Safety, Preliminary Efficacy and PK of Isatuximab (SAR650984) Alone or in Combination With Atezolizumab in Patients With Advanced Malignancies
- Registration Number
- NCT03637764
- Lead Sponsor
- Sanofi
- Brief Summary
Primary Objectives:
* Phase 1: To characterize the safety and tolerability of isatuximab in combination with atezolizumab in participants with unresectable hepatocellular carcinoma (HCC), platinum-refractory recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN), platinum-resistant/refractory epithelial ovarian cancer (EOC), or recurrent glioblastoma multiforme (GBM), and to determine the recommended Phase 2 dose (RP2D).
* Phase 2: To assess response rate (RR) of isatuximab in combination with atezolizumab in participants with HCC or SCCHN or EOC.
* Phase 2: To assess the progression free survival rate at 6 months (PFS-6) of isatuximab in combination with atezolizumab, or as a single agent in participants with GBM.
Secondary Objectives:
* To evaluate the safety profile of isatuximab monotherapy (GBM only), or in combination with atezolizumab in Phase 2.
* To evaluate the immunogenicity of isatuximab and atezolizumab.
* To characterize the pharmacokinetic (PK) profile of isatuximab single agent (GBM only) and atezolizumab in combination with isatuximab.
* To assess the overall efficacy of isatuximab in combination with atezolizumab, or single agent (GBM only).
- Detailed Description
The total study duration per participant was up to 28 months including up to 28 days screening period, up to 24 months treatment period, and a 3 month safety follow up period.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 107
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Cohort D-1: GBM: Isatuximab + Atezolizumab Isatuximab SAR650984 Participants with glioblastoma multiforme (GBM) received atezolizumab 1200 mg, Q3W, IV infusion along with isatuximab 10 mg/kg, IV infusion, once weekly for 3 weeks (i.e., on Day 1, Day 8 and Day 15 of Cycle 1) and then Q3W (i.e., on Day 1 of each 21- day treatment cycle) until disease progression, unacceptable AE, participant's decision to stop the treatment, or death or study cut-off whichever occurred first (maximum duration of exposure: 54 weeks). Cohort C: EOC: Isatuximab + Atezolizumab Isatuximab SAR650984 Participants with epithelial ovarian cancer (EOC) received atezolizumab 1200 mg, Q3W, IV infusion along with isatuximab 10 mg/kg, IV infusion, once weekly for 3 weeks (i.e., on Day 1, Day 8 and Day 15 of Cycle 1) and then Q3W (i.e., on Day 1 of each 21- day treatment cycle) until disease progression, unacceptable AE, participant's decision to stop the treatment, or death or study cut-off whichever occurred first (maximum duration of exposure: 61 weeks). Cohort A: HCC: Isatuximab + Atezolizumab Isatuximab SAR650984 Participants with hepatocellular carcinoma (HCC) received atezolizumab 1200 milligrams, every 3 weeks (Q3W), intravenous (IV) infusion along with isatuximab 10 milligrams per kilogram (mg/kg), IV infusion, once weekly for 3 weeks (i.e., on Day 1, Day 8 and Day 15 of Cycle 1) and then Q3W (i.e., on Day 1 of each 21- day treatment cycle) until disease progression, unacceptable adverse events (AE), participant's decision to stop the treatment, or death or study cut-off whichever occurred first (maximum duration of exposure: 106 weeks). Cohort B: SCCHN: Isatuximab + Atezolizumab Isatuximab SAR650984 Participants with squamous cell carcinoma of the head and neck (SCCHN) received atezolizumab 1200 milligrams,Q3W, IV infusion along with isatuximab 10 mg/kg, IV infusion, once weekly for 3 weeks (i.e., on Day 1, Day 8 and Day 15 of Cycle 1) and then Q3W (i.e., on Day 1 of each 21- day treatment cycle) until disease progression, unacceptable AE, participant's decision to stop the treatment, or death or study cut-off whichever occurred first (maximum duration of exposure: 108 weeks). Cohort A: HCC: Isatuximab + Atezolizumab Atezolizumab Participants with hepatocellular carcinoma (HCC) received atezolizumab 1200 milligrams, every 3 weeks (Q3W), intravenous (IV) infusion along with isatuximab 10 milligrams per kilogram (mg/kg), IV infusion, once weekly for 3 weeks (i.e., on Day 1, Day 8 and Day 15 of Cycle 1) and then Q3W (i.e., on Day 1 of each 21- day treatment cycle) until disease progression, unacceptable adverse events (AE), participant's decision to stop the treatment, or death or study cut-off whichever occurred first (maximum duration of exposure: 106 weeks). Cohort B: SCCHN: Isatuximab + Atezolizumab Atezolizumab Participants with squamous cell carcinoma of the head and neck (SCCHN) received atezolizumab 1200 milligrams,Q3W, IV infusion along with isatuximab 10 mg/kg, IV infusion, once weekly for 3 weeks (i.e., on Day 1, Day 8 and Day 15 of Cycle 1) and then Q3W (i.e., on Day 1 of each 21- day treatment cycle) until disease progression, unacceptable AE, participant's decision to stop the treatment, or death or study cut-off whichever occurred first (maximum duration of exposure: 108 weeks). Cohort C: EOC: Isatuximab + Atezolizumab Atezolizumab Participants with epithelial ovarian cancer (EOC) received atezolizumab 1200 mg, Q3W, IV infusion along with isatuximab 10 mg/kg, IV infusion, once weekly for 3 weeks (i.e., on Day 1, Day 8 and Day 15 of Cycle 1) and then Q3W (i.e., on Day 1 of each 21- day treatment cycle) until disease progression, unacceptable AE, participant's decision to stop the treatment, or death or study cut-off whichever occurred first (maximum duration of exposure: 61 weeks). Cohort D-1: GBM: Isatuximab + Atezolizumab Atezolizumab Participants with glioblastoma multiforme (GBM) received atezolizumab 1200 mg, Q3W, IV infusion along with isatuximab 10 mg/kg, IV infusion, once weekly for 3 weeks (i.e., on Day 1, Day 8 and Day 15 of Cycle 1) and then Q3W (i.e., on Day 1 of each 21- day treatment cycle) until disease progression, unacceptable AE, participant's decision to stop the treatment, or death or study cut-off whichever occurred first (maximum duration of exposure: 54 weeks).
- Primary Outcome Measures
Name Time Method Number of Participants With Abnormal Electrolyte Parameters From Baseline up to 30 days after last study treatment administration (maximum duration of exposure: 106 weeks for Cohort A, 108 weeks for Cohort B, 61 weeks for Cohort C and 54 weeks for Cohort D-1) Electrolyte parameters assessed were hyponatremia, hypernatremia, hypokalemia, hyperkalemia, hypocalcemia, hypercalcemia, hypoalbuminemia, hypoglycemia and hyperglycemia. Parameters were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Experience version 4.03, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs.
Maximum Tolerated Dose (MTD) Cycle 1 (21 days) MTD was defined as the highest dose level at which no more than 1 out of 6 participants (starting dose or DL-1) or 2 out of 12 participants (starting dose) experienced a DLT related to the investigational medicinal product. DLTs: AE occurring during 1st treatment cycle, unless due to disease progression/obviously unrelated cause included: hematological abnormalities: G4 N for 7 or more consecutive days, G3 to G4 N with fever, G3 or G4 thrombocytopenia. Non-hematological abnormalities: G\>=2 AST/ ALT elevation simultaneous with G \>=2 total bilirubin elevation without cholestasis or any other reason found, G4 non-hematologic AE, G3 to 4 cytokine release syndrome, G3 non-hematological AE lasting \>3 days, delay in initiation of Cycle 2 \>14 days due to treatment related laboratory abnormalities or AEs.
Number of Participants With Dose Limiting Toxicities (DLTs) Cycle 1 (21 days) DLTs: AEs occurring during 1st treatment cycle, unless due to disease progression/obviously unrelated cause which included: hematological abnormalities: Grade(G) 4 neutropenia(N) for 7 or more consecutive days, G3 to G4 N with fever (temperature greater than or equal to \[\>=\] 38.5 degree Celsius on more than 1 occasion) or microbiologically/radiographically documented infection, G3 thrombocytopenia with clinically significant bleeding/ G4 thrombocytopenia. Non-hematological abnormalities: G \>=2 Aspartate transaminase (AST)/ Alanine transaminase (ALT) elevation simultaneous with G \>=2 total bilirubin elevation without initial findings of cholestasis or any other reason found, G4 non-hematologic AE, G3 to 4 cytokine release syndrome, G3 non-hematological AE lasting greater than (\>)3 days, delay in initiation of Cycle 2 \>14 days due to treatment related laboratory abnormalities/AE. Any other AE that study committee deemed to be dose-limiting, regardless of grade, was also considered DLT.
Percentage of Participants With Overall Response (OR): For HCC/SCCHN/EOC Cohorts From randomization until disease progression, or death or study cut-off whichever occurred first (maximum duration of exposure: up to 108 weeks) OR was defined as the percentage of participants with complete response (CR) and partial response (PR) as best overall response, assessed per RECIST 1.1 criteria. Best overall response was derived per RECIST 1.1 criteria using disease assessments performed from the first dose of treatment throughout the study excluding any assessments performed after the cut-off date or following the initiation of a further anticancer treatment. CR was defined as the disappearance of all target lesions, pathological lymph nodes (target/non-target)- reduction in short axis \<10 mm; PR was defined as at least 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. Disease progression was defined as at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum, sum with an absolute increase of diameter of at least 5 mm and appearance of \>1 new lesion.
Recommended Phase 2 Dose (RP2D) Cycle 1 (21 days) RP2D was the starting dose selected for Phase 2 part of the study. RP2D was the selected dose at which no more than 1 out of 6 participants (starting dose or dose level minus -1 \[DL-1\]) or 2 out of 12 participants (starting dose) experienced a DLT related to the investigational medicinal product. DLTs: Adverse Event (AE) occurring during 1st treatment cycle, unless due to disease progression/obviously unrelated cause included: hematological abnormalities: G4 N for 7/ more consecutive days, G3 to G4 N with fever, G3/G4 thrombocytopenia. Non-hematological abnormalities: G\>=2 AST/ALT elevation simultaneous with G \>=2 total bilirubin elevation without cholestasis or any other reason found, G4 non-hematologic AE, G3 to 4 cytokine release syndrome, G3 non-hematological AE lasting \>3 days, delay in initiation of Cycle 2 \>14 days due to treatment related laboratory abnormalities/AE.
Probability of Participants With Progression Free Survival at 6 Months (PFS-6): GBM Cohort From randomization until 6 months after the last participant's first treatment in the GBM Cohort D-1 PFS-6 was defined as the probability of participants alive without disease progression at 6 months as assessed by RANO criteria. Participants who didn't experience documented progression or death before analysis cut-off date or date of initiation of new anticancer treatment, PFS was censored at date of last valid disease assessment not showing progression performed prior to initiation of further anticancer treatment or analysis cut-off date, whichever was 1st. Per RANO criteria, progressive disease was defined as \>=25% increase size of T1- gadolinium enhancing disease, or increased T2/FLAIR signal, or presence of new lesion, or worsening clinical status. PFS-6 was evaluated by Kaplan-Meier method.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Treatment-emergent Adverse Events (TESAEs) From Baseline up to 30 days after last study treatment administration (maximum duration of exposure: 106 weeks for Cohort A, 108 weeks for Cohort B, 61 weeks for Cohort C and 54 weeks for Cohort D-1) An AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily have to have a causal relationship with the treatment. Serious adverse events (SAEs) were any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were defined as AEs that developed, worsened or became serious during the TEAE period (defined as the time from the first dose of study treatment up to 30 days after the last dose of study treatment).
Number of Participants With Hematological Abnormalities From Baseline up to 30 days after last study treatment administration (maximum duration of exposure: 106 weeks for Cohort A, 108 weeks for Cohort B, 61 weeks for Cohort C and 54 weeks for Cohort D-1) Hematological parameters assessed were anemia, white blood cell (WBC) decreased, platelet count decreased, lymphocyte count decreased, and neutrophil count decreased. Parameters were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Experience version 4.03, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs.
Number of Participants With Renal Function Abnormalities From Baseline up to 30 days after last study treatment administration (maximum duration of exposure: 106 weeks for Cohort A, 108 weeks for Cohort B, 61 weeks for Cohort C and 54 weeks for Cohort D-1) Abnormal renal parameters assessed were creatinine clearance (CrCl), creatinine increased and hyperuricemia. Creatinine clearance was assessed in categories: \>=60 - less than (\<) 90 milliliters per minute per 1.73 square meter (mL/min/1.73m\^2), \>=30 - \<60 mL/min/1.73m\^2, \>=15 - \<30 mL/min/1.73m\^2 and \<15 mL/min/1.73m\^2. Parameters were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Experience version 4.03, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs.
Number of Participants With Liver Abnormalities From Baseline up to 30 days after last study treatment administration (maximum duration of exposure: 106 weeks for Cohort A, 108 weeks for Cohort B, 61 weeks for Cohort C and 54 weeks for Cohort D-1) Abnormal liver function parameters assessed were AST increased, ALT increased, alkaline phosphatase (ALP) increased, blood bilirubin (BB) increased. Parameters were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Experience version 4.03, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs.
- Secondary Outcome Measures
Name Time Method Number of Participants With Anti-drug Antibodies (ADA) Response Against Isatuximab From Baseline up to 30 days after last study treatment administration (maximum duration of exposure:106 weeks for Cohort A, 108 weeks for Cohort B, 61 weeks for Cohort C and 54 weeks for Cohort D-1) ADA responses were categorized as treatment boosted ADA and treatment-induced ADA. Treatment boosted ADA was defined as pre-existing ADAs with a significant increase in the ADA titer during the study compared to the Baseline titer. Treatment-induced ADA was defined as ADA that developed at any time during the ADA on-study observation period in participants without pre-existing ADA (including participants without pretreatment samples).
Number of Participants With Anti-drug Antibodies (ADA) Response Against Atezolizumab From Baseline up to 30 days after last study treatment administration (maximum duration of exposure: 106 weeks for Cohort A, 108 weeks for Cohort B, 61 weeks for Cohort C and 54 weeks for Cohort D-1) ADA responses were categorized as treatment boosted ADA and treatment-induced ADA. Treatment boosted ADA was defined as pre-existing ADAs with a significant increase in the ADA titer during the study compared to the Baseline titer. Treatment-induced ADA was defined as ADA that developed at any time during the ADA on-study observation period in participants without pre-existing ADA (including participants without pretreatment samples).
Pharmacokinetics (PK): Concentration Observed at the End of Intravenous Infusion (Ceoi) of Isatuximab At end of infusion on Cycle 1 Day 1 Ceoi is the plasma concentration observed at the end of intravenous infusion of isatuximab.
Pharmacokinetics (PK): Area Under the Plasma Concentration Time Curve From Time 0 to Last Quantifiable Concentration (AUClast) After First Infusion of Isatuximab At SOI, EOI, EOI+4 hours, 72 hours and 168 hours post-dose on Day 1 of Cycle 1 AUClast was defined as area under the plasma concentration versus time curve calculated from time 0 to last quantifiable concentration. AUClast was calculated using the non-compartmental analysis after the intravenous infusion of isatuximab.
Pharmacokinetics (PK): Area Under the Plasma Concentration Time Curve Over the Dosing Interval (AUC0-168h) After First Infusion of Isatuximab At SOI, EOI, EOI+4 hours, 72 hours and 168 hours post-dose on Day 1 of Cycle 1 AUC0-168h was defined as the area under the plasma concentration versus time curve from time 0 to 168 hours post dose calculated using non-compartmental analysis after first infusion of isatuximab.
Pharmacokinetics (PK): Maximum Concentration Observed (Cmax) After the First Infusion of Isatuximab At start of infusion (SOI), end of infusion (EOI), EOI+4 hours, 72 hours and 168 hours post-dose on Day 1 of Cycle 1 Cmax was defined as the maximum concentration observed after the first administration calculated using the noncompartmental analysis after the intravenous infusion of isatuximab.
Pharmacokinetics (PK): Time to Reach Cmax (Tmax) After First Infusion of Isatuximab At SOI, EOI, EOI+4 hours, 72 hours and 168 hours post-dose on Day 1 of Cycle 1 Tmax was defined as the time to reach Cmax, calculated using the non-compartmental analysis after the intravenous infusion of isatuximab.
Pharmacokinetics (PK): Last Concentration Observed Above the Lower Limit of Quantification (Clast) After the First Infusion of Isatuximab At SOI, EOI, EOI+4 hours, 72 hours and 168 hours post-dose on Day 1 of Cycle 1 Clast was defined as the last concentration of isatuximab observed above the lower limit of quantification.
Pharmacokinetics (PK): Time of Clast (Tlast) After First Infusion of Isatuximab At SOI, EOI, EOI+4 hours, 72 hours and 168 hours post-dose on Day 1 of Cycle 1 Tlast was defined as the time of last concentration observed above the lower limit of quantification, calculated using the non-compartmental analysis after the intravenous infusion of isatuximab.
Pharmacokinetics (PK): Trough Plasma Concentrations (Ctrough) of Isatuximab Pre-infusion on Cycle 1 Day 1, Cycle 1 Day 8 and Cycle 1 Day 15 Ctrough was the plasma concentration of isatuximab observed just before treatment administration during repeated dosing.
Plasma Concentration of Atezolizumab Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 8 Day 1 and Cycle 16 Day 1 Best Percent Change From Baseline in Tumor Burden From randomization until progression or death or study cut-off date whichever occurred first (maximum duration of exposure: up to 108 weeks) Best tumor burden change was defined as the best percent-change from baseline in a sum of the diameters (longest for non-nodal lesion, short axis for nodal lesions) for all target lesions.
Percentage of Participants With Disease Control (DC) >=6 Months From the date of first response to disease progression or death, or study cut-off whichever occurred first (maximum duration of exposure: up to 108 weeks) DC: percentage of participants with complete response (CR), partial response (PR) \& stable disease (SD) rate. RANO criteria, CR: no change in size of T1-gadolinium-enhancing (T1-Gd+) disease, stable/ reduced (red) T2/FLAIR signal, no new lesion (NL), no corticosteroid use (CU) \& stable/ red clinical status (CS); PR: \>=50% change in size of T1-Gd+ disease, stable/red T2/FLAIR signal, no NL, stable/ red CU \& stable/ improved CS (ICS). SD: \<50% reduction to \<25% increase (inc) size of T1-Gd+ disease, stable/red T2/FLAIR signal, no NL, stable/red CU \& stable/ICS. Progressive disease (PD): \>=25% inc size of T1-Gd+ disease/ inc T2/FLAIR signal/ presence of NL/ worsening CS. RECIST criteria: CR: Disappearance of target lesions. Reduction in short axis to \<10 mm of lymph nodes; PR: 30% decrease in sum of diameters of target lesions; PD: 20% inc in sum of diameters of target lesions; SD: Neither sufficient shrinkage from baseline study to qualify for PR nor sufficient inc to qualify for PD.
Duration of Response (DOR) From the date of first response until disease progression or death, or study cut-off date whichever occurred first (maximum duration of exposure: up to 108 weeks) Time from date of 1st response until date of first documented recurrent/progressive disease (PD) or death whichever occurred 1st. In absence of disease progression or death before analysis cut-off date or date of initiation of further anticancer treatment, DOR was censored at date of last valid response. RECIST 1.1 criteria was used for assessment in HCC/SCCHN/EOC Cohorts and RANO criteria for GBM Cohort. Per RECIST 1.1, CR: disappearance of all target lesions; PR: at least 30% decrease in sum of diameters of target lesions, PD: at least 20% increase in sum of diameters of target lesions. Per RANO criteria; CR: no change in size of T1-Gd+ disease, stable/reduced T2/FLAIR signal, no new lesion, no corticosteroid use, and stable/improved status; PR: \>=50% change in size of T1-Gd+, stable/reduced T2/FLAIR signal, no new lesion, stable/reduced corticosteroid use, and stable/improved status. PD:\>=25% increase size of T1-Gd+/increased T2/FLAIR signal/presence of new lesion/worsening status.
Progression-free Survival (PFS) From date of first study treatment administration until disease progression or death or study cut-off whichever occurred first (maximum duration of exposure: up to 108 weeks) PFS was defined as time (in months) from 1st study treatment administration to date of 1st documented radiographic progression or date of death from any cause, whichever was 1st. Participants who didn't experience progression or death before analysis cut-off date/date of initiation of new anticancer treatment, PFS was censored at date of last valid disease assessment not showing progression performed prior to initiation of further anticancer treatment or analysis cut-off date, whichever was 1st. RECIST 1.1 criteria was used for assessment in HCC/SCCHN/EOC Cohorts and RANO criteria for GBM Cohort. Per RECIST 1.1 criteria, PD: at least 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study. Appearance of 1 or more new lesions was also considered progression. Per RANO criteria, PD: \>=25% increase in product of perpendicular diameters of any target lesion, or worsening neurologic status not explained by causes unrelated to tumor progression.
Percentage of Participants With Response as Per Response Assessment for Neuro-Oncology (RANO) Criteria: GBM Cohort From randomization until progression, or death, or study cut-off whichever occurred first (maximum duration of exposure: 54 weeks for Cohort D-1) Response rate for participants with GBM was defined as percentage of participants with CR \& PR as best overall response (BOR), assessed by Investigators using RANO criteria. BOR was derived per RANO criteria using disease assessments performed from 1st dose of treatment through study excluding any assessments performed after cut-off date or following initiation of further anticancer treatment. Per RANO criteria; CR was defined as no change in size of T1-gadolinium-enhancing (T1-Gd+) disease, stable or reduced T2/FLAIR signal, no new lesion, no corticosteroid use, and stable or improved clinical status; PR was defined as \>=50% change in size of T1-Gd+ disease, stable or reduced T2/FLAIR signal, no new lesion, stable or reduced corticosteroid use, and stable or improved clinical status. Progressive disease was defined as \>=25% increase size of T1-Gd+ disease, or increased T2/FLAIR signal, or presence of new lesion, or worsening clinical status.
Trial Locations
- Locations (26)
Investigational Site Number :8400007
🇺🇸Boston, Massachusetts, United States
Investigational Site Number :8400004
🇺🇸Santa Monica, California, United States
Investigational Site Number :8400002
🇺🇸Houston, Texas, United States
Investigational Site Number :0560001
🇧🇪Bruxelles, Belgium
Investigational Site Number :0560002
🇧🇪Gent, Belgium
Investigational Site Number :1580003
🇨🇳Taipei, Taiwan
Investigational Site Number :1580005
🇨🇳Kaohsiung, Taiwan
Investigational Site Number :2030001
🇨🇿Brno, Czechia
Investigational Site Number :7240007
🇪🇸Madrid, Spain
Investigational Site Number :2030003
🇨🇿Olomouc, Czechia
Investigational Site Number :3800003
🇮🇹Rozzano, Milano, Italy
Investigational Site Number :2030002
🇨🇿Praha 2, Czechia
Investigational Site Number :7240004
🇪🇸Madrid, Madrid, Comunidad De, Spain
Investigational Site Number :3800004
🇮🇹Padova, Italy
Investigational Site Number :7240006
🇪🇸Hospitalet de Llobregat, Castilla Y León, Spain
Investigational Site Number :1580002
🇨🇳Tainan, Taiwan
Investigational Site Number :1240001
🇨🇦Toronto, Ontario, Canada
Investigational Site Number :3800009
🇮🇹Milano, Italy
Investigational Site Number :7240001
🇪🇸Barcelona, Barcelona [Barcelona], Spain
Investigational Site Number :7240003
🇪🇸Madrid / Madrid, Madrid, Comunidad De, Spain
Investigational Site Number :1580001
🇨🇳Taipei 100, Taiwan
Investigational Site Number :1580006
🇨🇳Taipei, Taiwan
Investigational Site Number :1580004
🇨🇳Taipei, Taiwan
Investigational Site Number :3800007
🇮🇹Meldola, Forlì-Cesena, Italy
Investigational Site Number :5280001
🇳🇱Rotterdam, Netherlands
Investigational Site Number :7240008
🇪🇸Pamplona, Navarra, Spain