Safety, Preliminary Efficacy and PK of Isatuximab (SAR650984) Alone or in Combination With Atezolizumab in Patients With Advanced Malignancies

Neoplasm Clinical Trial

Official title:

A Phase 1/2 Open-label, Multi-center, Safety, Preliminary Efficacy and Pharmacokinetic (PK) Study of Isatuximab (SAR650984) in Combination With Atezolizumab or Isatuximab Alone in Patients With Advanced Malignancies

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03637764
• Other study ID #: ACT15377
• Secondary ID: 2018-000390-67U1
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: August 6, 2018
• Est. completion date: May 11, 2022

Study information

• Verified date: May 2023
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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 information / eligibility

• Status: Terminated
• Enrollment: 107
• Est. completion date: May 11, 2022
• Est. primary completion date: May 11, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria:

• Participants must have a known diagnosis of either unresectable HCC, platinum-refractory recurrent/metastatic SCCHN, platinum-resistant/refractory EOC with evidence of measurable disease or recurrent GBM.
• Greater than or equal to (>=)18 years of age.
• For participants with HCC: Documentation of progressive disease (PD) during or after treatment with either sorafenib or lenvatinib, or intolerance to the therapy.
• For participants with SCCHN: Received and failed up to 2 lines of prior systemic anti-cancer therapy with documentation of tumor recurrence or PD within 6 months of last platinum-based therapy in primary, recurrent, or metastatic setting.
• For participants with EOC: Received up to 3 lines of prior platinum-containing therapy when the disease was platinum-sensitive, and the participants should not have received any systemic therapy for platinum-resistant/refractory disease. Specific to France only: Documentation of PD on or after 1 line of anti-cancer therapy for platinum resistant/refractory disease (unless participants are ineligible or intolerant to standard of care for platinum-resistant/refractory disease).
• For participants with GBM: Documentation of PD or first recurrence during or after temozolomide maintenance therapy for newly diagnosed GBM treated with 1st line radiotherapy plus concurrent temozolomide.

Exclusion criteria:

• Prior exposure to agent that blocks CD38 or participation in clinical studies with isatuximab.
• For participants with HCC, SCCHN, EOC or GBM prior exposure to any agent (approved or investigational) that blocks the PD-1/PD-L1 pathway.
• Evidence of other immune related disease /conditions.
• History of non-infectious pneumonitis requiring steroids or current pneumonitis; history of the thoracic radiation.
• Received a live-virus vaccination within 28 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted.
• Prior solid organ or bone marrow transplantation.
• Eastern Cooperative Oncology Group performance status >=2 for participants with HCC, SCCHN or EOC or Karnofsky performance score less than or equal to (<=) 70 for participants with GBM.
• Poor bone marrow reserve.
• Poor organ function. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Related Conditions & MeSH terms

• Neoplasm
• Neoplasms

Intervention

Drug:
• Isatuximab SAR650984
Pharmaceutical form: solution for infusion Route of administration: intravenous
• Atezolizumab
Pharmaceutical form: solution for infusion Route of administration: intravenous

Locations

Country	Name	City	State
Belgium	Investigational Site Number :0560001	Bruxelles
Belgium	Investigational Site Number :0560002	Gent
Canada	Investigational Site Number :1240001	Toronto	Ontario
Czechia	Investigational Site Number :2030001	Brno
Czechia	Investigational Site Number :2030003	Olomouc
Czechia	Investigational Site Number :2030002	Praha 2
Italy	Investigational Site Number :3800007	Meldola	Forlì-Cesena
Italy	Investigational Site Number :3800009	Milano
Italy	Investigational Site Number :3800004	Padova
Italy	Investigational Site Number :3800003	Rozzano	Milano
Netherlands	Investigational Site Number :5280001	Rotterdam
Spain	Investigational Site Number :7240001	Barcelona	Barcelona [Barcelona]
Spain	Investigational Site Number :7240006	Hospitalet de Llobregat	Castilla Y León
Spain	Investigational Site Number :7240004	Madrid	Madrid, Comunidad De
Spain	Investigational Site Number :7240007	Madrid
Spain	Investigational Site Number :7240003	Madrid / Madrid	Madrid, Comunidad De
Spain	Investigational Site Number :7240008	Pamplona	Navarra
Taiwan	Investigational Site Number :1580005	Kaohsiung
Taiwan	Investigational Site Number :1580002	Tainan
Taiwan	Investigational Site Number :1580003	Taipei
Taiwan	Investigational Site Number :1580004	Taipei
Taiwan	Investigational Site Number :1580006	Taipei
Taiwan	Investigational Site Number :1580001	Taipei 100
United States	Investigational Site Number :8400007	Boston	Massachusetts
United States	Investigational Site Number :8400002	Houston	Texas
United States	Investigational Site Number :8400004	Santa Monica	California

Sponsors (1)

Lead Sponsor	Collaborator
Sanofi

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  Czechia,  Italy,  Netherlands,  Spain,  Taiwan, 

References & Publications (1)

Simonelli M, Garralda E, Eskens F, Gil-Martin M, Yen CJ, Obermannova R, Chao Y, Lonardi S, Melichar B, Moreno V, Yu ML, Bongiovanni A, Calvo E, Rottey S, Machiels JP, Gonzalez-Martin A, Paz-Ares L, Chang CL, Mason W, Lin CC, Reardon DA, Vieito M, Santoro A, Meng R, Abbadessa G, Menas F, Lee H, Liu Q, Combeau C, Ternes N, Ziti-Ljajic S, Massard C. Isatuximab plus atezolizumab in patients with advanced solid tumors: results from a phase I/II, open-label, multicenter study. ESMO Open. 2022 Oct;7(5):100562. doi: 10.1016/j.esmoop.2022.100562. Epub 2022 Aug 18. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Dose Limiting Toxicities (DLTs)	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.	Cycle 1 (21 days)
Primary	Recommended Phase 2 Dose (RP2D)	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.	Cycle 1 (21 days)
Primary	Maximum Tolerated Dose (MTD)	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.	Cycle 1 (21 days)
Primary	Percentage of Participants With Overall Response (OR): For HCC/SCCHN/EOC Cohorts	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.	From randomization until disease progression, or death or study cut-off whichever occurred first (maximum duration of exposure: up to 108 weeks)
Primary	Probability of Participants With Progression Free Survival at 6 Months (PFS-6): GBM Cohort	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.	From randomization until 6 months after the last participant's first treatment in the GBM Cohort D-1
Primary	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Treatment-emergent Adverse Events (TESAEs)	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).	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)
Primary	Number of Participants With Hematological Abnormalities	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.	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)
Primary	Number of Participants With Abnormal Electrolyte Parameters	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.	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)
Primary	Number of Participants With Renal Function Abnormalities	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.	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)
Primary	Number of Participants With Liver Abnormalities	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.	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)
Secondary	Number of Participants With Anti-drug Antibodies (ADA) Response Against Isatuximab	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).	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)
Secondary	Number of Participants With Anti-drug Antibodies (ADA) Response Against Atezolizumab	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).	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)
Secondary	Pharmacokinetics (PK): Maximum Concentration Observed (Cmax) After the First Infusion of Isatuximab	Cmax was defined as the maximum concentration observed after the first administration calculated using the noncompartmental analysis after the intravenous 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
Secondary	Pharmacokinetics (PK): Concentration Observed at the End of Intravenous Infusion (Ceoi) of Isatuximab	Ceoi is the plasma concentration observed at the end of intravenous infusion of isatuximab.	At end of infusion on Cycle 1 Day 1
Secondary	Pharmacokinetics (PK): Time to Reach Cmax (Tmax) After First Infusion of Isatuximab	Tmax was defined as the time to reach Cmax, calculated using the non-compartmental analysis after the intravenous infusion of isatuximab.	At SOI, EOI, EOI+4 hours, 72 hours and 168 hours post-dose on Day 1 of Cycle 1
Secondary	Pharmacokinetics (PK): Last Concentration Observed Above the Lower Limit of Quantification (Clast) After the First Infusion of Isatuximab	Clast was defined as the last concentration of isatuximab observed above the lower limit of quantification.	At SOI, EOI, EOI+4 hours, 72 hours and 168 hours post-dose on Day 1 of Cycle 1
Secondary	Pharmacokinetics (PK): Time of Clast (Tlast) After First Infusion of Isatuximab	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.	At SOI, EOI, EOI+4 hours, 72 hours and 168 hours post-dose on Day 1 of Cycle 1
Secondary	Pharmacokinetics (PK): Area Under the Plasma Concentration Time Curve From Time 0 to Last Quantifiable Concentration (AUClast) After First Infusion of Isatuximab	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.	At SOI, EOI, EOI+4 hours, 72 hours and 168 hours post-dose on Day 1 of Cycle 1
Secondary	Pharmacokinetics (PK): Area Under the Plasma Concentration Time Curve Over the Dosing Interval (AUC0-168h) After First Infusion of Isatuximab	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.	At SOI, EOI, EOI+4 hours, 72 hours and 168 hours post-dose on Day 1 of Cycle 1
Secondary	Pharmacokinetics (PK): Trough Plasma Concentrations (Ctrough) of Isatuximab	Ctrough was the plasma concentration of isatuximab observed just before treatment administration during repeated dosing.	Pre-infusion on Cycle 1 Day 1, Cycle 1 Day 8 and Cycle 1 Day 15
Secondary	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
Secondary	Best Percent Change From Baseline in Tumor Burden	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.	From randomization until progression or death or study cut-off date whichever occurred first (maximum duration of exposure: up to 108 weeks)
Secondary	Percentage of Participants With Disease Control (DC) >=6 Months	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.	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)
Secondary	Duration of Response (DOR)	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.	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)
Secondary	Progression-free Survival (PFS)	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.	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)
Secondary	Percentage of Participants With Response as Per Response Assessment for Neuro-Oncology (RANO) Criteria: GBM Cohort	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.	From randomization until progression, or death, or study cut-off whichever occurred first (maximum duration of exposure: 54 weeks for Cohort D-1)