Malignant Melanoma
Conditions
Brief summary
This study will evaluate the preliminary efficacy, safety, and pharmacokinetics of cobimetinib and atezolizumab in participants with advanced BRAF V600-wild type (WT), metastatic, or unresectable locally advanced melanoma who have progressed on prior anti-PD-1 therapy. In addition, this study will evaluate the efficacy, safety, and pharmacokinetics of atezolizumab monotherapy in participants with BRAFV600-WT metastatic or unresectable locally advanced melanoma, who have not been previously treated.
Interventions
DRUGCobimetinib
Cobimetinib, 60 mg orally once daily (QD) on Days 1-21 of each 28-day cycle, until loss of clinical benefit
BIOLOGICALAtezolizumab
Atezolizumab, 840 mg intravenously every two weeks (Q2W) on Days 1 and 15 of each 28-day cycle, until loss of clinical benefit
Sponsors
Hoffmann-La Roche
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
Disease-Specific Inclusion Criteria: Cohorts A and B: * Histologically confirmed Stage IV (metastatic) or unresectable Stage IIIc BRAF V600 WT (locally advanced) melanoma * Documentation of BRAF V600 mutation-negative status in melanoma tumor tissue (archival \[\< 5 years old\] or newly obtained) through use of a clinical mutation test approved by the local health authority * Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 * Disease progression on or after treatment with a programmed death (PD)-1 inhibitor either as monotherapy or in combination with other agent(s) Additional Disease-Specific Inclusion Criteria in Cohort B (Biopsy Cohort): * Progressed on or after anti-PD-1 therapy within 12 weeks before study start * Received a minimum of two cycles of anti-PD-1 therapy * Meet the following criteria for resistance to an anti-PD-1 agent: primary resistance defined as disease progression, according to RECIST v1.1, as best response; secondary resistance defined as disease progression after initial confirmed response according to RECIST v1.1 * Consent to undergo tumor biopsies of accessible lesions, before and during treatment and at radiographic progression, for biomarker analyses. * Have at least two accessible lesions that are amenable to excisional or core-needle (minimum three cores and minimum diameter 18 gauge; however, 16 gauge is desirable) biopsy without unacceptable risk of a major procedural complication. Exceptions may be made if patient has only one lesion that allows multiple biopsies. Disease-Specific Inclusion Criteria: Cohort C: * Histologically confirmed Stage IV (metastatic) or unresectable Stage IIIc BRAFV600-WT (locally advanced) melanoma * Naive to prior systemic anti-cancer therapy for melanoma * Documentation of BRAFV600 mutation-negative status in melanoma tumor tissue (archival \[\< 5 years old\] or newly obtained) through use of a clinical mutation test approved by the local health authority * A representative, formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or 20 slides containing unstained, freshly cut, serial sections must be submitted along with an associated pathology report prior to study entry. * Measurable disease according to RECIST v1.1. General Inclusion Criteria: * Ability to comply with the study protocol, in the investigator's judgment * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 * Available and adequate baseline tumor tissue sample * Life expectancy ≥ 18 weeks * Adequate hematologic and end-organ function, defined by laboratory test results, obtained within 14 days before initiation of study treatment * For women of childbearing potential: abstinent or use an effective form of contraceptive method for at least 3 months for cobimetinib and at least 5 months for atezolizumab. Women must refrain from donating eggs during this same period. * For men: abstinent or use contraceptive measures and agreement to refrain from donating sperm for at least 3 months after cobimetinib and atezolizumab
Exclusion criteria
* Prior treatment with a mitogen activated-protein kinase (MAPK) inhibitor * Ocular melanoma * Major surgical procedure other than for diagnosis within 4 weeks before initiation of study treatment, or anticipation of need for a major surgical procedure during the course of the study * Traumatic injury within 2 weeks before initiation of study treatment * Palliative radiotherapy within 14 days before initiation of study treatment * Active malignancy (other than BRAF V600 mutation-negative melanoma) or malignancy within 3 years * Treatment with any anti-cancer agent 14 days prior to Cycle, Day 1 other than aPD-1 based therapy * Adverse events from prior anti-cancer therapy that have not resolved to Grade ≤ 1. Clinically stable patients with manageable immune-related adverse events resulting from prior cancer immunotherapy may be eligible for the study. * For Cohort C only: any prior anti-cancer therapy for advanced melanoma * History or evidence of ongoing serous retinopathy or retinal vein occlusion (RVO) at baseline * History of clinically significant cardiac dysfunction * Active or untreated central nervous system (CNS) metastases * History of metastases to brain stem, midbrain, pons, or medulla, or within 10 millimeter (mm) of the optic apparatus (optic nerves and chiasm) * History of leptomeningeal metastatic disease * Human immunodeficiency virus (HIV) infection * Active tuberculosis * Severe infection within 4 weeks before initiation of study treatment * Signs or symptoms of infection within 2 weeks before initiation of study treatment * Treatment with oral or intravenous (IV) antibiotics within 2 weeks prior to Day 1 of Cycle 1 * Active or chronic viral hepatitis B or C infection * Active or history of autoimmune disease or immune deficiency * Prior allogeneic stem cell or solid organ transplantation * History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan * Treatment with systemic immunosuppressive medications with the following exceptions: * Patients who have received acute, low-dose systemic immunosuppressant medication (≤ 10 mg/day oral prednisone or equivalent) or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study after Medical Monitor approval has been obtained. * Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study. * Current severe, uncontrolled systemic disease other than cancer * Any Grade \>/=3 hemorrhage or bleeding event within 28 days of Day 1 of Cycle 1 * History of stroke, reversible ischemic neurological defect, or transient ischemic attack within 6 months prior to Day 1 * Anticipated use of any concomitant medication during or within 7 days before initiation of study treatment that is known to cause QT prolongation * Any psychological, familial, sociological, or geographic condition that may hamper compliance with the protocol and follow-up after treatment discontinuation * History of malabsorption or other clinically significant metabolic dysfunction that may interfere with absorption of oral study treatment * Pregnant or breastfeeding, or intending to become pregnant during the study * Known clinically significant liver disease * Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the participant at high risk for treatment complications * Treatment with a live, attenuated vaccine within 4 weeks before initiation of study treatment, or anticipation of need for such a vaccine during the course of the study * Known hypersensitivity to any component of the atezolizumab or cobimetinib formulations * History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins * Treatment with any other investigational agent or participation in another clinical study with therapeutic intent * Inability or unwillingness to swallow pills * Requirement for concomitant therapy or food that is prohibited during the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Investigator-Assessed Objective Response Rate (ORR) | Up to approximately 2 years | ORR is defined as the percentage of participants with confirmed objective response (OR). Confirmed OR is defined as complete response (CR) or partial response (PR) on two consecutive occasions ≥ 4 weeks apart, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. |
| Investigator-Assessed Disease Control Rate (DCR) | Week 16 | DCR is defined as the percentage of participants with CR, PR, or stable disease (SD) at 16 weeks. Per RECIST v1.1, CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression, taking as reference the smallest sum on study. Disease progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including baseline, or the appearance of one or more new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Investigator-Assessed Progression-Free Survival (PFS) | Up to approximately 2 years | PFS is defined as the time from Cycle 1, Day 1 to the first occurrence of disease progression, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first. Disease progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including baseline; or the appearance of one or more new lesions. |
| Serum Concentration of Atezolizumab | Cycle 1, Day 15; Day 1 of Cycles 2, 3, 4, 8 | — |
| Plasma Concentration of Cobimetinib | Cycle 1, Day 15 | — |
| Percentage of Participants With Adverse Events | Baseline through follow up | An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. |
| Investigator-Assessed Duration of Response (DOR) | Up to approximately 2 years | DOR is defined as the time from the first occurrence of documented OR to disease progression, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first. Disease progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including baseline; or the appearance of one or more new lesions. |
| Cohort C: Independent-Review-Committee-Assessed (IRC) ORR | Approximately 2 years for Cohorts A and B and 19 months for Cohort C | ORR is defined as the percentage of participants with confirmed objective response (OR), as determined by an independent review committee (IRC) according to RECIST v1.1. Confirmed OR is defined as complete response (CR) or partial response (PR) on two consecutive occasions ≥ 4 weeks apart, as determined by an independent review committee (IRC) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. |
| Cohort C: IRC-Assessed DCR | Approximately 21 months | DCR is defined as the percentage of participants with CR, PR, or stable disease (SD), as determined by an independent review committee (IRC) according to RECIST v1.1. CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression, taking as reference the smallest sum on study. Disease progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including baseline, or the appearance of one or more new lesions. |
| Cohort C: IRC-Assessed DOR | Approximately 21 months | DOR is defined as the time from the first occurrence of documented OR to disease progression, as determined by an independent review committee (IRC) according to RECIST v1.1, or death from any cause, whichever occurs first. Disease progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including baseline; or the appearance of one or more new lesions. |
| Cohort C: IRC-Assessed PFS | Approximately 21 months | PFS is defined as the time from Cycle 1, Day 1 to the first occurrence of disease progression, as determined by an independent review committee (IRC) according to RECIST v1.1, or death from any cause, whichever occurs first. Disease progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including baseline; or the appearance of one or more new lesions. |
| Change From Baseline in Percentage of Participants With Anti-drug Antibodies (ADAs) to Atezolizumab | Cycle 1 Day 1 pre-dose to 120 days after the last dose of study medication | To evaluate the immune response to atezolizumab the percentage of participants with ADAs to atezolizumab will be determined at baseline and during the study. |
| Overall Survival (OS) | Up to approximately 2 years | OS is defined as the time from Cycle 1, Day 1 to death from any cause. |
Countries
Australia, Bosnia and Herzegovina, Brazil, South Africa, Spain, Ukraine, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort A Participants with disease progression on or after treatment with an anti-PD-1 agent initiated dosing with atezolizumab concurrently with cobimetinib. Participants received intravenous (IV) atezolizumab every two weeks (Q2W) on Days 1 and 15 of all cycles. Participants received oral cobimetinib once daily (QD) on Days 1-21 of each 28-day cycle. | 92 |
| Cohort B Participants with disease progression on or after treatment with an anti-PD-1 agent received cobimetinib prior to initiating IV atezolizumab treatment on Day 15 of Cycle 1. Participants continued to receive atezolizumab on Days 1 and 15 from Cycle 2 onwards. Oral cobimetinib was given QD on Days 1-21 of each 28-day cycle. Participants in this cohort underwent tumor biopsies before and during treatment. | 11 |
| Cohort C Participants with advanced melanoma, who had not received previous treatment, received IV atezolizumab monotherapy every 3 weeks (Q3W). | 52 |
| Total | 155 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 |
| Overall Study | Death | 48 | 2 | 25 |
| Overall Study | Lost to Follow-up | 5 | 2 | 0 |
| Overall Study | Study Termination by Sponsor | 31 | 7 | 26 |
| Overall Study | Withdrawal by Subject | 8 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort A | Cohort B | Cohort C | Total |
|---|---|---|---|---|
| Age, Continuous | 60.7 Years STANDARD_DEVIATION 11.8 | 62.3 Years STANDARD_DEVIATION 9.6 | 61.2 Years STANDARD_DEVIATION 11.8 | 61.0 Years STANDARD_DEVIATION 11.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 1 Participants | 25 Participants | 32 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 82 Participants | 10 Participants | 26 Participants | 118 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 0 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 4 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 88 Participants | 11 Participants | 46 Participants | 145 Participants |
| Sex: Female, Male Female | 33 Participants | 3 Participants | 17 Participants | 53 Participants |
| Sex: Female, Male Male | 59 Participants | 8 Participants | 35 Participants | 102 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 48 / 92 | 2 / 11 | 25 / 52 |
| other Total, other adverse events | 90 / 92 | 11 / 11 | 50 / 52 |
| serious Total, serious adverse events | 42 / 92 | 5 / 11 | 15 / 52 |
Outcome results
Primary
Investigator-Assessed Disease Control Rate (DCR)
DCR is defined as the percentage of participants with CR, PR, or stable disease (SD) at 16 weeks. Per RECIST v1.1, CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression, taking as reference the smallest sum on study. Disease progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including baseline, or the appearance of one or more new lesions.
Time frame: Week 16
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A | Investigator-Assessed Disease Control Rate (DCR) | 37.0 Percentage of Participants |
| Cohort B | Investigator-Assessed Disease Control Rate (DCR) | 54.5 Percentage of Participants |
| Cohort C | Investigator-Assessed Disease Control Rate (DCR) | 46.2 Percentage of Participants |
Primary
Investigator-Assessed Objective Response Rate (ORR)
ORR is defined as the percentage of participants with confirmed objective response (OR). Confirmed OR is defined as complete response (CR) or partial response (PR) on two consecutive occasions ≥ 4 weeks apart, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
Time frame: Up to approximately 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A | Investigator-Assessed Objective Response Rate (ORR) | 12.0 Percentage of Participants |
| Cohort B | Investigator-Assessed Objective Response Rate (ORR) | 36.4 Percentage of Participants |
| Cohort C | Investigator-Assessed Objective Response Rate (ORR) | 38.5 Percentage of Participants |
Secondary
Change From Baseline in Percentage of Participants With Anti-drug Antibodies (ADAs) to Atezolizumab
To evaluate the immune response to atezolizumab the percentage of participants with ADAs to atezolizumab will be determined at baseline and during the study.
Time frame: Cycle 1 Day 1 pre-dose to 120 days after the last dose of study medication
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A | Change From Baseline in Percentage of Participants With Anti-drug Antibodies (ADAs) to Atezolizumab | 32.5 Percentage of Participants |
| Cohort B | Change From Baseline in Percentage of Participants With Anti-drug Antibodies (ADAs) to Atezolizumab | 30.0 Percentage of Participants |
| Cohort C | Change From Baseline in Percentage of Participants With Anti-drug Antibodies (ADAs) to Atezolizumab | 10.0 Percentage of Participants |
Secondary
Cohort C: Independent-Review-Committee-Assessed (IRC) ORR
ORR is defined as the percentage of participants with confirmed objective response (OR), as determined by an independent review committee (IRC) according to RECIST v1.1. Confirmed OR is defined as complete response (CR) or partial response (PR) on two consecutive occasions ≥ 4 weeks apart, as determined by an independent review committee (IRC) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
Time frame: Approximately 2 years for Cohorts A and B and 19 months for Cohort C
Population: The analysis populations included all participants with measureable disease at baseline as measured by either the investigator or by an IRC.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A | Cohort C: Independent-Review-Committee-Assessed (IRC) ORR | 27.3 Percentage of Participants |
Secondary
Cohort C: IRC-Assessed DCR
DCR is defined as the percentage of participants with CR, PR, or stable disease (SD), as determined by an independent review committee (IRC) according to RECIST v1.1. CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression, taking as reference the smallest sum on study. Disease progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including baseline, or the appearance of one or more new lesions.
Time frame: Approximately 21 months
Population: The analysis populations included all participants with measureable disease at baseline as measured by either the investigator or by an IRC.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A | Cohort C: IRC-Assessed DCR | 38.6 Percentage of Participants |
Secondary
Cohort C: IRC-Assessed DOR
DOR is defined as the time from the first occurrence of documented OR to disease progression, as determined by an independent review committee (IRC) according to RECIST v1.1, or death from any cause, whichever occurs first. Disease progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including baseline; or the appearance of one or more new lesions.
Time frame: Approximately 21 months
Population: The analysis populations included all participants with measureable disease at baseline as measured by either the investigator or by an IRC.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A | Cohort C: IRC-Assessed DOR | NA Months |
Secondary
Cohort C: IRC-Assessed PFS
PFS is defined as the time from Cycle 1, Day 1 to the first occurrence of disease progression, as determined by an independent review committee (IRC) according to RECIST v1.1, or death from any cause, whichever occurs first. Disease progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including baseline; or the appearance of one or more new lesions.
Time frame: Approximately 21 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A | Cohort C: IRC-Assessed PFS | 3.7 Months |
Secondary
Investigator-Assessed Duration of Response (DOR)
DOR is defined as the time from the first occurrence of documented OR to disease progression, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first. Disease progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including baseline; or the appearance of one or more new lesions.
Time frame: Up to approximately 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A | Investigator-Assessed Duration of Response (DOR) | 24.2 Months |
| Cohort B | Investigator-Assessed Duration of Response (DOR) | NA Months |
| Cohort C | Investigator-Assessed Duration of Response (DOR) | NA Months |
Secondary
Investigator-Assessed Progression-Free Survival (PFS)
PFS is defined as the time from Cycle 1, Day 1 to the first occurrence of disease progression, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first. Disease progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including baseline; or the appearance of one or more new lesions.
Time frame: Up to approximately 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A | Investigator-Assessed Progression-Free Survival (PFS) | 3.7 Months |
| Cohort B | Investigator-Assessed Progression-Free Survival (PFS) | 9.3 Months |
| Cohort C | Investigator-Assessed Progression-Free Survival (PFS) | 3.7 Months |
Secondary
Overall Survival (OS)
OS is defined as the time from Cycle 1, Day 1 to death from any cause.
Time frame: Up to approximately 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A | Overall Survival (OS) | 12.5 Months |
| Cohort B | Overall Survival (OS) | NA Months |
| Cohort C | Overall Survival (OS) | 22.0 Months |
Secondary
Percentage of Participants With Adverse Events
An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
Time frame: Baseline through follow up
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A | Percentage of Participants With Adverse Events | 98.9 Percentage of Participants |
| Cohort B | Percentage of Participants With Adverse Events | 100 Percentage of Participants |
| Cohort C | Percentage of Participants With Adverse Events | 100 Percentage of Participants |
Secondary
Plasma Concentration of Cobimetinib
Time frame: Cycle 1, Day 15
Population: Pharmacokinetic (PK) analyses were performed on all participants that received at least one dose of study drug and who had at least one evaluable PK sample.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A | Plasma Concentration of Cobimetinib | Cycle 1 Day 15 - Ctrough | 165 ug/mL | Geometric Coefficient of Variation 137 |
| Cohort A | Plasma Concentration of Cobimetinib | Cycle 1 Day 15 - Css | 318 ug/mL | Geometric Coefficient of Variation 75.2 |
| Cohort B | Plasma Concentration of Cobimetinib | Cycle 1 Day 15 - Ctrough | 125 ug/mL | Geometric Coefficient of Variation 86.6 |
| Cohort B | Plasma Concentration of Cobimetinib | Cycle 1 Day 15 - Css | 208 ug/mL | Geometric Coefficient of Variation 59.6 |
Secondary
Serum Concentration of Atezolizumab
Time frame: Cycle 1, Day 15; Day 1 of Cycles 2, 3, 4, 8
Population: Pharmacokinetic (PK) analyses were performed on all participants that received at least one dose of study drug and who had at least one evaluable PK sample.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A | Serum Concentration of Atezolizumab | Cmin - Cycle 4 Day 1 | 121 ug/mL | Geometric Coefficient of Variation 237 |
| Cohort A | Serum Concentration of Atezolizumab | Cmin - Cycle 3 Day 1 | 92.4 ug/mL | Geometric Coefficient of Variation 442 |
| Cohort A | Serum Concentration of Atezolizumab | Cmax - Cycle 1 Day 15 | 271 ug/mL | Geometric Coefficient of Variation 22.1 |
| Cohort A | Serum Concentration of Atezolizumab | Cmin - Cycle 2 Day 1 | 65.3 ug/mL | Geometric Coefficient of Variation 330 |
| Cohort A | Serum Concentration of Atezolizumab | Cmin - Cycle 8 Day 1 | 210 ug/mL | Geometric Coefficient of Variation 46.8 |
| Cohort B | Serum Concentration of Atezolizumab | Cmin - Cycle 3 Day 1 | 37.6 ug/mL | Geometric Coefficient of Variation 7490 |
| Cohort B | Serum Concentration of Atezolizumab | Cmax - Cycle 1 Day 15 | 275 ug/mL | Geometric Coefficient of Variation 21.9 |
| Cohort B | Serum Concentration of Atezolizumab | Cmin - Cycle 2 Day 1 | 32.9 ug/mL | Geometric Coefficient of Variation 1540 |
| Cohort B | Serum Concentration of Atezolizumab | Cmin - Cycle 4 Day 1 | 83.7 ug/mL | Geometric Coefficient of Variation 844 |
| Cohort B | Serum Concentration of Atezolizumab | Cmin - Cycle 8 Day 1 | NA ug/mL | — |
| Cohort C | Serum Concentration of Atezolizumab | Cmin - Cycle 8 Day 1 | 159 ug/mL | Geometric Coefficient of Variation 58.7 |
| Cohort C | Serum Concentration of Atezolizumab | Cmin - Cycle 4 Day 1 | 128 ug/mL | Geometric Coefficient of Variation 50.8 |
| Cohort C | Serum Concentration of Atezolizumab | Cmax - Cycle 1 Day 15 | 388 ug/mL | Geometric Coefficient of Variation 20.5 |
| Cohort C | Serum Concentration of Atezolizumab | Cmin - Cycle 3 Day 1 | 113 ug/mL | Geometric Coefficient of Variation 47.8 |
| Cohort C | Serum Concentration of Atezolizumab | Cmin - Cycle 2 Day 1 | 73.2 ug/mL | Geometric Coefficient of Variation 55 |