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A Study to Investigate the Efficacy and Safety of Cobimetinib Plus Atezolizumab in Participants With Solid Tumors

Sponsor
Hoffmann-La Roche (Industry)
Overall Status
Completed
CT.gov ID
NCT03264066
Collaborator
(none)
87
Enrollment
19
Locations
7
Arms
31
Actual Duration (Months)
4.6
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a study to evaluate the efficacy, safety, and pharmacokinetics of cobimetinib plus atezolizumab in participants with advanced solid tumors including the following cohorts: squamous cell carcinoma of the head and neck (SCCHN), urothelial carcinoma (UC), and renal cell carcinoma (RCC).

Condition or Disease Intervention/Treatment Phase
Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
87 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase II, Open-Label, Multicenter, Multicohort Study to Investigate the Efficacy and Safety of Cobimetinib Plus Atezolizumab in Patients With Solid Tumors
Actual Study Start Date :
Nov 23, 2017
Actual Primary Completion Date :
Jun 25, 2020
Actual Study Completion Date :
Jun 25, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: Cohort 1 - SCCHN - Treatment Naive

In participants with recurrent or advanced / metastatic SSCHN who are anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib will be administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle.

Drug: Cobimetinib
Participants will receive cobimetinib 60 mg (3 tablets of 20 mg each) orally once a day on Days 1-21 of each 28-day cycle.
Other Names:
  • Cotellic

    • Drug: Atezolizumab
    Atezolizumab will be given at a fixed dose of 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle.
    Other Names:
  • Tecentriq

    		•
    Experimental: Cohort 2 - UC - Treatment Naive

    In participants with advanced / metastatic UC who are anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib will be administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle.

    Drug: Cobimetinib
    Participants will receive cobimetinib 60 mg (3 tablets of 20 mg each) orally once a day on Days 1-21 of each 28-day cycle.
    Other Names:
  • Cotellic

    • Drug: Atezolizumab
    Atezolizumab will be given at a fixed dose of 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle.
    Other Names:
  • Tecentriq

    		•
    Experimental: Cohort 3 - RCC - Treatment Naive

    In participants with metastatic RCC who are anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib will be administered at the approved dose and schedule of 60 milligrams (mg) once daily (QD) for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle.

    Drug: Cobimetinib
    Participants will receive cobimetinib 60 mg (3 tablets of 20 mg each) orally once a day on Days 1-21 of each 28-day cycle.
    Other Names:
  • Cotellic

    • Drug: Atezolizumab
    Atezolizumab will be given at a fixed dose of 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle.
    Other Names:
  • Tecentriq

    		•
    Experimental: Cohort 4 - SCCHN - Previous Treatment Exposure

    In participants with SCCHN whose disease has progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib will be administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle.

    Drug: Cobimetinib
    Participants will receive cobimetinib 60 mg (3 tablets of 20 mg each) orally once a day on Days 1-21 of each 28-day cycle.
    Other Names:
  • Cotellic

    • Drug: Atezolizumab
    Atezolizumab will be given at a fixed dose of 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle.
    Other Names:
  • Tecentriq

    		•
    Experimental: Cohort 5 - UC - Previous Treatment Exposure

    In participants with UC whose disease has progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib will be administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle.

    Drug: Cobimetinib
    Participants will receive cobimetinib 60 mg (3 tablets of 20 mg each) orally once a day on Days 1-21 of each 28-day cycle.
    Other Names:
  • Cotellic

    • Drug: Atezolizumab
    Atezolizumab will be given at a fixed dose of 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle.
    Other Names:
  • Tecentriq

    		•
    Experimental: Cohort 6 - RCC - Previous Treatment Exposure

    In participants with RCC whose disease has progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib will be administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle.

    Drug: Cobimetinib
    Participants will receive cobimetinib 60 mg (3 tablets of 20 mg each) orally once a day on Days 1-21 of each 28-day cycle.
    Other Names:
  • Cotellic

    • Drug: Atezolizumab
    Atezolizumab will be given at a fixed dose of 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle.
    Other Names:
  • Tecentriq

    		•
    Experimental: Cohort 7 - Biopsy Cohort

    In participants with solid non-melanoma, non- hematologic tumors who previously developed primary or secondary resistance to an anti-PD-1 or anti-PD-L1 agent, cobimetinib will be administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle. The first dose of atezolizumab of 840 mg by IV infusions on Day 15 of Cycle 1. Thereafter, they will receive atezolizumab 840 mg IV infusion Q2W on Days 1 and 15 of Cycle 2 and all subsequent cycles.

    Drug: Cobimetinib
    Participants will receive cobimetinib 60 mg (3 tablets of 20 mg each) orally once a day on Days 1-21 of each 28-day cycle.
    Other Names:
  • Cotellic

    • Drug: Atezolizumab Cohort 7
    Only for participants in cohort 7, the first dose of atezolizumab of 840 mg will be given by IV infusion on Day 15 of Cycle 1; thereafter, they will receive atezolizumab 840 mg IV infusion Q2W on Days 1 and 15 of Cycle 2 and all subsequent cycles.
    Other Names:
  • Tecentriq

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Objective Response Rate (ORR) [Up to approximately 31 months]

      Objective response rate was defined as the percentage of participants with a complete response (CR) or a partial response (PR) on two consecutive tumor assessments ≥4 weeks apart, as determined by the investigators using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1). CR was defined as disappearance of all lesions. PR was defined as ≥30% decrease in the sum of diameters of target lesions, in the absence of CR, new lesions, and unequivocal progression in non-target lesions.

    Secondary Outcome Measures

    1. Overall Survival (OS) [Up to approximately 31 months]

      Overall survival was defined as the time from enrollment to death from any cause. The median for OS is Kaplan-Meier estimate. 95% CI for median was computed using the method of Brookmeyer and Crowley.

    2. Progression-Free Survival (PFS) [Up to approximately 31 months]

      PFS was defined as the time from enrollment to the first occurrence of disease progression as determined by the investigator(s), using RECIST v1.1, or to death from any cause, whichever occurs first. Disease progression was defined as ≥20% increase in in the sum of diameters of target lesions, unequivocal progression in non-target lesions, and/or appearance of new lesions.

    3. Duration of Response (DOR) [Up to approximately 22 months]

      DOR was defined as the time from the first occurrence of a documented, confirmed objective response to disease progression as determined by the investigator, using RECIST v1.1, or to death from any cause, whichever occurs first. Objective response was defined as a complete response (CR) or a partial response (PR) on two consecutive tumor assessments ≥4 weeks apart. CR was defined as disappearance of all lesions. PR was defined as ≥30% decrease in the sum of diameters of target lesions, in the absence of CR, new lesions, and unequivocal progression in non-target lesions. Disease progression was defined as ≥20% increase in the sum of diameters of target lesions, unequivocal progression in non-target lesions, and/or appearance of new lesions. Presented here is median DOR at the time of primary analysis. The median for the duration of response is Kaplan-Meier estimate. 95% CI for median was computed using the method of Brookmeyer and Crowley.

    4. Disease Control Rate (DCR) [At 16 weeks]

      DCR was defined as the percentage of participants with a complete response (CR), a partial response (PR), or stable disease at 16 weeks as determined by the investigator using RECIST v1.1. CR was defined as disappearance of all lesions. PR was defined as ≥30% decrease in the sum of diameters of target lesions, in the absence of CR, new lesions, and unequivocal progression in non-target lesions. Stable disease was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for disease progression. Disease progression was defined as ≥20% increase in the sum of diameters of target lesions, unequivocal progression in non-target lesions, and/or appearance of new lesions.

    5. Number of Participants With Adverse Events [Up to approximately 31 months]

      An adverse event is any untoward medical occurrence in a subject 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.

    6. Maximum Plasma Concentration (Cmax) of Cobimetinib [Day 15 of Cycle 3 (cycle is 28 days): 2-4 hours after cobimetinib dose]

      Cmax is the maximum (or peak) concentration that a study drug achieves in the body.

    7. Minimum Plasma Concentration (Cmin) of Cobimetinib [Day 15 of Cycle 3 (cycle is 28 days): prior to cobimetinib dose]

      Cmin is the minimum (or trough) concentration that a study drug achieves in the body.

    8. Maximum Serum Concentration (Cmax) of Atezolizumab [30 minutes following end of atezolizumab infusion on Day 15 of Cycle 3 (each cycle is 28 days)]

      Cmax is the maximum (or peak) concentration that a study drug achieves in the body.

    9. Minimum Serum Concentration (Cmin) of Atezolizumab [Prior to atezolizumab infusion on Day 1 of Cycles (each cycle is 28 days) 2, 4, 8, 12, and 16, Day 15 of Cycle 3]

      Cmin is the minimum (or trough) concentration that a study drug achieves in the body.

    10. Number of Participants With Anti-drug Antibodies (ADAs) [Day 1 of Cycles (each cycle is 28 days) 1, 2, 4, 8, 12, and 16; Day 15 of Cycle 3; at atezolizumab treatment discontinuation visit, and <90 days after last atezolizumab infusion (up to approximately 31 months)]

      Participants were considered to be ADA positive if they were missing data at baseline but developed an ADA response following study drug administration (treatment-induced ADA response), or if they were ADA positive at baseline and the titer of one or more post-baseline samples was at least 4-fold greater (i.e., ≥0.60-titer units) than the titer of the baseline sample (treatment-enhanced ADA response). Participants were considered to be ADA negative if they were missing data at baseline, had a post-baseline ADA result, and all post-baseline samples were negative, or if they were ADA positive at baseline but did not have any post-baseline samples with a titer that was at least 4-fold greater than the titer of the baseline sample (treatment unaffected).

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    General Inclusion Criteria:

    • Age ≥18 years

    • Ability to comply with the study protocol, in the investigator's judgment

    • Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1

    • Life expectancy ≥3 months, as determined by the investigator

    • Adequate hematologic and end-organ function

    Cancer-Related Inclusion Criteria:

    • Patients must have measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) scan per RECIST v1.1.

    • Availability to provide a representative tumor specimen biopsy

    • Evidence of tumor progression on or after the last treatment regimen received and within 6 months prior to study enrollment

    • For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a non-hormonal contraceptive method with a failure rate of <1% per year during the treatment period and for at least 5 months after the last dose of atezolizumab and within 3 months after the last dose of cobimetinib

    • For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm during the treatment period and for at least 3 months after the last dose of cobimetinib

    Exclusion Criteria:
    General Exclusion Criteria:

    • Inability to swallow medications

    • Malabsorption condition that would alter the absorption of orally administered medications

    • Poor peripheral venous access

    • Prior treatment with cobimetinib or a MEK inhibitor

    • Prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies

    • Treatment with investigational therapy within 14 days prior to initiation of study treatment

    • Any anti-cancer therapy, including chemotherapy or hormonal therapy, within 2 weeks prior to initiation of study treatment

    • History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins

    • Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster ovary cells or any component of the atezolizumab formulation, or any component of the cobimetinib formulation

    • History of serous retinopathy, retinal vein occlusion (RVO), or evidence of ongoing serous retinopathy or RVO at baseline

    • Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study

    • Uncontrolled tumor-related pain

    • Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage more than once every 28 days

    • Uncontrolled hypercalcemia (ionized calcium >1.5 millimoles per liter [mmol/L], calcium >12 milligrams per deciliter [mg/dL], or corrected calcium greater than the upper limit of normal [ULN]) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy

    • Active or untreated central nervous system (CNS) metastases

    • Pregnancy or breastfeeding, or intending to become pregnant during the study

    Exclusion Criteria based on Organ Function or Medical History

    Cardiovascular

    Patients who meet the following cardiovascular exclusion criterion will be excluded from study entry:

    • Left ventricular ejection fraction (LVEF) below the institutional lower limit of normal or <50%, whichever is lower

    Infections Patients who meet any of the following infection exclusion criteria will be excluded from study entry:

    • Positive human immunodeficiency virus (HIV) test at screening

    • Active hepatitis B virus (HBV) infection (chronic or acute)

    • Active hepatitis C virus (HCV) infection

    • Active tuberculosis

    • Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia

    • Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Georgetown University Medical Center Washington District of Columbia United States 20007
    2 Kansas City - Menorah Medical Center Kansas City Kansas United States 66209
    3 Memorial Sloan-Kettering Cancer Center Commack New York United States 11725
    4 Memorial Sloan Kettering - Basking Ridge New York New York United States 10065
    5 Memorial Sloan Kettering Cancer Center New York New York United States 10065
    6 Sarah Cannon Research Institute Nashville Tennessee United States 37203
    7 AZ Groeninge Kortrijk Belgium 8500
    8 Universitatsklinik Heidelberg; Universitätshautklinik und Nationales Centrum für Tumorerkrankungen Heidelberg Germany 69120
    9 Universitätsklinikum Tübingen; Klinik für Urologie Tübingen Germany 72076
    10 Orszagos Onkologiai Intezet Budapest Hungary 1122
    11 Debreceni Egyetem Klinikai Kozpont Debrecen Hungary 4032
    12 Jósa András Oktatókórház Nyíregyháza Hungary 4400
    13 Samsung Medical Center Seoul Korea, Republic of (0)6351
    14 Seoul National University Hospital Seoul Korea, Republic of 03080
    15 Asan Medical Center Seoul Korea, Republic of 05505
    16 Yonsei Cancer Center Seoul Korea, Republic of 120-752
    17 Barts & London School of Med; Medical Oncology London United Kingdom EC1A 7BE
    18 Royal Marsden Hospital - Fulham London United Kingdom SW3 6JJ
    19 The Royal Marsden London United Kingdom SW7 3RP

    Sponsors and Collaborators

    • Hoffmann-La Roche

    Investigators

    • Study Director: Clinical Trials, Hoffmann-La Roche

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Hoffmann-La Roche
    ClinicalTrials.gov Identifier:
    NCT03264066
    Other Study ID Numbers:
    • WO39760
    • 2017-000794-37
    First Posted:
    Aug 28, 2017
    Last Update Posted:
    May 11, 2021
    Last Verified:
    Apr 1, 2021
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Neoplasms
    Atezolizumab
    Antibodies, Monoclonal

    Study Results

    Participant Flow

    Recruitment Details Enrollment took place in six countries: Republic of Korea, Belgium, Germany, United Kingdom, Hungary and United States. No participants were enrolled in Cohort 7. Participants in long term follow up and who continued to receive treatment(s) in a post-trial access program are designated in Participant Flow as "Study terminated by Sponsor".
    Pre-assignment Detail Participants with advanced solid tumors were included in the study: squamous cell carcinoma of head and neck (SCCHN), urothelial carcinoma (UC), and renal cell carcinoma (RCC).
    Arm/Group Title Cohort 1 - SCCHN - Treatment Naive Cohort 2 - UC - Treatment Naive Cohort 3 - RCC - Treatment Naive Cohort 4 - SCCHN - Previous Treatment Exposure Cohort 5 - UC - Previous Treatment Exposure Cohort 6 - RCC - Previous Treatment Exposure
    Arm/Group Description In participants with recurrent or advanced / metastatic squamous cell carcinoma of the head and neck (SSCHN) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg once daily (QD) for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. In participants with advanced / metastatic urothelial carcinoma (UC) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with metastatic renal cell carcinoma (RCC) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with SCCHN whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with UC whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with RCC whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle.
    Period Title: Overall Study
    STARTED 20 20 17 20 7 3
    COMPLETED 0 0 0 0 0 0
    NOT COMPLETED 20 20 17 20 7 3

    Baseline Characteristics

    Arm/Group Title Cohort 1 - SCCHN - Treatment Naive Cohort 2 - UC - Treatment Naive Cohort 3 - RCC - Treatment Naive Cohort 4 - SCCHN - Previous Treatment Exposure Cohort 5 - UC - Previous Treatment Exposure Cohort 6 - RCC - Previous Treatment Exposure Total
    Arm/Group Description In participants with recurrent or advanced / metastatic squamous cell carcinoma of the head and neck (SSCHN) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg once daily (QD) for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. In participants with advanced / metastatic urothelial carcinoma (UC) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with metastatic renal cell carcinoma (RCC) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with SCCHN whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with UC whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with RCC whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. Total of all reporting groups
    Overall Participants 20 20 17 20 7 3 87
    Age, Customized (Count of Participants)
    Adults (18-64 years)
    12
    60%
    6
    30%
    10
    58.8%
    12
    60%
    3
    42.9%
    1
    33.3%
    44
    50.6%
    From 65-84 years
    8
    40%
    13
    65%
    7
    41.2%
    8
    40%
    4
    57.1%
    2
    66.7%
    42
    48.3%
    Missing
    0
    0%
    1
    5%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.1%
    Sex: Female, Male (Count of Participants)
    Female
    2
    10%
    8
    40%
    6
    35.3%
    1
    5%
    2
    28.6%
    2
    66.7%
    21
    24.1%
    Male
    18
    90%
    12
    60%
    11
    64.7%
    19
    95%
    5
    71.4%
    1
    33.3%
    66
    75.9%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    33.3%
    1
    1.1%
    Not Hispanic or Latino
    15
    75%
    20
    100%
    17
    100%
    19
    95%
    7
    100%
    2
    66.7%
    80
    92%
    Unknown or Not Reported
    5
    25%
    0
    0%
    0
    0%
    1
    5%
    0
    0%
    0
    0%
    6
    6.9%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    2
    10%
    10
    50%
    10
    58.8%
    0
    0%
    2
    28.6%
    0
    0%
    24
    27.6%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    White
    18
    90%
    10
    50%
    7
    41.2%
    20
    100%
    5
    71.4%
    3
    100%
    63
    72.4%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%

    Outcome Measures

    1. Primary Outcome
    Title Objective Response Rate (ORR)
    Description Objective response rate was defined as the percentage of participants with a complete response (CR) or a partial response (PR) on two consecutive tumor assessments ≥4 weeks apart, as determined by the investigators using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1). CR was defined as disappearance of all lesions. PR was defined as ≥30% decrease in the sum of diameters of target lesions, in the absence of CR, new lesions, and unequivocal progression in non-target lesions.
    Time Frame Up to approximately 31 months

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat (ITT) population included all participants enrolled in the study.
    Arm/Group Title Cohort 1 - SCCHN - Treatment Naive Cohort 2 - UC - Treatment Naive Cohort 3 - RCC - Treatment Naive Cohort 4 - SCCHN - Previous Treatment Exposure Cohort 5 - UC - Previous Treatment Exposure Cohort 6 - RCC - Previous Treatment Exposure
    Arm/Group Description In participants with recurrent or advanced / metastatic squamous cell carcinoma of the head and neck (SSCHN) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg once daily (QD) for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. In participants with advanced / metastatic urothelial carcinoma (UC) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with metastatic renal cell carcinoma (RCC) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with SCCHN whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with UC whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with RCC whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle.
    Measure Participants 20 20 17 20 7 3
    Number (95% Confidence Interval) [percentage of participants]
    20.0
    100%
    30.0
    150%
    17.6
    103.5%
    0
    0%
    0
    0%
    0
    0%
    2. Secondary Outcome
    Title Overall Survival (OS)
    Description Overall survival was defined as the time from enrollment to death from any cause. The median for OS is Kaplan-Meier estimate. 95% CI for median was computed using the method of Brookmeyer and Crowley.
    Time Frame Up to approximately 31 months

    Outcome Measure Data

    Analysis Population Description
    The ITT population included all participants enrolled in the study.
    Arm/Group Title Cohort 1 - SCCHN - Treatment Naive Cohort 2 - UC - Treatment Naive Cohort 3 - RCC - Treatment Naive Cohort 4 - SCCHN - Previous Treatment Exposure Cohort 5 - UC - Previous Treatment Exposure Cohort 6 - RCC - Previous Treatment Exposure
    Arm/Group Description In participants with recurrent or advanced / metastatic squamous cell carcinoma of the head and neck (SSCHN) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg once daily (QD) for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. In participants with advanced / metastatic urothelial carcinoma (UC) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with metastatic renal cell carcinoma (RCC) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with SCCHN whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with UC whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with RCC whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle.
    Measure Participants 20 20 17 20 7 3
    Median (95% Confidence Interval) [months]
    16.8
    18.7
    21.7
    7.7
    5.9
    NA
    3. Secondary Outcome
    Title Progression-Free Survival (PFS)
    Description PFS was defined as the time from enrollment to the first occurrence of disease progression as determined by the investigator(s), using RECIST v1.1, or to death from any cause, whichever occurs first. Disease progression was defined as ≥20% increase in in the sum of diameters of target lesions, unequivocal progression in non-target lesions, and/or appearance of new lesions.
    Time Frame Up to approximately 31 months

    Outcome Measure Data

    Analysis Population Description
    The ITT population included all participants enrolled in the study.
    Arm/Group Title Cohort 1 - SCCHN - Treatment Naive Cohort 2 - UC - Treatment Naive Cohort 3 - RCC - Treatment Naive Cohort 4 - SCCHN - Previous Treatment Exposure Cohort 5 - UC - Previous Treatment Exposure Cohort 6 - RCC - Previous Treatment Exposure
    Arm/Group Description In participants with recurrent or advanced / metastatic squamous cell carcinoma of the head and neck (SSCHN) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg once daily (QD) for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. In participants with advanced / metastatic urothelial carcinoma (UC) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with metastatic renal cell carcinoma (RCC) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with SCCHN whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with UC whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with RCC whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle.
    Measure Participants 20 20 17 20 7 3
    Median (Full Range) [months]
    5.5
    3.4
    3.4
    3.6
    2.1
    2.7
    4. Secondary Outcome
    Title Duration of Response (DOR)
    Description DOR was defined as the time from the first occurrence of a documented, confirmed objective response to disease progression as determined by the investigator, using RECIST v1.1, or to death from any cause, whichever occurs first. Objective response was defined as a complete response (CR) or a partial response (PR) on two consecutive tumor assessments ≥4 weeks apart. CR was defined as disappearance of all lesions. PR was defined as ≥30% decrease in the sum of diameters of target lesions, in the absence of CR, new lesions, and unequivocal progression in non-target lesions. Disease progression was defined as ≥20% increase in the sum of diameters of target lesions, unequivocal progression in non-target lesions, and/or appearance of new lesions. Presented here is median DOR at the time of primary analysis. The median for the duration of response is Kaplan-Meier estimate. 95% CI for median was computed using the method of Brookmeyer and Crowley.
    Time Frame Up to approximately 22 months

    Outcome Measure Data

    Analysis Population Description
    ITT population: all participants enrolled in the study. Median DOR is presented at the time of primary analysis. DOR analyses were not performed at final analysis because Kaplan-Meier was not estimable at primary analysis due to too few events in Cohorts 1 and 3. There were no subsequent events in Cohorts 1 and 3. Cohorts 4-6 had no events.
    Arm/Group Title Cohort 1 - SCCHN - Treatment Naive Cohort 2 - UC - Treatment Naive Cohort 3 - RCC - Treatment Naive Cohort 4 - SCCHN - Previous Treatment Exposure Cohort 5 - UC - Previous Treatment Exposure Cohort 6 - RCC - Previous Treatment Exposure
    Arm/Group Description In participants with recurrent or advanced / metastatic squamous cell carcinoma of the head and neck (SSCHN) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg once daily (QD) for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. In participants with advanced / metastatic urothelial carcinoma (UC) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with metastatic renal cell carcinoma (RCC) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with SCCHN whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with UC whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with RCC whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle.
    Measure Participants 20 20 17 0 0 0
    Median (95% Confidence Interval) [days]
    NA
    149.0
    NA
    5. Secondary Outcome
    Title Disease Control Rate (DCR)
    Description DCR was defined as the percentage of participants with a complete response (CR), a partial response (PR), or stable disease at 16 weeks as determined by the investigator using RECIST v1.1. CR was defined as disappearance of all lesions. PR was defined as ≥30% decrease in the sum of diameters of target lesions, in the absence of CR, new lesions, and unequivocal progression in non-target lesions. Stable disease was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for disease progression. Disease progression was defined as ≥20% increase in the sum of diameters of target lesions, unequivocal progression in non-target lesions, and/or appearance of new lesions.
    Time Frame At 16 weeks

    Outcome Measure Data

    Analysis Population Description
    The ITT population included all participants enrolled in the study.
    Arm/Group Title Cohort 1 - SCCHN - Treatment Naive Cohort 2 - UC - Treatment Naive Cohort 3 - RCC - Treatment Naive Cohort 4 - SCCHN - Previous Treatment Exposure Cohort 5 - UC - Previous Treatment Exposure Cohort 6 - RCC - Previous Treatment Exposure
    Arm/Group Description In participants with recurrent or advanced / metastatic squamous cell carcinoma of the head and neck (SSCHN) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg once daily (QD) for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. In participants with advanced / metastatic urothelial carcinoma (UC) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with metastatic renal cell carcinoma (RCC) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with SCCHN whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with UC whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with RCC whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle.
    Measure Participants 20 20 17 20 7 3
    Number (95% Confidence Interval) [percentage of participants]
    50.0
    250%
    40.0
    200%
    23.5
    138.2%
    25.0
    125%
    0
    0%
    0
    0%
    6. Secondary Outcome
    Title Number of Participants With Adverse Events
    Description An adverse event is any untoward medical occurrence in a subject 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 Up to approximately 31 months

    Outcome Measure Data

    Analysis Population Description
    The safety population included all enrolled participants who received at least one dose of study drug.
    Arm/Group Title Cohort 1 - SCCHN - Treatment Naive Cohort 2 - UC - Treatment Naive Cohort 3 - RCC - Treatment Naive Cohort 4 - SCCHN - Previous Treatment Exposure Cohort 5 - UC - Previous Treatment Exposure Cohort 6 - RCC - Previous Treatment Exposure
    Arm/Group Description In participants with recurrent or advanced / metastatic squamous cell carcinoma of the head and neck (SSCHN) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg once daily (QD) for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. In participants with advanced / metastatic urothelial carcinoma (UC) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with metastatic renal cell carcinoma (RCC) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with SCCHN whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with UC whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with RCC whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle.
    Measure Participants 20 19 17 20 7 3
    Number [participants]
    20
    100%
    19
    95%
    17
    100%
    20
    100%
    7
    100%
    3
    100%
    7. Secondary Outcome
    Title Maximum Plasma Concentration (Cmax) of Cobimetinib
    Description Cmax is the maximum (or peak) concentration that a study drug achieves in the body.
    Time Frame Day 15 of Cycle 3 (cycle is 28 days): 2-4 hours after cobimetinib dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) analysis population consisted of participants with sufficient data to enable estimation of key parameters, with participants grouped according to treatment received.
    Arm/Group Title Cohorts 1-6
    Arm/Group Description In all participants cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle.
    Measure Participants 33
    Geometric Mean (Geometric Coefficient of Variation) [nanogram per milliliter (ng/mL)]
    285
    (56.5)
    8. Secondary Outcome
    Title Minimum Plasma Concentration (Cmin) of Cobimetinib
    Description Cmin is the minimum (or trough) concentration that a study drug achieves in the body.
    Time Frame Day 15 of Cycle 3 (cycle is 28 days): prior to cobimetinib dose

    Outcome Measure Data

    Analysis Population Description
    PK analysis population consisted of participants with sufficient data to enable estimation of key parameters, with participants grouped according to treatment received.
    Arm/Group Title Cohorts 1-6
    Arm/Group Description In all participants cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle.
    Measure Participants 30
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    174
    (152)
    9. Secondary Outcome
    Title Maximum Serum Concentration (Cmax) of Atezolizumab
    Description Cmax is the maximum (or peak) concentration that a study drug achieves in the body.
    Time Frame 30 minutes following end of atezolizumab infusion on Day 15 of Cycle 3 (each cycle is 28 days)

    Outcome Measure Data

    Analysis Population Description
    PK analysis population consisted of participants with sufficient data to enable estimation of key parameters, with participants grouped according to treatment received.
    Arm/Group Title Cohorts 1-6
    Arm/Group Description In all participants cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle.
    Measure Participants 40
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    417000
    (50.2)
    10. Secondary Outcome
    Title Minimum Serum Concentration (Cmin) of Atezolizumab
    Description Cmin is the minimum (or trough) concentration that a study drug achieves in the body.
    Time Frame Prior to atezolizumab infusion on Day 1 of Cycles (each cycle is 28 days) 2, 4, 8, 12, and 16, Day 15 of Cycle 3

    Outcome Measure Data

    Analysis Population Description
    PK analysis population consisted of participants with sufficient data to enable estimation of key parameters, with participants grouped according to treatment received.
    Arm/Group Title Cohorts 1-6
    Arm/Group Description In all participants cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle.
    Measure Participants 61
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    112000
    (219)
    11. Secondary Outcome
    Title Number of Participants With Anti-drug Antibodies (ADAs)
    Description Participants were considered to be ADA positive if they were missing data at baseline but developed an ADA response following study drug administration (treatment-induced ADA response), or if they were ADA positive at baseline and the titer of one or more post-baseline samples was at least 4-fold greater (i.e., ≥0.60-titer units) than the titer of the baseline sample (treatment-enhanced ADA response). Participants were considered to be ADA negative if they were missing data at baseline, had a post-baseline ADA result, and all post-baseline samples were negative, or if they were ADA positive at baseline but did not have any post-baseline samples with a titer that was at least 4-fold greater than the titer of the baseline sample (treatment unaffected).
    Time Frame Day 1 of Cycles (each cycle is 28 days) 1, 2, 4, 8, 12, and 16; Day 15 of Cycle 3; at atezolizumab treatment discontinuation visit, and <90 days after last atezolizumab infusion (up to approximately 31 months)

    Outcome Measure Data

    Analysis Population Description
    The safety population included all enrolled participants who received at least one dose of study drug. Number analyzed is the number of participants with data available for analysis.
    Arm/Group Title Cohort 1 - SCCHN - Treatment Naive Cohort 2 - UC - Treatment Naive Cohort 3 - RCC - Treatment Naive Cohort 4 - SCCHN - Previous Treatment Exposure Cohort 5 - UC - Previous Treatment Exposure Cohort 6 - RCC - Previous Treatment Exposure
    Arm/Group Description In participants with recurrent or advanced / metastatic squamous cell carcinoma of the head and neck (SSCHN) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg once daily (QD) for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. In participants with advanced / metastatic urothelial carcinoma (UC) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with metastatic renal cell carcinoma (RCC) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with SCCHN whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with UC whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with RCC whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle.
    Measure Participants 19 19 17 10 1 2
    Count of Participants [Participants]
    1
    5%
    10
    50%
    6
    35.3%
    5
    25%
    0
    0%
    2
    66.7%

    Adverse Events

    Time Frame Up to approximately 31 months
    Adverse Event Reporting Description The safety population included all enrolled participants who received at least one dose of study drug.
    Arm/Group Title Cohort 1 - SCCHN - Treatment Naive Cohort 2 - UC - Treatment Naive Cohort 3 - RCC - Treatment Naive Cohort 4 - SCCHN - Previous Treatment Exposure Cohort 5 - UC - Previous Treatment Exposure Cohort 6 - RCC - Previous Treatment Exposure
    Arm/Group Description In participants with recurrent or advanced / metastatic squamous cell carcinoma of the head and neck (SSCHN) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg once daily (QD) for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. In participants with advanced / metastatic urothelial carcinoma (UC) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with metastatic renal cell carcinoma (RCC) who were anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with SCCHN whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with UC whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle. In participants with RCC whose disease had progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib was administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by IV infusion on Days 1 and 15 of each 28-day cycle.
    All Cause Mortality
    Cohort 1 - SCCHN - Treatment Naive Cohort 2 - UC - Treatment Naive Cohort 3 - RCC - Treatment Naive Cohort 4 - SCCHN - Previous Treatment Exposure Cohort 5 - UC - Previous Treatment Exposure Cohort 6 - RCC - Previous Treatment Exposure
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 12/20 (60%) 12/19 (63.2%) 8/17 (47.1%) 12/20 (60%) 6/7 (85.7%) 1/3 (33.3%)
    Serious Adverse Events
    Cohort 1 - SCCHN - Treatment Naive Cohort 2 - UC - Treatment Naive Cohort 3 - RCC - Treatment Naive Cohort 4 - SCCHN - Previous Treatment Exposure Cohort 5 - UC - Previous Treatment Exposure Cohort 6 - RCC - Previous Treatment Exposure
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 13/20 (65%) 9/19 (47.4%) 8/17 (47.1%) 10/20 (50%) 4/7 (57.1%) 1/3 (33.3%)
    Blood and lymphatic system disorders
    ANAEMIA 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    Cardiac disorders
    ATRIAL FIBRILLATION 0/20 (0%) 0 1/19 (5.3%) 1 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    PERICARDITIS 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    Gastrointestinal disorders
    COLITIS 1/20 (5%) 1 1/19 (5.3%) 2 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    DIARRHOEA 0/20 (0%) 0 0/19 (0%) 0 2/17 (11.8%) 2 0/20 (0%) 0 1/7 (14.3%) 1 1/3 (33.3%) 1
    DYSPHAGIA 2/20 (10%) 2 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    ENTEROCOLITIS 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    GASTRITIS EROSIVE 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    ILEUS 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    INTESTINAL OBSTRUCTION 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    LARGE INTESTINAL OBSTRUCTION 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    LARGE INTESTINE PERFORATION 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    NAUSEA 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 1/3 (33.3%) 1
    PNEUMATOSIS INTESTINALIS 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    RECTAL HAEMORRHAGE 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    UPPER GASTROINTESTINAL HAEMORRHAGE 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    VOMITING 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    General disorders
    ASTHENIA 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 1/3 (33.3%) 2
    CHILLS 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 1/3 (33.3%) 1
    FACE OEDEMA 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    FATIGUE 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 1/3 (33.3%) 1
    GENERAL PHYSICAL HEALTH DETERIORATION 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    PYREXIA 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 1/3 (33.3%) 1
    Hepatobiliary disorders
    IMMUNE-MEDIATED HEPATITIS 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0
    Infections and infestations
    DEVICE RELATED SEPSIS 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    ENDOCARDITIS 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0
    LOWER RESPIRATORY TRACT INFECTION 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    PHARYNGITIS STREPTOCOCCAL 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 1/3 (33.3%) 1
    PNEUMONIA 3/20 (15%) 3 2/19 (10.5%) 2 2/17 (11.8%) 2 2/20 (10%) 2 0/7 (0%) 0 0/3 (0%) 0
    SEPSIS 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 1/7 (14.3%) 1 0/3 (0%) 0
    URINARY TRACT INFECTION 0/20 (0%) 0 2/19 (10.5%) 3 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    Injury, poisoning and procedural complications
    HUMERUS FRACTURE 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0
    INFUSION RELATED REACTION 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0
    POSTOPERATIVE RESPIRATORY FAILURE 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    ASPARTATE AMINOTRANSFERASE INCREASED 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    EJECTION FRACTION DECREASED 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    TUMOUR HAEMORRHAGE 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    Nervous system disorders
    ALTERED STATE OF CONSCIOUSNESS 0/20 (0%) 0 0/19 (0%) 0 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    IMMUNE-MEDIATED ENCEPHALITIS 1/20 (5%) 1 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    Product Issues
    DEVICE DISLOCATION 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    Renal and urinary disorders
    NEPHRITIS 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    URINARY RETENTION 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    DYSPNOEA 1/20 (5%) 1 0/19 (0%) 0 2/17 (11.8%) 3 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    PLEURAL EFFUSION 1/20 (5%) 1 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    PNEUMONIA ASPIRATION 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    PNEUMONITIS 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    PULMONARY EMBOLISM 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 1/3 (33.3%) 1
    RESPIRATORY TRACT OEDEMA 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    Skin and subcutaneous tissue disorders
    RASH 0/20 (0%) 0 1/19 (5.3%) 1 1/17 (5.9%) 1 0/20 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0
    RASH MACULAR 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    RASH MACULO-PAPULAR 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    Surgical and medical procedures
    GASTROSTOMY 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    Vascular disorders
    HYPOTENSION 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    Other (Not Including Serious) Adverse Events
    Cohort 1 - SCCHN - Treatment Naive Cohort 2 - UC - Treatment Naive Cohort 3 - RCC - Treatment Naive Cohort 4 - SCCHN - Previous Treatment Exposure Cohort 5 - UC - Previous Treatment Exposure Cohort 6 - RCC - Previous Treatment Exposure
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 20/20 (100%) 19/19 (100%) 17/17 (100%) 19/20 (95%) 7/7 (100%) 3/3 (100%)
    Blood and lymphatic system disorders
    ANAEMIA 8/20 (40%) 9 6/19 (31.6%) 6 4/17 (23.5%) 5 2/20 (10%) 4 1/7 (14.3%) 1 0/3 (0%) 0
    IRON DEFICIENCY ANAEMIA 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    LEUKOCYTOSIS 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    LEUKOPENIA 1/20 (5%) 2 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    LYMPH NODE PAIN 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    LYMPHADENITIS 0/20 (0%) 0 0/19 (0%) 0 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    LYMPHOPENIA 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    NEUTROPENIA 2/20 (10%) 7 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 1/3 (33.3%) 1
    THROMBOCYTOPENIA 1/20 (5%) 1 1/19 (5.3%) 1 0/17 (0%) 0 1/20 (5%) 1 2/7 (28.6%) 2 1/3 (33.3%) 1
    Cardiac disorders
    ATRIAL FIBRILLATION 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 1/3 (33.3%) 1
    ATRIOVENTRICULAR BLOCK FIRST DEGREE 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    CARDIAC FAILURE CONGESTIVE 0/20 (0%) 0 0/19 (0%) 0 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    CORONARY ARTERY DISEASE 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    PERICARDITIS 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    SINUS BRADYCARDIA 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    SINUS TACHYCARDIA 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    TACHYCARDIA 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0
    VENTRICULAR DYSFUNCTION 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    Ear and labyrinth disorders
    HYPOACUSIS 0/20 (0%) 0 0/19 (0%) 0 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    INNER EAR DISORDER 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    VERTIGO 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    Endocrine disorders
    HYPERTHYROIDISM 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    HYPOTHYROIDISM 3/20 (15%) 4 1/19 (5.3%) 1 1/17 (5.9%) 1 2/20 (10%) 2 0/7 (0%) 0 0/3 (0%) 0
    THYROIDITIS 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    Eye disorders
    CATARACT 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    CHORIORETINOPATHY 2/20 (10%) 2 3/19 (15.8%) 4 2/17 (11.8%) 2 0/20 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0
    ENTROPION 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    EYELID OEDEMA 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    EYELID PTOSIS 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    GLAUCOMA 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    LACRIMATION INCREASED 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 1/3 (33.3%) 1
    MACULAR OEDEMA 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    OPTIC NERVE DISORDER 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    PERIORBITAL OEDEMA 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    RETINAL OEDEMA 0/20 (0%) 0 0/19 (0%) 0 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    RETINOPATHY 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    SUBRETINAL FLUID 0/20 (0%) 0 0/19 (0%) 0 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    SWELLING OF EYELID 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    TRICHIASIS 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    VISION BLURRED 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 2/20 (10%) 3 0/7 (0%) 0 0/3 (0%) 0
    VISUAL IMPAIRMENT 1/20 (5%) 1 1/19 (5.3%) 1 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    VITREOUS FLOATERS 0/20 (0%) 0 0/19 (0%) 0 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    Gastrointestinal disorders
    ABDOMINAL DISCOMFORT 1/20 (5%) 1 0/19 (0%) 0 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    ABDOMINAL DISTENSION 0/20 (0%) 0 1/19 (5.3%) 1 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    ABDOMINAL PAIN 0/20 (0%) 0 2/19 (10.5%) 3 2/17 (11.8%) 2 1/20 (5%) 3 2/7 (28.6%) 3 0/3 (0%) 0
    ANAL HAEMORRHAGE 0/20 (0%) 0 0/19 (0%) 0 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    ANGULAR CHEILITIS 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    ASCITES 0/20 (0%) 0 0/19 (0%) 0 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    CHEILITIS 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 1/3 (33.3%) 1
    CONSTIPATION 1/20 (5%) 1 5/19 (26.3%) 7 3/17 (17.6%) 3 4/20 (20%) 4 1/7 (14.3%) 2 0/3 (0%) 0
    DIAPHRAGMATIC HERNIA 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    DIARRHOEA 7/20 (35%) 9 11/19 (57.9%) 15 9/17 (52.9%) 13 13/20 (65%) 16 5/7 (71.4%) 6 2/3 (66.7%) 2
    DRY MOUTH 1/20 (5%) 1 1/19 (5.3%) 1 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    DYSPEPSIA 2/20 (10%) 2 4/19 (21.1%) 4 3/17 (17.6%) 3 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    DYSPHAGIA 2/20 (10%) 2 2/19 (10.5%) 3 1/17 (5.9%) 1 3/20 (15%) 3 0/7 (0%) 0 0/3 (0%) 0
    FLATULENCE 0/20 (0%) 0 1/19 (5.3%) 2 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    GASTRIC ULCER 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    GASTRITIS 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    GASTROOESOPHAGEAL REFLUX DISEASE 1/20 (5%) 1 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0
    GINGIVAL BLEEDING 0/20 (0%) 0 0/19 (0%) 0 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    GLOSSITIS 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 1/3 (33.3%) 1
    GLOSSODYNIA 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    HAEMATEMESIS 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    HAEMATOCHEZIA 0/20 (0%) 0 2/19 (10.5%) 2 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    HAEMORRHOIDS 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    LIP OEDEMA 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 2 0/7 (0%) 0 0/3 (0%) 0
    LIP PAIN 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    LIP SWELLING 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    MOUTH ULCERATION 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 2/20 (10%) 2 0/7 (0%) 0 0/3 (0%) 0
    MUCOUS STOOLS 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    NAUSEA 6/20 (30%) 6 3/19 (15.8%) 3 5/17 (29.4%) 5 6/20 (30%) 8 4/7 (57.1%) 5 0/3 (0%) 0
    OESOPHAGITIS 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    ORAL DISCHARGE 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    ORAL PAIN 1/20 (5%) 2 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    RECTAL HAEMORRHAGE 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    STOMATITIS 2/20 (10%) 3 5/19 (26.3%) 5 2/17 (11.8%) 2 4/20 (20%) 4 0/7 (0%) 0 1/3 (33.3%) 1
    TOOTHACHE 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    VOMITING 7/20 (35%) 9 4/19 (21.1%) 8 3/17 (17.6%) 3 4/20 (20%) 4 1/7 (14.3%) 2 1/3 (33.3%) 1
    General disorders
    ASTHENIA 1/20 (5%) 1 3/19 (15.8%) 3 2/17 (11.8%) 2 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    CHEST PAIN 0/20 (0%) 0 0/19 (0%) 0 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    CHILLS 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 2/7 (28.6%) 2 0/3 (0%) 0
    FACE OEDEMA 2/20 (10%) 3 2/19 (10.5%) 2 2/17 (11.8%) 2 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    FACIAL PAIN 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    FATIGUE 6/20 (30%) 6 9/19 (47.4%) 14 5/17 (29.4%) 7 5/20 (25%) 5 5/7 (71.4%) 5 0/3 (0%) 0
    GENERALISED OEDEMA 0/20 (0%) 0 0/19 (0%) 0 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    INFLUENZA LIKE ILLNESS 1/20 (5%) 1 3/19 (15.8%) 3 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    LOCALISED OEDEMA 0/20 (0%) 0 1/19 (5.3%) 2 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    MALAISE 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    MUCOSAL INFLAMMATION 1/20 (5%) 1 1/19 (5.3%) 1 2/17 (11.8%) 2 1/20 (5%) 1 1/7 (14.3%) 1 1/3 (33.3%) 1
    OEDEMA 0/20 (0%) 0 1/19 (5.3%) 1 2/17 (11.8%) 2 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    OEDEMA PERIPHERAL 3/20 (15%) 3 2/19 (10.5%) 2 3/17 (17.6%) 3 2/20 (10%) 2 2/7 (28.6%) 2 0/3 (0%) 0
    PAIN 3/20 (15%) 3 2/19 (10.5%) 2 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    PERIPHERAL SWELLING 0/20 (0%) 0 2/19 (10.5%) 3 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    PYREXIA 2/20 (10%) 2 7/19 (36.8%) 9 5/17 (29.4%) 9 1/20 (5%) 1 4/7 (57.1%) 4 0/3 (0%) 0
    SWELLING FACE 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    Immune system disorders
    HYPERSENSITIVITY 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 1/3 (33.3%) 1
    Infections and infestations
    BRONCHITIS 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    CANDIDA INFECTION 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    CELLULITIS 0/20 (0%) 0 0/19 (0%) 0 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    CONJUNCTIVITIS 2/20 (10%) 2 0/19 (0%) 0 1/17 (5.9%) 1 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    CYSTITIS 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    CYSTITIS BACTERIAL 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    DEVICE RELATED INFECTION 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    DIVERTICULITIS 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    INFECTION 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    INFLUENZA 0/20 (0%) 0 0/19 (0%) 0 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    LOWER RESPIRATORY TRACT INFECTION 3/20 (15%) 4 0/19 (0%) 0 1/17 (5.9%) 1 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    NASOPHARYNGITIS 0/20 (0%) 0 1/19 (5.3%) 1 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    ORAL CANDIDIASIS 1/20 (5%) 1 0/19 (0%) 0 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    ORAL HERPES 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    OTITIS EXTERNA 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    OTITIS MEDIA 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    RASH PUSTULAR 2/20 (10%) 2 2/19 (10.5%) 2 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    RESPIRATORY TRACT INFECTION 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    RHINITIS 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    SKIN INFECTION 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    STAPHYLOCOCCAL INFECTION 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    TONGUE FUNGAL INFECTION 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    TOOTH INFECTION 1/20 (5%) 4 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    UPPER RESPIRATORY TRACT INFECTION 0/20 (0%) 0 1/19 (5.3%) 1 2/17 (11.8%) 2 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    URINARY TRACT INFECTION 0/20 (0%) 0 4/19 (21.1%) 5 2/17 (11.8%) 2 0/20 (0%) 0 4/7 (57.1%) 4 0/3 (0%) 0
    URINARY TRACT INFECTION STAPHYLOCOCCAL 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0
    VIRAL INFECTION 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 1/3 (33.3%) 1
    Injury, poisoning and procedural complications
    CONTUSION 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    FACE INJURY 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    FALL 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0
    INFUSION RELATED REACTION 0/20 (0%) 0 3/19 (15.8%) 4 1/17 (5.9%) 1 0/20 (0%) 0 1/7 (14.3%) 2 1/3 (33.3%) 1
    INJURY 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    LIMB INJURY 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0
    POST PROCEDURAL SWELLING 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    SKIN LACERATION 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    STRESS FRACTURE 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    WOUND COMPLICATION 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED 0/20 (0%) 0 2/19 (10.5%) 2 1/17 (5.9%) 1 2/20 (10%) 3 0/7 (0%) 0 0/3 (0%) 0
    ASPARTATE AMINOTRANSFERASE INCREASED 0/20 (0%) 0 3/19 (15.8%) 3 0/17 (0%) 0 2/20 (10%) 4 1/7 (14.3%) 1 0/3 (0%) 0
    BLOOD ALKALINE PHOSPHATASE INCREASED 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 1/7 (14.3%) 1 0/3 (0%) 0
    BLOOD BILIRUBIN INCREASED 1/20 (5%) 2 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    BLOOD CREATINE PHOSPHOKINASE INCREASED 4/20 (20%) 4 7/19 (36.8%) 9 3/17 (17.6%) 3 1/20 (5%) 1 3/7 (42.9%) 3 0/3 (0%) 0
    BLOOD CREATININE INCREASED 1/20 (5%) 1 4/19 (21.1%) 4 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    BLOOD MAGNESIUM DECREASED 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    BLOOD POTASSIUM DECREASED 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    BLOOD PRESSURE DECREASED 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    BLOOD PRESSURE INCREASED 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    BLOOD THYROID STIMULATING HORMONE INCREASED 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    BLOOD URIC ACID INCREASED 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    BRAIN NATRIURETIC PEPTIDE INCREASED 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0
    C-REACTIVE PROTEIN INCREASED 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    CYTOMEGALOVIRUS TEST POSITIVE 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0
    EJECTION FRACTION DECREASED 1/20 (5%) 1 0/19 (0%) 0 2/17 (11.8%) 3 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    GAMMA-GLUTAMYLTRANSFERASE INCREASED 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0
    HAEMOGLOBIN DECREASED 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 1/7 (14.3%) 1 0/3 (0%) 0
    INTERNATIONAL NORMALISED RATIO INCREASED 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    PLATELET COUNT DECREASED 1/20 (5%) 1 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0
    PLATELET COUNT INCREASED 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    VITAMIN B12 DECREASED 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    VITAMIN D DECREASED 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    WEIGHT DECREASED 2/20 (10%) 3 3/19 (15.8%) 3 1/17 (5.9%) 1 4/20 (20%) 5 0/7 (0%) 0 1/3 (33.3%) 1
    Metabolism and nutrition disorders
    CACHEXIA 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    DECREASED APPETITE 4/20 (20%) 4 7/19 (36.8%) 8 3/17 (17.6%) 4 0/20 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0
    DEHYDRATION 2/20 (10%) 2 0/19 (0%) 0 1/17 (5.9%) 2 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    HYPERCALCAEMIA 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    HYPERGLYCAEMIA 0/20 (0%) 0 0/19 (0%) 0 1/17 (5.9%) 1 0/20 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0
    HYPERKALAEMIA 1/20 (5%) 1 0/19 (0%) 0 1/17 (5.9%) 1 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    HYPOALBUMINAEMIA 0/20 (0%) 0 3/19 (15.8%) 4 6/17 (35.3%) 7 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    HYPOCALCAEMIA 2/20 (10%) 2 0/19 (0%) 0 0/17 (0%) 0 2/20 (10%) 2 0/7 (0%) 0 0/3 (0%) 0
    HYPOKALAEMIA 2/20 (10%) 3 1/19 (5.3%) 1 0/17 (0%) 0 2/20 (10%) 2 0/7 (0%) 0 0/3 (0%) 0
    HYPOMAGNESAEMIA 1/20 (5%) 2 0/19 (0%) 0 0/17 (0%) 0 2/20 (10%) 2 1/7 (14.3%) 1 0/3 (0%) 0
    HYPONATRAEMIA 0/20 (0%) 0 3/19 (15.8%) 3 1/17 (5.9%) 1 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    HYPOPHOSPHATAEMIA 1/20 (5%) 1 2/19 (10.5%) 2 0/17 (0%) 0 0/20 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0
    IRON DEFICIENCY 1/20 (5%) 1 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA 2/20 (10%) 2 2/19 (10.5%) 3 3/17 (17.6%) 3 2/20 (10%) 2 1/7 (14.3%) 1 0/3 (0%) 0
    BACK PAIN 0/20 (0%) 0 1/19 (5.3%) 1 1/17 (5.9%) 1 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    BONE PAIN 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    FLANK PAIN 0/20 (0%) 0 0/19 (0%) 0 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    GROIN PAIN 0/20 (0%) 0 1/19 (5.3%) 1 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    JOINT SWELLING 2/20 (10%) 3 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    MUSCLE SPASMS 2/20 (10%) 2 1/19 (5.3%) 1 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    MUSCULAR WEAKNESS 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    MUSCULOSKELETAL CHEST PAIN 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0
    MUSCULOSKELETAL PAIN 1/20 (5%) 1 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0
    MYALGIA 0/20 (0%) 0 2/19 (10.5%) 2 1/17 (5.9%) 1 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    MYOSITIS 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    NECK PAIN 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    OSTEONECROSIS OF JAW 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    PAIN IN EXTREMITY 3/20 (15%) 3 2/19 (10.5%) 2 1/17 (5.9%) 1 1/20 (5%) 1 2/7 (28.6%) 2 0/3 (0%) 0
    SYNOVITIS 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    TRISMUS 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 2/20 (10%) 2 0/7 (0%) 0 0/3 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ADENOCARCINOMA OF COLON 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    CANCER PAIN 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    KERATOACANTHOMA 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    TUMOUR HAEMORRHAGE 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    Nervous system disorders
    APHASIA 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 1/3 (33.3%) 1
    CAUDA EQUINA SYNDROME 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    CEREBRAL INFARCTION 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    DIZZINESS 0/20 (0%) 0 4/19 (21.1%) 4 2/17 (11.8%) 2 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    DIZZINESS POSTURAL 1/20 (5%) 1 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    DYSARTHRIA 0/20 (0%) 0 0/19 (0%) 0 1/17 (5.9%) 1 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    DYSGEUSIA 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 2/7 (28.6%) 2 0/3 (0%) 0
    HEADACHE 1/20 (5%) 1 0/19 (0%) 0 1/17 (5.9%) 1 3/20 (15%) 3 2/7 (28.6%) 2 1/3 (33.3%) 1
    LETHARGY 0/20 (0%) 0 0/19 (0%) 0 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    LUMBAR RADICULOPATHY 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    NEUROPATHY PERIPHERAL 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    PARAESTHESIA 0/20 (0%) 0 0/19 (0%) 0 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    PRESYNCOPE 0/20 (0%) 0 2/19 (10.5%) 2 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    RESTLESS LEGS SYNDROME 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    SCIATICA 0/20 (0%) 0 0/19 (0%) 0 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    STATUS EPILEPTICUS 0/20 (0%) 0 0/19 (0%) 0 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    SYNCOPE 1/20 (5%) 1 1/19 (5.3%) 1 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    TASTE DISORDER 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    Psychiatric disorders
    ANGER 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    ANXIETY 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    CONFUSIONAL STATE 2/20 (10%) 2 1/19 (5.3%) 1 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    DEPRESSION 0/20 (0%) 0 0/19 (0%) 0 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    DISORIENTATION 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    INSOMNIA 3/20 (15%) 3 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY 0/20 (0%) 0 1/19 (5.3%) 1 1/17 (5.9%) 1 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    DYSURIA 0/20 (0%) 0 2/19 (10.5%) 2 0/17 (0%) 0 0/20 (0%) 0 3/7 (42.9%) 3 0/3 (0%) 0
    HAEMATURIA 0/20 (0%) 0 3/19 (15.8%) 4 0/17 (0%) 0 0/20 (0%) 0 2/7 (28.6%) 2 0/3 (0%) 0
    NOCTURIA 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    POLLAKIURIA 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    PROTEINURIA 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    RENAL FAILURE 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    RENAL IMPAIRMENT 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    URINARY RETENTION 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 1/7 (14.3%) 3 0/3 (0%) 0
    URINARY TRACT OBSTRUCTION 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    URINARY TRACT PAIN 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    Reproductive system and breast disorders
    SCROTAL OEDEMA 0/20 (0%) 0 1/19 (5.3%) 2 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    TESTICULAR SWELLING 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    VAGINAL DISCHARGE 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    VAGINAL HAEMORRHAGE 0/20 (0%) 0 2/19 (10.5%) 2 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    COUGH 1/20 (5%) 1 4/19 (21.1%) 5 2/17 (11.8%) 2 2/20 (10%) 2 1/7 (14.3%) 1 0/3 (0%) 0
    DYSPHONIA 1/20 (5%) 1 1/19 (5.3%) 1 0/17 (0%) 0 2/20 (10%) 2 0/7 (0%) 0 0/3 (0%) 0
    DYSPNOEA 0/20 (0%) 0 4/19 (21.1%) 4 1/17 (5.9%) 1 2/20 (10%) 2 0/7 (0%) 0 0/3 (0%) 0
    DYSPNOEA EXERTIONAL 1/20 (5%) 1 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    EPISTAXIS 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 2/20 (10%) 2 0/7 (0%) 0 0/3 (0%) 0
    HAEMOPTYSIS 1/20 (5%) 2 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0
    LARYNGEAL OEDEMA 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    NASAL CONGESTION 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    NASAL OBSTRUCTION 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    OROPHARYNGEAL PAIN 2/20 (10%) 2 1/19 (5.3%) 1 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    PNEUMONITIS 2/20 (10%) 2 0/19 (0%) 0 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    PRODUCTIVE COUGH 1/20 (5%) 1 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    RALES 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    WHEEZING 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    Skin and subcutaneous tissue disorders
    ALOPECIA 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    BLISTER 0/20 (0%) 0 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 1/3 (33.3%) 1
    DERMATITIS 3/20 (15%) 3 0/19 (0%) 0 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    DERMATITIS ACNEIFORM 0/20 (0%) 0 2/19 (10.5%) 2 3/17 (17.6%) 3 5/20 (25%) 5 2/7 (28.6%) 3 0/3 (0%) 0
    DERMATITIS PSORIASIFORM 0/20 (0%) 0 0/19 (0%) 0 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    DRY SKIN 3/20 (15%) 3 0/19 (0%) 0 1/17 (5.9%) 1 4/20 (20%) 5 1/7 (14.3%) 2 0/3 (0%) 0
    ECZEMA 1/20 (5%) 1 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    ERYTHEMA 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    INTERTRIGO 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    NIGHT SWEATS 0/20 (0%) 0 0/19 (0%) 0 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    ONYCHOCLASIS 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    PRURITUS 2/20 (10%) 2 3/19 (15.8%) 3 1/17 (5.9%) 2 4/20 (20%) 4 3/7 (42.9%) 6 0/3 (0%) 0
    RASH 9/20 (45%) 10 9/19 (47.4%) 11 12/17 (70.6%) 14 5/20 (25%) 6 5/7 (71.4%) 7 1/3 (33.3%) 1
    RASH ERYTHEMATOUS 0/20 (0%) 0 1/19 (5.3%) 2 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    RASH MACULO-PAPULAR 0/20 (0%) 0 0/19 (0%) 0 1/17 (5.9%) 1 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    RASH PAPULAR 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    RASH PRURITIC 0/20 (0%) 0 1/19 (5.3%) 1 0/17 (0%) 0 1/20 (5%) 1 0/7 (0%) 0 0/3 (0%) 0
    SKIN FISSURES 1/20 (5%) 1 1/19 (5.3%) 2 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 1/3 (33.3%) 1
    STASIS DERMATITIS 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    URTICARIA 0/20 (0%) 0 0/19 (0%) 0 1/17 (5.9%) 3 2/20 (10%) 2 0/7 (0%) 0 0/3 (0%) 0
    Vascular disorders
    FLUSHING 0/20 (0%) 0 0/19 (0%) 0 1/17 (5.9%) 1 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    HYPERTENSION 1/20 (5%) 1 1/19 (5.3%) 1 0/17 (0%) 0 3/20 (15%) 8 0/7 (0%) 0 0/3 (0%) 0
    HYPOTENSION 1/20 (5%) 1 0/19 (0%) 0 2/17 (11.8%) 2 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    LYMPHOEDEMA 1/20 (5%) 1 0/19 (0%) 0 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0
    ORTHOSTATIC HYPOTENSION 0/20 (0%) 0 1/19 (5.3%) 2 0/17 (0%) 0 0/20 (0%) 0 0/7 (0%) 0 0/3 (0%) 0

    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 presentation 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.

    Results Point of Contact

    Name/Title Medical Communications
    Organization Hoffmann-La Roche
    Phone 800 821-8590
    Email genentech@druginfo.com
    Responsible Party:
    Hoffmann-La Roche
    ClinicalTrials.gov Identifier:
    NCT03264066
    Other Study ID Numbers:
    • WO39760
    • 2017-000794-37
    First Posted:
    Aug 28, 2017
    Last Update Posted:
    May 11, 2021
    Last Verified:
    Apr 1, 2021