Cobimetinib (Targeted Therapy) Plus Atezolizumab (Immunotherapy) in Participants With Advanced Melanoma Whose Cancer Has Worsened During or After Treatment With Previous Immunotherapy and Atezolizumab Monotherapy in Participants With Previously Untreated Advanced Melanoma

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03178851
• Collaborator: (none)
• Enrollment: 155
• Locations: 43
• Arms: 3
• Actual Duration (Months): 39.1
• Patients Per Site: 3.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Malignant Melanoma	Biological: Atezolizumab; Drug: Cobimetinib; Biological: Atezolizumab; Biological: Atezolizumab	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 155 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase Ib Study Evaluating Cobimetinib Plus Atezolizumab in Patients With Advanced BRAF V600 Wild-Type Melanoma Who Have Progressed During or After Treatment With Anti-PD-1 Therapy and Atezolizumab Monotherapy in Patients With Previously Untreated Advanced BRAF V600 Wild-Type Melanoma
• Actual Study Start Date: Jun 20, 2017
• Actual Primary Completion Date: May 29, 2019
• Actual Study Completion Date: Sep 21, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort A Participants with disease progression on or after treatment with an anti-PD-1 agent will receive cobimetinib and atezolizumab treatment during 28-day cycles.	Biological: Atezolizumab; Atezolizumab, 840 mg intravenously every two weeks (Q2W) on Days 1 and 15 of each 28-day cycle, until loss of clinical benefit; Other Names: Tecentriq ; Drug: Cobimetinib; Cobimetinib, 60 mg orally once daily (QD) on Days 1-21 of each 28-day cycle, until loss of clinical benefit; Other Names: Cotellic
Experimental: Cohort B Participants with disease progression on or after treatment with an anti-PD-1 agent will receive cobimetinib prior to initiating atezolizumab treatment during Cycle 1. During subsequent 28-day cycles participants will initiate both atezolizumab and cobimetinib on Day 1 of each cycle. Participants in this cohort will undergo tumor biopsies before and during treatment.	Drug: Cobimetinib; Cobimetinib, 60 mg orally once daily (QD) on Days 1-21 of each 28-day cycle, until loss of clinical benefit; Other Names: Cotellic ; Biological: Atezolizumab; Atezolizumab, 840 mg intravenously on Day 15 of Cycle 1; thereafter Q2W on Days 1 and 15 of Cycle 2 and all subsequent 28-day cycles, until loss of clinical benefit; Other Names: Tecentriq
Experimental: Cohort C Participants with advanced melanoma, who have not received previous treatment, will receive atezolizumab monotherapy during 21-day cycles.	Biological: Atezolizumab; Atezolizumab, 1200 mg intravenously every three weeks (Q3W) on Day 1 of each 21-day cycle, until loss of clinical benefit; Other Names: Tecentriq

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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.

2. Overall Survival (OS) [Up to approximately 2 years]

   OS is defined as the time from Cycle 1, Day 1 to death from any cause.

3. 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.

4. Serum Concentration of Atezolizumab [Cycle 1, Day 15; Day 1 of Cycles 2, 3, 4, 8]

5. Plasma Concentration of Cobimetinib [Cycle 1, Day 15]

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	HonorHealth Research Institute - Bisgrove	Scottsdale	Arizona	United States	85258
2	University of Colorado Hospital - Anschutz Cancer Pavilion	Aurora	Colorado	United States	80045
3	Karmanos Cancer Institute	Detroit	Michigan	United States	48201
4	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
5	Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
6	Baylor University Medical Center	Dallas	Texas	United States	75231
7	Blacktown Hospital	Blacktown	New South Wales	Australia	2148
8	Melanoma Institute Australia	North Sydney	New South Wales	Australia	2060
9	Mid North Coast Cancer Institute	Port Macquarie	New South Wales	Australia	2444
10	Greenslopes Private Hospital; Clinic Pharmacy	Greenslopes	Queensland	Australia	4120
11	Flinders Medical Centre	Bedford Park	South Australia	Australia	5042
12	Peter Maccallum Cancer Centre	Melbourne	Victoria	Australia	3000
13	Alfred Hospital	Melbourne	Victoria	Australia	3004
14	University Clinical Centre of the Republic of Srpska	Banja Luka		Bosnia and Herzegovina	78000
15	University Clinic Ctr Sarajevo	Sarajevo		Bosnia and Herzegovina	71 000
16	Instituto de Ensino e Pesquisa Clinica do Ceara	Fortaleza	CE	Brazil	60130-241
17	Cenantron - Centro Avancado de Tratamento Oncologico	Belo Horizonte	MG	Brazil	30130-090
18	Instituto Nacional de Cancer - INCa; Oncologia	Rio de Janeiro	RJ	Brazil	20560-120
19	Hospital Sao Vicente de Paulo	Passo Fundo	RS	Brazil	99010-090
20	Hospital das Clinicas - UFRGS	Porto Alegre	RS	Brazil	90035-903
21	Hospital Sao Lucas - PUCRS	Porto Alegre	RS	Brazil	90610-000
22	Hospital Amaral Carvalho	Jau	SP	Brazil	17210-120
23	Cape Town Oncology Trials	Cape Town		South Africa	7570
24	GVI Constantiaberg	Cape Town		South Africa	7800
25	Johese Clinical Research	Centurion		South Africa	1692
26	Cancercare	George		South Africa	6529
27	Wits Clinical Research; Charlotte Maxeke Johannesburg Academic Hospital	Johannesburg		South Africa	2193
28	Cancercare	Port Elizabeth		South Africa	6045
29	Steve Biko Academic Hospital; Oncology	Pretoria		South Africa	0002
30	Hospital Clinico Universitario de Santiago	Santiago de Compostela	LA Coruña	Spain	15706
31	Clínica Universidad de Navarra	Pamplona	Navarra	Spain	31620
32	Hospital Universitario Virgen Macarena	Seville	Sevilla	Spain	41071
33	Hospital Universitari Quiron Dexeus	Barcelona		Spain	08028
34	Hospital Clinic I Provincial	Barcelona		Spain	08036
35	MD Anderson Cancer Center	Madrid		Spain	28033
36	Hospital Universitario Ramón y Cajal; Pharmacy	Madrid		Spain	28034
37	Hospital Universitario 12 de Octubre; Servicio de Oncologia	Madrid		Spain	28041
38	Hospital Universitario La Paz; Servicio de Oncologia	Madrid		Spain	28046
39	Central Municipal Hospital - Uzhgorod State University	Uzhgorod	Chernihiv Governorate	Ukraine	88017
40	Public Institution: City Multispecialty Clinical Hospital #4 under Dnipropetrovsk Regional Council	Dnipropetrovsk		Ukraine	49102
41	National Cancer Institute MOH of Ukraine	Kiev		Ukraine	36022
42	Lviv State Oncology Regional Treatment and Diagnostic Centre	Lviv		Ukraine	79031
43	Sumy Regional Clinical Onc Ctr	Sumy		Ukraine	40005

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 26, 2018

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT03178851
• Other Study ID Numbers: CO39721; 2016-004402-34
• First Posted: Jun 7, 2017
• Last Update Posted: Nov 19, 2021
• Last Verified: Nov 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Melanoma; Atezolizumab; Antibodies, Monoclonal

Study Results

Participant Flow

Arm/Group Title	Cohort A	Cohort B	Cohort C
Arm/Group Description	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.	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.	Participants with advanced melanoma, who had not received previous treatment, received IV atezolizumab monotherapy every 3 weeks (Q3W).
Period Title: Overall Study
STARTED	92	11	52
COMPLETED	0	0	0
NOT COMPLETED	92	11	52

Baseline Characteristics

Arm/Group Title	Cohort A	Cohort B	Cohort C	Total
Arm/Group Description	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.	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.	Participants with advanced melanoma, who had not received previous treatment, received IV atezolizumab monotherapy every 3 weeks (Q3W).	Total of all reporting groups
Overall Participants	92	11	52	155
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	60.7 (11.8)	62.3 (9.6)	61.2 (11.8)	61.0 (11.6)
Sex: Female, Male (Count of Participants)
Female	33 35.9%	3 27.3%	17 32.7%	53 34.2%
Male	59 64.1%	8 72.7%	35 67.3%	102 65.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	6 6.5%	1 9.1%	25 48.1%	32 20.6%
Not Hispanic or Latino	82 89.1%	10 90.9%	26 50%	118 76.1%
Unknown or Not Reported	4 4.3%	0 0%	1 1.9%	5 3.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	2 3.8%	2 1.3%
Asian	2 2.2%	0 0%	0 0%	2 1.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	1 1.1%	0 0%	4 7.7%	5 3.2%
White	88 95.7%	11 100%	46 88.5%	145 93.5%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	1 1.1%	0 0%	0 0%	1 0.6%

Outcome Measures

1. Primary Outcome

Title	Investigator-Assessed Objective Response Rate (ORR)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort A	Cohort B	Cohort C
Arm/Group Description	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.	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.	Participants with advanced melanoma, who had not received previous treatment, received IV atezolizumab monotherapy every 3 weeks (Q3W).
Measure Participants	92	11	52
Number (95% Confidence Interval) [Percentage of Participants]	12.0 13%	36.4 330.9%	38.5 74%

2. Primary Outcome

Title	Investigator-Assessed Disease Control Rate (DCR)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort A	Cohort B	Cohort C
Arm/Group Description	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.	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.	Participants with advanced melanoma, who had not received previous treatment, received IV atezolizumab monotherapy every 3 weeks (Q3W).
Measure Participants	92	11	52
Number (95% Confidence Interval) [Percentage of Participants]	37.0 40.2%	54.5 495.5%	46.2 88.8%

3. Secondary Outcome

Title	Investigator-Assessed Duration of Response (DOR)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort A	Cohort B	Cohort C
Arm/Group Description	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.	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.	Participants with advanced melanoma, who had not received previous treatment, received IV atezolizumab monotherapy every 3 weeks (Q3W).
Measure Participants	92	11	52
Median (95% Confidence Interval) [Months]	24.2	NA	NA

4. Secondary Outcome

Title	Overall Survival (OS)
Description	OS is defined as the time from Cycle 1, Day 1 to death from any cause.
Time Frame	Up to approximately 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort A	Cohort B	Cohort C
Arm/Group Description	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.	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.	Participants with advanced melanoma, who had not received previous treatment, received IV atezolizumab monotherapy every 3 weeks (Q3W).
Measure Participants	92	11	52
Median (95% Confidence Interval) [Months]	12.5	NA	22.0

5. Secondary Outcome

Title	Investigator-Assessed Progression-Free Survival (PFS)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort A	Cohort B	Cohort C
Arm/Group Description	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.	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.	Participants with advanced melanoma, who had not received previous treatment, received IV atezolizumab monotherapy every 3 weeks (Q3W).
Measure Participants	92	11	52
Median (95% Confidence Interval) [Months]	3.7	9.3	3.7

6. Secondary Outcome

Title	Serum Concentration of Atezolizumab
Time Frame	Cycle 1, Day 15; Day 1 of Cycles 2, 3, 4, 8

Outcome Measure Data

Analysis Population Description

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/Group Title	Cohort A	Cohort B	Cohort C
Arm/Group Description	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.	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.	Participants with advanced melanoma, who had not received previous treatment, received IV atezolizumab monotherapy every 3 weeks (Q3W).
Measure Participants	92	11	52
Cmax - Cycle 1 Day 15	271 (22.1)	275 (21.9)	388 (20.5)
Cmin - Cycle 2 Day 1	65.3 (330)	32.9 (1540)	73.2 (55.0)
Cmin - Cycle 3 Day 1	92.4 (442)	37.6 (7490)	113 (47.8)
Cmin - Cycle 4 Day 1	121 (237)	83.7 (844)	128 (50.8)
Cmin - Cycle 8 Day 1	210 (46.8)	NA (NA)	159 (58.7)

7. Secondary Outcome

Title	Plasma Concentration of Cobimetinib
Time Frame	Cycle 1, Day 15

Outcome Measure Data

Analysis Population Description

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/Group Title	Cohort A	Cohort B
Arm/Group Description	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.	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.
Measure Participants	92	11
Cycle 1 Day 15 - Ctrough	165 (137)	125 (86.6)
Cycle 1 Day 15 - Css	318 (75.2)	208 (59.6)

8. Secondary Outcome

Title	Percentage of Participants With Adverse Events
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort A	Cohort B	Cohort C
Arm/Group Description	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.	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.	Participants with advanced melanoma, who had not received previous treatment, received IV atezolizumab monotherapy every 3 weeks (Q3W).
Measure Participants	92	11	52
Number [Percentage of Participants]	98.9 107.5%	100 909.1%	100 192.3%

9. Secondary Outcome

Title	Change From Baseline in Percentage of Participants With Anti-drug Antibodies (ADAs) to Atezolizumab
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort A	Cohort B	Cohort C
Arm/Group Description	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.	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.	Participants with advanced melanoma, who had not received previous treatment, received IV atezolizumab monotherapy every 3 weeks (Q3W).
Measure Participants	92	11	52
Number [Percentage of Participants]	32.5 35.3%	30.0 272.7%	10.0 19.2%

10. Secondary Outcome

Title	Cohort C: Independent-Review-Committee-Assessed (IRC) ORR
Description	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

Outcome Measure Data

Analysis Population Description

The analysis populations included all participants with measureable disease at baseline as measured by either the investigator or by an IRC.

Arm/Group Title	Cohort C
Arm/Group Description	Participants with advanced melanoma, who had not received previous treatment, received IV atezolizumab monotherapy every 3 weeks (Q3W).
Measure Participants	44
Number (95% Confidence Interval) [Percentage of Participants]	27.3 29.7%

11. Secondary Outcome

Title	Cohort C: IRC-Assessed DCR
Description	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

Outcome Measure Data

Analysis Population Description

The analysis populations included all participants with measureable disease at baseline as measured by either the investigator or by an IRC.

Arm/Group Title	Cohort C
Arm/Group Description	Participants with advanced melanoma, who had not received previous treatment, received IV atezolizumab monotherapy every 3 weeks (Q3W).
Measure Participants	44
Number (95% Confidence Interval) [Percentage of Participants]	38.6 42%

12. Secondary Outcome

Title	Cohort C: IRC-Assessed DOR
Description	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

Outcome Measure Data

Analysis Population Description

The analysis populations included all participants with measureable disease at baseline as measured by either the investigator or by an IRC.

Arm/Group Title	Cohort C
Arm/Group Description	Participants with advanced melanoma, who had not received previous treatment, received IV atezolizumab monotherapy every 3 weeks (Q3W).
Measure Participants	52
Median (95% Confidence Interval) [Months]	NA

13. Secondary Outcome

Title	Cohort C: IRC-Assessed PFS
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort C
Arm/Group Description	Participants with advanced melanoma, who had not received previous treatment, received IV atezolizumab monotherapy every 3 weeks (Q3W).
Measure Participants	52
Median (95% Confidence Interval) [Months]	3.7

Adverse Events

Time Frame	Baseline through follow up
Arm/Group Title	Cohort A		Cohort B		Cohort C
Arm/Group Description	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.		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.		Participants with advanced melanoma, who had not received previous treatment, received IV atezolizumab monotherapy every 3 weeks (Q3W).
All Cause Mortality
	Cohort A		Cohort B		Cohort C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	48/92 (52.2%)		2/11 (18.2%)		25/52 (48.1%)
Serious Adverse Events
	Cohort A		Cohort B		Cohort C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	42/92 (45.7%)		5/11 (45.5%)		15/52 (28.8%)
Blood and lymphatic system disorders
Anaemia	1/92 (1.1%)	1	0/11 (0%)	0	1/52 (1.9%)	1
Thrombocytopenia	1/92 (1.1%)	1	0/11 (0%)	0	1/52 (1.9%)	1
Febrile neutropenia	0/92 (0%)	0	0/11 (0%)	0	1/52 (1.9%)	1
Cardiac disorders
Cardiomyopathy	1/92 (1.1%)	1	0/11 (0%)	0	0/52 (0%)	0
Myocarditis	3/92 (3.3%)	3	0/11 (0%)	0	0/52 (0%)	0
Stress cardiomyopathy	1/92 (1.1%)	1	0/11 (0%)	0	0/52 (0%)	0
Acute coronary syndrome	0/92 (0%)	0	1/11 (9.1%)	1	0/52 (0%)	0
Endocrine disorders
Adrenal insufficiency	0/92 (0%)	0	1/11 (9.1%)	1	0/52 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/92 (1.1%)	1	0/11 (0%)	0	0/52 (0%)	0
Abdominal pain upper	1/92 (1.1%)	1	0/11 (0%)	0	0/52 (0%)	0
Colitis	2/92 (2.2%)	3	0/11 (0%)	0	1/52 (1.9%)	1
Diarrhoea	4/92 (4.3%)	4	0/11 (0%)	0	1/52 (1.9%)	1
Diarrhoea haemorrhagic	1/92 (1.1%)	1	0/11 (0%)	0	0/52 (0%)	0
Oesophagitis	1/92 (1.1%)	1	0/11 (0%)	0	0/52 (0%)	0
Small intestinal perforation	1/92 (1.1%)	1	0/11 (0%)	0	0/52 (0%)	0
Vomiting	2/92 (2.2%)	2	0/11 (0%)	0	0/52 (0%)	0
Gastric haemorrhage	0/92 (0%)	0	0/11 (0%)	0	1/52 (1.9%)	1
Dysphagia	0/92 (0%)	0	0/11 (0%)	0	1/52 (1.9%)	1
General disorders
Mucosal inflammation	1/92 (1.1%)	1	0/11 (0%)	0	0/52 (0%)	0
Pyrexia	4/92 (4.3%)	4	0/11 (0%)	0	2/52 (3.8%)	2
Chest pain	0/92 (0%)	0	1/11 (9.1%)	1	0/52 (0%)	0
Hepatobiliary disorders
Hepatitis	1/92 (1.1%)	1	0/11 (0%)	0	0/52 (0%)	0
Immune-mediated hepatitis	1/92 (1.1%)	1	0/11 (0%)	0	0/52 (0%)	0
Infections and infestations
Cellulitis	2/92 (2.2%)	2	0/11 (0%)	0	0/52 (0%)	0
Encephalitis	3/92 (3.3%)	3	0/11 (0%)	0	0/52 (0%)	0
Helicobacter infection	1/92 (1.1%)	1	0/11 (0%)	0	0/52 (0%)	0
Meningitis	0/92 (0%)	0	1/11 (9.1%)	1	0/52 (0%)	0
Respiratory tract infection	1/92 (1.1%)	1	0/11 (0%)	0	0/52 (0%)	0
Sepsis	1/92 (1.1%)	1	0/11 (0%)	0	0/52 (0%)	0
Urinary tract infection	1/92 (1.1%)	1	0/11 (0%)	0	0/52 (0%)	0
Viral infection	1/92 (1.1%)	1	0/11 (0%)	0	0/52 (0%)	0
Wound infection	1/92 (1.1%)	1	0/11 (0%)	0	0/52 (0%)	0
Gastroenteritis	0/92 (0%)	0	0/11 (0%)	0	1/52 (1.9%)	1
Lung infection	0/92 (0%)	0	0/11 (0%)	0	1/52 (1.9%)	1
Mastoiditis	0/92 (0%)	0	0/11 (0%)	0	1/52 (1.9%)	1
Septic shock	1/92 (1.1%)	1	0/11 (0%)	0	0/52 (0%)	0
Pneumonia	0/92 (0%)	0	0/11 (0%)	0	1/52 (1.9%)	1
Injury, poisoning and procedural complications
Fracture	0/92 (0%)	0	1/11 (9.1%)	1	0/52 (0%)	0
Pelvic fracture	0/92 (0%)	0	0/11 (0%)	0	1/52 (1.9%)	1
Infusion related reaction	1/92 (1.1%)	1	0/11 (0%)	0	0/52 (0%)	0
Investigations
Amylase increased	2/92 (2.2%)	2	0/11 (0%)	0	0/52 (0%)	0
Aspartase aminotransferase increased	1/92 (1.1%)	1	0/11 (0%)	0	0/52 (0%)	0
Blood creatine phosphokinase increased	1/92 (1.1%)	1	0/11 (0%)	0	1/52 (1.9%)	1
Lipase increased	1/92 (1.1%)	1	0/11 (0%)	0	1/52 (1.9%)	2
Angiogram	0/92 (0%)	0	1/11 (9.1%)	1	0/52 (0%)	0
Metabolism and nutrition disorders
Hyponatraemia	3/92 (3.3%)	3	0/11 (0%)	0	0/52 (0%)	0
Musculoskeletal and connective tissue disorders
Pathological fracture	1/92 (1.1%)	1	0/11 (0%)	0	0/52 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon neoplasm	0/92 (0%)	0	0/11 (0%)	0	1/52 (1.9%)	1
Nervous system disorders
Encephalitis autoimmune	2/92 (2.2%)	2	0/11 (0%)	0	0/52 (0%)	0
Encephalopathy	1/92 (1.1%)	1	0/11 (0%)	0	0/52 (0%)	0
Syncope	1/92 (1.1%)	1	0/11 (0%)	0	1/52 (1.9%)	1
Headache	1/92 (1.1%)	1	0/11 (0%)	0	0/52 (0%)	0
Immune-mediated encephalitis	1/92 (1.1%)	1	0/11 (0%)	0	0/52 (0%)	0
Renal and urinary disorders
Acute kidney injury	1/92 (1.1%)	1	1/11 (9.1%)	1	0/52 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/92 (1.1%)	1	1/11 (9.1%)	1	1/52 (1.9%)	1
Hypoxia	1/92 (1.1%)	1	0/11 (0%)	0	0/52 (0%)	0
Pneumonitis	2/92 (2.2%)	2	0/11 (0%)	0	0/52 (0%)	0
Respiratory failure	1/92 (1.1%)	1	0/11 (0%)	0	0/52 (0%)	0
Pleurisy	0/92 (0%)	0	0/11 (0%)	0	1/52 (1.9%)	1
Skin and subcutaneous tissue disorders
Dermatitis acneiform	2/92 (2.2%)	2	0/11 (0%)	0	0/52 (0%)	0
Rash	1/92 (1.1%)	1	0/11 (0%)	0	0/52 (0%)	0
Vascular disorders
Deep vein thrombosis	1/92 (1.1%)	1	0/11 (0%)	0	1/52 (1.9%)	1
Hypertension	1/92 (1.1%)	1	0/11 (0%)	0	0/52 (0%)	0
Hypotension	2/92 (2.2%)	2	0/11 (0%)	0	0/52 (0%)	0
Arterial thrombosis	0/92 (0%)	0	0/11 (0%)	0	1/52 (1.9%)	1
Other (Not Including Serious) Adverse Events
	Cohort A		Cohort B		Cohort C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	90/92 (97.8%)		11/11 (100%)		50/52 (96.2%)
Blood and lymphatic system disorders
Anaemia	14/92 (15.2%)	20	1/11 (9.1%)	1	15/52 (28.8%)	19
Neutropenia	3/92 (3.3%)	3	1/11 (9.1%)	5	0/52 (0%)	0
Thrombocytopenia	5/92 (5.4%)	6	1/11 (9.1%)	1	0/52 (0%)	0
Leukopenia	2/92 (2.2%)	2	1/11 (9.1%)	1	0/52 (0%)	0
Ear and labyrinth disorders
Eustachian tube dysfunction	0/92 (0%)	0	1/11 (9.1%)	1	0/52 (0%)	0
Endocrine disorders
Cushingoid	0/92 (0%)	0	1/11 (9.1%)	1	0/52 (0%)	0
Hypothyroidism	3/92 (3.3%)	3	2/11 (18.2%)	2	11/52 (21.2%)	11
Hyperthyroidism	0/92 (0%)	0	0/11 (0%)	0	3/52 (5.8%)	3
Adrenal insufficiency	0/92 (0%)	0	1/11 (9.1%)	1	0/52 (0%)	0
Eye disorders
Chorioretinopathy	5/92 (5.4%)	7	0/11 (0%)	0	0/52 (0%)	0
Diplopia	0/92 (0%)	0	1/11 (9.1%)	1	0/52 (0%)	0
Eyelid disorder	0/92 (0%)	0	1/11 (9.1%)	1	0/52 (0%)	0
Iridocyclitis	0/92 (0%)	0	1/11 (9.1%)	1	0/52 (0%)	0
MEK inhibitor-assessed serous retinopathy	14/92 (15.2%)	15	1/11 (9.1%)	1	0/52 (0%)	0
Vision blurred	1/92 (1.1%)	1	1/11 (9.1%)	1	0/52 (0%)	0
Visual impairment	0/92 (0%)	0	1/11 (9.1%)	1	0/52 (0%)	0
Eye pruritis	0/92 (0%)	0	1/11 (9.1%)	1	0/52 (0%)	0
Gastrointestinal disorders
Abdominal discomfort	4/92 (4.3%)	4	1/11 (9.1%)	1	0/52 (0%)	0
Abdominal pain	7/92 (7.6%)	7	1/11 (9.1%)	1	3/52 (5.8%)	3
Abdominal pain upper	4/92 (4.3%)	4	1/11 (9.1%)	1	0/52 (0%)	0
Constipation	27/92 (29.3%)	37	4/11 (36.4%)	8	9/52 (17.3%)	11
Diarrhoea	65/92 (70.7%)	111	10/11 (90.9%)	26	9/52 (17.3%)	10
Dry mouth	12/92 (13%)	13	1/11 (9.1%)	1	0/52 (0%)	0
Dyspepsia	4/92 (4.3%)	4	1/11 (9.1%)	1	0/52 (0%)	0
Gastrooesophageal reflux disease	4/92 (4.3%)	4	1/11 (9.1%)	1	0/52 (0%)	0
Mouth ulceration	11/92 (12%)	11	0/11 (0%)	0	0/52 (0%)	0
Nausea	48/92 (52.2%)	67	4/11 (36.4%)	5	7/52 (13.5%)	13
Rectal haemorrhage	1/92 (1.1%)	1	1/11 (9.1%)	1	0/52 (0%)	0
Stomatitis	6/92 (6.5%)	6	0/11 (0%)	0	0/52 (0%)	0
Vomiting	35/92 (38%)	44	3/11 (27.3%)	4	7/52 (13.5%)	8
General disorders
Asthenia	12/92 (13%)	15	1/11 (9.1%)	1	11/52 (21.2%)	14
Chest discomfort	0/92 (0%)	0	1/11 (9.1%)	1	0/52 (0%)	0
Chills	12/92 (13%)	13	2/11 (18.2%)	2	0/52 (0%)	0
Fatigue	42/92 (45.7%)	49	7/11 (63.6%)	7	5/52 (9.6%)	7
Oedema	2/92 (2.2%)	2	1/11 (9.1%)	1	0/52 (0%)	0
Oedema peripheral	16/92 (17.4%)	20	3/11 (27.3%)	4	3/52 (5.8%)	3
Peripheral swelling	3/92 (3.3%)	3	1/11 (9.1%)	2	0/52 (0%)	0
Pyrexia	37/92 (40.2%)	47	1/11 (9.1%)	1	3/52 (5.8%)	8
Chest pain	0/92 (0%)	0	0/11 (0%)	0	3/52 (5.8%)	3
Influenza like illness	0/92 (0%)	0	0/11 (0%)	0	3/52 (5.8%)	7
Hepatobiliary disorders
Autoimmune hepatitis	1/92 (1.1%)	1	1/11 (9.1%)	1	0/52 (0%)	0
Hypertransaminasaemia	0/92 (0%)	0	1/11 (9.1%)	1	0/52 (0%)	0
Infections and infestations
Cellulitis	6/92 (6.5%)	6	0/11 (0%)	0	0/52 (0%)	0
Oral candidiasis	3/92 (3.3%)	4	1/11 (9.1%)	1	0/52 (0%)	0
Sinusitis	2/92 (2.2%)	2	1/11 (9.1%)	1	3/52 (5.8%)	4
Upper respiratory tract infection	6/92 (6.5%)	6	1/11 (9.1%)	1	4/52 (7.7%)	6
Urinary tract infection	13/92 (14.1%)	14	1/11 (9.1%)	1	5/52 (9.6%)	5
Bronchitis	0/92 (0%)	0	0/11 (0%)	0	3/52 (5.8%)	5
Influenza	0/92 (0%)	0	0/11 (0%)	0	3/52 (5.8%)	3
Pharyngitis	0/92 (0%)	0	0/11 (0%)	0	3/52 (5.8%)	4
Pneumonia	0/92 (0%)	0	0/11 (0%)	0	4/52 (7.7%)	4
Injury, poisoning and procedural complications
Fall	5/92 (5.4%)	5	0/11 (0%)	0	0/52 (0%)	0
Infusion related reaction	7/92 (7.6%)	13	0/11 (0%)	0	4/52 (7.7%)	4
Sunburn	0/92 (0%)	0	1/11 (9.1%)	2	0/52 (0%)	0
Investigations
Alanine aminotransferase increased	7/92 (7.6%)	10	4/11 (36.4%)	6	5/52 (9.6%)	6
Aspartate aminotrasferase increased	10/92 (10.9%)	15	4/11 (36.4%)	4	6/52 (11.5%)	6
Blood alkaline phosphatase increased	2/92 (2.2%)	3	2/11 (18.2%)	3	4/52 (7.7%)	5
Blood creatine phosphokinase increased	25/92 (27.2%)	41	2/11 (18.2%)	3	5/52 (9.6%)	7
Blood pressure increased	0/92 (0%)	0	1/11 (9.1%)	1	0/52 (0%)	0
Ejection fraction decreased	4/92 (4.3%)	5	1/11 (9.1%)	2	0/52 (0%)	0
Gamma-glutamyltransferase increased	2/92 (2.2%)	2	1/11 (9.1%)	1	0/52 (0%)	0
Lipase increased	7/92 (7.6%)	11	1/11 (9.1%)	4	9/52 (17.3%)	10
Urine output decreased	0/92 (0%)	0	1/11 (9.1%)	1	0/52 (0%)	0
Weight increased	0/92 (0%)	0	2/11 (18.2%)	2	0/52 (0%)	0
Amylase increased	0/92 (0%)	0	0/11 (0%)	0	6/52 (11.5%)	8
Blood lactate dehydrogenase increased	0/92 (0%)	0	0/11 (0%)	0	5/52 (9.6%)	5
Weight decreased	0/92 (0%)	0	0/11 (0%)	0	6/52 (11.5%)	7
Blood creatinine increased	5/92 (5.4%)	7	0/11 (0%)	0	0/52 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	22/92 (23.9%)	23	2/11 (18.2%)	2	6/52 (11.5%)	7
Dehydration	6/92 (6.5%)	7	0/11 (0%)	0	0/52 (0%)	0
Fluid retention	3/92 (3.3%)	3	2/11 (18.2%)	3	0/52 (0%)	0
Hyperglycaemia	7/92 (7.6%)	8	0/11 (0%)	0	7/52 (13.5%)	10
Hyperkalaemia	1/92 (1.1%)	1	1/11 (9.1%)	1	3/52 (5.8%)	4
Hyperalbuminaemia	4/92 (4.3%)	6	1/11 (9.1%)	2	0/52 (0%)	0
Hypokalaemia	8/92 (8.7%)	11	0/11 (0%)	0	5/52 (9.6%)	7
Hyponatraemia	7/92 (7.6%)	7	0/11 (0%)	0	0/52 (0%)	0
Hypophosphataemia	9/92 (9.8%)	17	1/11 (9.1%)	1	0/52 (0%)	0
Hypertriglyceridaemia	0/92 (0%)	0	0/11 (0%)	0	3/52 (5.8%)	3
Hyperuricaemia	0/92 (0%)	0	0/11 (0%)	0	4/52 (7.7%)	7
Hypoalbuminaemia	4/92 (4.3%)	6	1/11 (9.1%)	2	5/52 (9.6%)	5
Hypomagnesaemia	2/92 (2.2%)	3	1/11 (9.1%)	1	4/52 (7.7%)	4
Hypoproteinaemia	0/92 (0%)	0	1/11 (9.1%)	1	0/52 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	8/92 (8.7%)	10	1/11 (9.1%)	1	9/52 (17.3%)	10
Back pain	9/92 (9.8%)	9	0/11 (0%)	0	7/52 (13.5%)	8
Bone pain	0/92 (0%)	0	1/11 (9.1%)	1	0/52 (0%)	0
Flank pain	7/92 (7.6%)	8	1/11 (9.1%)	1	0/52 (0%)	0
Groin pain	0/92 (0%)	0	1/11 (9.1%)	1	0/52 (0%)	0
Muscle spasms	1/92 (1.1%)	1	2/11 (18.2%)	3	4/52 (7.7%)	4
Muscular weakness	5/92 (5.4%)	5	1/11 (9.1%)	1	0/52 (0%)	0
Myalgia	6/92 (6.5%)	7	1/11 (9.1%)	1	4/52 (7.7%)	4
Neck pain	1/92 (1.1%)	1	1/11 (9.1%)	1	0/52 (0%)	0
Pain in extremity	0/92 (0%)	0	0/11 (0%)	0	10/52 (19.2%)	12
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lip neoplasm	0/92 (0%)	0	1/11 (9.1%)	1	0/52 (0%)	0
Nasal neoplasm	0/92 (0%)	0	1/11 (9.1%)	1	0/52 (0%)	0
Tumour pain	0/92 (0%)	0	0/11 (0%)	0	4/52 (7.7%)	4
Nervous system disorders
Dizziness	13/92 (14.1%)	14	1/11 (9.1%)	1	0/52 (0%)	0
Dysgeusia	6/92 (6.5%)	6	0/11 (0%)	0	0/52 (0%)	0
Headache	10/92 (10.9%)	12	2/11 (18.2%)	2	14/52 (26.9%)	19
Neuropathy peripheral	1/92 (1.1%)	1	1/11 (9.1%)	1	0/52 (0%)	0
Presyncope	2/92 (2.2%)	2	1/11 (9.1%)	1	0/52 (0%)	0
Syncope	3/92 (3.3%)	3	1/11 (9.1%)	1	0/52 (0%)	0
Taste disorder	1/92 (1.1%)	1	1/11 (9.1%)	1	0/52 (0%)	0
Psychiatric disorders
Insomnia	5/92 (5.4%)	5	0/11 (0%)	0	4/52 (7.7%)	4
Depression	0/92 (0%)	0	0/11 (0%)	0	4/52 (7.7%)	4
Renal and urinary disorders
Dysuria	4/92 (4.3%)	4	1/11 (9.1%)	1	0/52 (0%)	0
Haematuria	0/92 (0%)	0	1/11 (9.1%)	1	0/52 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	7/92 (7.6%)	8	2/11 (18.2%)	2	5/52 (9.6%)	5
Dyspnoea	10/92 (10.9%)	10	0/11 (0%)	0	3/52 (5.8%)	5
Dyspnoea exertional	2/92 (2.2%)	2	1/11 (9.1%)	1	0/52 (0%)	0
Nasal polyps	0/92 (0%)	0	1/11 (9.1%)	1	0/52 (0%)	0
Pneumonitis	7/92 (7.6%)	8	0/11 (0%)	0	0/52 (0%)	0
Epistaxis	0/92 (0%)	0	0/11 (0%)	0	3/52 (5.8%)	4
Oropharyngeal pain	5/92 (5.4%)	5	0/11 (0%)	0	0/52 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	6/92 (6.5%)	6	1/11 (9.1%)	1	0/52 (0%)	0
Dermatitis acneiform	49/92 (53.3%)	62	7/11 (63.6%)	11	0/52 (0%)	0
Dry skin	5/92 (5.4%)	5	1/11 (9.1%)	1	0/52 (0%)	0
Pruritis	16/92 (17.4%)	19	4/11 (36.4%)	6	5/52 (9.6%)	7
Rash	31/92 (33.7%)	44	5/11 (45.5%)	5	6/52 (11.5%)	6
Rash maculo-papular	10/92 (10.9%)	18	0/11 (0%)	0	0/52 (0%)	0
Rash pruritic	5/92 (5.4%)	5	1/11 (9.1%)	1	0/52 (0%)	0
Skin ulcer	0/92 (0%)	0	1/11 (9.1%)	1	0/52 (0%)	0
Vitiligo	2/92 (2.2%)	2	1/11 (9.1%)	1	7/52 (13.5%)	11
Vascular disorders
Hypertension	6/92 (6.5%)	6	0/11 (0%)	0	10/52 (19.2%)	13
Hypotension	7/92 (7.6%)	9	1/11 (9.1%)	1	3/52 (5.8%)	7

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or present ation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.