Study Comparing Combination of LGX818 Plus MEK162 Versus Vemurafenib and LGX818 Monotherapy in BRAF Mutant Melanoma
- Registration Number
- NCT01909453
- Lead Sponsor
- Pfizer
- Brief Summary
This is 2-part, randomized, open label, multi-center, parallel group, phase III study comparing the efficacy and safety of LGX818 plus MEK162 to vemurafenib and LGX818 monotherapy in patients with locally advanced unresectable or metastatic melanoma with BRAF V600 mutation. A total of approximately 900 patients will be randomized.
Part 1:
Patients will be randomized in a 1:1:1 ratio to one of 3 treatment arms:
1. LGX818 450 mg QD plus MEK162 45 mg BID (denoted as Combo 450 arm)
2. LGX818 300 mg QD monotherapy (denoted as LGX818 arm) or
3. vemurafenib 960 mg BID (denoted as vemurafenib arm)
Part 2:
Patients will be randomized in a 3:1 ratio to one of the 2 treatment arms:
1. LGX818 300 mg QD plus MEK162 45 mg BID (denoted as Combo 300 arm) or
2. LGX818 300 mg QD monotherapy (denoted as LGX818 arm)
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 922
- Diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma (AJCC Stage IIIB, IIIC, or IV)
- Presence of BRAF V600E or V600K mutation in tumor tissue prior to randomization
- Naïve untreated patients or patients who have progressed on or after prior first line immunotherapy for resectable locally advanced or metastatic melanoma; prior adjuvant therapy is permitted (e.g. IFN, IL-2 therapy, any other immunotherapy, radiotherapy or chemotherapy), except the administration of BRAF or MEK inhibitors
- Evidence of at least one measurable lesion as detected by radiological or photographic methods
- ECOG performance status of 0 or 1
- Adequate bone marrow, organ function, cardiac and laboratory parameters
- Normal functioning of daily living activities
- Any untreated central nervous system (CNS) lesion
- Uveal and mucosal melanoma
- History of leptomeningeal metastases
- History of or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO) or history of retinal degenerative disease
- Any previous systemic chemotherapy treatment, extensive radiotherapy or investigational agent other than immunotherapy, or patients who have received more than one line of immunotherapy for locally advanced unresectable or metastatic melanoma; Ipilimumab (adjuvant) or other immunotherapy treatment must have ended at least 6 weeks prior to randomization
- History of Gilbert's syndrome
- Prior therapy with a BRAF inhibitor and/or a MEK- inhibitor
- Impaired cardiovascular function or clinically significant cardiovascular diseases
- Uncontrolled arterial hypertension despite medical treatment
- HIV positive or active Hepatitis B, and/or active Hepatitis C
- Impairment of gastrointestinal function
- Patients with neuromuscular disorders that are associated with elevated CK
- Pregnant or nursing (lactating) women
- Medical, psychiatric, cognitive or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study
Other protocol-defined inclusion/exclusion criteria may apply
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description LGX818 300 mg + MEK162 LGX818 LGX818 300 mg QD + MEK162 45 mg BID LGX818 300 mg + MEK162 MEK162 LGX818 300 mg QD + MEK162 45 mg BID LGX818 450 mg + MEK162 LGX818 LGX818 450 mg QD + MEK162 45 mg BID LGX818 450 mg + MEK162 MEK162 LGX818 450 mg QD + MEK162 45 mg BID LGX818 LGX818 LGX818 300 mg QD Vemurafenib vemurafenib Vemurafenib 960 mg BID
- Primary Outcome Measures
Name Time Method Part 1: Progression Free Survival (PFS) by Blinded Independent Review Committee (BIRC) in Combo 450 Group as Compared to Vemurafenib Group From randomization until documented disease progression (PD), initiation of new anti-cancer therapy, censoring date or death, whichever occurred first (up to 29 months) PFS was defined as the time from the date of randomization to the date of the first documented disease progression (PD) or death due to any cause, whichever occurs first. PFS was determined based on tumor assessment (RECIST version 1.1 criteria) as per BIRC/central review and survival information. If a participant did not had an event at the time of the analysis cut-off or at the start of any new anti-cancer therapy, data was censored at the date of last adequate tumor assessment. PD was defined as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 square millimeter (mm\^2).
Part 1: Progression Free Survival (PFS) by Blinded Independent Review Committee (BIRC) in Combo 450 Group as Compared to LGX818 Group From randomization until documented disease progression (PD), initiation of new anti-cancer therapy, censoring date or death, whichever occurred first (up to 29 months), excluding Part 1: LGX818 300 mg group; up to 35 months for Part 1: LGX 300 mg group PFS was defined as the time from the date of randomization to the date of the first documented disease progression (PD) or death due to any cause, whichever occurs first. PFS was determined based on tumor assessment (RECIST version 1.1 criteria) as per BIRC and survival information. If a participant did not had an event at the time of the analysis cut-off or at the start of any new anti-cancer therapy, data was censored at the date of last adequate tumor assessment. PD was defined as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm\^2.
- Secondary Outcome Measures
Name Time Method Part 1: Number of Participants With Worst Post-baseline Left Ventricular Dysfunction Events (LVEF) Values by Multigated Acquisition (MUGA) Scans or Transthoracic Echocardiograms (ECHO), by CTCAE Grade Baseline up to 30 days from last dose of study drug (up to 30 months), excluding Part 1: LGX818 300 mg group; up to 36 months for Part 1 LGX 300 mg group Participants with worst post-baseline LVEF Values were graded as Grade 0: Non missing value below Grade 2; Grade 2: LVEF between 40% and 50% or absolute reduction from baseline \>=10% and \< 20%; Grade 3: LVEF between 20% and 39% or absolute reduction from baseline \>=20%; Grade 4: LVEF lower than 20%. Baseline was defined as the last non-missing value prior to the first dose of study treatment. Missing data were due to participants who died or withdrew consent prior to the first scheduled evaluation or missed evaluations as protocol deviations.
Part 1: Number of Participants With Ocular-related Adverse Events of Special Interest (AESI) Graded According to the National Cancer Institute Common Terminology Criteria (NCI-CTCAE) v4.03 Baseline up to 30 days from last dose of study drug (up to 30 months), excluding Part 1: LGX818 300 mg group; up to 36 months for Part 1 LGX 300 mg group AESI consisted of events for which there was a specific clinical interest with regard to LGX818 and/or MEK162 treatment. Ocular-related AESI included retinopathy excluding retinal vein occlusion (RVO), RVO and uveitis-type events. As per NCI-CTCAE version 4.03, severity was graded as Grade 1: asymptomatic/mild symptoms, clinical/diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local/noninvasive intervention indicated, limiting age-appropriate instrumental ADL; Grade 3: severe/medically significant but not immediately life-threatening, hospitalization/prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. AEs of grade 3 or 4 are reported in this outcome measure.
Part 2: Number of Participants With Newly Occurring Notably Abnormal Vital Signs Baseline up to 30 days after last dose of study drug (up to 36 months) Notably abnormal vital signs were: Low/high systolic blood pressure (SBP) in millimeter of mercury (mmHg): less than or equal to (\<=) 90 mmHg with decrease from baseline of greater than or equal to (\>=) 20 mmHg/\>= 160 mmHg with increase from baseline of \>=20 mmHg, Low/high diastolic blood pressure (DBP) \[mmHg\]: \<=50 mmHg with decrease from baseline of \>=15 mmHg/\>=100 mmHg with increase from baseline of \>=15 mmHg, Low/high pulse rate \[bpm\]: \<=50 bpm with decrease from baseline of \>=15 bpm/\>=120 bpm with increase from baseline of \>=15 bpm, Low/high weight (kg): \>=20 % decrease from baseline/\>= 10% increase from baseline Low/high Body temperature degree C): \<= 36°C/\>= 37.5 degree C.
Part 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as Graded by National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 Baseline up to 30 days from last dose of study drug (up to 30 months), excluding Part 1: LGX818 300 mg group; up to 36 months for Part 1 LGX 300 mg group AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was any untoward medical occurrence at any dose that results in death; is life-threatening; requires inpatient hospitalization/prolongation of existing hospitalization; results in persistent/significant disability/incapacity; results in congenital anomaly/birth defect or that is considered to be important medical event. As per NCI-CTCAE version 4.03, severity was graded as Grade 1: asymptomatic/mild symptoms, clinical/diagnostic observations only; Grade 2: moderate, minimal, local/noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe/medically significant but not immediately life-threatening, hospitalization/prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence; Grade 5: death. AEs of all grades were reported.
Part 1: Number of Participants With Newly Occurring Notably Abnormal Vital Signs Baseline up to 30 days from last dose of study drug (up to 30 months), excluding Part 1: LGX818 300 mg group; up to 36 months for Part 1 LGX 300 mg group Notably abnormal vital signs were: Low/high systolic blood pressure (SBP) (millimeter of mercury \[mmHg\]): less than or equal to (\<=) 90 mmHg with decrease from baseline of greater than or equal to (\>=) 20 mmHg/\>= 160 mmHg with increase from baseline of \>=20 mmHg. Low/high diastolic blood pressure (DBP) \[mmHg\]: \<= 50 mmHg with decrease from baseline of \>=15 mmHg/\>=100 mmHg with increase from baseline of \>=15 mmHg. Low/high Pulse rate: \<=50 beats per minute (bpm) with decrease from baseline of \>=15 bpm/\>= 120 bpm with increase from baseline of \>=15 bpm. Low/high Weight \[kilogram\]: \>=20 percent (%) decrease from baseline/\>= 10% increase from baseline. Low/high Body temperature degree Celsius (C): \<= 36 degree C/\>= 37.5 degree C.
Part 1: Overall Survival (OS) From randomization until documented disease progression (PD), initiation of new anti-cancer therapy, censoring date or death, whichever occurred first (up to 38 months) Overall survival was defined as the time from the date of randomization to the date of death due to any cause. If a death had not been observed by the date of analysis cutoff, OS was censored at the date of last contact.
Part 1: Number of Participants With Clinically Notable Shift From Baseline in Laboratory Parameter Values Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.03 Baseline up to 30 days from last dose of study drug (up to 30 months), excluding Part 1: LGX818 300 mg group; up to 36 months for Part 1 LGX 300 mg group Number of participants with clinically notable shift from baseline in laboratory parameter values based on national cancer institute common terminology criteria (NCI-CTCAE) grade, Version 4.03 were graded from Grades 1 to 5. Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local or noninvasive intervention indicated. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death. Clinically notable shift from baseline in laboratory parameter = worsening by at least 2 grades or to \>=grade 3.
Part 1: Number of Participants With Dermatologic-related Adverse Events of Special Interest (AESI) Graded According to the National Cancer Institute Common Terminology Criteria (NCI-CTCAE) v4.03 Baseline up to 30 days from last dose of study drug (up to 30 months), excluding Part 1: LGX818 300 mg group; up to 36 months for Part 1 LGX 300 mg group AESI consisted of events for which there was a specific clinical interest with regard to LGX818 and/or MEK162 treatment. Dermatologic-related AESI included rash, photosensitivity, nail disorders, skin infections, severe cutaneous adverse reactions and Palmar-plantar erythrodysaesthesia (PPE) syndrome. As per NCI-CTCAE version 4.03, severity was graded as Grade 1: asymptomatic/mild symptoms, clinical/diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local/noninvasive intervention indicated, limiting age-appropriate instrumental ADL; Grade 3: severe/medically significant but not immediately life-threatening, hospitalization/prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. AEs of grade 3 or 4 are reported in this outcome measure.
Part 2: Progression Free Survival (PFS) by BIRC in Combo 300 Group as Compared to LGX818 Group From randomization until documented disease progression (PD), initiation of new anti-cancer therapy, censoring date or death, whichever occurred first (up to 35 months) PFS was defined as the time from the date of randomization to the date of the first documented disease progression (PD) or death due to any cause, whichever occurs first. PFS was determined based on tumor assessment (RECIST version 1.1 criteria) as per BIRC and survival information. If a participant did not had an event at the time of the analysis cut-off or at the start of any new anti-cancer therapy, data was censored at the date of last adequate tumor assessment. PD was defined as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm\^2.
Part 1: Number of Participants With Newly Occurring Notable Electrocardiogram (ECG) Values Baseline up to 30 days from last dose of study drug (up to 30 months), excluding Part 1: LGX818 300 mg group; up to 36 months for Part 1 LGX 300 mg group Newly occurring notable ECG values were reported for QT (millisecond \[ms\]), QTcF (millisecond), QTcB (millisecond) and heart rate (beats per minute). Newly occurring was defined as participants not meeting criterion at baseline and meeting criterion post-baseline. Ranges for newly occurring notable ECG values (QT, QTcF, QTcB) are New greater than (\>) 450, New \>480, New \>500, Increase from baseline \>30, Increase from baseline \>60. Heart rate: New \<60, New \>100 was considered as newly occurring notable value.
Part 2: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as Graded by National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 Baseline up to 30 days after last dose of study drug (up to 36 months) AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was any untoward medical occurrence at any dose that results in death; is life-threatening; requires inpatient hospitalization/prolongation of existing hospitalization; results in persistent/significant disability/incapacity; results in congenital anomaly/birth defect or that is considered to be important medical event. As per NCI-CTCAE version 4.03, severity was graded as Grade 1: asymptomatic/mild symptoms, clinical/diagnostic observations only; Grade 2: moderate, minimal, local/noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe/medically significant but not immediately life-threatening, hospitalization/prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence; Grade 5: death. AEs of all grades were reported.
Part 2: Number of Participants With Newly Occurring Notable ECG Values Baseline up to 30 days after last dose of study drug (up to 36 months) Newly occurring notable ECG values were reported for QT (ms), QTcF (ms), QTcB (ms) and heart rate (bpm). Newly occurring was defined as participants not meeting criterion at baseline and meeting criterion post-baseline. Ranges for newly occurring notable ECG values (QT, QTcF, QTcB) are New \>450, New \>480, New \>500, increase from baseline \>30, Increase from baseline \>60. Heart rate: New \< 60, New \>100 was considered as newly occurring notable value.
Part 2: Number of Participants With Worst Post-baseline Left Ventricular Dysfunction Events (LVEF) Values by Multigated Acquisition (MUGA) Scans or Transthoracic Echocardiograms (ECHO), by CTCAE Grade Baseline up to 30 days after last dose of study drug (up to 36 months) Participants with worst post-baseline LVEF Values were graded as Grade 0: Non missing value below Grade 2; Grade 2: LVEF between 40% and 50% or absolute reduction from baseline \>=10% and \< 20%;Grade 3: LVEF between 20% and 39% or absolute reduction from baseline \>=20%; Grade 4: LVEF lower than 20%. Baseline was defined as the last non-missing value prior to the first dose of study treatment. Missing data were due to participants who died or withdrew consent prior to the first scheduled evaluation or missed evaluations as protocol deviations.
Part 2: Number of Participants With Dermatologic-related Adverse Events of Special Interest (AESI) Graded According to the National Cancer Institute Common Terminology Criteria (NCI-CTCAE) v4.03 Baseline up to 30 days after last dose of study drug (up to 36 months) AESI consisted of events for which there was a specific clinical interest with regard to LGX818 and/or MEK162 treatment. Dermatologic-related AESI included rash, photosensitivity, nail disorders, skin infections, severe cutaneous adverse reactions and PPE syndrome. As per NCI-CTCAE version 4.03, severity was graded as Grade 1: asymptomatic/mild symptoms, clinical/diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local/noninvasive intervention indicated, limiting age-appropriate instrumental ADL; Grade 3: severe/medically significant but not immediately life-threatening, hospitalization/prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. AEs of grade 3 or 4 are reported are reported in this outcome measure.
Part 2: Number of Participants With Clinically Notable Shift From Baseline in Laboratory Parameter Values Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.0 Baseline up to 30 days after last dose of study drug (up to 36 months) Number of participants with clinically notable shift from baseline in laboratory parameter values based on national cancer institute common terminology criteria (NCI-CTCAE) grade, Version 4.0 were graded from Grades 1 to 5. Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local or noninvasive intervention indicated. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death. Clinically notable shift from baseline in laboratory parameter = worsening by at least 2 grades or to \>=grade 3.
Part 1 and Part 2: Objective Response Rate (ORR) From randomization until disease progression, censoring date or death, whichever occurred first (up to 29 months for Part 1, excluding Part 1: LGX818 300 mg group; up to 35 months for Part 2 and Part 1 LGX 300 mg group) ORR, calculated as the percentage of participants with a best overall response of complete response (CR) or partial response (PR). CR was defined as disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Results are reported for confirmed BIRC response.
Part 1 and Part 2: Time to Objective Response (TTR) From randomization until disease progression, censoring date or death, whichever occurred first (up to 29 months for Part 1, excluding Part 1: LGX818 300 mg group; up to 35 months for Part 2 and Part 1 LGX 300 mg group) TTR was the time between date of randomization until first documented response of CR or PR. Participants who did not achieve a PR or CR were censored at the last adequate tumor assessment date when they did not have a PFS event or at maximum follow-up (i.e. first patient first visit \[FPFV\] to last patient last visit \[LPLV\] used for the analysis) when they had a PFS event. CR was defined as disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. TTR was estimated in the treatment arms using a Kaplan-Meier method. TTR was based on central review.
Part 1 and Part 2: Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit Baseline (Day 1 of Cycle 1), Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and end of treatment visit (within14 days after the last dose of study drug) EORTC QLQ-C30 contains 30 items and is composed of multi-item and single-item measures. These include 5 functional scales (physical, role, emotional, cognitive and social functioning), 3 symptom scales (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global health status/quality of life (QOL) scale. The questionnaire employs 28 4-point Likert scales with responses from "not at all" to "very much" and two 7-point Likert scales for global health and overall QOL. Responses to all items converted to 0 to 100 scale. For functional and global QOL scales, higher scores represent a better level of functioning/QOL. For symptom-oriented scales, a higher score represents more severe symptoms.
Part 1: Plasma Concentrations of MEK162 Cycle 1 Day 1: pre-dose, 0.5, 1.5, 4 to 8, hours post dose; Cycle 2 Day 1: pre-dose; Cycle 3 Day 1: pre-dose Part 2: Number of Participants With Ocular-related Adverse Events of Special Interest (AESI) Graded According to the National Cancer Institute Common Terminology Criteria (NCI-CTCAE) v4.03 Baseline up to 30 days after last dose of study drug (up to 36 months) AESI consisted of events for which there was a specific clinical interest with regard to LGX818 and/or MEK162 treatment. Ocular-related AESI included retinopathy excluding RVO, RVO and uveitis-type events. As per NCI-CTCAE version 4.03, severity was graded as Grade 1: asymptomatic/mild symptoms, clinical/diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local/noninvasive intervention indicated, limiting age-appropriate instrumental ADL; Grade 3: severe/medically significant but not immediately life-threatening, hospitalization/prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. AEs of grade 3 or 4 are reported in this outcome measure.
Part 2: Overall Survival (OS) From randomization until documented disease progression (PD), initiation of new anti-cancer therapy, censoring date or death, whichever occurred first (up to 38 months) Part 1 and Part 2: Number of Participants With Change From Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG PS) Part 1 and Part 2: Baseline, Day 1 of each cycle (Cycle 2 to Cycle 31) ECOG: participant's performance status was measured on a 6-point scale: 0= fully active/able to carry on all pre-disease activities without restriction; 1= restricted in physically strenuous activity but ambulatory and able to carry out work of a light and sedentary nature; 2= ambulatory and capable of all self-care, but unable to carry out any work activities, up and about more than 50% of waking hours; 3= capable of only limited self-care, confined to bed/chair \>50% of waking hours; 4= completely disabled, cannot carry on any self-care, totally confined to bed/chair: 5= dead.
Part 1 and Part 2: Time to Definitive 1 Point Deterioration in Eastern Cooperative Oncology Group Performance Status (ECOG PS) Baseline up to 30 days from last dose of study drug (up to 30 months for Part 1, excluding Part 1: LGX818 300 mg group; up to 36 months for Part 2 and Part 1 LGX 300 mg group) ECOG: participant's performance status was measured on a 6-point scale: 0= fully active/able to carry on all pre-disease activities without restriction; 1= restricted in physically strenuous activity but ambulatory and able to carry out work of a light and sedentary nature; 2= ambulatory and capable of all self-care, but unable to carry out any work activities, up and about more than 50 percent (%) of waking hours; 3= capable of only limited self-care, confined to bed/chair \>50% of waking hours; 4= completely disabled, cannot carry on any self-care, totally confined to bed/chair: 5= dead. Definitive deterioration was defined as death due to any cause or decrease in ECOG PS by at least one category from baseline score with no subsequent improvement.
Part 1 and Part 2: Disease Control Rate (DCR) From randomization until disease progression or death, whichever occurred first (up to 29 months for Part 1, excluding Part 1: LGX818 300 mg group; up to 35 months for Part 2 and Part 1 LGX 300 mg group) DCR was calculated as the percentage of participants with a best overall response (BOR) of CR, PR, or stable disease (SD). CR was defined as disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Two sets of DCR were considered, one for confirmed and one for unconfirmed responses. Results are reported for confirmed and unconfirmed responses combined. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD. DCR was based on central review.
Part 1 and Part 2: Time to Definitive 10% Deterioration in the Function Assessment Cancer Therapy-melanoma (FACT-M) Subscale Date of randomization to date of event or death due to any cause, which ever occurred first (up to 29 months for Part 1, excluding Part 1: LGX818 300 mg group; up to 35 months for Part 2 and Part 1 LGX 300 mg group) FACT-M:melanoma specific questionnaire to assess participant health-related quality of life. Melanoma specific subscale consists of 16 items related to signs,symptoms,physical/social activities most relevant to participants with advanced-stage melanoma. Other items include physical, functional and social/family well-being (7 items each),emotional well-being (6 items),surgery specific concerns related to melanoma(8 items,not included in this study). Each item range from 0(not at all) to 4(very much), combined to produce subscale scores.Total score range for FACT-M excluding surgery specific items is 0 to 172,higher scores represent better quality of life.Melanoma subscale score range from 0(worst response) to 64(best response),higher score indicated better quality of life. Time to definitive 10% deterioration:time from date of randomization to date of event with at least 10% relative to baseline worsening of corresponding scale score with no later improvement or death due to any cause.
Part 1 and Part 2: Time to Definitive 10% Deterioration in the Global Health Status Score of the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC QLQ-C30) Date of randomization to date of event or death due to any cause, which ever occurred first (maximum up to 29 months for Part 1, excluding Part 1: LGX818 300 mg group; up to 35 months for Part 2 and Part 1 LGX 300 mg group) EORTC QLQ-C30 is 30 item questionnaire composed of 5 multi-item functional subscales (physical, role, cognitive, emotional, social functioning), 3 multi-item symptom scales (fatigue, nausea/vomiting, and pain), global health/quality of life (QOL) subscale and 6 single items assessing other cancer related symptoms (dyspnea, sleep disturbance, appetite, diarrhea, constipation and financial impact of cancer). It employed twenty-eight 4 point Likert scales with responses from "not at all" to "very much" and two 7 point Likert scales for global health and overall QOL. Global health status scale score ranged from 0 to 100. Higher score represented better level of functioning. Time to definitive 10% deterioration: time from date of randomization to date of event with at least 10% relative to baseline worsening of corresponding scale score with no later improvement or death due to any cause.
Part 1 and Part 2: Duration of Response (DOR) From randomization until disease progression, censoring date or death, whichever occurred first (up to 29 months for Part 1, excluding Part 1: LGX818 300 mg group; up to 35 months for Part 2 and Part 1 LGX 300 mg group) DOR was calculated, as the time from the date of first documented response (CR or PR) to the first documented progression or death due to underlying cancer. DOR was estimated for responders (i.e. participants achieving at least once CR or PR) only using a Kaplan-Meier method. CR was defined as disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. If a participant with a CR or PR had no progression or death due to underlying disease, the participant was censored at the date of last adequate tumor assessment. Results are based on confirmed BIRC response.
Part 1 and Part 2: Change From Baseline in the Function Assessment Cancer Therapy-melanoma (FACT-M) Subscale at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit Baseline (Day 1 of Cycle 1), Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and end of treatment visit (within14 days after the last dose of study drug) FACT-M: melanoma specific questionnaire to assess participant health-related quality of life. Melanoma specific subscale consists of 16 items related to signs, symptoms, physical/social activities most relevant to participants with advanced-stage melanoma. Other items include physical, functional and social/family well-being (7 items each),emotional well-being (6 items),surgery specific concerns related to melanoma(8 items, not included in this study). Each item range from 0(not at all) to 4(very much), combined to produce subscale scores. Total score range for FACT-M excluding surgery specific items is 0 to 172,higher scores represented better quality of life. Melanoma subscale score range from 0(worst response) to 64(best response),higher score indicated better quality of life.
Part 1 and Part 2: Change From Baseline in EuroQoL-5 Dimension-5 Level (EQ-5D-5L) Index Score at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit Baseline (Day 1 of Cycle 1), Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and end of treatment visit (within14 days after the last dose of study drug) EQ-5D-5L is a standardized participant completed questionnaire that measures health status in terms of a single index value or utility score. EQ-5D-5L consisted of two components: a health state profile (descriptive system) and a visual analogue scale (VAS) in which participants rate their overall health status from 0 (worst imaginable) to 100 (best imaginable), where higher scores indicated better health status. EQ-5D health state profile is comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 response levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems and 5=extreme problems. EQ-5D-5L health status index score range between 0 to 1. Higher score indicated better health status.
Part 1 and Part 2: Change From Baseline in Emotional Functioning Scale Score of the EORTC QLQ-C30 at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit Baseline (Day 1 of Cycle 1), Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and end of treatment visit (within14 days after the last dose of study drug) EORTC QLQ-C30 contains 30 items and is composed of multi-item and single-item measures. These include 5 functional scales (physical, role, emotional, cognitive and social functioning), 3 symptom scales (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global health status/quality of life (QOL) scale. The questionnaire employs 28 4-point Likert scales with responses from "not at all" to "very much" and two 7-point Likert scales for global health and overall QOL. Responses to all items converted to 0 to 100 scale. For functional and global QOL scales, higher scores represent a better level of functioning/QOL. For symptom-oriented scales, a higher score represented more severe symptoms.
Part 1 and Part 2: Change From Baseline in Physical Functioning Scale Score of the EORTC QLQ-C30 at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit Baseline (Day 1 of Cycle 1), Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and end of treatment visit (within14 days after the last dose of study drug) EORTC QLQ-C30 contains 30 items and is composed of multi-item and single-item measures. These include 5 functional scales (physical, role, emotional, cognitive and social functioning), 3 symptom scales (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global health status/quality of life (QOL) scale. The questionnaire employs 28 4-point Likert scales with responses from "not at all" to "very much" and two 7-point Likert scales for global health and overall QOL. Responses to all items converted to 0 to 100 scale. For functional and global QOL scales, higher scores represented a better level of functioning/QOL. For symptom-oriented scales, a higher score represented more severe symptoms.
Part 1 and Part 2: Change From Baseline in Social Functioning Scale Score of the EORTC QLQ-C30 at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit Baseline (Day 1 of Cycle 1), Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and end of treatment visit (within14 days after the last dose of study drug) EORTC QLQ-C30 contains 30 items and is composed of multi-item and single-item measures. These include 5 functional scales (physical, role, emotional, cognitive and social functioning), 3 symptom scales (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global health status/quality of life (QOL) scale. The questionnaire employs 28 4-point Likert scales with responses from "not at all" to "very much" and two 7-point Likert scales for global health and overall QOL. Responses to all items converted to 0 to 100 scale. For functional and global QOL scales, higher scores represented a better level of functioning/QOL. For symptom-oriented scales, a higher score represented more severe symptoms.
Part 1: Plasma Concentrations of LGX 818 Cycle 1 Day 1: pre-dose, 0.5, 1.5, 4 to 8 hours post dose; Cycle 2 Day 1: pre-dose; Cycle 3 Day 1: pre-dose Part 2: Plasma Concentrations of LGX 818 Cycle 1 Day 1: pre-dose, 0.5, 1.5, 4 to 8 hours post dose; Cycle 2 Day 1: pre-dose; Cycle 3 Day 1: pre-dose Part 2: Plasma Concentrations of MEK162 Cycle 1 Day 1: pre-dose, 0.5, 1.5, 4 to 8, hours post dose; Cycle 2 Day 1: pre-dose; Cycle 3 Day 1: pre-dose
Trial Locations
- Locations (349)
Tulsa Cancer Institute PLLC
🇺🇸Tulsa, Oklahoma, United States
University of Pittsburgh Cancer Institute
🇺🇸Pittsburgh, Pennsylvania, United States
University of Tennessee Medical Center Cancer Institute
🇺🇸Knoxville, Tennessee, United States
Universitatsklinikum Leipzig
🇩🇪Leipzig, Sachsen, Germany
University Hospital Schleswig-Holstein, Campus Kiel
🇩🇪Kiel, Germany
Universitatsklinikum Schleswig-Holstein
🇩🇪Lübeck, Germany
Universitatsklinikum Schleswig-Holstein - Kiel
🇩🇪Kiel, Germany
Universitatsklinikum Schleswig-Holstein, Campus Lubeck
🇩🇪Lübeck, Schleswig-holstein, Germany
Charite-Universitaetsmedizin Berlin
🇩🇪Berlin, Germany
Universitätsklinikum Bonn
🇩🇪Bonn, Germany
University Hospital Carl Gustav Carus at the Technical University of Dresden
🇩🇪Dresden, Germany
Universitätsklinikum Carl Gustav Carus an der TU Dresden
🇩🇪Dresden, Germany
Überörtliche Radiologische Gemeinschaftspraxis Dresden
🇩🇪Dresden, Germany
Diagnostische und interventionelle Radiologie und Neuroradiologie
🇩🇪Erfurt, Germany
Klinik fur Hautkrankheiten und Allergologie, Helios Hauttumorzentrum Erfurt, Helios Klinikum Erfurt
🇩🇪Erfurt, Germany
Zuyderland Medisch Centrum
🇳🇱Heerlen, Limburg, Netherlands
VU Medisch Centrum
🇳🇱Amsterdam, Noord Holland, Netherlands
Amphia Ziekenhuis
🇳🇱Breda, Noord-brabant, Netherlands
Hospital Civil (Hospital Regional Universitario de Malaga)
🇪🇸Malaga, Spain
Hospital Regional Universitario de Malaga ? Hospital General
🇪🇸Malaga, Spain
Hospital Universitario Virgen del Rocio - PPDS
🇪🇸Sevilla, Spain
Fundacion Instituto Valenciano de Oncologia
🇪🇸Valencia, Spain
Gävle Sjukhus
🇸🇪Gavle, Sweden
Sahlgrenska Universitetssjukhuset
🇸🇪Göteborg, Sweden
Skanes Universitetssjukhus Lund
🇸🇪Lund, Sweden
Karolinska Universitetssjukhuset Solna
🇸🇪Solna, Sweden
Uppsala Universitet
🇸🇪Uppsala, Sweden
Universitätsspital Zürich
🇨🇭Zurich Flughafen, Switzerland
Inselspital Bern
🇨🇭Bern, Switzerland
Dr. med. Nicole Gasser
🇨🇭Zürich, Switzerland
Dr.med. Ursula Urner
🇨🇭Zürich, Switzerland
Institut für diagnostische und interventionelle Radiologie
🇨🇭Zürich, Switzerland
Ege University Medical Faculty
🇹🇷Bornova, Turkey
Ege University Medical aculty
🇹🇷Izmir, Turkey
Sifa Universitesi Bornova Egitim Arastirma Hastanesi
🇹🇷Izmir, Turkey
Addenbrookes Hospital
🇬🇧Cambridge, Cambridgeshire, United Kingdom
Mid Essex Hospital Services NHS Trust
🇬🇧Broomfield, Chelmsford, Essex, United Kingdom
The Royal Marsden NHS Foundation Trust
🇬🇧London, Chelsea, United Kingdom
CHU de Reims - Hôpital Robert Debré
🇫🇷Reims, France
Nouvel Hopital Civil
🇫🇷Strasbourg, France
Cardiologist Private Practice
🇫🇷Templemars, France
Fondazione IRCCS Policlinico San Matteo di Pavia
🇮🇹Pavia, Italy
Azienda Ospedaliera Civile Maria Paternò Arezzo Ragusa
🇮🇹Ragusa, Italy
S. C. Oncologia Medica Presidio Ospedaliero Maria Paterno Arezzo
🇮🇹Ragusa, Italy
Policlinico Universitario Campus Biomedico
🇮🇹Rome, Italy
Azienza Ospedaliera Universitaria Senese
🇮🇹Siena, Italy
Ospedale Koelliker
🇮🇹Torino, Italy
Azienda Sanitaria Universitaria Integrata di Udine - PO Universitario Santa Maria della Misericordia
🇮🇹Udine, Italy
Kyushu University Hospital
🇯🇵Fukuoka-shi, Fukuoka, Japan
Shinshu University Hospital
🇯🇵Matsumoto, Nagano, Japan
Niigata Cancer Center Hospital
🇯🇵Niigata, Japan
National Cancer Center Hospital
🇯🇵Chuo-ku, Tokyo, Japan
National Hospital Organization Osaka National Hospital
🇯🇵Osaka, Ôsaka, Japan
Samsung Medical Center - PPDS
🇰🇷Seoul, Korea, Republic of
Asan Medical Center - PPDS
🇰🇷Seoul, Korea, Republic of
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
Severance Hospital Yonsei University Health System - PPDS
🇰🇷Seoul, Korea, Republic of
Instituto Nacional de Cancerologia
🇲🇽Mexico, DF, Mexico
Medica Sur, S. A. B de C. V. (Centro de Investigación Farmacológica y Biotecnológica CIF-BIOTEC)
🇲🇽Mexico, Mexico
Instituto Nacional de Cardiología Ignacio Chavez
🇲🇽Mexico, Mexico
Radboud University Nijmegen Medical Centre
🇳🇱Nijmegen, Gelderland, Netherlands
Singapore General Hospital (SGH)
🇸🇬Singapore, Singapore
Hospital Arnau de Vilanova
🇪🇸Lleida, Spain
Hospital Universitari Arnau de Vilanova
🇪🇸Lleida, Spain
Hospital General Universitario Gregorio Maranon
🇪🇸Madrid, Spain
Hospital Universitario 12 de Octubre
🇪🇸Madrid, Spain
Hospital Universitario Ramon y Cajal
🇪🇸Madrid, Spain
University of Miami
🇺🇸Miami, Florida, United States
Hattiesburg Clinic Oncology Hem
🇺🇸Hattiesburg, Mississippi, United States
UT Southwestern Medical Center at Dallas
🇺🇸Dallas, Texas, United States
The Queen Elizabeth Hospital
🇦🇺Woodville, South Australia, Australia
AMO - Assistência Multidisciplinar em Oncologia
🇧🇷Salvador, Bahia, Brazil
Klinikum Bayreuth GmbH
🇩🇪Bayreuth, Bayern, Germany
Istituto Dermopatico dell'Immacolata IRCCS
🇮🇹Roma, Lazio, Italy
Hospital Universitario Dr. Jose Eleuterio Gonzalez
🇲🇽Monterrey, Nuevo LEON, Mexico
Vision Optical
🇦🇺Southport, Queensland, Australia
Cancun Oncology Center Galenia
🇲🇽Cancun, Quintana ROO, Mexico
Gazi University Medical Faculty Gazi Hospital
🇹🇷Ankara, Turkey
Medisch Centrum Leeuwarden
🇳🇱Leeuwarden, Friesland, Netherlands
Hospital Universitario La Paz - PPDS
🇪🇸Madrid, Spain
Universitetssjukhuset i Linköping
🇸🇪Linköping, Sweden
ASST degli Spedali Civili di Brescia - Spedali Civili di Brescia - INCIPIT - PIN
🇮🇹Brescia, Lombardia, Italy
Istituto Nazionale Dei Tumori
🇮🇹Milano, Lombardia, Italy
ASST Grande Ospedale Metropolitano Niguarda - Presidio Ospedaliero Ospedale Niguarda
🇮🇹Milano, Lombardia, Italy
Mount Vernon Hospital
🇬🇧Northwood, London, CITY OF, United Kingdom
UAB Comprehensive Cancer Center
🇺🇸Birmingham, Alabama, United States
University of Illinois Hospital and Health Sciences System - Investigational Drug Service
🇺🇸Chicago, Illinois, United States
Eye & Ear Infirmary- Opthalmology
🇺🇸Chicago, Illinois, United States
UAB The Kirklin Clinic
🇺🇸Birmingham, Alabama, United States
Retinal Consultants of Alabama P.C.
🇺🇸Birmingham, Alabama, United States
UAB Callahan Eye Hospital
🇺🇸Birmingham, Alabama, United States
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
Highlands Oncology Group
🇺🇸Rogers, Arkansas, United States
Highlands Oncology Group - Fayetteville
🇺🇸Springdale, Arkansas, United States
UC Irvine Medical Center
🇺🇸Orange, California, United States
Rocky Mountain Cancer Centers (Williams) - USOR
🇺🇸Denver, Colorado, United States
Rocky Mountain Cancer Centers
🇺🇸Pueblo, Colorado, United States
Specialty Eye Care
🇺🇸Parker, Colorado, United States
University Cancer Institute
🇺🇸Boynton Beach, Florida, United States
University of Illinois at Chicago
🇺🇸Chicago, Illinois, United States
University of Illinois Hospital and Health Sciences System
🇺🇸Chicago, Illinois, United States
University of Illinois Medical Center
🇺🇸Chicago, Illinois, United States
University of Vermont Medical Center
🇺🇸Burlington, Vermont, United States
University of Vermont Cancer Center
🇺🇸Burlington, Vermont, United States
Goshen Center For Cancer Care
🇺🇸Goshen, Indiana, United States
Lack's Cancer Center at Mercy Health Saint Mary's
🇺🇸Grand Rapids, Michigan, United States
Mercy Health Hauenstein Neuroscience Center Neuro-Ophthalmology (Clinic)
🇺🇸Grand Rapids, Michigan, United States
Retina Specialists of Michigan
🇺🇸Grand Rapids, Michigan, United States
Jackson Oncology Associates - St. Dominic Hospital
🇺🇸Jackson, Mississippi, United States
Jackson Oncology Associates, PLLC
🇺🇸Jackson, Mississippi, United States
Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States
Hackensack University Medical Cente
🇺🇸Hackensack, New Jersey, United States
Investigational Drug Service, Department of Pharmacy (Investigational Product)
🇺🇸Rochester, New York, United States
University of Rochester Medical Center - PPDS
🇺🇸Rochester, New York, United States
Dr. Dennis B. Kay (Ophthalmologist)
🇺🇸Dallas, Texas, United States
Texas Oncology - Baylor Charles A. Sammons Cancer Center
🇺🇸Dallas, Texas, United States
Virginia Cancer Specialists, PC
🇺🇸Leesburg, Virginia, United States
Virginia Cancer Specialists
🇺🇸Fairfax, Virginia, United States
Virginia Cancer Specialists (Leesburg) - USOR
🇺🇸Leesburg, Virginia, United States
Northern Virginia Ophthalmology Associates
🇺🇸Falls Church, Virginia, United States
Wenatchee Valley Hospital & Clinics
🇺🇸Wenatchee, Washington, United States
Wenatchee Valley Hospitals & Clinics
🇺🇸Wenatchee, Washington, United States
Wenatchee Valley Medical Center
🇺🇸Wenatchee, Washington, United States
Lake Macquarie Private Hospital
🇦🇺Gateshead, New South Wales, Australia
HPS Pharmacy
🇦🇺Southport, Queensland, Australia
Tasman Oncology Research
🇦🇺Southport, Queensland, Australia
Fundación CENIT para la Investigación en Neurociencias
🇦🇷Caba, Buenos Aires, Argentina
Organización Médica de Investigación
🇦🇷Buenos Aires, Ciudad Autónoma DE Buenosaires, Argentina
Fundación Investigar
🇦🇷Buenos Aires, Ciudad Autónoma DE Buenosaires, Argentina
Sanatorio de La Providencia
🇦🇷Buenos Aires, Ciudad Autónoma DE Buenosaires, Argentina
Hospital Italiano de Buenos Aires
🇦🇷Buenos Aires, Ciudad Autónoma DE Buenosaires, Argentina
Instituto Médico Especializado Alexander Fleming
🇦🇷Buenos Aires, Ciudad Autónoma DE Buenosaires, Argentina
Centro de Diagnóstico Dr. Enrique Rossi
🇦🇷Buenos Aires, Ciudad Autónoma DE Buenosaires, Argentina
Princess Alexandra Hospital
🇦🇺Woolloongabba, Queensland, Australia
The Alfred Hospital
🇦🇺Prahran, Victoria, Australia
Sir Charles Gairdner Hospital Pharmacy Department
🇦🇺Nedlands, Western Australia, Australia
Sir Charles Gairdner Hospital
🇦🇺Nedlands, Western Australia, Australia
Instituto de Medicina Integral Professor Fernando Figueira
🇧🇷Recife, Pernambuco, Brazil
Associação Hospital de Caridade Ijuí
🇧🇷Ijuí, RIO Grande DO SUL, Brazil
Hospital de Clinicas de Porto Alegre (HCPA) - PPDS
🇧🇷Porto Alegre, RIO Grande DO SUL, Brazil
Fundação PIO XII
🇧🇷Barretos, SÃO Paulo, Brazil
Liga Norte Riograndense Contra O Cancer
🇧🇷Natal, Brazil
Hospital do Cancer I - Instituto Nacional de Cancer - INCA
🇧🇷Rio de Janeiro, Brazil
INCA Instituto Nacional de Cancer
🇧🇷Rio de Janeiro, Brazil
Hospital BP Mirante
🇧🇷Sao Paulo, Brazil
Tom Baker Cancer Centre
🇨🇦Calgary, Alberta, Canada
SunnyBrook Health Sciences Centre
🇨🇦Toronto, Ontario, Canada
Sunnybrook Research Institute
🇨🇦Toronto, Ontario, Canada
Toronto General Hospital
🇨🇦Toronto, Ontario, Canada
Princess Margaret Cancer Centre
🇨🇦Toronto, Ontario, Canada
Centre Hospitalier De L'Universite De Montreal Hospital Notre Dame
🇨🇦Montreal, Quebec, Canada
CHUM Notrea Dame Hospital
🇨🇦Montreal, Quebec, Canada
Centre Hospitalier de l'Universite de Montreal
🇨🇦Montreal, Quebec, Canada
McGill University Health center
🇨🇦Montreal, Quebec, Canada
CHU de Quebec-Universite Laval
🇨🇦Quebec City, Quebec, Canada
CHU de Quebec- L'Hotel-Dieu de Quebec
🇨🇦Québec, Quebec, Canada
Centre de Sante Et Services Sociaux Richelieu Yamaska
🇨🇦Sainte Hyacinthe, Quebec, Canada
Centre Hospitalier Universitaire de Quebec - Hotel - Dieu de Quebec - Universite Laval
🇨🇦Quebec, Canada
CHU de Quebec-Universite Laval - L' Hotel - Dieu de Quebec
🇨🇦Quebec, Canada
Service de PneumologieCHU Lyon Sud
🇫🇷Pierre-bénite, France
Hospital Universitario San Ignacio
🇨🇴Bogotá, Pbx (57-1), Colombia
Mou/Mmci - Ppds
🇨🇿Brno, Jihomoravský KRAJ, Czechia
Fakultni nemocnice Ostrava
🇨🇿Ostrava Poruba, Czechia
Fakultni nemocnice Kralovske Vinohrady
🇨🇿Praha 10, Praha, Hlavní Mesto, Czechia
Vseobecna Fakultni Nemocnice V Praze
🇨🇿Praha, Czechia
Fakultni nemocnice u sv. Anny v Brne
🇨🇿Brno, Czechia
Fakultni nemocnice Olomouc
🇨🇿Olomouc, Czechia
General Faculty Hospital
🇨🇿Praha 2, Czechia
Vseobecna Fakultni Nemocnice V Praze-U Nemocnice 499/2
🇨🇿Praha, Czechia
CHU de Nice
🇫🇷Nice, Alpes-maritimes, France
Hôpital Saint-André
🇫🇷Bordeaux, Gironde, France
CHU de Grenoble
🇫🇷Grenoble, Isère, France
Hôpital Robert Debré
🇫🇷Reims, Marne, France
CHRU de Lille - Hôpital Huriet
🇫🇷Lille, Nord, France
Centre Léon Bérard Centre Régional de Lutte Contre Le Cancer Rhône Alpes
🇫🇷Lyon, Rhone, France
Hôpital de La Croix Rousse
🇫🇷Lyon, Rhône, France
Centre Hospitalier Le Mans
🇫🇷Le Mans, Sarthe, France
Institut Gustave Roussy
🇫🇷Villejuif, France
CHU de Bordeaux - Hopital Saint Andre
🇫🇷Bordeaux, France
Hopital Saint Andre Unite de Cancerologie Service de Dermatologie
🇫🇷Bordeaux, France
Centre Hospitalier Universitaire Ambroise Paré
🇫🇷Boulogne-Billancourt, France
Clinique de la Louvière
🇫🇷Lille, France
Hôpital D'Instruction des Armées Desgenettes
🇫🇷Lyon, France
Groupe Hospitalier Archet I Et II
🇫🇷Nice, France
Hopital Lariboisiere
🇫🇷Paris, France
Institut Mutualiste Montsouris
🇫🇷Paris, France
Ophtalmologist office
🇫🇷Paris, France
Hôpital Saint louis
🇫🇷Paris, France
Hospices Civils de Lyon - Hopital Lyon Sud
🇫🇷Pierre Benite, France
Universitaetsklinikum Freiburg
🇩🇪Freiburg im Breisgau, Baden-württemberg, Germany
University Clinic Heidelberg - PPDS
🇩🇪Heidelberg, Germany
Klinikum Mannheim Universitätsklinikum gGmbH
🇩🇪Mannheim, Baden-württemberg, Germany
Universitätsklinikum Tübingen
🇩🇪Tübingen, Germany
Universitätsklinikum Ulm
🇩🇪Ulm, Germany
Hautklinik, Klinikum Nürnberg, Universitätsklinik der Paracelsus Medizinischen Privatuniversität
🇩🇪München, Germany
LMU Klinikum der Universität München
🇩🇪München, Bayern, Germany
LMU Klinikum
🇩🇪München, Bayern, Germany
Institut für Röntgendiagnostik
🇩🇪Regensburg, Bayern, Germany
University Clinic Regensburg - PPDS
🇩🇪Regensburg, Bayern, Germany
Universitätsklinikum Würzburg
🇩🇪Würzburg, Bayern, Germany
Universitätsklinikum Frankfurt
🇩🇪Frankfurt, Hessen, Germany
Gesundheit Nordhessen Holding AG
🇩🇪Kassel, Hessen, Germany
Klinikum Kassel
🇩🇪Kassel, Hessen, Germany
Zentrum für Radiologie
🇩🇪Kassel, Hessen, Germany
Augenarztzentrum Buxtehude
🇩🇪Buxtehude, Niedersachsen, Germany
Elben Klinken Stade ? Buxtehude
🇩🇪Buxtehude, Niedersachsen, Germany
Augenklinik Universitätsklinikum Bonn
🇩🇪Bonn, Nordrhein-westfalen, Germany
Institut für Diagnostische Radiologie, Neuroradiologie und Nuklearmedizin
🇩🇪Minden, Nordrhein-westfalen, Germany
Johannes Wesling Klinikum Minden
🇩🇪Minden, Nordrhein-westfalen, Germany
Mühlenkreiskliniken - Johannes Wesling Klinikum Minden
🇩🇪Minden, Nordrhein-westfalen, Germany
Universitätsmedizin der Johannes Gutenberg-Universität Mainz
🇩🇪Mainz, Rheinland-pfalz, Germany
Universitätsklinik Magdeburg
🇩🇪Magdeburg, Sachsen-anhalt, Germany
Universitätsklinikum Magdeburg A.ö.R.
🇩🇪Magdeburg, Sachsen-anhalt, Germany
Klinik und Poliklinik für Augenheilkunde
🇩🇪Dresden, Sachsen, Germany
Universitatsklinikum Leipzig AoR
🇩🇪Leipzig, Sachsen, Germany
Universitätsklinikum Essen
🇩🇪Essen, Germany
Goethe-University Frankfurt/Main
🇩🇪Frankfurt/Main, Germany
Universitätsklinikum Freiburg, Klinik für Radiologie
🇩🇪Freiburg, Germany
Institut für Diagnostische und Interventionelle Radiologie
🇩🇪Gera, Germany
SRH Wald-Klinikum Gera GmbH
🇩🇪Gera, Germany
Klinik für Augenheilkunde
🇩🇪Gera, Germany
Universitätsklinik Hamburg Eppendorf
🇩🇪Hamburg, Germany
Augenärzte am Kröpcke
🇩🇪Hannover, Germany
Medizinische Hochschule Hannover (Hannover Medical School)
🇩🇪Hannover, Germany
Institut für Diagnostische und Interventionelle Radilogie
🇩🇪Hannover, Germany
Universität des Saarlandes
🇩🇪Homburg, Germany
Universitätsaugenklinik
🇩🇪Magdeburg, Germany
Universitätsklinik für Radiologie und Nuklearmedizin
🇩🇪Magdeburg, Germany
University Hospital Mainz
🇩🇪Mainz, Germany
Augenklinik Universitätsklinikum Mannheim
🇩🇪Mannheim, Germany
Augen-Praxis_Minden
🇩🇪Minden, Germany
LMU Klinikum der Universität
🇩🇪München, Germany
Fachklinik Hornheide Abteilung für Internistische Onkologie und Hämatologie
🇩🇪Münster, Germany
Klinikum Nürnberg - Campus Nord
🇩🇪Nürnberg, Germany
Klinik & Poliklinik für Augenheilkunde
🇩🇪Regensburg, Germany
Internistische Schwerpunktpraxis Kardiologie Hämatologie Onkologie
🇩🇪Ulm, Germany
Hygeia Diagnostic and Therapeutic Centre of Athens
🇬🇷Athens, Attiki, Greece
Laiko General Hospital of Athens
🇬🇷Athens, Greece
Metropolitan Hospital
🇬🇷Piraeus, Greece
Debreceni Egyetem Klinikai Kozpont
🇭🇺Debrecen, Hungary
Magyar Honvédség Egészségügyi Központ
🇭🇺Budapest, Hungary
Eszak-Pesti Centrumkorhaz -Honvedkorhaz- Podmaniczky utcai telephely
🇭🇺Budapest, Hungary
Orszagos Onkologiai Intezet
🇭🇺Budapest, Hungary
Jasz-Nagykun-Szolnok Megyei Hetenyi Geza Korhaz-Rendelointezet
🇭🇺Szolnok, Hungary
Jasz-Nagykun-Szolnok Varmegyei Hetenyi Geza Korhaz-Rendelointezet
🇭🇺Szolnok, Hungary
Rambam Health Care Campus
🇮🇱Haifa, Ḥeifā, Israel
Sheba Medical Center - PPDS
🇮🇱Ramat Gan, Tel-aviv, Israel
Hadassah Medical Center - PPDS
🇮🇱Jerusalem, Israel
Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona-Umberto I G.M. Lancisi G. Salesi
🇮🇹Torrette Site, Ancona, Italy
Azienda Ospedaliera Universitaria Federico II
🇮🇹Napoli, Campania, Italy
Azienda Ospedaliero Universitaria Di Bologna Policlinico S Orsola Malpighi-Via Massarenti
🇮🇹Bologna, Emilia-romagna, Italy
Azienda Ospedaliero Universitaria Di Bologna Policlinico S Orsola Malpighi
🇮🇹Bologna, Emilia-romagna, Italy
Policlinico Universitario Campus Biomedico Di Roma
🇮🇹Roma, Lazio, Italy
Istituto Nazionale Tumori Regina Elena
🇮🇹Roma, Lazio, Italy
Azienda Ospedaliera Sant'Andrea
🇮🇹Roma, Lazio, Italy
Azienda Ospedaliera Ospedale Di Lecco
🇮🇹Lecco, Lombardia, Italy
Istituto Europeo Di Oncologia
🇮🇹Milano, Italy
ASST di Monza - Azienda Ospedaliera San Gerardo
🇮🇹Monza, Lombardia, Italy
Azienda Ospedaliera San Gerardo
🇮🇹Monza, Lombardia, Italy
Istituto Clinico Humanitas - Humanitas Cancer Center
🇮🇹Rozzano, Lombardia, Italy
Istituto Clinico Humanitas
🇮🇹Rozzano, Lombardia, Italy
Fondazione del Piemonte per l'Oncologia (IRCCS)
🇮🇹Candiolo, Torino, Italy
Azienda Ospedaliero Universitaria Pisana
🇮🇹Pisa, Toscana, Italy
Azienda Ospedaliera S Maria Di Terni
🇮🇹Terni, Umbria, Italy
Azienda Ospedaliera Santa Maria di Terni
🇮🇹Terni, Umbria, Italy
Clinica Oculistica
🇮🇹Padua, Veneto, Italy
IRCCS Az. Osp. Universitaria San Martino- IST
🇮🇹Genoa, Italy
IRCCS Giovanni Paolo II Cancer Institute
🇮🇹Bari, Italy
ASST Papa Giovanni XXIII - Azienda Ospedaliera Papa Giovanni XXIII
🇮🇹Bergamo, Italy
Azienda Ospedaliero Universitaria Di Bologna - Policlinico S.Orsola Malpighi
🇮🇹Bologna, Italy
Istituto Nazionale per lo studio e la cura dei tumori Fondazione Giovanni Pascale
🇮🇹Napoli, Italy
Istituto Nazionale Tumori IRCCS Fondazione Giovanni Pascale
🇮🇹Napoli, Italy
Istituto Oncologico Veneto - I.R.C.C.S.
🇮🇹Padova, Italy
Maxima Medisch Centrum
🇳🇱Veldhoven, Noord-brabant, Netherlands
Medisch Spectrum Twente
🇳🇱Enschede, Netherlands
Isala Zwolle
🇳🇱Zwolle, Overijssel, Netherlands
Medisch Spectrum Twente - Hospital
🇳🇱Ariënsplein Enschede, Netherlands
Universitair Medisch Centrum Groningen
🇳🇱Groningen, Netherlands
Zuyderland Medisch Centrum - Heerlen
🇳🇱Heerlen, Netherlands
Leids Universitair Medisch Centrum
🇳🇱Leiden, Netherlands
Maastricht University Medical Center
🇳🇱Maastricht, Netherlands
Erasmus MC
🇳🇱Rotterdam, Netherlands
Erasmus MC-Daniel den Hoed Oncologisch Centrum
🇳🇱Rotterdam, Netherlands
Zuyerland Medisch Centrum
🇳🇱Sittard-Geleen, Netherlands
Oslo universitetssykehus HF, Utprøvingsenheten
🇳🇴Oslo, Norway
Oslo universitetssykehus HF
🇳🇴Oslo, Norway
Oslo Myeloma Center - PPDS
🇳🇴Oslo, Norway
Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy w Warszawie
🇵🇱Warsaw, Mazowieckie, Poland
Centrum Medyczne MAVIT Sp. z o.o.
🇵🇱Warszawa, Mazowieckie, Poland
Lux Med
🇵🇱Warszawa, Poland
Instituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E.
🇵🇹Lisboa, Portugal
Instituto Portugues de Oncologia Do Porto Francisco Gentil Epe - PPDS
🇵🇹Porto, Portugal
Hospital Garcia de Orta*E.P.E.
🇵🇹Almada, Portugal
Centro Hospitalar de Lisboa Norte, E.P.E- Hospital de Santa Maria
🇵🇹Lisboa, Portugal
Centro Hospitalar Universitario Lisboa Norte E.P.E
🇵🇹Lisboa, Portugal
Hospital de Santa Maria-Avenida Prof. Egas Moniz - PPDS
🇵🇹Lisboa, Portugal
Hospital de Santa Maria
🇵🇹Lisboa, Portugal
Russian Oncology Research Center n a N N Blokhin
🇷🇺Moscow, Russian Federation
Ryazan Regional Clinical Oncology Dispensary
🇷🇺Ryazan, Russian Federation
Ryazan Clinical Hospital n.a. Semashko
🇷🇺Ryazan, Russian Federation
Scientific Research Institute of Oncology n.a. N.N. Petrov
🇷🇺St. Petersburg, Russian Federation
National Cancer Centre - 30 Hospital Blvd
🇸🇬Singapore, Singapore
National Cancer Centre Singapore
🇸🇬Singapore, Singapore
Singapore National Eye Research Centre
🇸🇬Singapore, Singapore
Nemocnica Svateho Michala, a.s.
🇸🇰Bratislava, Slovakia
Narodny onkologicky ustav - PPDS
🇸🇰Bratislava, Slovakia
BIONT, a.s.
🇸🇰Bratislava, Slovakia
POKO POPRAD, s.r.o.
🇸🇰Poprad, Slovakia
Steve Biko Academic Hospital
🇿🇦Pretoria, South Africa
Mary Potter Oncology Centre
🇿🇦Pretoria, South Africa
Hospital Universitario de Jerez
🇪🇸Jerez De La Frontera, Andalucía, Spain
Hospital Universitario Central de Asturias
🇪🇸Oviedo, Asturias, Spain
Hospital Universitario Germans Trias i Pujol
🇪🇸Badalona, Spain
Cetir, Centre Mèdic, S.L
🇪🇸Barcelona, Cataluña, Spain
Hospital Universitario Puerta de Hierro Majadahonda
🇪🇸Majadahonda, Madrid, Spain
Hospital Universitario Puerta de Hierro - Majadahonda
🇪🇸Majadahonda, Spain
Hospital Clinico Universitario Virgen de la Arrixaca
🇪🇸El Palmar, Murcia, Spain
Clinica Universidad Navarra
🇪🇸Pamplona, Navarra, Spain
Clinica Universidad de Navarra
🇪🇸Pamplona, Navarra, Spain
Complejo Hospitalario de Navarra
🇪🇸Pamplona, Navarra, Spain
Hospital Universitario de Navarra
🇪🇸Pamplona, Navarra, Spain
Hospital Nuestra Señora de Valme
🇪🇸Seville, Sevilla, Spain
Hospital General Universitario de Alicante
🇪🇸Alicante, Spain
Hospital General Universitario Dr. Balmis
🇪🇸Alicante, Spain
Centro de Oftalmologia Barraquer
🇪🇸Barcelona, Spain
Hospital Universitario Vall d'Hebron - PPDS
🇪🇸Barcelona, Spain
Hospital Clinic de Barcelona
🇪🇸Barcelona, Spain
Hospital Clinic provincial de Barcelona
🇪🇸Barcelona, Spain
Hospital de La Santa Creu i Sant Pau
🇪🇸Barcelona, Spain
Onkologikoa
🇪🇸Donostia-san Sebastián, Spain
Hospital Universitario Virgen de las Nieves
🇪🇸Granada, Spain
Hospital Universitario A Coruña
🇪🇸La Coruna, Spain
Royal Preston Hospital
🇬🇧Preston, Lancashire, United Kingdom
Royal Marsden Hospital - Surrey
🇬🇧London, London, CITY OF, United Kingdom
The Royal Marsden in Sutton, Surrey - Downs Rd
🇬🇧London, London, CITY OF, United Kingdom
Royal Surrey County Hospital
🇬🇧Guildford, Surrey, United Kingdom
Clatterbridge Hospital - NWCRN - PPDS
🇬🇧Bebbington, Wirral, United Kingdom
Clatterbridge Hospital - PPDS
🇬🇧Bebington, Wirral, United Kingdom
The Clatterbridge Cancer Centre NHS Foundation Trust
🇬🇧Bebington, Wirral, United Kingdom
Weston Park Hospital
🇬🇧Sheffield, York, United Kingdom
Broomfield Hospital
🇬🇧Broomfield, United Kingdom
Cambridge University Hospitals NHS Foundation Trust
🇬🇧Cambridge, United Kingdom
St James University Hospital
🇬🇧Leeds, United Kingdom
Royal Free Hospital
🇬🇧London, United Kingdom
The Christie NHS Foundation Trust - PPDS
🇬🇧Manchester, United Kingdom
Churchill Hospital
🇬🇧Oxford, United Kingdom
Royal Preston Hospital - NWCRN- PPDS
🇬🇧Preston, United Kingdom
Royal Preston Hospital - PPDS
🇬🇧Preston, United Kingdom
Clatterbridge Cancer Centre
🇬🇧Wirral, United Kingdom