Renal Cell Carcinoma
Conditions
Brief summary
To investigate the safety of Nivolumab in combination with Ipilimumab in subjects with previously untreated advanced or metastatic Renal Cell Cancer.
Interventions
DRUGNivolumab
Specified dose on specified day
DRUGIpilimumab
Specified Dose on Specified Day
Sponsors
Bristol-Myers Squibb
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1\. Type of Participant and Target Disease Characteristics 1. Advanced or metastatic RCC 2. Histologically confirmed, previously untreated (treatment-naive) RCC 3. No prior systemic therapy for RCC except for one prior adjuvant or neoadjuvant therapy for completely resectable RCC 4. Measurable disease as per RECIST 1.1. Subject must have extracranial metastasis as measurable disease 5. Karnofsky Performance Status (KPS) of at least 70% for Cohort 1, 2, and 3; KPS of 50-60% for Cohort 4 6. Tumor tissue need be received by the central vendor (block or unstained slides). Note: Fine Needle Aspiration (FNA)and bone metastases samples are not acceptable for submission.
Exclusion criteria
1. Medical Conditions 1. Subjects with any active autoimmune disease or a history of known autoimmune disease 2. Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured 3. Known HIV or AIDS-related illness 4. Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection. 2. Prior/Concomitant Therapy 1. Prior systemic treatment in the metastatic setting with Vascular epithelial growth factor(VEGF) or VEGF receptor targeted therapy 2. Prior treatment with an anti-Programmed Death (PD) -1, anti-PD-L1, anti-PD-L2, anti-cluster of differentiation 137 (CD137), or anti-cytotoxic T-lymphocyte-associated antigen 4(CTLA-4) antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways. This includes the utilization of these agents in the neo-adjuvant or adjuvant setting. 3. Anti-cancer therapy less than 28 days prior to the first dose of study drug or palliative, focal radiation therapy less than 14 days prior to the first dose of study drug. Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Approximately 39 Months | Number of participants with IMAEs in the following categories: Skin, Endocrine, Gastrointestinal, Hepatic, Renal, Pulmonary and Hypersensitivity |
| Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Approximately 39 Months | Number of participants with IMAEs in the following categories: Skin, Endocrine, Gastrointestinal, Hepatic, Renal, Pulmonary and Hypersensitivity |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | From first dose up to 100 days post last dose (up to approximately 29 months) | The number of participants who received immune modulating medication for participants experiencing all high grade (CTCAE v4 Grade 3-4 and Grade 5) Immune Mediated Adverse Events (IMAEs) in the following categories will be included: Skin, Endocrine, Gastrointestinal, Hepatic, Renal, Pulmonary and Hypersensitivity. IMAEs are specific events (or groups of preferred terms describing specific events) considered as potential immune-mediated events by investigator, that meet the following definition: (1) those occurring within 100 days of the last dose (2) regardless of causality (3) with no clear alternate etiology based on investigator assessment, or with an immune-mediated component and (4) treated with immune-modulating medication. Grade 3= Severe reaction, Grade 4 = Life-threatening, Grade 5 = Death |
| Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | From first dose up to 100 days post last dose (up to approximately 29 months) | The number of participants who received Hormone Replacement Therapy for experiencing all high grade (CTCAE v4 Grade 3-4 and Grade 5) Immune Mediated Adverse Events (IMAEs) in the following categories will be included: Skin, Endocrine, Gastrointestinal, Hepatic, Renal, Pulmonary and Hypersensitivity. IMAEs are specific events (or groups of preferred terms describing specific events) considered as potential immune-mediated events by investigator, that meet the following definition: (1) those occurring within 100 days of the last dose (2) regardless of causality (3) with no clear alternate etiology based on investigator assessment, or with an immune-mediated component and (4) treated with immune-modulating medication. Grade 3= Severe reaction, Grade 4 = Life-threatening, Grade 5 = Death |
| Number of Participants Who Received ≥ 40mg of Prednisone for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | From first dose up to 100 days post last dose (up to approximately 29 months) | The number of participants who received ≥ 40mg of prednisone for high grade (grades 3-5) IMAEs. Participants experiencing all high grade (CTCAE v4 Grade 3-4 and Grade 5) Immune Mediated Adverse Events (IMAEs) in the following categories will be included: Skin, Endocrine, Gastrointestinal, Hepatic, Renal, Pulmonary and Hypersensitivity. IMAEs are specific events (or groups of preferred terms describing specific events) considered as potential immune-mediated events by investigator, that meet the following definition: (1) those occurring within 100 days of the last dose (2) regardless of causality (3) with no clear alternate etiology based on investigator assessment, or with an immune-mediated component and (4) treated with immune-modulating medication. Grade 3= Severe reaction, Grade 4 = Life-threatening, Grade 5 = Death |
| Time to Onset of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | From first dose to the earliest IMAE (grade 3-5) event onset date (up to approximately 116 weeks) | Time to onset is defined as the duration of time in weeks from the first dosing to the immune modulating adverse event onset date. Participants experiencing all high grade (CTCAE v4 Grade 3-4 and Grade 5) Immune Mediated Adverse Events (IMAEs) in the following categories will be included: Skin, Endocrine, Gastrointestinal, Hepatic, Renal, Pulmonary and Hypersensitivity. IMAEs are specific events (or groups of preferred terms describing specific events) considered as potential immune-mediated events by investigator, that meet the following definition: (1) those occurring within 100 days of the last dose (2) regardless of causality (3) with no clear alternate etiology based on investigator assessment, or with an immune-mediated component and (4) treated with immune-modulating medication. Grade 3= Severe reaction, Grade 4 = Life-threatening, Grade 5 = Death |
| Objective Response Rate (ORR) | From first dose up to the date of objectively documented progression or the date of subsequent therapy, whichever occurs first (up to approximately 26 months) | ORR is defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of response evaluable participants. Best overall response is defined as the best response recorded from the start of the study treatment until the end of treatment. The participant's best overall response assignment will depend on the findings of both target and non-target disease and will also take into consideration the appearance of new lesions. Partial response is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Complete response is defined as the disappearance of all lesions and normalization of tumor marker level. All lymph nodes (whether target or non-target) must be non-pathological in size (\< 10mm short axis). |
| Time to Response Rate (TRR) | From the date of first dose to first documented CR or PR, up to approximately 15 months | TTR is defined as the median percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of response evaluable participants. Best overall response is defined as the best response recorded from the start of the study treatment until the end of treatment. The participant's best overall response assignment will depend on the findings of both target and non-target disease and will also take into consideration the appearance of new lesions. Partial response is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Complete response is defined as the disappearance of all lesions and normalization of tumor marker level. All lymph nodes (whether target or non-target) must be non-pathological in size (\< 10mm short axis). |
| Duration of Response (DOR) | From first confirmed response to the date of the first documented tumor progression or death, up to approximately 48 months | DOR is defined as the time between the date of first confirmed response to the date of the first documented tumor progression per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, or death due to any cause, whichever occurs first. DOR will be computed for participants who achieve partial response (PR) or complete response (CR) only. Partial response is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Complete response is defined as the disappearance of all lesions and normalization of tumor marker level. All lymph nodes (whether target or non-target) must be non-pathological in size (\< 10mm short axis). |
| Median Progression Free Survival (PFS) | From first dose to the date of the first documented progressive disease, up to approximately 12 months | PFS is defined as the time from first dose to the date of the first documented progressive disease (PD) as determined by the investigator (per RECIST 1.1 criteria or clinical) or death due to any cause whichever occur first. Progressive disease is defined as progression of existing non-target lesions or at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. |
| Time to Resolution of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | From the IMAE onset date to the IMAE end date, up to approximately 194 weeks | Time to resolution is defined as the longest time from IMAE onset date to complete resolution or improvement to the grade at baseline experienced by the participant (the IMAE end date). Participants experiencing all high grade (CTCAE v4 Grade 3-4 and Grade 5) Immune Mediated Adverse Events (IMAEs) in the following categories will be included: Skin, Endocrine, Gastrointestinal, Hepatic, Renal, Pulmonary and Hypersensitivity. IMAEs are specific events (or groups of preferred terms describing specific events) considered as potential immune-mediated events by investigator, that meet the following definition: (1) those occurring within 100 days of the last dose (2) regardless of causality (3) with no clear alternate etiology based on investigator assessment, or with an immune-mediated component and (4) treated with immune-modulating medication. Grade 3= Severe reaction, Grade 4 = Life-threatening, Grade 5 = Death |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Nivolumab 6mg/kg IV plus, Ipilimumab 1mg/kg IV every 8 weeks alternating with Nivolumab 480 mg IV every 8 weeks, staggered every 4 weeks | 106 |
| Cohort 2 Nivolumab 3mg/kg IV combined with Ipilimumab 1mg/kg IV every 3 weeks for 4 doses | 52 |
| Cohort 3 Nivolumab 3mg/kg IV combined with Ipilimumab 1mg/kg IV every 3 weeks for 4 doses | 28 |
| Cohort 4 Nivolumab 3 mg/kg IV combined with Ipilimumab 1 mg/kg IV every 3 weeks for 4 doses | 25 |
| Total | 211 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 55 | 29 | 15 | 20 |
| Overall Study | Lost to Follow-up | 2 | 1 | 0 | 0 |
| Overall Study | Other reasons | 42 | 17 | 12 | 3 |
| Overall Study | Participant withdrew consent | 7 | 5 | 1 | 1 |
| Overall Study | Premature site closure | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Cohort 1 | Cohort 2 | Cohort 3 | Cohort 4 | Total |
|---|---|---|---|---|---|
| Age, Continuous | 62.8 Years STANDARD_DEVIATION 9.43 | 60.1 Years STANDARD_DEVIATION 14.09 | 61.3 Years STANDARD_DEVIATION 11.06 | 65.2 Years STANDARD_DEVIATION 12.54 | 62.2 Years STANDARD_DEVIATION 11.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 3 Participants | 1 Participants | 1 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 101 Participants | 48 Participants | 27 Participants | 24 Participants | 200 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 6 Participants | 1 Participants | 1 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 4 Participants | 0 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) White | 104 Participants | 40 Participants | 26 Participants | 24 Participants | 194 Participants |
| Sex: Female, Male Female | 20 Participants | 16 Participants | 4 Participants | 6 Participants | 46 Participants |
| Sex: Female, Male Male | 86 Participants | 36 Participants | 24 Participants | 19 Participants | 165 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 55 / 106 | 29 / 52 | 15 / 28 | 20 / 25 |
| other Total, other adverse events | 103 / 106 | 50 / 52 | 27 / 28 | 24 / 25 |
| serious Total, serious adverse events | 63 / 106 | 29 / 52 | 14 / 28 | 17 / 25 |
Outcome results
Primary
Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs)
Number of participants with IMAEs in the following categories: Skin, Endocrine, Gastrointestinal, Hepatic, Renal, Pulmonary and Hypersensitivity
Time frame: Approximately 39 Months
Population: All Treated Participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Hepatitis | 3 Participants |
| Cohort 1 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Adrenal Insufficiency | 3 Participants |
| Cohort 1 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Hypophysitis | 0 Participants |
| Cohort 1 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Nephritis and Renal Dysfunction | 0 Participants |
| Cohort 1 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Hyperthyroidism | 0 Participants |
| Cohort 1 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Hypothyroidism and Thyroiditis | 0 Participants |
| Cohort 1 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Hypersensitivity | 0 Participants |
| Cohort 1 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Rash | 7 Participants |
| Cohort 1 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Pneumonitis | 1 Participants |
| Cohort 1 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Diabetes Mellitus | 3 Participants |
| Cohort 1 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Diarrhoea/Colitis | 8 Participants |
| Cohort 2 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Diabetes Mellitus | 0 Participants |
| Cohort 2 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Hyperthyroidism | 0 Participants |
| Cohort 2 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Nephritis and Renal Dysfunction | 2 Participants |
| Cohort 2 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Hypophysitis | 1 Participants |
| Cohort 2 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Hepatitis | 1 Participants |
| Cohort 2 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Hypersensitivity | 0 Participants |
| Cohort 2 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Adrenal Insufficiency | 1 Participants |
| Cohort 2 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Diarrhoea/Colitis | 4 Participants |
| Cohort 2 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Hypothyroidism and Thyroiditis | 0 Participants |
| Cohort 2 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Pneumonitis | 0 Participants |
| Cohort 2 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Rash | 3 Participants |
| Cohort 3 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Diabetes Mellitus | 1 Participants |
| Cohort 3 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Rash | 1 Participants |
| Cohort 3 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Hypersensitivity | 0 Participants |
| Cohort 3 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Adrenal Insufficiency | 0 Participants |
| Cohort 3 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Hypothyroidism and Thyroiditis | 0 Participants |
| Cohort 3 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Pneumonitis | 0 Participants |
| Cohort 3 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Hyperthyroidism | 0 Participants |
| Cohort 3 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Hypophysitis | 1 Participants |
| Cohort 3 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Diarrhoea/Colitis | 2 Participants |
| Cohort 3 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Hepatitis | 1 Participants |
| Cohort 3 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Nephritis and Renal Dysfunction | 0 Participants |
| Cohort 4 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Hypothyroidism and Thyroiditis | 1 Participants |
| Cohort 4 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Adrenal Insufficiency | 1 Participants |
| Cohort 4 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Nephritis and Renal Dysfunction | 0 Participants |
| Cohort 4 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Diarrhoea/Colitis | 0 Participants |
| Cohort 4 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Hypersensitivity | 0 Participants |
| Cohort 4 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Rash | 0 Participants |
| Cohort 4 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Pneumonitis | 0 Participants |
| Cohort 4 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Hyperthyroidism | 0 Participants |
| Cohort 4 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Hepatitis | 1 Participants |
| Cohort 4 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Hypophysitis | 0 Participants |
| Cohort 4 | Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) | Diabetes Mellitus | 0 Participants |
Primary
Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs)
Number of participants with IMAEs in the following categories: Skin, Endocrine, Gastrointestinal, Hepatic, Renal, Pulmonary and Hypersensitivity
Time frame: Approximately 39 Months
Population: All Treated Participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Hypersensitivity | 0 Participants |
| Cohort 1 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Hepatitis | 0 Participants |
| Cohort 1 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Hypophysitis | 0 Participants |
| Cohort 1 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Pneumonitis | 0 Participants |
| Cohort 1 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Hyperthyroidism | 0 Participants |
| Cohort 1 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Nephritis and Renal Dysfunction | 0 Participants |
| Cohort 1 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Diarrhoea/Colitis | 0 Participants |
| Cohort 1 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Hypothyroidism and Thyroiditis | 0 Participants |
| Cohort 1 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Diabetes Mellitus | 0 Participants |
| Cohort 1 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Rash | 0 Participants |
| Cohort 1 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Adrenal Insufficiency | 0 Participants |
| Cohort 2 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Rash | 0 Participants |
| Cohort 2 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Hypersensitivity | 0 Participants |
| Cohort 2 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Diabetes Mellitus | 0 Participants |
| Cohort 2 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Adrenal Insufficiency | 0 Participants |
| Cohort 2 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Diarrhoea/Colitis | 0 Participants |
| Cohort 2 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Hypophysitis | 0 Participants |
| Cohort 2 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Hyperthyroidism | 0 Participants |
| Cohort 2 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Hepatitis | 0 Participants |
| Cohort 2 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Nephritis and Renal Dysfunction | 0 Participants |
| Cohort 2 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Pneumonitis | 0 Participants |
| Cohort 2 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Hypothyroidism and Thyroiditis | 0 Participants |
| Cohort 3 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Hypothyroidism and Thyroiditis | 0 Participants |
| Cohort 3 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Diabetes Mellitus | 0 Participants |
| Cohort 3 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Pneumonitis | 0 Participants |
| Cohort 3 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Diarrhoea/Colitis | 0 Participants |
| Cohort 3 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Hepatitis | 0 Participants |
| Cohort 3 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Nephritis and Renal Dysfunction | 0 Participants |
| Cohort 3 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Hypersensitivity | 0 Participants |
| Cohort 3 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Adrenal Insufficiency | 0 Participants |
| Cohort 3 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Rash | 0 Participants |
| Cohort 3 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Hyperthyroidism | 0 Participants |
| Cohort 3 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Hypophysitis | 0 Participants |
| Cohort 4 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Diabetes Mellitus | 0 Participants |
| Cohort 4 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Hypothyroidism and Thyroiditis | 0 Participants |
| Cohort 4 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Nephritis and Renal Dysfunction | 0 Participants |
| Cohort 4 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Hepatitis | 0 Participants |
| Cohort 4 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Diarrhoea/Colitis | 0 Participants |
| Cohort 4 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Hypophysitis | 0 Participants |
| Cohort 4 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Hyperthyroidism | 0 Participants |
| Cohort 4 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Pneumonitis | 0 Participants |
| Cohort 4 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Adrenal Insufficiency | 0 Participants |
| Cohort 4 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Hypersensitivity | 0 Participants |
| Cohort 4 | Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) | Rash | 0 Participants |
Secondary
Duration of Response (DOR)
DOR is defined as the time between the date of first confirmed response to the date of the first documented tumor progression per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, or death due to any cause, whichever occurs first. DOR will be computed for participants who achieve partial response (PR) or complete response (CR) only. Partial response is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Complete response is defined as the disappearance of all lesions and normalization of tumor marker level. All lymph nodes (whether target or non-target) must be non-pathological in size (\< 10mm short axis).
Time frame: From first confirmed response to the date of the first documented tumor progression or death, up to approximately 48 months
Population: All response evaluable participants: all treated participants who have baseline and at least one on-study evaluable tumor measurement.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Duration of Response (DOR) | 11.01 Months |
| Cohort 2 | Duration of Response (DOR) | 37.68 Months |
| Cohort 3 | Duration of Response (DOR) | 16.51 Months |
| Cohort 4 | Duration of Response (DOR) | 19.48 Months |
Secondary
Median Progression Free Survival (PFS)
PFS is defined as the time from first dose to the date of the first documented progressive disease (PD) as determined by the investigator (per RECIST 1.1 criteria or clinical) or death due to any cause whichever occur first. Progressive disease is defined as progression of existing non-target lesions or at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.
Time frame: From first dose to the date of the first documented progressive disease, up to approximately 12 months
Population: All Treated Participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Median Progression Free Survival (PFS) | 4.8 Months |
| Cohort 2 | Median Progression Free Survival (PFS) | 3.7 Months |
| Cohort 3 | Median Progression Free Survival (PFS) | 8.5 Months |
| Cohort 4 | Median Progression Free Survival (PFS) | 3.6 Months |
Secondary
Number of Participants Who Received ≥ 40mg of Prednisone for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs)
The number of participants who received ≥ 40mg of prednisone for high grade (grades 3-5) IMAEs. Participants experiencing all high grade (CTCAE v4 Grade 3-4 and Grade 5) Immune Mediated Adverse Events (IMAEs) in the following categories will be included: Skin, Endocrine, Gastrointestinal, Hepatic, Renal, Pulmonary and Hypersensitivity. IMAEs are specific events (or groups of preferred terms describing specific events) considered as potential immune-mediated events by investigator, that meet the following definition: (1) those occurring within 100 days of the last dose (2) regardless of causality (3) with no clear alternate etiology based on investigator assessment, or with an immune-mediated component and (4) treated with immune-modulating medication. Grade 3= Severe reaction, Grade 4 = Life-threatening, Grade 5 = Death
Time frame: From first dose up to 100 days post last dose (up to approximately 29 months)
Population: All Treated Participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Number of Participants Who Received ≥ 40mg of Prednisone for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | 19 Participants |
| Cohort 2 | Number of Participants Who Received ≥ 40mg of Prednisone for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | 9 Participants |
| Cohort 3 | Number of Participants Who Received ≥ 40mg of Prednisone for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | 5 Participants |
| Cohort 4 | Number of Participants Who Received ≥ 40mg of Prednisone for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | 2 Participants |
Secondary
Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs)
The number of participants who received Hormone Replacement Therapy for experiencing all high grade (CTCAE v4 Grade 3-4 and Grade 5) Immune Mediated Adverse Events (IMAEs) in the following categories will be included: Skin, Endocrine, Gastrointestinal, Hepatic, Renal, Pulmonary and Hypersensitivity. IMAEs are specific events (or groups of preferred terms describing specific events) considered as potential immune-mediated events by investigator, that meet the following definition: (1) those occurring within 100 days of the last dose (2) regardless of causality (3) with no clear alternate etiology based on investigator assessment, or with an immune-mediated component and (4) treated with immune-modulating medication. Grade 3= Severe reaction, Grade 4 = Life-threatening, Grade 5 = Death
Time frame: From first dose up to 100 days post last dose (up to approximately 29 months)
Population: Treated participants who experienced at least one Grade 3 to 5 Immune-Mediate Event from the category
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Rash | 7 Participants |
| Cohort 1 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Diabetes Mellitus | 0 Participants |
| Cohort 1 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Adrenal Insufficiency | 2 Participants |
| Cohort 1 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Diarrhoea/Colitis | 8 Participants |
| Cohort 1 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Pneumonitis | 1 Participants |
| Cohort 1 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Hypophysitis | 0 Participants |
| Cohort 1 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Hepatitis | 3 Participants |
| Cohort 1 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Nephritis and Renal Dysfunction | 0 Participants |
| Cohort 2 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Pneumonitis | 0 Participants |
| Cohort 2 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Diabetes Mellitus | 0 Participants |
| Cohort 2 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Rash | 3 Participants |
| Cohort 2 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Nephritis and Renal Dysfunction | 2 Participants |
| Cohort 2 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Adrenal Insufficiency | 1 Participants |
| Cohort 2 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Hypophysitis | 1 Participants |
| Cohort 2 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Hepatitis | 1 Participants |
| Cohort 2 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Diarrhoea/Colitis | 3 Participants |
| Cohort 3 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Nephritis and Renal Dysfunction | 0 Participants |
| Cohort 3 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Pneumonitis | 0 Participants |
| Cohort 3 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Diarrhoea/Colitis | 2 Participants |
| Cohort 3 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Hepatitis | 1 Participants |
| Cohort 3 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Rash | 1 Participants |
| Cohort 3 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Adrenal Insufficiency | 0 Participants |
| Cohort 3 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Diabetes Mellitus | 1 Participants |
| Cohort 3 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Hypophysitis | 0 Participants |
| Cohort 4 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Nephritis and Renal Dysfunction | 0 Participants |
| Cohort 4 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Hepatitis | 1 Participants |
| Cohort 4 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Hypophysitis | 0 Participants |
| Cohort 4 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Diabetes Mellitus | 0 Participants |
| Cohort 4 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Diarrhoea/Colitis | 0 Participants |
| Cohort 4 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Rash | 0 Participants |
| Cohort 4 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Pneumonitis | 0 Participants |
| Cohort 4 | Number of Participants Who Received Hormone Replacement Therapy for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Adrenal Insufficiency | 1 Participants |
Secondary
Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs)
The number of participants who received immune modulating medication for participants experiencing all high grade (CTCAE v4 Grade 3-4 and Grade 5) Immune Mediated Adverse Events (IMAEs) in the following categories will be included: Skin, Endocrine, Gastrointestinal, Hepatic, Renal, Pulmonary and Hypersensitivity. IMAEs are specific events (or groups of preferred terms describing specific events) considered as potential immune-mediated events by investigator, that meet the following definition: (1) those occurring within 100 days of the last dose (2) regardless of causality (3) with no clear alternate etiology based on investigator assessment, or with an immune-mediated component and (4) treated with immune-modulating medication. Grade 3= Severe reaction, Grade 4 = Life-threatening, Grade 5 = Death
Time frame: From first dose up to 100 days post last dose (up to approximately 29 months)
Population: All Treated Participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Diarrhoea/Colitis | 8 Participants |
| Cohort 1 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Diabetes Mellitus | 3 Participants |
| Cohort 1 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Hypersensitivity | 0 Participants |
| Cohort 1 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Adrenal Insufficiency | 3 Participants |
| Cohort 1 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Hepatitis | 3 Participants |
| Cohort 1 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Pneumonitis | 1 Participants |
| Cohort 1 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Hypophysitis | 0 Participants |
| Cohort 1 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Hypothyroidism/Thyroiditis | 0 Participants |
| Cohort 1 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Nephritis and Renal Dysfunction | 0 Participants |
| Cohort 1 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Hyperthyroidism | 0 Participants |
| Cohort 1 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Rash | 7 Participants |
| Cohort 2 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Nephritis and Renal Dysfunction | 2 Participants |
| Cohort 2 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Diabetes Mellitus | 0 Participants |
| Cohort 2 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Rash | 3 Participants |
| Cohort 2 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Hypothyroidism/Thyroiditis | 0 Participants |
| Cohort 2 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Pneumonitis | 0 Participants |
| Cohort 2 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Hyperthyroidism | 0 Participants |
| Cohort 2 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Hepatitis | 1 Participants |
| Cohort 2 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Hypersensitivity | 0 Participants |
| Cohort 2 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Diarrhoea/Colitis | 4 Participants |
| Cohort 2 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Adrenal Insufficiency | 1 Participants |
| Cohort 2 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Hypophysitis | 1 Participants |
| Cohort 3 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Hyperthyroidism | 0 Participants |
| Cohort 3 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Nephritis and Renal Dysfunction | 0 Participants |
| Cohort 3 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Adrenal Insufficiency | 0 Participants |
| Cohort 3 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Pneumonitis | 0 Participants |
| Cohort 3 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Diarrhoea/Colitis | 2 Participants |
| Cohort 3 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Hepatitis | 1 Participants |
| Cohort 3 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Rash | 1 Participants |
| Cohort 3 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Hypersensitivity | 0 Participants |
| Cohort 3 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Hypothyroidism/Thyroiditis | 0 Participants |
| Cohort 3 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Diabetes Mellitus | 1 Participants |
| Cohort 3 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Hypophysitis | 1 Participants |
| Cohort 4 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Rash | 0 Participants |
| Cohort 4 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Hypophysitis | 0 Participants |
| Cohort 4 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Diabetes Mellitus | 0 Participants |
| Cohort 4 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Nephritis and Renal Dysfunction | 0 Participants |
| Cohort 4 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Hepatitis | 1 Participants |
| Cohort 4 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Pneumonitis | 0 Participants |
| Cohort 4 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Hyperthyroidism | 0 Participants |
| Cohort 4 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Adrenal Insufficiency | 1 Participants |
| Cohort 4 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Diarrhoea/Colitis | 0 Participants |
| Cohort 4 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Hypothyroidism/Thyroiditis | 1 Participants |
| Cohort 4 | Number of Participants Who Received Immune Modulating Medication for High Grade (Grades 3-5) Immune Mediated Adverse Events (IMAEs) | Hypersensitivity | 0 Participants |
Secondary
Objective Response Rate (ORR)
ORR is defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of response evaluable participants. Best overall response is defined as the best response recorded from the start of the study treatment until the end of treatment. The participant's best overall response assignment will depend on the findings of both target and non-target disease and will also take into consideration the appearance of new lesions. Partial response is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Complete response is defined as the disappearance of all lesions and normalization of tumor marker level. All lymph nodes (whether target or non-target) must be non-pathological in size (\< 10mm short axis).
Time frame: From first dose up to the date of objectively documented progression or the date of subsequent therapy, whichever occurs first (up to approximately 26 months)
Population: All response evaluable participants: all treated participants who have baseline and at least one on-study evaluable tumor measurement.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Objective Response Rate (ORR) | 35.4 Percentage of Participants |
| Cohort 2 | Objective Response Rate (ORR) | 21.7 Percentage of Participants |
| Cohort 3 | Objective Response Rate (ORR) | 30.8 Percentage of Participants |
| Cohort 4 | Objective Response Rate (ORR) | 33.3 Percentage of Participants |
Secondary
Time to Onset of Grade 3-5 Immune Mediated Adverse Events (IMAEs)
Time to onset is defined as the duration of time in weeks from the first dosing to the immune modulating adverse event onset date. Participants experiencing all high grade (CTCAE v4 Grade 3-4 and Grade 5) Immune Mediated Adverse Events (IMAEs) in the following categories will be included: Skin, Endocrine, Gastrointestinal, Hepatic, Renal, Pulmonary and Hypersensitivity. IMAEs are specific events (or groups of preferred terms describing specific events) considered as potential immune-mediated events by investigator, that meet the following definition: (1) those occurring within 100 days of the last dose (2) regardless of causality (3) with no clear alternate etiology based on investigator assessment, or with an immune-mediated component and (4) treated with immune-modulating medication. Grade 3= Severe reaction, Grade 4 = Life-threatening, Grade 5 = Death
Time frame: From first dose to the earliest IMAE (grade 3-5) event onset date (up to approximately 116 weeks)
Population: All Treated Participants Who Experienced at Least 1 IMAE Where Immune-modulating Medication was Initiated
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 | Time to Onset of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Pneumonitis | 12.7 Weeks |
| Cohort 1 | Time to Onset of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Diarrhoea/Colitis | 21.79 Weeks |
| Cohort 1 | Time to Onset of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Rash | 4.00 Weeks |
| Cohort 1 | Time to Onset of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Hepatitis | 8.43 Weeks |
| Cohort 1 | Time to Onset of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Adrenal Insufficiency | 36.21 Weeks |
| Cohort 2 | Time to Onset of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Adrenal Insufficiency | 12.7 Weeks |
| Cohort 2 | Time to Onset of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Diarrhoea/Colitis | 10.43 Weeks |
| Cohort 2 | Time to Onset of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Hepatitis | 9.4 Weeks |
| Cohort 2 | Time to Onset of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Hypophysitis | 18.7 Weeks |
| Cohort 2 | Time to Onset of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Nephritis and Renal Dysfunction | 9.43 Weeks |
| Cohort 2 | Time to Onset of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Rash | 6.14 Weeks |
| Cohort 2 | Time to Onset of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Immune Mediated Arthritis | 38.9 Weeks |
| Cohort 3 | Time to Onset of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Diarrhoea/Colitis | 11.0 Weeks |
| Cohort 3 | Time to Onset of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Diabetes Mellitus | 2.0 Weeks |
| Cohort 3 | Time to Onset of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Rash | 8.3 Weeks |
| Cohort 3 | Time to Onset of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Hepatitis | 11.6 Weeks |
| Cohort 4 | Time to Onset of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Hepatitis | 10.1 Weeks |
| Cohort 4 | Time to Onset of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Adrenal Insufficiency | 14.9 Weeks |
Secondary
Time to Resolution of Grade 3-5 Immune Mediated Adverse Events (IMAEs)
Time to resolution is defined as the longest time from IMAE onset date to complete resolution or improvement to the grade at baseline experienced by the participant (the IMAE end date). Participants experiencing all high grade (CTCAE v4 Grade 3-4 and Grade 5) Immune Mediated Adverse Events (IMAEs) in the following categories will be included: Skin, Endocrine, Gastrointestinal, Hepatic, Renal, Pulmonary and Hypersensitivity. IMAEs are specific events (or groups of preferred terms describing specific events) considered as potential immune-mediated events by investigator, that meet the following definition: (1) those occurring within 100 days of the last dose (2) regardless of causality (3) with no clear alternate etiology based on investigator assessment, or with an immune-mediated component and (4) treated with immune-modulating medication. Grade 3= Severe reaction, Grade 4 = Life-threatening, Grade 5 = Death
Time frame: From the IMAE onset date to the IMAE end date, up to approximately 194 weeks
Population: All Treated Participants Who Experienced at Least 1 IMAE Where Immune-modulating Medication was Initiated
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 | Time to Resolution of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Pneumonitis | 0.9 Weeks |
| Cohort 1 | Time to Resolution of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Diarrhoea/Colitis | 2.71 Weeks |
| Cohort 1 | Time to Resolution of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Rash | 26.86 Weeks |
| Cohort 1 | Time to Resolution of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Hepatitis | NA Weeks |
| Cohort 1 | Time to Resolution of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Adrenal Insufficiency | NA Weeks |
| Cohort 2 | Time to Resolution of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Hepatitis | NA Weeks |
| Cohort 2 | Time to Resolution of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Hypophysitis | 7.6 Weeks |
| Cohort 2 | Time to Resolution of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Immune Mediated Arthritis | 37.0 Weeks |
| Cohort 2 | Time to Resolution of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Diarrhoea/Colitis | 5.93 Weeks |
| Cohort 2 | Time to Resolution of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Nephritis and Renal Dysfunction | 7.79 Weeks |
| Cohort 2 | Time to Resolution of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Rash | 8.00 Weeks |
| Cohort 3 | Time to Resolution of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Diarrhoea/Colitis | 1.14 Weeks |
| Cohort 3 | Time to Resolution of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Hepatitis | 3.00 Weeks |
| Cohort 3 | Time to Resolution of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Diabetes Mellitus | 1.1 Weeks |
| Cohort 3 | Time to Resolution of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Rash | 5.3 Weeks |
| Cohort 4 | Time to Resolution of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Hepatitis | 2.1 Weeks |
| Cohort 4 | Time to Resolution of Grade 3-5 Immune Mediated Adverse Events (IMAEs) | Adrenal Insufficiency | 6.0 Weeks |
Secondary
Time to Response Rate (TRR)
TTR is defined as the median percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of response evaluable participants. Best overall response is defined as the best response recorded from the start of the study treatment until the end of treatment. The participant's best overall response assignment will depend on the findings of both target and non-target disease and will also take into consideration the appearance of new lesions. Partial response is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Complete response is defined as the disappearance of all lesions and normalization of tumor marker level. All lymph nodes (whether target or non-target) must be non-pathological in size (\< 10mm short axis).
Time frame: From the date of first dose to first documented CR or PR, up to approximately 15 months
Population: All response evaluable participants: all treated participants who have baseline and at least one on-study evaluable tumor measurement.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Time to Response Rate (TRR) | 2.8 Months |
| Cohort 2 | Time to Response Rate (TRR) | 2.8 Months |
| Cohort 3 | Time to Response Rate (TRR) | 2.8 Months |
| Cohort 4 | Time to Response Rate (TRR) | 4.5 Months |