeat assessments \>/=4 weeks after initial documentation. CR was defined as disappearance of all target, non-target lesions; normalization of tumor marker level; and reduction in all lymph nodes size to \<10 mm. PR was defined as \>/=30% decrease in the SoD of target lesions (taking as reference the baseline SoD). The 95% CI was computed using Clopper-Pearson method.
Tlast of Alectinib Metabolite Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1 Tlast for alectinib metabolite was estimated from plasma concentration versus time data by non-compartmental methods of analysis using Phoenix WinNonlin v6.2 software.
Percentage of Participants With PD as Assessed by IRC According to RECIST v1.1 or Death From Any Cause in Safety Population Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years) According to RECIST v1.1, PD was defined as \>/=20% relative increase and \>/=5 mm of absolute increase in the SoD, taking as reference the smallest SoD recorded since treatment started; 1 or more new lesion(s); and/or unequivocal progression of non-target lesions.
Progression Free Survival (PFS) as Assessed by IRC in Safety Population Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years) PFS was defined as the time interval between the date of the first treatment and the date of PD or death from any cause, whichever occurred first. PD: \>/=20% relative increase and \>/=5 mm of absolute increase in the SoD, taking as reference the smallest SoD recorded since treatment started; 1 or more new lesion(s); and/or unequivocal progression of non-target lesions. PFS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley. Participants who neither progressed nor died at the time of assessment or who were lost to follow-up were censored at the date of the last tumor assessment. Participants with no post-baseline assessments were censored at the date of first dose.
Overall Survival (OS) Baseline up to death from any cause (up to approximately 4 years) OS was defined as the time from the date of first treatment to the date of death, regardless of the cause of death. OS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley. Participants who did not die were censored at the date last known to be alive.
Duration of Response (DoR) as Assessed by IRC in RE Population Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years) DoR was defined as the time from the first observation of an objective tumor response (CR or PR) until first observation of progressive disease (PD) according to RECIST v1.1 or death from any cause. CR: disappearance of all target, non-target lesions; normalization of tumor marker level; and reduction in all lymph nodes size to \<10 mm. PR: \>/=30% decrease in the SoD of target lesions (taking as reference the baseline SoD). PD: \>/=20% relative increase and \>/=5 mm of absolute increase in the SoD, taking as reference the smallest SoD recorded since treatment started; 1 or more new lesion(s); and/or unequivocal progression of non-target lesions. Duration of response was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley. Participants who did not progress or die after a confirmed objective response were censored at the date of their last tumor assessment.
Percentage of Participants Achieving CR, PR or Stable Disease (SD) According to RECIST v1.1 in RE Population Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years) The disease control rate (DCR) was defined as the percentage of participants achieving CR, PR, or SD that lasted for at least 16 weeks. Tumor response was assessed by the investigator and IRC according to RECIST v1.1. CR: disappearance of all target, non-target lesions; normalization of tumor marker level; and reduction in all lymph nodes size to \<10 mm. PR: \>/=30% decrease in the SoD of target lesions (taking as reference the baseline SoD). PD: \>/=20% relative increase and \>/=5 mm of absolute increase in the SoD, taking as reference the smallest SoD recorded since treatment started; 1 or more new lesion(s); and/or unequivocal progression of non-target lesions. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SoD while on study. The 95% CI was computed using Clopper-Pearson method.
CDoR as Assessed by IRC According to RANO Criteria Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator; then survival follow-up until cutoff 18 August 2014 (up to approximately 53 weeks) CDoR: time from the CNS objective response until CNS progression as assessed by IRC according to RANO criteria or death from any cause. CR: complete disappearance of all enhancing measurable, non-measurable disease; stable/improved non-enhancing lesions; no new lesions; no corticosteroids, and clinically stable/improved. PR: \>/=50% decrease compared to screening in SPD of enhancing measurable lesions; no progression of non-measurable disease; no new lesions; no corticosteroids, and clinically stable/improved. Progression: \>/=25% increase in SPD of enhancing measurable lesions compared to best response on study; stable/increasing doses of corticosteroids; significant increase in non-enhancing lesions not caused by co-morbid events; any new lesions; progression of non-measurable disease; or clinical deterioration not attributable to other non-tumor causes. CDoR was estimated by Kaplan-Meier method and 95% CI was assessed using method of Brookmeyer and Crowley.
Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by IRC in Chemotherapy-Naive Participants Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years) Tumor response was assessed by IRC according to RECIST v1.1. Objective response was defined as percentage of participants with a CR or PR that was confirmed by repeat assessments \>/=4 weeks after initial documentation. CR was defined as disappearance of all target, non-target lesions; normalization of tumor marker level; and reduction in all lymph nodes size to \<10 mm. PR was defined as \>/=30% decrease in the SoD of target lesions (taking as reference the baseline SoD).
Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by Investigator in Chemotherapy-Pretreated Participants Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years) Tumor response was assessed by the investigator according to RECIST v1.1. Objective response was defined as percentage of participants with a CR or PR that was confirmed by repeat assessments \>/=4 weeks after initial documentation. CR was defined as disappearance of all target, non-target lesions; normalization of tumor marker level; and reduction in all lymph nodes size to \<10 mm. PR was defined as \>/=30% decrease in the SoD of target lesions (taking as reference the baseline SoD).
Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by Investigator in Chemotherapy-Naive Participants Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years) Tumor response was assessed by the investigator according to RECIST v1.1. Objective response was defined as percentage of participants with a CR or PR that was confirmed by repeat assessments \>/=4 weeks after initial documentation. CR was defined as disappearance of all target, non-target lesions; normalization of tumor marker level; and reduction in all lymph nodes size to \<10 mm. PR was defined as \>/=30% decrease in the SoD of target lesions (taking as reference the baseline SoD).
Time to Cmax (Tmax) of Alectinib Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1 Tmax for alectinib was estimated from plasma concentration versus time data by non-compartmental methods of analysis using Phoenix WinNonlin v6.2 software.
Percentage of Participants Who Died of Any Cause Baseline up to death from any cause (up to approximately 4 years) Percentage of participants who died of any cause was reported.
AUC(0-last) of Alectinib Metabolite Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1 The AUC(0-last) of alectinib metabolite was calculated using the linear trapezoidal rule and actual sampling times (with the exception of pre-dose which was set to zero).
Accumulation Ratio of Alectinib Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hours post-dose on Day 1 and Day 21 of Cycle 1 Accumulation ratio after repeat dosing was computed as AUC(0-10) on Day 21 divided by AUC(0-10) on Day 1.
Percentage of Participants Achieving Central Nervous System (CNS) Objective Response as Assessed by IRC According to RECIST v1.1 Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years) CNS response was assessed by IRC according to RECIST v1.1. CNS Objective response was defined as percentage of participants with a CR or PR. CR was defined as disappearance of all CNS lesions. PR was defined as \>/=30% decrease in the SoD of measurable CNS lesions (taking as reference the baseline SoD). The 95% CI was computed using Clopper-Pearson method.
Percentage of Participants Achieving CNS Objective Response as Assessed by IRC According to Radiology Assessment in Neuro-Oncology (RANO) Criteria Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator; then survival follow-up until cutoff 18 August 2014 (up to approximately 53 weeks) CNS response was assessed by IRC according to RANO criteria. CNS Objective response: percentage of participants with a CR or PR that was confirmed by repeat assessments \>/=4 weeks after initial documentation. CR was defined as complete disappearance of all enhancing measurable, non-measurable disease; stable or improved non-enhancing lesions; no new lesions; no corticosteroids (or only physiologic replacement dose), and clinically stable or improved. PR was defined as \>/=50% decrease compared to screening in the sum of the products of the diameters (SPD) of enhancing measurable lesions; no progression of non-measurable disease (enhancing and non-enhancing lesions); no new lesions; no corticosteroids (or only physiologic replacement dose), and clinically stable or improved. The 95% CI was computed using Clopper-Pearson method.
CNS Duration of Response (CDoR) as Assessed by IRC According to RECIST v1.1 Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years) CDoR was defined as the time from the first observation of a CNS objective response (CR or PR) until first observation of CNS progression as assessed by IRC according to RECIST v 1.1 or death from any cause. CR: disappearance of all CNS lesions. PR: \>/=30% decrease in the SoD of measurable CNS lesions (taking as reference the baseline SoD). CNS progression: \>/=20% increase in the SoD of measurable CNS lesions (with an absolute increase of at least 5 mm), taking as reference the baseline SoD; 1 or more new CNS lesion(s); and/or unequivocal progression of non-measurable CNS lesions. CDoR was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley.
Percentage of Participants With CNS Progression as Assessed by IRC According to RECIST v 1.1 Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator; then survival follow-up until cutoff 18 August 2014 (up to approximately 53 weeks) According to RECIST v 1.1, CNS progression was defined as \>/=20% increase in the SoD of measurable CNS lesions (with an absolute increase of at least 5 mm), taking as reference the baseline SoD; 1 or more new CNS lesion(s); and/or unequivocal progression of non-measurable CNS lesions.
Maximum Observed Plasma Concentration (Cmax) of Alectinib Pre-dose (0 hours [hrs]), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1 Cmax for alectinib was estimated from plasma concentration versus time data by non-compartmental methods of analysis using Phoenix WinNonlin v6.2 (Pharsight Corporation) software.
Area Under the Plasma Concentration-Time Curve From Time 0 to 10 Hours Post-dose (AUC[0-10]) of Alectinib Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1 The AUC(0-10) of alectinib was calculated using the linear trapezoidal rule and actual sampling times (with the exception of pre-dose which was set to zero).
Area Under the Plasma Concentration-Time Curve From Time 0 to Tlast (AUC[0-last]) of Alectinib Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1 The AUC(0-last) of alectinib was calculated using the linear trapezoidal rule and actual sampling times (with the exception of pre-dose which was set to zero).
Cmax of Alectinib Metabolite Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1 Cmax for alectinib metabolite was estimated from plasma concentration versus time data by non-compartmental methods of analysis using Phoenix WinNonlin v6.2 software.
Tmax of Alectinib Metabolite Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1 Tmax for alectinib metabolite was estimated from plasma concentration versus time data by non-compartmental methods of analysis using Phoenix WinNonlin v6.2 software.
Time to Last Measurable Plasma Concentration (Tlast) of Alectinib Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1 Tlast for alectinib was estimated from plasma concentration versus time data by non-compartmental methods of analysis using Phoenix WinNonlin v6.2 software.
Metabolite to Parent Ratio Based on AUC(0-last) Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1 Metabolite to parent ratio based on AUC(0-last) was computed as AUC(0-last) of metabolite divided by AUC(0-last) of parent drug (alectinib) corrected for the molecular weight of parent divided by the molecular weight of the metabolite.
AUC(0-10) of Alectinib Metabolite Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1 The AUC(0-10) of alectinib metabolite was calculated using the linear trapezoidal rule and actual sampling times (with the exception of pre-dose which was set to zero).
Metabolite to Parent Ratio Based on AUC(0-10) Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1 Metabolite to parent ratio based on AUC(0-10) was computed as AUC(0-10) of metabolite divided by AUC(0-10) of parent drug (alectinib) corrected for the molecular weight of parent divided by the molecular weight of the metabolite.
Trough Plasma Concentration (Ctrough) of Alectinib Pre-dose (0 hrs) on Day 21 of Cycle 1 Ctrough of Alectinib Metabolite Pre-dose (0 hrs) on Day 21 of Cycle 1 Peak to Trough Ratio of Alectinib Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hours post-dose on Day 21 of Cycle 1 Accumulation Ratio of Alectinib Metabolite Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hours post-dose on Day 1 and Day 21 of Cycle 1 Accumulation ratio after repeat dosing was computed as AUC(0-10) on Day 21 divided by AUC(0-10) on Day 1.
Trial Locations
- Locations (84)
Rush University Medical Center
🇺🇸Chicago, Illinois, United States
UCLA Cancer Center; Premiere Oncology, A Medical Corporation
🇺🇸Santa Monica, California, United States
Washington University; Wash Uni. Sch. Of Med
🇺🇸Saint Louis, Missouri, United States
Klinikum Koeln-Merheim
🇩🇪Koeln, Germany
Istituto Europeo Di Oncologia
🇮🇹Milano, Lombardia, Italy
Virginia Cancer Specialists, PC
🇺🇸Fairfax, Virginia, United States
Diakonie Kaiserswerth; Florence-Nightingale-Krankenhaus
🇩🇪Düsseldorf, Germany
Coastal Integrative Cancer Care
🇺🇸San Luis Obispo, California, United States
Charité Campus Virchow-Klinikum; Department of Cardiology
🇩🇪Berlin, Germany
Comprehensive Cancer Centers of Nevada
🇺🇸Henderson, Nevada, United States
Texas Oncology, P.A.
🇺🇸Dallas, Texas, United States
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
Prince Charles Hospital
🇦🇺Chermside, Queensland, Australia
Centre Georges François Leclerc; Service Pharmacie, Bp 77980
🇫🇷Dijon, France
Hospital Clínic i Provincial de Barcelona
🇪🇸Barcelona, Spain
LungenClinic Großhansdorf
🇩🇪Großhansdorf, Germany
Hosp Clinico Univ Lozano Blesa
🇪🇸Zaragoza, Spain
St. Jude Heritage Healthcare
🇺🇸Fullerton, California, United States
Advanced Medical Specialties
🇺🇸Miami, Florida, United States
AO San Camillo Forlanini
🇮🇹Roma, Lazio, Italy
Azienda Socio Sanitaria Territoriale Niguarda (Ospedale Niguarda Ca' Granda)
🇮🇹Milano, Lombardia, Italy
Ospedale Versilia
🇮🇹Lido Di Camaiore, Toscana, Italy
Hospital Universitario Ramón y Cajal
🇪🇸Madrid, Spain
Nouvel Hopital Civil - CHU Strasbourg
🇫🇷Strasbourg, France
Royal Marsden Hospital - London
🇬🇧London, United Kingdom
Seoul National University Bundang Hospital
🇰🇷Gyeonggi-do, Korea, Republic of
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
CHU Angers - Hôpital Hôtel Dieu
🇫🇷Angers, France
Lungenklinik Hemer
🇩🇪Hemer, Germany
Hospital Regional Universitario de Malaga
🇪🇸Malaga, Spain
Centre Leon Berard
🇫🇷Lyon, France
Universitair Medisch Centrum Groningen
🇳🇱Groningen, Netherlands
Centre Francois Baclesse
🇫🇷Caen, France
Ospedale San Raffaele
🇮🇹Milano, Lombardia, Italy
Azienda Ospedaliera Universitaria Careggi
🇮🇹Firenze, Toscana, Italy
Hospital General Univ. de Alicante
🇪🇸Alicante, Spain
Asan Medical Center
🇰🇷Seoul, Korea, Republic of
Aberdeen Royal Infirmary
🇬🇧Aberdeen, United Kingdom
National Cancer Center
🇰🇷Gyeonggi-do, Korea, Republic of
Hospital Universitario La Paz
🇪🇸Madrid, Spain
ICO Rene Gauducheau; CEC
🇫🇷St Herblain, France
Hospital del Mar
🇪🇸Barcelona, Spain
Maastricht University Medical Centre; Afdeling Klinische Farmacie en Toxicologie
🇳🇱Maastricht, Netherlands
Hospital Universitario Quiron Dexeus
🇪🇸Barcelona, Spain
Mathias-Spital Rheine
🇩🇪Rheine, Germany
Hospital Universitario Clínico San Carlos; Servicio de Oncologia
🇪🇸Madrid, Spain
A.O. Universitaria Di Parma
🇮🇹Parma, Emilia-Romagna, Italy
Hospital Universitario 12 de Octubre
🇪🇸Madrid, Spain
FSBSI "Russian Oncological Scientific Center n.a. N.N. Blokhin"; Chemotherapy Departement
🇷🇺Moskva, Moskovskaja Oblast, Russian Federation
Centre Oscar Lambret
🇫🇷Lille, France
National University Hospital; Investigational Medicine Unit
🇸🇬Singapore, Singapore
Antoni van Leeuwenhoek Ziekenhuis
🇳🇱Amsterdam, Netherlands
Karolinska
🇸🇪Stockholm, Sweden
Azienda Ospedaliera di Perugia Ospedale S. Maria della Misericordia
🇮🇹Perugia, Umbria, Italy
Severance Hospital, Yonsei University Health System; Pharmacy
🇰🇷Seoul, Korea, Republic of
Royal Marsden Hospital;Dept of Haematology Oncology Research
🇬🇧London, United Kingdom
University Hospital Herlev
🇩🇰Herlev, Denmark
Irccs Centro Di Riferimento Oncologico (CRO)
🇮🇹Aviano, Friuli-Venezia Giulia, Italy
Presidio Ospedaliero Campo di Marte
🇮🇹Lucca, Toscana, Italy
CHU de Grenoble - Hôpital Nord; Service d'Oncologie Thoracique
🇫🇷Grenoble, France
Groupe Hospitalier Sud - Hôpital Haut Lévêque
🇫🇷Pessac, France
Hôpital Nord - AP-HM Marseille#; Gastroenterology and Hepatology
🇫🇷Marseille cedex 20, France
CHU de Toulouse - Hôpital Larrey
🇫🇷Toulouse, France
Hopital Pontchaillou - CHU de Rennes
🇫🇷Rennes, France
UC Irvine Medical Center
🇺🇸Orange, California, United States
Columbia University Medical Center; Department of Hematology/Oncology
🇺🇸New York, New York, United States
University Hospitals Case Medical Center
🇺🇸Cleveland, Ohio, United States
Royal North Shore Hospital
🇦🇺St. Leonards, New South Wales, Australia
Midwestern Regional Medical Center; Office of Research
🇺🇸Zion, Illinois, United States
UZ Antwerpen
🇧🇪Edegem, Belgium
Townsville General Hospital
🇦🇺Douglas, Queensland, Australia
AZ Delta (Campus Wilgenstraat)
🇧🇪Roeselare, Belgium
UZ Gent
🇧🇪Gent, Belgium
Hopital Morvan
🇫🇷Brest, France
Istituto Nazionale Tumori Regina Elena IRCCS
🇮🇹Roma, Lazio, Italy
Johns Hopkins Singapore
🇸🇬Singapore, Singapore
Centre Hospitalier de Luxembourg
🇱🇺Luxembourg, Luxembourg
National Taiwan University Hospital
🇨🇳Taipei, Taiwan
Taichung Veterans General Hospital
🇨🇳Taichung, Taiwan
National Cheng Kung Univ Hosp
🇨🇳Tainan, Taiwan
Sharp Memorial Hospital
🇺🇸San Diego, California, United States
Cancer Care Centers of South Texas
🇺🇸San Antonio, Texas, United States
Florida Hospital Cancer Inst
🇺🇸Orlando, Florida, United States
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States