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A Study to Evaluate the Safety and Efficacy of Nivolumab Monotherapy and Nivolumab in Combination With Ipilimumab in Pediatric Participants With High Grade Primary Central Nervous System (CNS) Malignancies

Phase Ib /II Clinical Trial of Nivolumab Monotherapy and Nivolumab in Combination With Ipilimumab in Pediatric Subjects With High Grade Primary CNS Malignancies

Status
Completed
Phases
Phase 2
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT03130959
Acronym
CheckMate 908
Enrollment
166
Registered
2017-04-27
Start date
2017-06-12
Completion date
2022-01-17
Last updated
2022-08-09

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Various Advanced Cancer

Brief summary

The purpose of this study is to determine the safety and effectiveness of nivolumab alone and in combination with ipilimumab in pediatric patients with high grade primary central nervous system (CNS) malignancies.

Interventions

BIOLOGICALNivolumab

Specified dose on specified days

BIOLOGICALIpilimumab

Specified dose on specified days

Sponsors

Bristol-Myers Squibb
Lead SponsorINDUSTRY

Study design

Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE

Eligibility

Sex/Gender
ALL
Age
6 Months to 21 Years
Healthy volunteers
No

Inclusion criteria

* Must have received standard of care therapy, and there must be no potentially-curative treatment available, in one of the following cohorts: * A newly diagnosed Diffuse Intrinsic Pontine Glioma (DIPG) that has been treated with radiation therapy (RT) but no chemotherapy * A histologically confirmed recurrent or progressive non-brainstem High Grade Glioma (HGG) previously treated with surgical resection and RT * A histologically confirmed medulloblastoma that has relapsed or is resistant to at least one line of prior therapy including surgery, RT, and chemotherapy * A histologically confirmed ependymoma that has relapsed or is resistant to at least one line of prior therapy including surgical resection and RT * A histologically-confirmed high grade CNS malignancy other than above which is recurrent or progressive after at least one line of prior therapy * Lansky play score (LPS) for ≤ 16 years of age or Karnofsky performance scale (KPS) for \> 16 years of age assessed within two weeks of enrollment must be \>= 60 * A tumor sample must be available for submission to central laboratory (not required for DIPG)

Exclusion criteria

* An active, known, or suspected autoimmune disease * A concurrent condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days of start of study treatment * Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). Other protocol defined inclusion/

Design outcomes

Primary

MeasureTime frameDescription
Number of Safety Lead-In Participants With Dose Limiting Toxicities (DLTs)up to 6 weeks post-dosingA dose-limiting toxicity (DLT) is defined as a drug-related AE occurring in the first 6 weeks of study treatment. A participant was considered evaluable for a DLT if study treatment was delayed \> 2 weeks or was discontinued due to a related Adverse Event (AE), or if planned study treatment (3 doses of nivolumab in Module A, 2 doses of nivolumab plus ipilimumab in Module B) was administered and safety evaluation after 6 weeks on study is available to the study steering committee (SSC).
Number of Safety Lead-In Participants With Serious Adverse Events (SAEs)up to 6 weeks post-dosingThe number of Safety Lead-In Participants who experienced a Serious Adverse Event (SAE) during the course of the study.
Number of Safety Lead-In Participants With Adverse Events (AEs) Leading to DiscontinuationFrom first dose to 30 days post-last dose (up to approximately 6 weeks)The number of Safety Lead-In Participants who experienced an Adverse Event (AE) during the course of the study that lead to discontinuation of study therapy.
Overall Survival (OS), Cohort 1 Onlyup to approximately 42 monthsOverall survival (OS) is defined as the time between the date of diagnosis and the date of death in Cohort 1.
Progression-Free Survival (PFS), Cohorts 2-4up to approximately 42 monthsProgression-free survival (PFS) is defined as the time from first dose to the date of the first documented tumor progression or death due to any cause.
Progression-Free Survival (PFS), Cohort 5 Onlyup to approximately 42 monthsProgression-free survival (PFS) is defined as the time from first dose to the date of the first documented tumor progression or death due to any cause.

Secondary

MeasureTime frameDescription
Number of Treated Participants With Drug-Related Adverse EventsFrom first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months)The number of treated participants who experienced a Drug-Related Adverse Event during the course of the study. An AE is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study drug and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug.
Number of Treated Participants With Adverse Events Leading to DiscontinuationFrom first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months)The number of treated participants who experienced an Adverse Event leading to discontinuation during the course of the study. An AE is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study drug and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug.
Progression-Free Survival (PFS), Cohort 1 OnlyFrom first dose to the date of the first documented tumor progression or death due to any cause (up to approximately 55 months)Progression-free survival (PFS) is defined as the time from first dose to the date of the first documented tumor progression or death due to any cause. Progression is defined as: * ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement * Significant increase in T2 or fast fluid-attenuated inversion recovery (FLAIR) non-enhancing lesions on stable or increasing doses of corticosteroids * Any new lesion * Clear clinical deterioration not attributable to other causes apart from the tumor * Failure to return for evaluation as a result of death or deteriorating condition * Clear progression of non-measurable disease
Number of Treated Participant With Laboratory Abnormalities - LiverFrom first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months)The number of treated participants who experienced a laboratory abnormality of the liver during the course of the study. Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Upper Limit of Normal (ULN) Units per Liter (U/L) Results reported in International System of Units (SI)
Number of Treated Participant With Laboratory Abnormalities - ThyroidFrom first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months)The number of treated participants who experienced a laboratory abnormality of the thyroid during the course of the study. Free T3 (FT3) Free T4 (FT4) Thyroid stimulating hormone (TSH) Lower Limit of Normal (LLN) Upper limit of normal (ULN) Milliunits per Liter (mlU/L) Results reported in International System of Units (SI)
Number of Treated Participant DeathsFrom first dose to the date of death (up to approximately 55 months)The number of treated participants who died during the course of the study.
Overall Survival at 12 Months (OS12), Cohorts 1-4From first dose to up to 12 months after first doseOverall survival at 12 months (OS12) is defined as the percentage of participants who are alive at 12 months, measured as the survival rate at 12 months from Kaplan-Meier product limit cumulative probability.
Progression-Free Survival at 6 Months (PFS6), Cohorts 2-5From first dose to up to 6 months after first doseProgression-free survival at 6 months (PFS6) is defined as the percentage of participants who are progression free and alive at 6 months following first dose date, measured as the survival rate at 6 months from Kaplan-Meier product limit cumulative probability of progression free. Progression is defined as: * ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement * Significant increase in T2 or fast fluid-attenuated inversion recovery (FLAIR) non-enhancing lesions on stable or increasing doses of corticosteroids * Any new lesion * Clear clinical deterioration not attributable to other causes apart from the tumor * Failure to return for evaluation as a result of death or deteriorating condition * Clear progression of non-measurable disease
Overall Survival (OS), Cohorts 2-5From first dose to the date of death (up to approximately 55 months)Overall survival (OS) is defined as the time between date of first dose and the date of death for Cohorts 2-5.
Number of Treated Participants With Adverse Events (AEs)From first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months)The number of treated participants who experienced an Adverse Event (AE) during the course of the study. An AE is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study drug and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug.
Number of Treated Participants With Serious Adverse Events (SAEs)From first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months)The number of treated participants who experienced a Serious Adverse Event (SAE) during the course of the study. SAE is defined as any untoward medical occurrence that, at any dose: * Results in death * Is life-threatening * Requires inpatient hospitalization or causes prolongation of existing hospitalization * Results in persistent or significant disability/incapacity * Is a congenital anomaly/birth defect * Is an important medical event Note: The reporting timeframe of the SAEs for this Outcome Measure (first dose to 30 days post last dose) differs than that of the reporting timeframe of the SAEs reported under the AE section of the results form (first dose to 100 days post last dose) and thus, the data in each table of SAEs reflects the specific timeframe applied.

Countries

Australia, Brazil, Canada, France, Germany, Hong Kong, Israel, Netherlands, Norway, Poland, Russia, Spain, Sweden, United Kingdom, United States

Participant flow

Pre-assignment details

166 participants were treated

Participants by arm

ArmCount
Arm A1
Module A: nivolumab 3 mg/kg every 2 weeks. Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.
23
Arm B1
Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter. Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.
22
Arm A2
Module A: nivolumab 3 mg/kg every 2 weeks. Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.
16
Arm B2
Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter. Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.
15
Arm A3
Module A: nivolumab 3 mg/kg every 2 weeks. Cohort 3: participants with relapsed or resistant medulloblastoma.
15
Arm B3
Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter. Cohort 3: participants with relapsed or resistant medulloblastoma.
15
Arm A4
Module A: nivolumab 3 mg/kg every 2 weeks. Cohort 4: participants with relapsed or resistant ependymoma.
12
Arm B4
Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter. Cohort 4: participants with relapsed or resistant ependymoma.
10
Arm A5
Module A: nivolumab 3 mg/kg every 2 weeks. Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).
19
Arm B5
Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter. Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).
19
Total166

Withdrawals & dropouts

PeriodReasonFG000FG001FG002FG003FG004FG005FG006FG007FG008FG009
Overall StudyAdministrative reason by sponsor1010000000
Overall StudyAdverse Event unrelated to drug0011101011
Overall StudyDisease progression19712712363158
Overall StudyLost to Follow-up1000000000
Overall StudyNot reported0001010001
Overall StudyOther reasons0000011000
Overall StudyParticipant withdrew consent0102100002
Overall StudyStudy drug toxicity2212113033
Overall StudySubject request to discontinue therapy0011001100

Baseline characteristics

CharacteristicArm A1TotalArm B5Arm A5Arm B4Arm A4Arm B3Arm A3Arm B2Arm A2Arm B1
Age, Customized
>= 12 and < 18 years old
6 Participants61 Participants6 Participants4 Participants3 Participants3 Participants9 Participants11 Participants8 Participants6 Participants5 Participants
Age, Customized
>= 18 years old
2 Participants15 Participants0 Participants1 Participants2 Participants1 Participants2 Participants0 Participants2 Participants4 Participants1 Participants
Age, Customized
>= 2 and < 12 years old
15 Participants87 Participants12 Participants13 Participants4 Participants8 Participants4 Participants4 Participants5 Participants6 Participants16 Participants
Age, Customized
< 2 years old
0 Participants3 Participants1 Participants1 Participants1 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants
Ethnicity (NIH/OMB)
Hispanic or Latino
2 Participants14 Participants0 Participants2 Participants1 Participants1 Participants1 Participants0 Participants2 Participants2 Participants3 Participants
Ethnicity (NIH/OMB)
Not Hispanic or Latino
7 Participants60 Participants6 Participants8 Participants5 Participants5 Participants4 Participants6 Participants5 Participants4 Participants10 Participants
Ethnicity (NIH/OMB)
Unknown or Not Reported
14 Participants92 Participants13 Participants9 Participants4 Participants6 Participants10 Participants9 Participants8 Participants10 Participants9 Participants
Race/Ethnicity, Customized
American Indian or Alaska Native
0 Participants1 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants1 Participants
Race/Ethnicity, Customized
Asian
0 Participants10 Participants2 Participants0 Participants1 Participants3 Participants0 Participants0 Participants1 Participants1 Participants2 Participants
Race/Ethnicity, Customized
Black or African American
2 Participants9 Participants0 Participants1 Participants0 Participants1 Participants1 Participants0 Participants0 Participants0 Participants4 Participants
Race/Ethnicity, Customized
Native Hawaiian or Other Pacific Islander
0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants
Race/Ethnicity, Customized
Other
2 Participants14 Participants4 Participants0 Participants0 Participants1 Participants0 Participants1 Participants0 Participants2 Participants4 Participants
Race/Ethnicity, Customized
White
19 Participants132 Participants13 Participants18 Participants9 Participants7 Participants14 Participants14 Participants14 Participants13 Participants11 Participants
Sex: Female, Male
Female
12 Participants70 Participants10 Participants4 Participants3 Participants6 Participants5 Participants5 Participants3 Participants6 Participants16 Participants
Sex: Female, Male
Male
11 Participants96 Participants9 Participants15 Participants7 Participants6 Participants10 Participants10 Participants12 Participants10 Participants6 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
EG002
affected / at risk
EG003
affected / at risk
EG004
affected / at risk
EG005
affected / at risk
EG006
affected / at risk
EG007
affected / at risk
EG008
affected / at risk
EG009
affected / at risk
deaths
Total, all-cause mortality
18 / 2318 / 2212 / 1613 / 1512 / 1511 / 159 / 127 / 1018 / 1915 / 19
other
Total, other adverse events
22 / 2321 / 2215 / 1614 / 1514 / 1514 / 1511 / 1210 / 1018 / 1918 / 19
serious
Total, serious adverse events
17 / 2316 / 2213 / 1612 / 157 / 1510 / 1511 / 126 / 1014 / 1915 / 19

Outcome results

Primary

Number of Safety Lead-In Participants With Adverse Events (AEs) Leading to Discontinuation

The number of Safety Lead-In Participants who experienced an Adverse Event (AE) during the course of the study that lead to discontinuation of study therapy.

Time frame: From first dose to 30 days post-last dose (up to approximately 6 weeks)

Population: Safety Lead-in participants: In Module A, the first 6 DLT-evaluable participants in Cohort 1 and the first 10 DLT-evaluable participants in Cohorts 2-5; in Module B, the first 10 DLT-evaluable participants.

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
Arm A1, Safety Lead-inNumber of Safety Lead-In Participants With Adverse Events (AEs) Leading to Discontinuation3 Participants
Arms A2-A5, Safety Lead-inNumber of Safety Lead-In Participants With Adverse Events (AEs) Leading to Discontinuation4 Participants
Arms B2-B5, Safety Lead-inNumber of Safety Lead-In Participants With Adverse Events (AEs) Leading to Discontinuation2 Participants
Primary

Number of Safety Lead-In Participants With Dose Limiting Toxicities (DLTs)

A dose-limiting toxicity (DLT) is defined as a drug-related AE occurring in the first 6 weeks of study treatment. A participant was considered evaluable for a DLT if study treatment was delayed \> 2 weeks or was discontinued due to a related Adverse Event (AE), or if planned study treatment (3 doses of nivolumab in Module A, 2 doses of nivolumab plus ipilimumab in Module B) was administered and safety evaluation after 6 weeks on study is available to the study steering committee (SSC).

Time frame: up to 6 weeks post-dosing

Population: Safety Lead-in participants: In Module A, the first 6 DLT-evaluable participants in Cohort 1 and the first 10 DLT-evaluable participants in Cohorts 2-5; in Module B, the first 10 DLT-evaluable participants.

ArmMeasureValue (NUMBER)
Arm A1, Safety Lead-inNumber of Safety Lead-In Participants With Dose Limiting Toxicities (DLTs)0 Number of participants
Arms A2-A5, Safety Lead-inNumber of Safety Lead-In Participants With Dose Limiting Toxicities (DLTs)0 Number of participants
Arms B2-B5, Safety Lead-inNumber of Safety Lead-In Participants With Dose Limiting Toxicities (DLTs)0 Number of participants
Primary

Number of Safety Lead-In Participants With Serious Adverse Events (SAEs)

The number of Safety Lead-In Participants who experienced a Serious Adverse Event (SAE) during the course of the study.

Time frame: up to 6 weeks post-dosing

Population: Safety Lead-in participants: In Module A, the first 6 DLT-evaluable participants in Cohort 1 and the first 10 DLT-evaluable participants in Cohorts 2-5; in Module B, the first 10 DLT-evaluable participants.

ArmMeasureValue (NUMBER)
Arm A1, Safety Lead-inNumber of Safety Lead-In Participants With Serious Adverse Events (SAEs)7 Number of participants
Arms A2-A5, Safety Lead-inNumber of Safety Lead-In Participants With Serious Adverse Events (SAEs)6 Number of participants
Arms B2-B5, Safety Lead-inNumber of Safety Lead-In Participants With Serious Adverse Events (SAEs)8 Number of participants
Primary

Overall Survival (OS), Cohort 1 Only

Overall survival (OS) is defined as the time between the date of diagnosis and the date of death in Cohort 1.

Time frame: up to approximately 42 months

Population: All treated participants

ArmMeasureValue (MEDIAN)
Arm A1, Safety Lead-inOverall Survival (OS), Cohort 1 Only11.66 months
Arms A2-A5, Safety Lead-inOverall Survival (OS), Cohort 1 Only10.78 months
Primary

Progression-Free Survival (PFS), Cohort 5 Only

Progression-free survival (PFS) is defined as the time from first dose to the date of the first documented tumor progression or death due to any cause.

Time frame: up to approximately 42 months

Population: All treated participants

ArmMeasureValue (MEDIAN)
Arm A1, Safety Lead-inProgression-Free Survival (PFS), Cohort 5 Only1.22 months
Arms A2-A5, Safety Lead-inProgression-Free Survival (PFS), Cohort 5 Only1.61 months
Primary

Progression-Free Survival (PFS), Cohorts 2-4

Progression-free survival (PFS) is defined as the time from first dose to the date of the first documented tumor progression or death due to any cause.

Time frame: up to approximately 42 months

Population: All treated participants

ArmMeasureValue (MEDIAN)
Arm A1, Safety Lead-inProgression-Free Survival (PFS), Cohorts 2-41.74 months
Arms A2-A5, Safety Lead-inProgression-Free Survival (PFS), Cohorts 2-41.31 months
Arms B2-B5, Safety Lead-inProgression-Free Survival (PFS), Cohorts 2-41.38 months
Arm B3Progression-Free Survival (PFS), Cohorts 2-42.76 months
Arm A4Progression-Free Survival (PFS), Cohorts 2-41.41 months
Arm B4Progression-Free Survival (PFS), Cohorts 2-44.60 months
Secondary

Number of Treated Participant Deaths

The number of treated participants who died during the course of the study.

Time frame: From first dose to the date of death (up to approximately 55 months)

Population: All treated participants

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
Arm A1, Safety Lead-inNumber of Treated Participant Deaths18 Participants
Arms A2-A5, Safety Lead-inNumber of Treated Participant Deaths18 Participants
Arms B2-B5, Safety Lead-inNumber of Treated Participant Deaths12 Participants
Arm B3Number of Treated Participant Deaths13 Participants
Arm A4Number of Treated Participant Deaths12 Participants
Arm B4Number of Treated Participant Deaths11 Participants
Arm A4Number of Treated Participant Deaths9 Participants
Arm B4Number of Treated Participant Deaths7 Participants
Arm A5Number of Treated Participant Deaths18 Participants
Arm B5Number of Treated Participant Deaths15 Participants
Secondary

Number of Treated Participants With Adverse Events (AEs)

The number of treated participants who experienced an Adverse Event (AE) during the course of the study. An AE is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study drug and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug.

Time frame: From first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months)

Population: All treated participants

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
Arm A1, Safety Lead-inNumber of Treated Participants With Adverse Events (AEs)23 Participants
Arms A2-A5, Safety Lead-inNumber of Treated Participants With Adverse Events (AEs)21 Participants
Arms B2-B5, Safety Lead-inNumber of Treated Participants With Adverse Events (AEs)15 Participants
Arm B3Number of Treated Participants With Adverse Events (AEs)14 Participants
Arm A4Number of Treated Participants With Adverse Events (AEs)14 Participants
Arm B4Number of Treated Participants With Adverse Events (AEs)15 Participants
Arm A4Number of Treated Participants With Adverse Events (AEs)12 Participants
Arm B4Number of Treated Participants With Adverse Events (AEs)10 Participants
Arm A5Number of Treated Participants With Adverse Events (AEs)18 Participants
Arm B5Number of Treated Participants With Adverse Events (AEs)18 Participants
Secondary

Number of Treated Participants With Adverse Events Leading to Discontinuation

The number of treated participants who experienced an Adverse Event leading to discontinuation during the course of the study. An AE is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study drug and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug.

Time frame: From first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months)

Population: All treated participants

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
Arm A1, Safety Lead-inNumber of Treated Participants With Adverse Events Leading to Discontinuation4 Participants
Arms A2-A5, Safety Lead-inNumber of Treated Participants With Adverse Events Leading to Discontinuation7 Participants
Arms B2-B5, Safety Lead-inNumber of Treated Participants With Adverse Events Leading to Discontinuation3 Participants
Arm B3Number of Treated Participants With Adverse Events Leading to Discontinuation5 Participants
Arm A4Number of Treated Participants With Adverse Events Leading to Discontinuation2 Participants
Arm B4Number of Treated Participants With Adverse Events Leading to Discontinuation3 Participants
Arm A4Number of Treated Participants With Adverse Events Leading to Discontinuation6 Participants
Arm B4Number of Treated Participants With Adverse Events Leading to Discontinuation1 Participants
Arm A5Number of Treated Participants With Adverse Events Leading to Discontinuation6 Participants
Arm B5Number of Treated Participants With Adverse Events Leading to Discontinuation8 Participants
Secondary

Number of Treated Participants With Drug-Related Adverse Events

The number of treated participants who experienced a Drug-Related Adverse Event during the course of the study. An AE is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study drug and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug.

Time frame: From first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months)

Population: All treated participants

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
Arm A1, Safety Lead-inNumber of Treated Participants With Drug-Related Adverse Events14 Participants
Arms A2-A5, Safety Lead-inNumber of Treated Participants With Drug-Related Adverse Events16 Participants
Arms B2-B5, Safety Lead-inNumber of Treated Participants With Drug-Related Adverse Events12 Participants
Arm B3Number of Treated Participants With Drug-Related Adverse Events8 Participants
Arm A4Number of Treated Participants With Drug-Related Adverse Events6 Participants
Arm B4Number of Treated Participants With Drug-Related Adverse Events11 Participants
Arm A4Number of Treated Participants With Drug-Related Adverse Events6 Participants
Arm B4Number of Treated Participants With Drug-Related Adverse Events6 Participants
Arm A5Number of Treated Participants With Drug-Related Adverse Events11 Participants
Arm B5Number of Treated Participants With Drug-Related Adverse Events10 Participants
Secondary

Number of Treated Participants With Serious Adverse Events (SAEs)

The number of treated participants who experienced a Serious Adverse Event (SAE) during the course of the study. SAE is defined as any untoward medical occurrence that, at any dose: * Results in death * Is life-threatening * Requires inpatient hospitalization or causes prolongation of existing hospitalization * Results in persistent or significant disability/incapacity * Is a congenital anomaly/birth defect * Is an important medical event Note: The reporting timeframe of the SAEs for this Outcome Measure (first dose to 30 days post last dose) differs than that of the reporting timeframe of the SAEs reported under the AE section of the results form (first dose to 100 days post last dose) and thus, the data in each table of SAEs reflects the specific timeframe applied.

Time frame: From first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months)

Population: All treated participants

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
Arm A1, Safety Lead-inNumber of Treated Participants With Serious Adverse Events (SAEs)10 Participants
Arms A2-A5, Safety Lead-inNumber of Treated Participants With Serious Adverse Events (SAEs)14 Participants
Arms B2-B5, Safety Lead-inNumber of Treated Participants With Serious Adverse Events (SAEs)10 Participants
Arm B3Number of Treated Participants With Serious Adverse Events (SAEs)9 Participants
Arm A4Number of Treated Participants With Serious Adverse Events (SAEs)6 Participants
Arm B4Number of Treated Participants With Serious Adverse Events (SAEs)7 Participants
Arm A4Number of Treated Participants With Serious Adverse Events (SAEs)7 Participants
Arm B4Number of Treated Participants With Serious Adverse Events (SAEs)5 Participants
Arm A5Number of Treated Participants With Serious Adverse Events (SAEs)13 Participants
Arm B5Number of Treated Participants With Serious Adverse Events (SAEs)14 Participants
Secondary

Number of Treated Participant With Laboratory Abnormalities - Liver

The number of treated participants who experienced a laboratory abnormality of the liver during the course of the study. Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Upper Limit of Normal (ULN) Units per Liter (U/L) Results reported in International System of Units (SI)

Time frame: From first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months)

Population: All treated participants

ArmMeasureGroupValue (COUNT_OF_PARTICIPANTS)
Arm A1, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 10XULN2 Participants
Arm A1, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 20XULN0 Participants
Arm A1, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 1.5*ULN within 30 days0 Participants
Arm A1, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 2*ULN within 30 days0 Participants
Arm A1, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverTOTAL BILIRUBIN > 2XULN0 Participants
Arm A1, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 2*ULN within 1 day0 Participants
Arm A1, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverALP > 1.5XULN0 Participants
Arm A1, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 3XULN3 Participants
Arm A1, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 5XULN2 Participants
Arm A1, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 1.5*ULN within 1 day0 Participants
Arms A2-A5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 20XULN1 Participants
Arms A2-A5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverTOTAL BILIRUBIN > 2XULN2 Participants
Arms A2-A5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 10XULN1 Participants
Arms A2-A5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 1.5*ULN within 30 days2 Participants
Arms A2-A5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverALP > 1.5XULN0 Participants
Arms A2-A5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 2*ULN within 30 days2 Participants
Arms A2-A5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 1.5*ULN within 1 day1 Participants
Arms A2-A5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 5XULN4 Participants
Arms A2-A5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 3XULN7 Participants
Arms A2-A5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 2*ULN within 1 day1 Participants
Arms B2-B5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverTOTAL BILIRUBIN > 2XULN0 Participants
Arms B2-B5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 3XULN2 Participants
Arms B2-B5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverALP > 1.5XULN0 Participants
Arms B2-B5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 20XULN1 Participants
Arms B2-B5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 1.5*ULN within 1 day1 Participants
Arms B2-B5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 1.5*ULN within 30 days1 Participants
Arms B2-B5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 10XULN1 Participants
Arms B2-B5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 2*ULN within 1 day0 Participants
Arms B2-B5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 2*ULN within 30 days0 Participants
Arms B2-B5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 5XULN1 Participants
Arm B3Number of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 2*ULN within 1 day0 Participants
Arm B3Number of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 3XULN0 Participants
Arm B3Number of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 2*ULN within 30 days0 Participants
Arm B3Number of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 5XULN0 Participants
Arm B3Number of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 1.5*ULN within 30 days0 Participants
Arm B3Number of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 1.5*ULN within 1 day0 Participants
Arm B3Number of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 20XULN0 Participants
Arm B3Number of Treated Participant With Laboratory Abnormalities - LiverTOTAL BILIRUBIN > 2XULN0 Participants
Arm B3Number of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 10XULN0 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 1.5*ULN within 30 days0 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 1.5*ULN within 1 day0 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 20XULN0 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 2*ULN within 1 day0 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 5XULN0 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - LiverTOTAL BILIRUBIN > 2XULN0 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 3XULN0 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 2*ULN within 30 days0 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 10XULN0 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 10XULN1 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 2*ULN within 1 day0 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 1.5*ULN within 1 day0 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 2*ULN within 30 days0 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 5XULN1 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 3XULN3 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 20XULN0 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - LiverTOTAL BILIRUBIN > 2XULN0 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 1.5*ULN within 30 days0 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 1.5*ULN within 1 day0 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - LiverTOTAL BILIRUBIN > 2XULN0 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 1.5*ULN within 30 days0 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 2*ULN within 1 day0 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 2*ULN within 30 days0 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 3XULN1 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 5XULN0 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 10XULN0 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 20XULN0 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 2*ULN within 1 day0 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 5XULN1 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - LiverTOTAL BILIRUBIN > 2XULN0 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 3XULN1 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 2*ULN within 30 days0 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 1.5*ULN within 30 days0 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 1.5*ULN within 1 day0 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 20XULN0 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 10XULN1 Participants
Arm A5Number of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 1.5*ULN within 1 day0 Participants
Arm A5Number of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 2*ULN within 30 days0 Participants
Arm A5Number of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 20XULN0 Participants
Arm A5Number of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 1.5*ULN within 30 days0 Participants
Arm A5Number of Treated Participant With Laboratory Abnormalities - LiverALP > 1.5XULN0 Participants
Arm A5Number of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 5XULN2 Participants
Arm A5Number of Treated Participant With Laboratory Abnormalities - LiverTOTAL BILIRUBIN > 2XULN1 Participants
Arm A5Number of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 10XULN2 Participants
Arm A5Number of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 2*ULN within 1 day0 Participants
Arm A5Number of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 3XULN3 Participants
Arm B5Number of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 3XULN2 Participants
Arm B5Number of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 2*ULN within 1 day1 Participants
Arm B5Number of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 5XULN2 Participants
Arm B5Number of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 1.5*ULN within 30 days1 Participants
Arm B5Number of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 1.5*ULN within 1 day1 Participants
Arm B5Number of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 10XULN2 Participants
Arm B5Number of Treated Participant With Laboratory Abnormalities - LiverALT OR AST > 20XULN2 Participants
Arm B5Number of Treated Participant With Laboratory Abnormalities - LiverALP > 1.5XULN1 Participants
Arm B5Number of Treated Participant With Laboratory Abnormalities - LiverTOTAL BILIRUBIN > 2XULN1 Participants
Arm B5Number of Treated Participant With Laboratory Abnormalities - LiverALT or AST > 3xULN w/ Tbili > 2*ULN within 30 days1 Participants
Secondary

Number of Treated Participant With Laboratory Abnormalities - Thyroid

The number of treated participants who experienced a laboratory abnormality of the thyroid during the course of the study. Free T3 (FT3) Free T4 (FT4) Thyroid stimulating hormone (TSH) Lower Limit of Normal (LLN) Upper limit of normal (ULN) Milliunits per Liter (mlU/L) Results reported in International System of Units (SI)

Time frame: From first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months)

Population: All treated participants with at least one on-treatment TSH measurement

ArmMeasureGroupValue (COUNT_OF_PARTICIPANTS)
Arm A1, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH TSH >= LLN AT BASELINE3 Participants
Arm A1, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN2 Participants
Arm A1, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH TSH <= ULN AT BASELINE2 Participants
Arm A1, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH FT3/FT4 TEST MISSING2 Participants
Arm A1, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH AT LEAST ONE FT3/FT4 TEST < LLN1 Participants
Arm A1, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH ALL OTHER FT3/FT4 TEST >= LLN0 Participants
Arm A1, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH ALL OTHER FT3/FT4 TEST <= ULN1 Participants
Arm A1, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH FT3/FT4 TEST MISSING1 Participants
Arm A1, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN3 Participants
Arm A1, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH<LLN, LLN WITH AT LEAST ONE FT3/FT4 TEST>ULN0 Participants
Arms A2-A5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH ALL OTHER FT3/FT4 TEST <= ULN2 Participants
Arms A2-A5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH FT3/FT4 TEST MISSING0 Participants
Arms A2-A5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN1 Participants
Arms A2-A5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH FT3/FT4 TEST MISSING4 Participants
Arms A2-A5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN7 Participants
Arms A2-A5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH AT LEAST ONE FT3/FT4 TEST < LLN1 Participants
Arms A2-A5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH TSH <= ULN AT BASELINE1 Participants
Arms A2-A5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH ALL OTHER FT3/FT4 TEST >= LLN0 Participants
Arms A2-A5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH<LLN, LLN WITH AT LEAST ONE FT3/FT4 TEST>ULN1 Participants
Arms A2-A5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH TSH >= LLN AT BASELINE6 Participants
Arms B2-B5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH ALL OTHER FT3/FT4 TEST >= LLN1 Participants
Arms B2-B5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN2 Participants
Arms B2-B5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH AT LEAST ONE FT3/FT4 TEST < LLN1 Participants
Arms B2-B5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH TSH <= ULN AT BASELINE2 Participants
Arms B2-B5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN3 Participants
Arms B2-B5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH<LLN, LLN WITH AT LEAST ONE FT3/FT4 TEST>ULN0 Participants
Arms B2-B5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH FT3/FT4 TEST MISSING1 Participants
Arms B2-B5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH TSH >= LLN AT BASELINE1 Participants
Arms B2-B5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH FT3/FT4 TEST MISSING1 Participants
Arms B2-B5, Safety Lead-inNumber of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH ALL OTHER FT3/FT4 TEST <= ULN1 Participants
Arm B3Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH TSH <= ULN AT BASELINE1 Participants
Arm B3Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH FT3/FT4 TEST MISSING0 Participants
Arm B3Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH ALL OTHER FT3/FT4 TEST >= LLN0 Participants
Arm B3Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH FT3/FT4 TEST MISSING0 Participants
Arm B3Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH AT LEAST ONE FT3/FT4 TEST < LLN1 Participants
Arm B3Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN2 Participants
Arm B3Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH ALL OTHER FT3/FT4 TEST <= ULN2 Participants
Arm B3Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH<LLN, LLN WITH AT LEAST ONE FT3/FT4 TEST>ULN0 Participants
Arm B3Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN1 Participants
Arm B3Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH TSH >= LLN AT BASELINE2 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH FT3/FT4 TEST MISSING0 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH TSH <= ULN AT BASELINE0 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN0 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH AT LEAST ONE FT3/FT4 TEST < LLN1 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH ALL OTHER FT3/FT4 TEST <= ULN0 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH ALL OTHER FT3/FT4 TEST >= LLN0 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN3 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH FT3/FT4 TEST MISSING2 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH<LLN, LLN WITH AT LEAST ONE FT3/FT4 TEST>ULN0 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH TSH >= LLN AT BASELINE0 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH FT3/FT4 TEST MISSING0 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH ALL OTHER FT3/FT4 TEST >= LLN0 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN3 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH ALL OTHER FT3/FT4 TEST <= ULN1 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH TSH <= ULN AT BASELINE7 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH TSH >= LLN AT BASELINE1 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN7 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH AT LEAST ONE FT3/FT4 TEST < LLN6 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH FT3/FT4 TEST MISSING1 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH<LLN, LLN WITH AT LEAST ONE FT3/FT4 TEST>ULN2 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH ALL OTHER FT3/FT4 TEST >= LLN0 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN2 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH TSH <= ULN AT BASELINE1 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH AT LEAST ONE FT3/FT4 TEST < LLN2 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH FT3/FT4 TEST MISSING0 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN0 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH TSH >= LLN AT BASELINE0 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH<LLN, LLN WITH AT LEAST ONE FT3/FT4 TEST>ULN0 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH ALL OTHER FT3/FT4 TEST <= ULN0 Participants
Arm A4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH FT3/FT4 TEST MISSING0 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH FT3/FT4 TEST MISSING0 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH TSH <= ULN AT BASELINE3 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH<LLN, LLN WITH AT LEAST ONE FT3/FT4 TEST>ULN0 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN3 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH TSH >= LLN AT BASELINE0 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN0 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH ALL OTHER FT3/FT4 TEST >= LLN0 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH AT LEAST ONE FT3/FT4 TEST < LLN2 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH ALL OTHER FT3/FT4 TEST <= ULN0 Participants
Arm B4Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH FT3/FT4 TEST MISSING1 Participants
Arm A5Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN0 Participants
Arm A5Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH TSH <= ULN AT BASELINE1 Participants
Arm A5Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH ALL OTHER FT3/FT4 TEST >= LLN1 Participants
Arm A5Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH FT3/FT4 TEST MISSING0 Participants
Arm A5Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN1 Participants
Arm A5Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH FT3/FT4 TEST MISSING0 Participants
Arm A5Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH<LLN, LLN WITH AT LEAST ONE FT3/FT4 TEST>ULN0 Participants
Arm A5Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH AT LEAST ONE FT3/FT4 TEST < LLN0 Participants
Arm A5Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH TSH >= LLN AT BASELINE0 Participants
Arm A5Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH ALL OTHER FT3/FT4 TEST <= ULN0 Participants
Arm B5Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH TSH >= LLN AT BASELINE1 Participants
Arm B5Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH FT3/FT4 TEST MISSING0 Participants
Arm B5Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH<LLN, LLN WITH AT LEAST ONE FT3/FT4 TEST>ULN0 Participants
Arm B5Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH ALL OTHER FT3/FT4 TEST >= LLN3 Participants
Arm B5Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH AT LEAST ONE FT3/FT4 TEST < LLN2 Participants
Arm B5Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH ALL OTHER FT3/FT4 TEST <= ULN1 Participants
Arm B5Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN, WITH TSH <= ULN AT BASELINE2 Participants
Arm B5Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH > ULN5 Participants
Arm B5Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN, WITH FT3/FT4 TEST MISSING0 Participants
Arm B5Number of Treated Participant With Laboratory Abnormalities - ThyroidTSH < LLN1 Participants
Secondary

Overall Survival at 12 Months (OS12), Cohorts 1-4

Overall survival at 12 months (OS12) is defined as the percentage of participants who are alive at 12 months, measured as the survival rate at 12 months from Kaplan-Meier product limit cumulative probability.

Time frame: From first dose to up to 12 months after first dose

Population: All treated participants in Cohorts 1-4

ArmMeasureValue (NUMBER)
Arm A1, Safety Lead-inOverall Survival at 12 Months (OS12), Cohorts 1-447.3 Percentage of participants
Arms A2-A5, Safety Lead-inOverall Survival at 12 Months (OS12), Cohorts 1-442.9 Percentage of participants
Arms B2-B5, Safety Lead-inOverall Survival at 12 Months (OS12), Cohorts 1-437.5 Percentage of participants
Arm B3Overall Survival at 12 Months (OS12), Cohorts 1-432.8 Percentage of participants
Arm A4Overall Survival at 12 Months (OS12), Cohorts 1-438.9 Percentage of participants
Arm B4Overall Survival at 12 Months (OS12), Cohorts 1-486.7 Percentage of participants
Arm A4Overall Survival at 12 Months (OS12), Cohorts 1-441.7 Percentage of participants
Arm B4Overall Survival at 12 Months (OS12), Cohorts 1-444.4 Percentage of participants
Secondary

Overall Survival (OS), Cohorts 2-5

Overall survival (OS) is defined as the time between date of first dose and the date of death for Cohorts 2-5.

Time frame: From first dose to the date of death (up to approximately 55 months)

Population: All treated participants in Cohorts 2-5

ArmMeasureValue (MEDIAN)
Arm A1, Safety Lead-inOverall Survival (OS), Cohorts 2-56.67 Months
Arms A2-A5, Safety Lead-inOverall Survival (OS), Cohorts 2-56.47 Months
Arms B2-B5, Safety Lead-inOverall Survival (OS), Cohorts 2-57.36 Months
Arm B3Overall Survival (OS), Cohorts 2-522.21 Months
Arm A4Overall Survival (OS), Cohorts 2-55.70 Months
Arm B4Overall Survival (OS), Cohorts 2-59.82 Months
Arm A4Overall Survival (OS), Cohorts 2-55.91 Months
Arm B4Overall Survival (OS), Cohorts 2-58.48 Months
Secondary

Progression-Free Survival at 6 Months (PFS6), Cohorts 2-5

Progression-free survival at 6 months (PFS6) is defined as the percentage of participants who are progression free and alive at 6 months following first dose date, measured as the survival rate at 6 months from Kaplan-Meier product limit cumulative probability of progression free. Progression is defined as: * ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement * Significant increase in T2 or fast fluid-attenuated inversion recovery (FLAIR) non-enhancing lesions on stable or increasing doses of corticosteroids * Any new lesion * Clear clinical deterioration not attributable to other causes apart from the tumor * Failure to return for evaluation as a result of death or deteriorating condition * Clear progression of non-measurable disease

Time frame: From first dose to up to 6 months after first dose

Population: All treated participants in Cohorts 2-5

ArmMeasureValue (NUMBER)
Arm A1, Safety Lead-inProgression-Free Survival at 6 Months (PFS6), Cohorts 2-59.4 Percentage of participants
Arms A2-A5, Safety Lead-inProgression-Free Survival at 6 Months (PFS6), Cohorts 2-514.3 Percentage of participants
Arms B2-B5, Safety Lead-inProgression-Free Survival at 6 Months (PFS6), Cohorts 2-50 Percentage of participants
Arm B3Progression-Free Survival at 6 Months (PFS6), Cohorts 2-520.0 Percentage of participants
Arm A4Progression-Free Survival at 6 Months (PFS6), Cohorts 2-520.0 Percentage of participants
Arm B4Progression-Free Survival at 6 Months (PFS6), Cohorts 2-511.4 Percentage of participants
Arm A4Progression-Free Survival at 6 Months (PFS6), Cohorts 2-55.3 Percentage of participants
Arm B4Progression-Free Survival at 6 Months (PFS6), Cohorts 2-514.0 Percentage of participants
Secondary

Progression-Free Survival (PFS), Cohort 1 Only

Progression-free survival (PFS) is defined as the time from first dose to the date of the first documented tumor progression or death due to any cause. Progression is defined as: * ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement * Significant increase in T2 or fast fluid-attenuated inversion recovery (FLAIR) non-enhancing lesions on stable or increasing doses of corticosteroids * Any new lesion * Clear clinical deterioration not attributable to other causes apart from the tumor * Failure to return for evaluation as a result of death or deteriorating condition * Clear progression of non-measurable disease

Time frame: From first dose to the date of the first documented tumor progression or death due to any cause (up to approximately 55 months)

Population: All treated participants in Cohort 1

ArmMeasureValue (MEDIAN)
Arm A1, Safety Lead-inProgression-Free Survival (PFS), Cohort 1 Only6.21 Months
Arms A2-A5, Safety Lead-inProgression-Free Survival (PFS), Cohort 1 Only4.53 Months
Post Hoc

Overall Survival (OS), Cohort 1 Only - Extended Collection

Overall survival (OS) is defined as the time between the date of diagnosis and the date of death in Cohort 1. Note: This outcome measure represents an updated version of the primary endpoint to include additional data collection that has occurred after the primary completion date. (Assessments were made until 17-Jan-2022).

Time frame: From first dose to the date of death (up to approximately 55 months)

Population: All treated participants in Cohort 1

ArmMeasureValue (MEDIAN)
Arm A1, Safety Lead-inOverall Survival (OS), Cohort 1 Only - Extended Collection11.66 Months
Arms A2-A5, Safety Lead-inOverall Survival (OS), Cohort 1 Only - Extended Collection10.78 Months
Post Hoc

Progression-Free Survival (PFS), Cohort 5 Only - Extended Collection

Progression-free survival (PFS) is defined as the time from first dose to the date of the first documented tumor progression or death due to any cause. Note: This outcome measure represents an updated version of the primary endpoint to include additional data collection that has occurred after the primary completion date. (Assessments were made until 17-Jan-2022). Progression is defined as: * ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement * Significant increase in T2 or fast fluid-attenuated inversion recovery (FLAIR) non-enhancing lesions on stable or increasing doses of corticosteroids * Any new lesion * Clear clinical deterioration not attributable to other causes apart from the tumor * Failure to return for evaluation as a result of death or deteriorating condition * Clear progression of non-measurable disease

Time frame: From first dose to the date of the first documented tumor progression or death due to any cause (up to approximately 55 months)

Population: All treated participants in Cohort 5

ArmMeasureValue (MEDIAN)
Arm A1, Safety Lead-inProgression-Free Survival (PFS), Cohort 5 Only - Extended Collection1.22 Months
Arms A2-A5, Safety Lead-inProgression-Free Survival (PFS), Cohort 5 Only - Extended Collection1.61 Months
Post Hoc

Progression-Free Survival (PFS), Cohorts 2-4 - Extended Collection

Progression-free survival (PFS) is defined as the time from first dose to the date of the first documented tumor progression or death due to any cause. Note: This outcome measure represents an updated version of the primary endpoint to include additional data collection that has occurred after the primary completion date. (Assessments were made until 17-Jan-2022). Progression is defined as: * ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement * Significant increase in T2 or fast fluid-attenuated inversion recovery (FLAIR) non-enhancing lesions on stable or increasing doses of corticosteroids * Any new lesion * Clear clinical deterioration not attributable to other causes apart from the tumor * Failure to return for evaluation as a result of death or deteriorating condition * Clear progression of non-measurable disease

Time frame: From first dose to the date of the first documented tumor progression or death due to any cause (up to approximately 55 months)

Population: All treated participants in Cohorts 2-4

ArmMeasureValue (MEDIAN)
Arm A1, Safety Lead-inProgression-Free Survival (PFS), Cohorts 2-4 - Extended Collection1.74 Months
Arms A2-A5, Safety Lead-inProgression-Free Survival (PFS), Cohorts 2-4 - Extended Collection1.38 Months
Arms B2-B5, Safety Lead-inProgression-Free Survival (PFS), Cohorts 2-4 - Extended Collection1.38 Months
Arm B3Progression-Free Survival (PFS), Cohorts 2-4 - Extended Collection2.69 Months
Arm A4Progression-Free Survival (PFS), Cohorts 2-4 - Extended Collection1.41 Months
Arm B4Progression-Free Survival (PFS), Cohorts 2-4 - Extended Collection4.60 Months

Source: ClinicalTrials.gov · Data processed: Feb 12, 2026