Colorectal Cancer, Colorectal Carcinoma, Colorectal Neoplasm, Colorectal Tumors
Conditions
Brief summary
The purpose of this study is to investigate treatment with nivolumab in combination with trametinib with or without ipilimumab in participants with previously treated cancer of the colon or rectum that has spread.
Interventions
BIOLOGICALNivolumab
Specified dose on specified days
DRUGTrametinib
Specified dose on specified days
BIOLOGICALIpilimumab
Specified dose on specified days
DRUGRegorafenib
Specified dose on specified days
Sponsors
Novartis
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed previously treated metastatic colorectal cancer with adenocarcinoma histology and in Stage IV per American Joint Committee on Cancer (version 4.0) at study entry * Microsatellite status should be performed per local standard of practice, immunohistochemistry (IHC) and/or PCR. If IHC results are equivocal, PCR is required for determining microsatellite stable (MSS) status * Must have measurable disease per RECIST 1.1. Participants with lesions in a previously irradiated field as the sole site of measurable disease will be permitted to enroll provided the lesion(s) have demonstrated clear progression and can be measured accurately * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 at screening and on cycle 1 day 1 (C1D1)
Exclusion criteria
* BRAF V600 mutant colorectal cancer * Active brain metastases or leptomeningeal metastases * Active, known or suspected autoimmune disease * Participants with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study treatment administration * History of interstitial lung disease or pneumonitis * Prior treatment with immune checkpoint inhibitors and mitogen-activated protein kinase enzymes (MEK) inhibitors * History of allergy or hypersensitivity to study drug components Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting Toxicities in Part 1 and Part 1A | 4 weeks for Doublet Reginmen and 8 weeks for triplet Regimen | Dose Limiting Toxicities are defined as adverse events have to be at least possibly related to study treatment, and not to disease progression, be clinically relevant and a clinically relevant shift from baseline. |
| Safety Related Events in Part 1 and Part 1 A | Assessed from first dose date to 100 days after last dose of study therapy. (Approximately: Part 1: ~ 6.5 Months Part 1A: ~ 5.5 Months) | Safety-related events in clinical trials include Adverse Events (AEs), Serious Adverse Events (SAEs), and deaths. An AE is any new or worsening medical issue in a participant receiving the study drug, regardless of its relation to the drug. This includes abnormal lab results, symptoms, or diseases. An SAE is a more severe AE that results in death, is life-threatening, requires or prolongs hospitalization, causes significant disability, involves a birth defect, or is deemed medically important-potentially jeopardizing the participant or requiring intervention, even if not immediately life-threatening. These definitions help ensure consistent reporting and evaluation of safety during clinical studies. |
| Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | Assessed from first dose date to 100 days after last dose of study therapy. (Approximately: Part 1: ~ 6.5 Months Part 1A: ~ 5.5 Months) | Number of participants with clinical laboratory abnormalities in specific thyroid tests |
| Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | Assessed from first dose date to 100 days after last dose of study therapy. (Approximately: Part 1: ~ 6.5 Months Part 1A: ~ 5.5 Months) | Number of participants with clinical laboratory abnormalities in specific liver tests. |
| Overal Response Rate in Part 1B and Part 2 | Approximately up to 30 Months | ORR is defined as the proportion of all treated participants whose BOR is either confirmed complete response (CR) or confirmed partial response (PR). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival in Part 1 and Part 1A | Approximately up to 69 Months | OS for a participant is defined as the time from the first dosing date to the date of death due to any cause. A participant who has not died will be censored at last known date alive. |
| Safety Related Events in Part 1B and Part 2 | Assessed from first dose date to 100 days after last dose of study therapy. (Approximately: 6.8 Months) | Safety-related events in clinical trials include Adverse Events (AEs), Serious Adverse Events (SAEs), and deaths. An AE is any new or worsening medical issue in a participant receiving the study drug, regardless of its relation to the drug. This includes abnormal lab results, symptoms, or diseases. An SAE is a more severe AE that results in death, is life-threatening, requires or prolongs hospitalization, causes significant disability, involves a birth defect, or is deemed medically important-potentially jeopardizing the participant or requiring intervention, even if not immediately life-threatening. These definitions help ensure consistent reporting and evaluation of safety during clinical studies. |
| Objective Response Rate in Part 1 and Part 1A | From the first dosing date and the date of the initial objectively documented tumor progression or subsequent therapy date (Approximately up to 21 Months) | ORR is defined as the proportion of all treated participants whose BOR is either confirmed complete response (CR) or confirmed partial response (PR). |
| Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Liver Tests | Assessed from first dose date to 100 days after last dose of study therapy. (Approximately: 6.8 Months) | Number of participants with clinical laboratory abnormalities in specific liver tests. |
| Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | Assessed from first dose date to 100 days after last dose of study therapy. (Approximately: 6.8 Months) | Number of participants with clinical laboratory abnormalities in specific thyroid tests |
| Disease Control Rate in Part 1 and Part 1A | From the first dosing date and the date of the initial objectively documented tumor progression or subsequent therapy date (Approximately up to 21 Months) | The disease control rate (DCR) is defined as the percentage of participants whose BOR is either confirmed CR or confirmed PR or stable disease (SD) |
| Duration of Response in Part 1 and Part 1A | Approximately up to 20 Months | DOR for a participant with a BOR of confirmed CR or PR, is defined as the time between the date of first confirmed response and the date of the first objectively documented tumor progression per RECIST 1.1 or death, whichever occurs first. |
| Time to Response in Part 1 and Part 1A | From the first dosing date to the date of first documented CR or PR per RECIST 1.1. (Approximately on average 10 months) | Time to response (TTR) is defined for participants who had a confirmed CR or PR as the time from the first dosing date to the date of first documented CR or PR per RECIST 1.1. |
| Progression Free Survival in Part 1 and Part 1A | from the first dosing date to the date of first objectively documented disease progression or death, whichever occurs first (Approximately up to 21 months) | PFS for a participant is defined as the time from the first dosing date to the date of first objectively documented disease progression per RECIST 1.1 (ie, radiologic) or death due to any cause, whichever occurs first. |
Countries
Argentina, Australia, Belgium, Canada, Chile, Czechia, Germany, Italy, Spain, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part 1 Cohort 1 Trame 1.5mg Cont | 3 |
| Part 1 Cohort 1B Trame 2 mg Int | 3 |
| Part 1 Cohort 1D Trame 2mg Cont | 6 |
| Part 1A Cohort 2 Trame 1.5mg Cont | 7 |
| Part 1A Cohort 2A Trame 1mg Cont | 3 |
| Part 1A Cohort 3 Trame 1.5mg Int | 3 |
| Part 1A Cohort 3B Trame 2mg Int | 7 |
| Part 2 Treatment 1 Nivo 6 + Ipi 1 + Trame 1.5 | 124 |
| Part 2 Treatment 2 Regorafenib 80/160 | 61 |
| Part 1B Nivo 6 + Ipi 1 + Trame 1.5 | 82 |
| Total | 299 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Pre-Treatment | Not Reported | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 0 |
| Pre-Treatment | Subject withdrew consent | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 1 | 0 |
| Treatment Period | Adverse Event Unrelated to Study Drug | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 2 | 3 | 0 |
| Treatment Period | Death | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 2 | 1 | 3 |
| Treatment Period | Disease Progression | 3 | 2 | 5 | 3 | 3 | 3 | 6 | 106 | 48 | 59 |
| Treatment Period | No longer meets study criteria | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Treatment Period | Other Reasons | 0 | 0 | 0 | 3 | 0 | 0 | 0 | 2 | 0 | 1 |
| Treatment Period | Study Drug Toxicity | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 7 | 2 | 16 |
| Treatment Period | Subject request to discontinue study treatment | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| Treatment Period | Subject Withdrew Consent | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 |
Baseline characteristics
| Characteristic | Total | Part 1 Cohort 1B | Part 1 Cohort 1 | Part 1 Cohort 1D | Part 1A Cohort 2 | Part 1A Cohort 2A | Part 1A Cohort 3 | Part 1A Cohort 3B | Part 2 Treatment 1 | Part 2 Treatment 2 | Part 1B |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 223 Participants | 3 Participants | 2 Participants | 5 Participants | 6 Participants | 2 Participants | 3 Participants | 6 Participants | 89 Participants | 47 Participants | 60 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 76 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 35 Participants | 14 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 25 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 10 Participants | 6 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 163 Participants | 3 Participants | 3 Participants | 6 Participants | 6 Participants | 3 Participants | 2 Participants | 7 Participants | 55 Participants | 27 Participants | 51 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 111 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 59 Participants | 28 Participants | 24 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 10 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 8 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 278 Participants | 3 Participants | 3 Participants | 4 Participants | 6 Participants | 3 Participants | 2 Participants | 6 Participants | 119 Participants | 58 Participants | 74 Participants |
| Sex: Female, Male Female | 129 Participants | 1 Participants | 3 Participants | 0 Participants | 4 Participants | 2 Participants | 1 Participants | 3 Participants | 48 Participants | 30 Participants | 37 Participants |
| Sex: Female, Male Male | 170 Participants | 2 Participants | 0 Participants | 6 Participants | 3 Participants | 1 Participants | 2 Participants | 4 Participants | 76 Participants | 31 Participants | 45 Participants |
Adverse events
| Event type | EG000 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 | 2 / 3 | 2 / 3 | 6 / 6 | 3 / 7 | 2 / 3 | 3 / 3 | 5 / 7 | 49 / 82 | 108 / 124 | 55 / 61 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 6 / 6 | 7 / 7 | 3 / 3 | 3 / 3 | 7 / 7 | 82 / 82 | 121 / 121 | 55 / 57 |
| serious Total, serious adverse events | 2 / 3 | 0 / 3 | 5 / 6 | 3 / 7 | 0 / 3 | 2 / 3 | 3 / 7 | 42 / 82 | 79 / 121 | 33 / 57 |
Outcome results
Primary
Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests
Number of participants with clinical laboratory abnormalities in specific liver tests.
Time frame: Assessed from first dose date to 100 days after last dose of study therapy. (Approximately: Part 1: ~ 6.5 Months Part 1A: ~ 5.5 Months)
Population: All treated participants in Part 1 and Part 1A with atleast 1 On-Treatment Liver Test Measurement
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT OR AST > 3XULN | 0 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT OR AST> 10XULN | 0 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 30 DAYS | 0 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT OR AST > 20XULN | 0 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT OR AST> 5XULN | 0 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | TOTAL BILIRUBIN > 2XULN | 0 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 1 DAY | 0 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT OR AST> 5XULN | 0 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | TOTAL BILIRUBIN > 2XULN | 0 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 1 DAY | 0 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT OR AST> 10XULN | 0 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 30 DAYS | 0 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT OR AST > 3XULN | 0 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT OR AST > 20XULN | 0 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 30 DAYS | 2 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT OR AST > 3XULN | 2 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT OR AST > 20XULN | 1 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 1 DAY | 2 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT OR AST> 5XULN | 2 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT OR AST> 10XULN | 2 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | TOTAL BILIRUBIN > 2XULN | 2 Participants |
| Part 1A Cohort 2 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 30 DAYS | 0 Participants |
| Part 1A Cohort 2 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | TOTAL BILIRUBIN > 2XULN | 0 Participants |
| Part 1A Cohort 2 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT OR AST> 5XULN | 1 Participants |
| Part 1A Cohort 2 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT OR AST > 20XULN | 1 Participants |
| Part 1A Cohort 2 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 1 DAY | 0 Participants |
| Part 1A Cohort 2 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT OR AST > 3XULN | 1 Participants |
| Part 1A Cohort 2 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT OR AST> 10XULN | 1 Participants |
| Part 1A Cohort 2A | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT OR AST > 3XULN | 1 Participants |
| Part 1A Cohort 2A | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 1 DAY | 0 Participants |
| Part 1A Cohort 2A | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT OR AST> 5XULN | 1 Participants |
| Part 1A Cohort 2A | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT OR AST> 10XULN | 0 Participants |
| Part 1A Cohort 2A | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 30 DAYS | 0 Participants |
| Part 1A Cohort 2A | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT OR AST > 20XULN | 0 Participants |
| Part 1A Cohort 2A | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | TOTAL BILIRUBIN > 2XULN | 0 Participants |
| Part 1A Cohort 3 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT OR AST > 3XULN | 0 Participants |
| Part 1A Cohort 3 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT OR AST > 20XULN | 0 Participants |
| Part 1A Cohort 3 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 1 DAY | 0 Participants |
| Part 1A Cohort 3 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT OR AST> 10XULN | 0 Participants |
| Part 1A Cohort 3 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 30 DAYS | 0 Participants |
| Part 1A Cohort 3 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | TOTAL BILIRUBIN > 2XULN | 0 Participants |
| Part 1A Cohort 3 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT OR AST> 5XULN | 0 Participants |
| Part 1A Cohort 3B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT OR AST > 3XULN | 2 Participants |
| Part 1A Cohort 3B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 30 DAYS | 1 Participants |
| Part 1A Cohort 3B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT OR AST > 20XULN | 0 Participants |
| Part 1A Cohort 3B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | TOTAL BILIRUBIN > 2XULN | 1 Participants |
| Part 1A Cohort 3B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT OR AST> 10XULN | 2 Participants |
| Part 1A Cohort 3B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 1 DAY | 1 Participants |
| Part 1A Cohort 3B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests | ALT OR AST> 5XULN | 2 Participants |
Primary
Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests
Number of participants with clinical laboratory abnormalities in specific thyroid tests
Time frame: Assessed from first dose date to 100 days after last dose of study therapy. (Approximately: Part 1: ~ 6.5 Months Part 1A: ~ 5.5 Months)
Population: All treated participants in Part 1 and Part 1A
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH >ULN WITH ALL OTHER FT3/FT4 TEST VALUES ≥ LLN | 0 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH >ULN WITH ATLEAST ONE FT3/FT4 TEST VALUE <LLN | 2 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH < LLN WITH FT3/FT4 TEST MISSING | 0 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH <LLN WITH ALL OTHER FT3/FT4 TEST VALUES ≤ ULN | 0 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH <LLN WITH ATLEAST ONE FT3/FT4 TEST VALUE > ULN | 2 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH <LLN WITH TSH ≥ LLN AT BASELINE | 1 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH < LLN | 2 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH > ULN WITH TSH ≤ ULN AT BASELINE | 2 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH > ULN | 2 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH > ULN WITH FT3/FT4 TEST MISSING | 0 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH > ULN WITH TSH ≤ ULN AT BASELINE | 1 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH > ULN | 1 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH >ULN WITH ATLEAST ONE FT3/FT4 TEST VALUE <LLN | 1 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH >ULN WITH ALL OTHER FT3/FT4 TEST VALUES ≥ LLN | 0 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH > ULN WITH FT3/FT4 TEST MISSING | 0 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH < LLN | 0 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH <LLN WITH TSH ≥ LLN AT BASELINE | 0 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH <LLN WITH ATLEAST ONE FT3/FT4 TEST VALUE > ULN | 0 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH <LLN WITH ALL OTHER FT3/FT4 TEST VALUES ≤ ULN | 0 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH < LLN WITH FT3/FT4 TEST MISSING | 0 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH <LLN WITH ALL OTHER FT3/FT4 TEST VALUES ≤ ULN | 1 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH <LLN WITH TSH ≥ LLN AT BASELINE | 2 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH > ULN WITH TSH ≤ ULN AT BASELINE | 1 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH > ULN WITH FT3/FT4 TEST MISSING | 0 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH <LLN WITH ATLEAST ONE FT3/FT4 TEST VALUE > ULN | 1 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH > ULN | 1 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH >ULN WITH ATLEAST ONE FT3/FT4 TEST VALUE <LLN | 1 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH < LLN WITH FT3/FT4 TEST MISSING | 0 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH < LLN | 2 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH >ULN WITH ALL OTHER FT3/FT4 TEST VALUES ≥ LLN | 0 Participants |
| Part 1A Cohort 2 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH > ULN WITH TSH ≤ ULN AT BASELINE | 0 Participants |
| Part 1A Cohort 2 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH > ULN | 3 Participants |
| Part 1A Cohort 2 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH >ULN WITH ALL OTHER FT3/FT4 TEST VALUES ≥ LLN | 2 Participants |
| Part 1A Cohort 2 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH < LLN WITH FT3/FT4 TEST MISSING | 1 Participants |
| Part 1A Cohort 2 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH > ULN WITH FT3/FT4 TEST MISSING | 0 Participants |
| Part 1A Cohort 2 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH <LLN WITH TSH ≥ LLN AT BASELINE | 1 Participants |
| Part 1A Cohort 2 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH <LLN WITH ATLEAST ONE FT3/FT4 TEST VALUE > ULN | 1 Participants |
| Part 1A Cohort 2 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH < LLN | 2 Participants |
| Part 1A Cohort 2 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH <LLN WITH ALL OTHER FT3/FT4 TEST VALUES ≤ ULN | 0 Participants |
| Part 1A Cohort 2 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH >ULN WITH ATLEAST ONE FT3/FT4 TEST VALUE <LLN | 1 Participants |
| Part 1A Cohort 2A | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH > ULN | 1 Participants |
| Part 1A Cohort 2A | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH <LLN WITH ATLEAST ONE FT3/FT4 TEST VALUE > ULN | 0 Participants |
| Part 1A Cohort 2A | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH >ULN WITH ATLEAST ONE FT3/FT4 TEST VALUE <LLN | 0 Participants |
| Part 1A Cohort 2A | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH > ULN WITH FT3/FT4 TEST MISSING | 0 Participants |
| Part 1A Cohort 2A | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH > ULN WITH TSH ≤ ULN AT BASELINE | 0 Participants |
| Part 1A Cohort 2A | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH < LLN | 2 Participants |
| Part 1A Cohort 2A | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH <LLN WITH ALL OTHER FT3/FT4 TEST VALUES ≤ ULN | 2 Participants |
| Part 1A Cohort 2A | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH <LLN WITH TSH ≥ LLN AT BASELINE | 2 Participants |
| Part 1A Cohort 2A | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH >ULN WITH ALL OTHER FT3/FT4 TEST VALUES ≥ LLN | 1 Participants |
| Part 1A Cohort 2A | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH < LLN WITH FT3/FT4 TEST MISSING | 0 Participants |
| Part 1A Cohort 3 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH < LLN WITH FT3/FT4 TEST MISSING | 0 Participants |
| Part 1A Cohort 3 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH >ULN WITH ALL OTHER FT3/FT4 TEST VALUES ≥ LLN | 2 Participants |
| Part 1A Cohort 3 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH > ULN WITH FT3/FT4 TEST MISSING | 0 Participants |
| Part 1A Cohort 3 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH < LLN | 1 Participants |
| Part 1A Cohort 3 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH > ULN | 3 Participants |
| Part 1A Cohort 3 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH <LLN WITH TSH ≥ LLN AT BASELINE | 1 Participants |
| Part 1A Cohort 3 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH <LLN WITH ATLEAST ONE FT3/FT4 TEST VALUE > ULN | 1 Participants |
| Part 1A Cohort 3 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH <LLN WITH ALL OTHER FT3/FT4 TEST VALUES ≤ ULN | 0 Participants |
| Part 1A Cohort 3 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH > ULN WITH TSH ≤ ULN AT BASELINE | 2 Participants |
| Part 1A Cohort 3 | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH >ULN WITH ATLEAST ONE FT3/FT4 TEST VALUE <LLN | 1 Participants |
| Part 1A Cohort 3B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH < LLN | 2 Participants |
| Part 1A Cohort 3B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH < LLN WITH FT3/FT4 TEST MISSING | 0 Participants |
| Part 1A Cohort 3B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH >ULN WITH ALL OTHER FT3/FT4 TEST VALUES ≥ LLN | 1 Participants |
| Part 1A Cohort 3B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH > ULN WITH TSH ≤ ULN AT BASELINE | 2 Participants |
| Part 1A Cohort 3B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH > ULN | 2 Participants |
| Part 1A Cohort 3B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH <LLN WITH ALL OTHER FT3/FT4 TEST VALUES ≤ ULN | 0 Participants |
| Part 1A Cohort 3B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH > ULN WITH FT3/FT4 TEST MISSING | 0 Participants |
| Part 1A Cohort 3B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH >ULN WITH ATLEAST ONE FT3/FT4 TEST VALUE <LLN | 1 Participants |
| Part 1A Cohort 3B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH <LLN WITH ATLEAST ONE FT3/FT4 TEST VALUE > ULN | 2 Participants |
| Part 1A Cohort 3B | Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests | TSH <LLN WITH TSH ≥ LLN AT BASELINE | 2 Participants |
Primary
Dose Limiting Toxicities in Part 1 and Part 1A
Dose Limiting Toxicities are defined as adverse events have to be at least possibly related to study treatment, and not to disease progression, be clinically relevant and a clinically relevant shift from baseline.
Time frame: 4 weeks for Doublet Reginmen and 8 weeks for triplet Regimen
Population: All treated participants in Part 1 and Part 1A
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 Cohort 1 | Dose Limiting Toxicities in Part 1 and Part 1A | 0 Participants |
| Part 1 Cohort 1B | Dose Limiting Toxicities in Part 1 and Part 1A | 0 Participants |
| Part 1 Cohort 1D | Dose Limiting Toxicities in Part 1 and Part 1A | 1 Participants |
| Part 1A Cohort 2 | Dose Limiting Toxicities in Part 1 and Part 1A | 1 Participants |
| Part 1A Cohort 2A | Dose Limiting Toxicities in Part 1 and Part 1A | 0 Participants |
| Part 1A Cohort 3 | Dose Limiting Toxicities in Part 1 and Part 1A | 0 Participants |
| Part 1A Cohort 3B | Dose Limiting Toxicities in Part 1 and Part 1A | 0 Participants |
Primary
Overal Response Rate in Part 1B and Part 2
ORR is defined as the proportion of all treated participants whose BOR is either confirmed complete response (CR) or confirmed partial response (PR).
Time frame: Approximately up to 30 Months
Population: All Randomized Participants in Part 1B and Part 2
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 Cohort 1 | Overal Response Rate in Part 1B and Part 2 | 9.8 Percentage of Participants |
| Part 1 Cohort 1B | Overal Response Rate in Part 1B and Part 2 | 1.6 Percentage of Participants |
| Part 1 Cohort 1D | Overal Response Rate in Part 1B and Part 2 | 1.6 Percentage of Participants |
Primary
Safety Related Events in Part 1 and Part 1 A
Safety-related events in clinical trials include Adverse Events (AEs), Serious Adverse Events (SAEs), and deaths. An AE is any new or worsening medical issue in a participant receiving the study drug, regardless of its relation to the drug. This includes abnormal lab results, symptoms, or diseases. An SAE is a more severe AE that results in death, is life-threatening, requires or prolongs hospitalization, causes significant disability, involves a birth defect, or is deemed medically important-potentially jeopardizing the participant or requiring intervention, even if not immediately life-threatening. These definitions help ensure consistent reporting and evaluation of safety during clinical studies.
Time frame: Assessed from first dose date to 100 days after last dose of study therapy. (Approximately: Part 1: ~ 6.5 Months Part 1A: ~ 5.5 Months)
Population: All treated participants in Part 1 and Part 1A
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1 Cohort 1 | Safety Related Events in Part 1 and Part 1 A | Serious Adverse Events (SAEs) | 2 Participants |
| Part 1 Cohort 1 | Safety Related Events in Part 1 and Part 1 A | Adverse Events (AEs) | 3 Participants |
| Part 1 Cohort 1 | Safety Related Events in Part 1 and Part 1 A | Deaths | 2 Participants |
| Part 1 Cohort 1 | Safety Related Events in Part 1 and Part 1 A | Drug-Related AEs | 3 Participants |
| Part 1 Cohort 1 | Safety Related Events in Part 1 and Part 1 A | Drug-Related SAEs | 0 Participants |
| Part 1 Cohort 1B | Safety Related Events in Part 1 and Part 1 A | Serious Adverse Events (SAEs) | 0 Participants |
| Part 1 Cohort 1B | Safety Related Events in Part 1 and Part 1 A | Drug-Related AEs | 3 Participants |
| Part 1 Cohort 1B | Safety Related Events in Part 1 and Part 1 A | Drug-Related SAEs | 0 Participants |
| Part 1 Cohort 1B | Safety Related Events in Part 1 and Part 1 A | Adverse Events (AEs) | 3 Participants |
| Part 1 Cohort 1B | Safety Related Events in Part 1 and Part 1 A | Deaths | 2 Participants |
| Part 1 Cohort 1D | Safety Related Events in Part 1 and Part 1 A | Deaths | 6 Participants |
| Part 1 Cohort 1D | Safety Related Events in Part 1 and Part 1 A | Drug-Related AEs | 6 Participants |
| Part 1 Cohort 1D | Safety Related Events in Part 1 and Part 1 A | Adverse Events (AEs) | 6 Participants |
| Part 1 Cohort 1D | Safety Related Events in Part 1 and Part 1 A | Serious Adverse Events (SAEs) | 4 Participants |
| Part 1 Cohort 1D | Safety Related Events in Part 1 and Part 1 A | Drug-Related SAEs | 2 Participants |
| Part 1A Cohort 2 | Safety Related Events in Part 1 and Part 1 A | Serious Adverse Events (SAEs) | 3 Participants |
| Part 1A Cohort 2 | Safety Related Events in Part 1 and Part 1 A | Adverse Events (AEs) | 7 Participants |
| Part 1A Cohort 2 | Safety Related Events in Part 1 and Part 1 A | Drug-Related AEs | 7 Participants |
| Part 1A Cohort 2 | Safety Related Events in Part 1 and Part 1 A | Drug-Related SAEs | 3 Participants |
| Part 1A Cohort 2 | Safety Related Events in Part 1 and Part 1 A | Deaths | 3 Participants |
| Part 1A Cohort 2A | Safety Related Events in Part 1 and Part 1 A | Adverse Events (AEs) | 3 Participants |
| Part 1A Cohort 2A | Safety Related Events in Part 1 and Part 1 A | Deaths | 2 Participants |
| Part 1A Cohort 2A | Safety Related Events in Part 1 and Part 1 A | Serious Adverse Events (SAEs) | 0 Participants |
| Part 1A Cohort 2A | Safety Related Events in Part 1 and Part 1 A | Drug-Related SAEs | 0 Participants |
| Part 1A Cohort 2A | Safety Related Events in Part 1 and Part 1 A | Drug-Related AEs | 3 Participants |
| Part 1A Cohort 3 | Safety Related Events in Part 1 and Part 1 A | Adverse Events (AEs) | 3 Participants |
| Part 1A Cohort 3 | Safety Related Events in Part 1 and Part 1 A | Deaths | 3 Participants |
| Part 1A Cohort 3 | Safety Related Events in Part 1 and Part 1 A | Drug-Related SAEs | 1 Participants |
| Part 1A Cohort 3 | Safety Related Events in Part 1 and Part 1 A | Drug-Related AEs | 3 Participants |
| Part 1A Cohort 3 | Safety Related Events in Part 1 and Part 1 A | Serious Adverse Events (SAEs) | 2 Participants |
| Part 1A Cohort 3B | Safety Related Events in Part 1 and Part 1 A | Drug-Related SAEs | 1 Participants |
| Part 1A Cohort 3B | Safety Related Events in Part 1 and Part 1 A | Drug-Related AEs | 7 Participants |
| Part 1A Cohort 3B | Safety Related Events in Part 1 and Part 1 A | Serious Adverse Events (SAEs) | 3 Participants |
| Part 1A Cohort 3B | Safety Related Events in Part 1 and Part 1 A | Adverse Events (AEs) | 7 Participants |
| Part 1A Cohort 3B | Safety Related Events in Part 1 and Part 1 A | Deaths | 5 Participants |
Secondary
Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Liver Tests
Number of participants with clinical laboratory abnormalities in specific liver tests.
Time frame: Assessed from first dose date to 100 days after last dose of study therapy. (Approximately: 6.8 Months)
Population: All Treated Participants in Part 1B and Part 2 with atleast 1 On-Treatment Liver test Measurement
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Liver Tests | ALT OR AST> 5XULN | 8 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Liver Tests | TOTAL BILIRUBIN > 2XULN | 3 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Liver Tests | ALT OR AST > 20XULN | 0 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Liver Tests | ALT OR AST > 3XULN | 18 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Liver Tests | ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 30 DAYS | 2 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Liver Tests | ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 1 DAY | 2 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Liver Tests | ALT OR AST> 10XULN | 1 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Liver Tests | ALT OR AST > 20XULN | 3 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Liver Tests | ALT OR AST > 3XULN | 38 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Liver Tests | ALT OR AST> 5XULN | 19 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Liver Tests | ALT OR AST> 10XULN | 5 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Liver Tests | TOTAL BILIRUBIN > 2XULN | 9 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Liver Tests | ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 1 DAY | 6 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Liver Tests | ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 30 DAYS | 7 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Liver Tests | TOTAL BILIRUBIN > 2XULN | 12 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Liver Tests | ALT OR AST> 5XULN | 8 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Liver Tests | ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 30 DAYS | 7 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Liver Tests | ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 1 DAY | 7 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Liver Tests | ALT OR AST > 20XULN | 2 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Liver Tests | ALT OR AST> 10XULN | 4 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Liver Tests | ALT OR AST > 3XULN | 11 Participants |
Secondary
Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests
Number of participants with clinical laboratory abnormalities in specific thyroid tests
Time frame: Assessed from first dose date to 100 days after last dose of study therapy. (Approximately: 6.8 Months)
Population: All Treated Participants in Part 1B and Part 2 with atleast 1 On-Treatment TSH Measurement
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH > ULN | 13 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH > ULN WITH TSH ≤ ULN AT BASELINE | 9 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH >ULN WITH ATLEAST ONE FT3/FT4 TEST VALUE <LLN | 9 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH >ULN WITH ALL OTHER FT3/FT4 TEST VALUES ≥ LLN | 3 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH > ULN WITH FT3/FT4 TEST MISSING | 1 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH < LLN | 14 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH <LLN WITH TSH ≥ LLN AT BASELINE | 11 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH <LLN WITH ATLEAST ONE FT3/FT4 TEST VALUE > ULN | 5 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH <LLN WITH ALL OTHER FT3/FT4 TEST VALUES ≤ ULN | 8 Participants |
| Part 1 Cohort 1 | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH < LLN WITH FT3/FT4 TEST MISSING | 1 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH <LLN WITH ALL OTHER FT3/FT4 TEST VALUES ≤ ULN | 7 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH > ULN | 31 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH < LLN | 24 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH > ULN WITH FT3/FT4 TEST MISSING | 4 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH > ULN WITH TSH ≤ ULN AT BASELINE | 18 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH < LLN WITH FT3/FT4 TEST MISSING | 5 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH <LLN WITH ATLEAST ONE FT3/FT4 TEST VALUE > ULN | 12 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH >ULN WITH ATLEAST ONE FT3/FT4 TEST VALUE <LLN | 14 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH <LLN WITH TSH ≥ LLN AT BASELINE | 21 Participants |
| Part 1 Cohort 1B | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH >ULN WITH ALL OTHER FT3/FT4 TEST VALUES ≥ LLN | 13 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH <LLN WITH ATLEAST ONE FT3/FT4 TEST VALUE > ULN | 0 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH >ULN WITH ALL OTHER FT3/FT4 TEST VALUES ≥ LLN | 14 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH > ULN WITH FT3/FT4 TEST MISSING | 4 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH < LLN | 0 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH <LLN WITH ALL OTHER FT3/FT4 TEST VALUES ≤ ULN | 0 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH <LLN WITH TSH ≥ LLN AT BASELINE | 0 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH > ULN | 21 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH < LLN WITH FT3/FT4 TEST MISSING | 0 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH > ULN WITH TSH ≤ ULN AT BASELINE | 16 Participants |
| Part 1 Cohort 1D | Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests | TSH >ULN WITH ATLEAST ONE FT3/FT4 TEST VALUE <LLN | 3 Participants |
Secondary
Disease Control Rate in Part 1 and Part 1A
The disease control rate (DCR) is defined as the percentage of participants whose BOR is either confirmed CR or confirmed PR or stable disease (SD)
Time frame: From the first dosing date and the date of the initial objectively documented tumor progression or subsequent therapy date (Approximately up to 21 Months)
Population: All treated participants in Part 1 and Part 1A
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 Cohort 1 | Disease Control Rate in Part 1 and Part 1A | 66.7 Percentage of Participants |
| Part 1 Cohort 1B | Disease Control Rate in Part 1 and Part 1A | 33.3 Percentage of Participants |
| Part 1 Cohort 1D | Disease Control Rate in Part 1 and Part 1A | 50.0 Percentage of Participants |
| Part 1A Cohort 2 | Disease Control Rate in Part 1 and Part 1A | 57.1 Percentage of Participants |
| Part 1A Cohort 2A | Disease Control Rate in Part 1 and Part 1A | 33.3 Percentage of Participants |
| Part 1A Cohort 3 | Disease Control Rate in Part 1 and Part 1A | 66.7 Percentage of Participants |
| Part 1A Cohort 3B | Disease Control Rate in Part 1 and Part 1A | 28.6 Percentage of Participants |
Secondary
Duration of Response in Part 1 and Part 1A
DOR for a participant with a BOR of confirmed CR or PR, is defined as the time between the date of first confirmed response and the date of the first objectively documented tumor progression per RECIST 1.1 or death, whichever occurs first.
Time frame: Approximately up to 20 Months
Population: All treated participants in Part 1 and Part 1A who had a response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1A Cohort 2 | Duration of Response in Part 1 and Part 1A | 9.46 Months |
| Part 1A Cohort 2A | Duration of Response in Part 1 and Part 1A | 19.42 Months |
Secondary
Objective Response Rate in Part 1 and Part 1A
ORR is defined as the proportion of all treated participants whose BOR is either confirmed complete response (CR) or confirmed partial response (PR).
Time frame: From the first dosing date and the date of the initial objectively documented tumor progression or subsequent therapy date (Approximately up to 21 Months)
Population: All treated participants in Part 1 and Part 1A
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 Cohort 1 | Objective Response Rate in Part 1 and Part 1A | 0 Percentage of Participants |
| Part 1 Cohort 1B | Objective Response Rate in Part 1 and Part 1A | 0 Percentage of Participants |
| Part 1 Cohort 1D | Objective Response Rate in Part 1 and Part 1A | 0 Percentage of Participants |
| Part 1A Cohort 2 | Objective Response Rate in Part 1 and Part 1A | 28.6 Percentage of Participants |
| Part 1A Cohort 2A | Objective Response Rate in Part 1 and Part 1A | 33.3 Percentage of Participants |
| Part 1A Cohort 3 | Objective Response Rate in Part 1 and Part 1A | 0 Percentage of Participants |
| Part 1A Cohort 3B | Objective Response Rate in Part 1 and Part 1A | 0 Percentage of Participants |
Secondary
Overall Survival in Part 1 and Part 1A
OS for a participant is defined as the time from the first dosing date to the date of death due to any cause. A participant who has not died will be censored at last known date alive.
Time frame: Approximately up to 69 Months
Population: All treated participants in Part 1 and Part 1A
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 Cohort 1 | Overall Survival in Part 1 and Part 1A | 8.99 Months |
| Part 1 Cohort 1B | Overall Survival in Part 1 and Part 1A | 18.50 Months |
| Part 1 Cohort 1D | Overall Survival in Part 1 and Part 1A | 9.61 Months |
| Part 1A Cohort 2 | Overall Survival in Part 1 and Part 1A | 42.09 Months |
| Part 1A Cohort 2A | Overall Survival in Part 1 and Part 1A | 19.02 Months |
| Part 1A Cohort 3 | Overall Survival in Part 1 and Part 1A | 11.33 Months |
| Part 1A Cohort 3B | Overall Survival in Part 1 and Part 1A | 36.24 Months |
Secondary
Progression Free Survival in Part 1 and Part 1A
PFS for a participant is defined as the time from the first dosing date to the date of first objectively documented disease progression per RECIST 1.1 (ie, radiologic) or death due to any cause, whichever occurs first.
Time frame: from the first dosing date to the date of first objectively documented disease progression or death, whichever occurs first (Approximately up to 21 months)
Population: All treated participants in Part 1 and Part 1A
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 Cohort 1 | Progression Free Survival in Part 1 and Part 1A | 3.58 Months |
| Part 1 Cohort 1B | Progression Free Survival in Part 1 and Part 1A | 1.91 Months |
| Part 1 Cohort 1D | Progression Free Survival in Part 1 and Part 1A | 2.66 Months |
| Part 1A Cohort 2 | Progression Free Survival in Part 1 and Part 1A | 7.36 Months |
| Part 1A Cohort 2A | Progression Free Survival in Part 1 and Part 1A | 1.74 Months |
| Part 1A Cohort 3 | Progression Free Survival in Part 1 and Part 1A | 4.14 Months |
| Part 1A Cohort 3B | Progression Free Survival in Part 1 and Part 1A | 1.81 Months |
Secondary
Safety Related Events in Part 1B and Part 2
Safety-related events in clinical trials include Adverse Events (AEs), Serious Adverse Events (SAEs), and deaths. An AE is any new or worsening medical issue in a participant receiving the study drug, regardless of its relation to the drug. This includes abnormal lab results, symptoms, or diseases. An SAE is a more severe AE that results in death, is life-threatening, requires or prolongs hospitalization, causes significant disability, involves a birth defect, or is deemed medically important-potentially jeopardizing the participant or requiring intervention, even if not immediately life-threatening. These definitions help ensure consistent reporting and evaluation of safety during clinical studies.
Time frame: Assessed from first dose date to 100 days after last dose of study therapy. (Approximately: 6.8 Months)
Population: All Treated Participants in Part 1B and Part 2
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1 Cohort 1 | Safety Related Events in Part 1B and Part 2 | Drug-Related SAEs | 20 Participants |
| Part 1 Cohort 1 | Safety Related Events in Part 1B and Part 2 | Serious Adverse Events (SAEs) | 36 Participants |
| Part 1 Cohort 1 | Safety Related Events in Part 1B and Part 2 | Adverse Events (AEs) | 82 Participants |
| Part 1 Cohort 1 | Safety Related Events in Part 1B and Part 2 | Drug-Related AEs | 80 Participants |
| Part 1 Cohort 1 | Safety Related Events in Part 1B and Part 2 | Deaths | 49 Participants |
| Part 1 Cohort 1B | Safety Related Events in Part 1B and Part 2 | Serious Adverse Events (SAEs) | 56 Participants |
| Part 1 Cohort 1B | Safety Related Events in Part 1B and Part 2 | Adverse Events (AEs) | 121 Participants |
| Part 1 Cohort 1B | Safety Related Events in Part 1B and Part 2 | Drug-Related AEs | 116 Participants |
| Part 1 Cohort 1B | Safety Related Events in Part 1B and Part 2 | Drug-Related SAEs | 21 Participants |
| Part 1 Cohort 1B | Safety Related Events in Part 1B and Part 2 | Deaths | 106 Participants |
| Part 1 Cohort 1D | Safety Related Events in Part 1B and Part 2 | Deaths | 53 Participants |
| Part 1 Cohort 1D | Safety Related Events in Part 1B and Part 2 | Drug-Related SAEs | 3 Participants |
| Part 1 Cohort 1D | Safety Related Events in Part 1B and Part 2 | Adverse Events (AEs) | 57 Participants |
| Part 1 Cohort 1D | Safety Related Events in Part 1B and Part 2 | Serious Adverse Events (SAEs) | 19 Participants |
| Part 1 Cohort 1D | Safety Related Events in Part 1B and Part 2 | Drug-Related AEs | 52 Participants |
Secondary
Time to Response in Part 1 and Part 1A
Time to response (TTR) is defined for participants who had a confirmed CR or PR as the time from the first dosing date to the date of first documented CR or PR per RECIST 1.1.
Time frame: From the first dosing date to the date of first documented CR or PR per RECIST 1.1. (Approximately on average 10 months)
Population: All treated participants in Part 1 and Part 1A who had a response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1A Cohort 2 | Time to Response in Part 1 and Part 1A | 5.63 Months |
| Part 1A Cohort 2A | Time to Response in Part 1 and Part 1A | 1.54 Months |