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iMATRIXcobi: Safety and Pharmacokinetics of Cobimetinib in Pediatric and Young Adult Participants With Previously Treated Solid Tumors

Sponsor
Hoffmann-La Roche (Industry)
Overall Status
Completed
CT.gov ID
NCT02639546
Collaborator
(none)
56
Enrollment
17
Locations
8
Arms
62
Actual Duration (Months)
3.3
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This open-label, dose-escalation study is designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of cobimetinib in pediatric and young adult participants with solid tumors with known or potential kinase pathway activation for which standard therapy has proven to be ineffective or intolerable or for which no curative standard-of-care treatment options exist. The study will be conducted in two stages: a dose-escalation stage and an expansion stage at the recommended dose.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
56 participants
Allocation:
Non-Randomized
Intervention Model:
Sequential Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase I/II, Multicenter, Open-Label, Dose-Escalation Study of the Safety and Pharmacokinetics of Cobimetinib In Pediatric and Young Adult Patients With Previously Treated Solid Tumors
Actual Study Start Date :
May 20, 2016
Actual Primary Completion Date :
Jul 21, 2021
Actual Study Completion Date :
Jul 21, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: Phase I (Tablet) Cobimetinib (0.6 mg/kg)

Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Drug: Cobimetinib
Cobimetinib tablet or suspension will be administered as per the schedule described in arm description.
Other Names:
  • RO5514041, GDC-0973, XL-518

    		•
    Experimental: Phase I (Tablet) Cobimetinib (0.8 mg/kg)

    Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Drug: Cobimetinib
    Cobimetinib tablet or suspension will be administered as per the schedule described in arm description.
    Other Names:
  • RO5514041, GDC-0973, XL-518

    		•
    Experimental: Phase I (Tablet) Cobimetinib (1 mg/kg)

    Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Drug: Cobimetinib
    Cobimetinib tablet or suspension will be administered as per the schedule described in arm description.
    Other Names:
  • RO5514041, GDC-0973, XL-518

    		•
    Experimental: Phase I (Suspension) Cobimetinib (0.6 mg/kg)

    Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Drug: Cobimetinib
    Cobimetinib tablet or suspension will be administered as per the schedule described in arm description.
    Other Names:
  • RO5514041, GDC-0973, XL-518

    		•
    Experimental: Phase I (Suspension) Cobimetinib (0.8 mg/kg)

    Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Drug: Cobimetinib
    Cobimetinib tablet or suspension will be administered as per the schedule described in arm description.
    Other Names:
  • RO5514041, GDC-0973, XL-518

    		•
    Experimental: Phase I (Suspension) Cobimetinib (1 mg/kg)

    Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Drug: Cobimetinib
    Cobimetinib tablet or suspension will be administered as per the schedule described in arm description.
    Other Names:
  • RO5514041, GDC-0973, XL-518

    		•
    Experimental: Phase I (Suspension) Cobimetinib (1.33 mg/kg)

    Dose-Escalation: Participants received 1.33 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Drug: Cobimetinib
    Cobimetinib tablet or suspension will be administered as per the schedule described in arm description.
    Other Names:
  • RO5514041, GDC-0973, XL-518

    		•
    Experimental: Phase II (Suspension) Cobimetinib (1 mg/kg)

    Dose-Expansion: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Drug: Cobimetinib
    Cobimetinib tablet or suspension will be administered as per the schedule described in arm description.
    Other Names:
  • RO5514041, GDC-0973, XL-518

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Percentage of Participants With Dose-Limiting Toxicities (DLTs) [Baseline up until 30 days after the last dose of study drug (up to 5 years, 2 months)]

      Dose-Limiting Toxicities (DLTs) were defined as cobimetinib-related adverse events occurring within the first 28 days of each administration of cobimetinib.

    2. Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) [Baseline up until 30 days after the last dose of study drug (up to 5 years, 2 months)]

      An AE 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 AE can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), 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 AEs.

    3. Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of Cobimetinib [Cycle 1 Day 1 up to Cycle 1 Day 28 (cycle length=28 days)]

      A prior dose level was defined as an MTD/MAD if at a certain dose level, there were greater than or equal to (>=) 2 out of 6 participants who had Dose Limiting Toxicities (DLTs).

    4. Percentage of Participants With Objective Response (Complete Response (CR) or Partial Response (PR)) as Determined by the Investigator Using Modified International Neuroblastoma Response Criteria (mINRC) for Participants With Neuroblastoma (Phase I) [Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)]

      Tumor assessment was performed using mINRC for Participants with Neuroblastoma.

    5. Percentage of Participants With Objective Response (CR or PR) as Determined by the Investigator Using RANO Criteria for Participants With High-Grade Glioma (HGG) (Phase I) and RECIST v1.1 for Participants With Low-Grade Glioma (LGG) (Phase I and II) [Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)]

      Tumor assessment was performed using Response Assessment in Neuro-Oncology (RANO) criteria for participants with HGG and Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) for participants with LGG. While the data for LGG in the phase II cohort is presented separately in other parts of the record, it was also considered useful to combine the data for LGG from phase I and phase II, which was done here.

    6. Percentage of Participants With Objective Response (CR or PR) as Determined by the Investigator Using RECIST v1.1 Criteria for Participants With All Other Tumours (Phase I) [Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)]

      Tumor assessment was performed using RECIST v1.1 for Participants with All Other Tumours.

    7. Percentage of Participants With Objective Response (CR or PR) as Determined by the Investigator Using RANO Criteria for Participants With LGG (Phase II) [Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)]

      Tumor assessment will be performed using RANO criteria for LGG.

    8. Progression-Free Survival (PFS) as Determined by the Investigator Using mINRC for Participants With Neuroblastoma (Phase I) [From the time of cobimetinib study drug initiation to the first documented disease progression, or death due to any cause, whichever occurs first (up to 5 years, 2 months)]

      Tumor assessment was performed using mINRC for Participants with Neuroblastoma.

    9. PFS as Determined by the Investigator Using RANO Criteria for Participants With HGG (Phase I) and RECIST v1.1 for Partcipants With LGG (Phase I and II) [From the time of cobimetinib study drug initiation to the first documented disease progression, or death due to any cause, whichever occurs first (up to 5 years, 2 months)]

      Tumor assessment was performed using RANO for participants with HGG and RECIST v1.1 for participants with LGG. While the data for LGG in the phase II cohort is presented separately in other parts of the record, it was also considered useful to combine the data for LGG from phase I and phase II, which was done here.

    10. PFS as Determined by the Investigator Using RECIST v1.1 Criteria for Participants With All Other Tumours (Phase I) [From the time of cobimetinib study drug initiation to the first documented disease progression, or death due to any cause, whichever occurs first (up to 5 years, 2 months)]

      Tumor assessment was performed using RECIST v1.1 for Participants with All Other Tumours.

    11. PFS as Determined by the Investigator Using RANO Criteria for Participants With LGG (Phase II) [From the time of cobimetinib study drug initiation to the first documented disease progression, or death due to any cause, whichever occurs first (up to 5 years, 2 months)]

      Tumor assessment was performed using RANO criteria for Participants with LGG.

    Secondary Outcome Measures

    1. Recommended Phase II Dose (RP2D) of Cobimetinib [Cycle 1 Day 1 up to Cycle 1 Day 28 (cycle length=28 days)]

      A prior dose level was defined as an RP2D if at a certain dose level, there were greater than or equal to (≥) 2 out of 6 participants who had Dose Limiting Toxicities (DLTs).

    2. Duration of Response (DOR) as Determined by the Investigator Using RECIST v1.1 for Participants With LGG (Phase I and II) [From first occurrence of objective response to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)]

      Tumor assessment was performed using RECIST v1.1 criteria for participants with LGG. While the data for LGG in the phase II cohort is presented separately in other parts of the record, it was also considered useful to combine the data for LGG from phase I and phase II, which was done here.

    3. DOR as Determined by the Investigator RANO Criteria for Participants With LGG (Phase II) [From first occurrence of objective response to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)]

      Tumor assessment was performed using RANO criteria for Participants with LGG.

    4. Overall Survival (OS) for Participants With Neuroblastoma (Phase I) [Baseline until death due to any cause (up to 5 years, 2 months)]

      OS was defined as the time from initiation of study drug to death from any cause.

    5. OS for Participants With High-Grade Glioma (HGG) (Phase I) and Low-Grade Glioma (LGG) (Phase I and II) [Baseline until death due to any cause (up to 5 years, 2 months)]

      OS was defined as the time from initiation of study drug to death from any cause. While the data for LGG in the phase II cohort is presented separately in other parts of the record, it was also considered useful to combine the data for LGG from phase I and phase II, which was done here.

    6. OS for Participants With All Other Tumours (Phase I) [Baseline until death due to any cause (up to 5 years, 2 months)]

      OS was defined as the time from initiation of study drug to death from any cause.

    7. Maximum Plasma Concentration Observed (Cmax) of Cobimetinib [Pre-dose, 2, 4, 6, and 24 hours post-dose on Cycle 1 Days 1 and 21 (predose=within 4 hours prior to dose; cycle length=28 days)]

      Plasma samples for determination of Cobimetinib concentration were collected prior to dosing and at 2, 4, 6 and 24 hours after dosing on Days 1 and 21 of Cycle 1. The sampling will allow determination of Cmax.

    8. Time to Cmax (Tmax) of Cobimetinib [Pre-dose, 2, 4, 6, and 24 hours post-dose on Cycle 1 Days 1 and 21 (pre-dose=within 4 hours prior to dose; cycle length=28 days)]

      Plasma samples for determination of Cobimetinib concentration were collected prior to dosing and at 2, 4, 6 and 24 hours after dosing on Days 1 and 21 of Cycle 1. The sampling will allow determination of Tmax.

    9. Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of Cobimetinib [Pre-dose, 2, 4, 6, and 24 hours post-dose on Cycle 1 Days 1 and 21 (pre-dose=within 4 hours prior to dose; cycle length=28 days)]

      Plasma samples for determination of Cobimetinib concentration were collected prior to dosing and at 2, 4, 6 and 24 hours after dosing on Days 1 and 21 of Cycle 1. The sampling will allow determination of AUC0-24.

    10. Apparent Clearance (CL/F) of Cobimetinib [Pre-dose, 2, 4, 6, and 24 hours post-dose on Cycle 1 Days 1 and 21; pre-dose on Cycle 2 Day 1 (pre-dose=within 4 hours prior to dose; cycle length=28 days)]

      Plasma samples for determination of Cobimetinib concentration were collected prior to dosing and at 2, 4, 6 and 24 hours after dosing on Days 1 and 21 of Cycle 1, and within 4 hours prior to dosing on Day 1 of Cycle 2.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    6 Months to 30 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • For dose-escalation stage (tablets): age at study entry >= 6 years to < 18 years

    • For dose-escalation stage (suspension): age at study entry >= 6 months to < 18 years. Participants <1 year of age will not be enrolled until >= 6 participants >= 1 year to < 18 years of age have received at least one cycle of therapy with suspension and until safety and pharmacokinetic assessment of these participants have been conducted.

    • For expansion stage: age at study entry to be >= 6 months (>=6 years if suspension is not available) to < 30 years. Participants >= 6 months to < 1 year of age may not be enrolled until >= 6 participants >= 1 year to < 18 years of age have received at least one cycle of therapy with suspension in the dose-escalation phase and until safety and pharmacokinetic assessment of these participants have been conducted.

    • Tumor for which prior treatment has proven to be ineffective or intolerable or for which no standard therapy exists

    • Tumor with known or expected RAS/RAF/MEK/ERK pathway involvement. Diagnosis must be one of the following tumor types:

    Central nervous system gliomas, including high- and low-grade gliomas, and diffuse intrinsic pontine glioma (DIPG) Embryonal rhabdomyosarcoma and other non-rhabdomyosarcoma soft tissue sarcomas Neuroblastoma Melanoma Malignant peripheral nerve sheath tumor Rhabdoid tumors, including atypical teratoid/rhabdoid tumor (ATRT) NF1-associated tumor (including plexiform neurofibroma), schwannoma, or RASopathy-associated tumor that in the judgment of the investigator is life threatening, results in severe symptoms (including severe pain), or is in close proximity to vital structures

    • Measurable disease as defined by mINRC, RANO criteria for HGG, RANO criteria for LGG, RECIST v1.1, or evaluable by nuclear medicine techniques, immunocytochemistry, tumor markers, or other reliable measures

    • Availability of tumor tissue at study enrollment

    • Lansky performance status or Karnofsky performance status of >= 50 percent

    • Life expectancy >= 3 months

    • Adequate hematologic, cardiac, and end-organ function

    • Body weight must be >= 20 kilograms (kg) if suspension is not available

    Exclusion Criteria:

    • Pregnant or lactating women

    • Close proximity in time to treatment with high-dose chemotherapy, stem-cell rescue, differentiation therapy, immunotherapy, thoracic or mediastinal radiotherapy, hormonal therapy, biologic therapy, herbal cancer therapy, hematopoietic growth factor, investigational therapy, or St. John's wort according to protocol-defined criteria prior to initiation of study drug

    • Inability to swallow oral medications

    • Impaired gastrointestinal absorption

    • History or evidence of retinal pathology according to protocol-defined criteria, including serous retinopathy

    • History of Grade >= 2 central nervous system (CNS) hemorrhage

    • History of CNS hemorrhage within 28 days of study entry. This criterion may be waived at the investigator's request if the CNS hemorrhage was asymptomatic, with approval of the Medical Monitor

    • Known active infection (excluding fungal infection of the nail beds) within 28 days prior to initiation of study drug that has not completely resolved

    • Major surgical procedure or significant traumatic injury within 4 weeks prior to initiation of study drug, or anticipation of need for major surgical procedure during the course of the study

    • Prior allogenic bone marrow transplantation or prior solid organ transplantation

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Arkansas Children'S Hospital Little Rock Arkansas United States 72202
    2 Arnold Palmer Hosp-Children Orlando Florida United States 32806
    3 Dana Farber Cancer Institute Boston Massachusetts United States 02215
    4 Memorial Sloan Kettering Cancer Center New York New York United States 10065
    5 University of Texas Health Science Center at San Antonio San Antonio Texas United States 78229
    6 Hôpital de la Timone, Oncologie Pédiatrique Marseille France 13385
    7 Institut Curie, Oncologie Pédiatrique Paris France 75231
    8 Institut Gustave Roussy; Service Pediatrique Villejuif France 94805
    9 Universitaetsklinikum Muenster Muenster Germany 48149
    10 Schneider Children's Medical Center Petach-Tikva Israel 49100
    11 Fondazione IRCCS Istituto Nazionale dei Tumori; Struttura Complessa di Pediatria Oncologica Milano Lombardia Italy 20133
    12 Hospital Universitari Vall d'Hebron Barcelona Spain 08035
    13 Hospital Infantil Universitario Nino Jesus Madrid Spain 28009
    14 Hospital Universitari i Politecnic La Fe de Valencia Valencia Spain 46026
    15 Alderhey Childrens Trust Liverpool United Kingdom L12 2AP
    16 Great Ormond Street Hospital; Dept. Of Pediatric Oncology London United Kingdom WC1N 3JH
    17 The Royal Victoria Infirmary; Paediatric and Adolescent Oncology Unit Newcastle Upon Tyne United Kingdom NE1 4LP

    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:
    NCT02639546
    Other Study ID Numbers:
    • GO29665
    • 2014-004685-25
    First Posted:
    Dec 24, 2015
    Last Update Posted:
    Mar 31, 2022
    Last Verified:
    Mar 1, 2022
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Neoplasms

    Study Results

    Participant Flow

    Recruitment Details The study was conducted at 17 centers in 7 countries.
    Pre-assignment Detail A total of 63 participants were screened, of which a total of 56 participants were enrolled. Tumor type was not a determinant of cohort assignment for the phase I portion of the study. The phase II portion of the study was restricted to participants with Low-Grade Glioma.
    Arm/Group Title Phase I (Tablet) Cobimetinib (0.6 mg/kg) Phase I (Tablet) Cobimetinib (0.8 mg/kg) Phase I (Tablet) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (0.6 mg/kg) Phase I (Suspension) Cobimetinib (0.8 mg/kg) Phase I (Suspension) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (1.33 mg/kg) Phase II (Suspension) Cobimetinib (1 mg/kg)
    Arm/Group Description Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 1.33 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Expansion: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.
    Period Title: Overall Study
    STARTED 6 6 6 6 7 8 5 12
    Tumor Type - Neuroblastoma 0 0 1 0 0 0 0 0
    Tumor Type - High-Grade Glioma 3 1 0 0 1 0 0 0
    Tumor Type - Low-Grade Glioma 1 2 4 5 3 2 3 12
    Tumor Type - Dnet In Noonan's Syndrome Tumor With RAS/RAF/MEK/ERK Pathway Activation 0 0 0 0 0 0 1 0
    Tumor Type - Malignant Peripheral Nerve Sheath Tumor 0 0 0 0 1 1 0 0
    Tumor Type - Metastatic Mediastinal Yolksac Tumor With RAS/RAF/MEK/ERK Pathway Activation 1 0 0 0 0 0 0 0
    Tumor Type - Non-Rhabdomyosarcoma Soft Tissue Sarcoma 0 1 0 0 0 0 0 0
    Tumor Type - Plexiform Neurofibroma 1 2 1 1 2 4 1 0
    Tumor Type - Rhabdoid Tumor/ATRT 0 0 0 0 0 1 0 0
    COMPLETED 0 0 0 0 0 0 0 0
    NOT COMPLETED 6 6 6 6 7 8 5 12

    Baseline Characteristics

    Arm/Group Title Phase I (Tablet) Cobimetinib (0.6 mg/kg) Phase I (Tablet) Cobimetinib (0.8 mg/kg) Phase I (Tablet) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (0.6 mg/kg) Phase I (Suspension) Cobimetinib (0.8 mg/kg) Phase I (Suspension) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (1.33 mg/kg) Phase II (Suspension) Cobimetinib (1 mg/kg) Total
    Arm/Group Description Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 1.33 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Expansion: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Total of all reporting groups
    Overall Participants 6 6 6 6 7 8 5 12 56
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    11.8
    (3.5)
    9.5
    (3.3)
    9.5
    (3.4)
    8.5
    (1.4)
    9.7
    (5.3)
    8.9
    (3.1)
    10.2
    (3.3)
    8.7
    (7.5)
    9.5
    (4.6)
    Sex: Female, Male (Count of Participants)
    Female
    1
    16.7%
    2
    33.3%
    4
    66.7%
    2
    33.3%
    0
    0%
    2
    25%
    5
    100%
    7
    58.3%
    23
    41.1%
    Male
    5
    83.3%
    4
    66.7%
    2
    33.3%
    4
    66.7%
    7
    100%
    6
    75%
    0
    0%
    5
    41.7%
    33
    58.9%
    Race/Ethnicity, Customized (Number) [Number]
    Hispanic or Latino
    1
    16.7%
    1
    16.7%
    0
    0%
    1
    16.7%
    2
    28.6%
    1
    12.5%
    1
    20%
    4
    33.3%
    11
    19.6%
    Not Hispanic or Latino
    5
    83.3%
    3
    50%
    4
    66.7%
    1
    16.7%
    2
    28.6%
    4
    50%
    3
    60%
    7
    58.3%
    29
    51.8%
    Not Stated
    0
    0%
    0
    0%
    2
    33.3%
    3
    50%
    1
    14.3%
    2
    25%
    0
    0%
    0
    0%
    8
    14.3%
    Unknown
    0
    0%
    2
    33.3%
    0
    0%
    1
    16.7%
    2
    28.6%
    1
    12.5%
    1
    20%
    1
    8.3%
    8
    14.3%
    Race/Ethnicity, Customized (Number) [Number]
    Asian
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    14.3%
    0
    0%
    0
    0%
    0
    0%
    1
    1.8%
    Black or African American
    0
    0%
    1
    16.7%
    1
    16.7%
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    3
    5.4%
    Unknown
    1
    16.7%
    1
    16.7%
    2
    33.3%
    5
    83.3%
    4
    57.1%
    3
    37.5%
    1
    20%
    1
    8.3%
    18
    32.1%
    White
    5
    83.3%
    4
    66.7%
    3
    50%
    0
    0%
    2
    28.6%
    5
    62.5%
    4
    80%
    11
    91.7%
    34
    60.7%
    Tumor Type (Count of Participants)
    Neuroblastoma
    0
    0%
    0
    0%
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.8%
    High-Grade Glioma
    3
    50%
    1
    16.7%
    0
    0%
    0
    0%
    1
    14.3%
    0
    0%
    0
    0%
    0
    0%
    5
    8.9%
    Low-Grade Glioma
    1
    16.7%
    2
    33.3%
    4
    66.7%
    5
    83.3%
    3
    42.9%
    2
    25%
    3
    60%
    12
    100%
    32
    57.1%
    Dnet In Noonan's Syndrome Tumor With RAS/RAF/MEK/ERK Pathway Activation
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    20%
    0
    0%
    1
    1.8%
    Malignant Peripheral Nerve Sheath Tumor
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    14.3%
    1
    12.5%
    0
    0%
    0
    0%
    2
    3.6%
    Metastatic Mediastinal Yolksac Tumor With RAS/RAF/MEK/ERK Pathway Activation
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.8%
    Non-Rhabdomyosarcoma Soft Tissue Sarcoma
    0
    0%
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.8%
    Plexiform Neurofibroma
    1
    16.7%
    2
    33.3%
    1
    16.7%
    1
    16.7%
    2
    28.6%
    4
    50%
    1
    20%
    0
    0%
    12
    21.4%
    Rhabdoid Tumor/ATRT
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    12.5%
    0
    0%
    0
    0%
    1
    1.8%

    Outcome Measures

    1. Primary Outcome
    Title Percentage of Participants With Dose-Limiting Toxicities (DLTs)
    Description Dose-Limiting Toxicities (DLTs) were defined as cobimetinib-related adverse events occurring within the first 28 days of each administration of cobimetinib.
    Time Frame Baseline up until 30 days after the last dose of study drug (up to 5 years, 2 months)

    Outcome Measure Data

    Analysis Population Description
    The safety evaluable population was defined as all participants who received at least one dose of study drug.
    Arm/Group Title Phase I (Tablet) Cobimetinib (0.6 mg/kg) Phase I (Tablet) Cobimetinib (0.8 mg/kg) Phase I (Tablet) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (0.6 mg/kg) Phase I (Suspension) Cobimetinib (0.8 mg/kg) Phase I (Suspension) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (1.33 mg/kg) Phase II (Suspension) Cobimetinib (1 mg/kg)
    Arm/Group Description Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 1.33 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Expansion: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.
    Measure Participants 6 6 6 6 7 8 5 12
    Number [Percentage of Participants]
    0
    0%
    0
    0%
    33.3
    555%
    16.7
    278.3%
    0
    0%
    0
    0%
    60.0
    1200%
    0
    0%
    2. Primary Outcome
    Title Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs)
    Description An AE 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 AE can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), 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 AEs.
    Time Frame Baseline up until 30 days after the last dose of study drug (up to 5 years, 2 months)

    Outcome Measure Data

    Analysis Population Description
    The safety evaluable population was defined as all participants who received at least one dose of study drug.
    Arm/Group Title Phase I (Tablet) Cobimetinib (0.6 mg/kg) Phase I (Tablet) Cobimetinib (0.8 mg/kg) Phase I (Tablet) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (0.6 mg/kg) Phase I (Suspension) Cobimetinib (0.8 mg/kg) Phase I (Suspension) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (1.33 mg/kg) Phase II (Suspension) Cobimetinib (1 mg/kg)
    Arm/Group Description Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 1.33 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Expansion: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.
    Measure Participants 6 6 6 6 7 8 5 12
    AEs
    100.0
    1666.7%
    100.0
    1666.7%
    100.0
    1666.7%
    100.0
    1666.7%
    100.0
    1428.6%
    100.0
    1250%
    100.0
    2000%
    100.0
    833.3%
    SAEs
    33.3
    555%
    33.3
    555%
    33.3
    555%
    33.3
    555%
    14.3
    204.3%
    25.0
    312.5%
    40.0
    800%
    41.7
    347.5%
    AESIs
    33.3
    555%
    33.3
    555%
    33.3
    555%
    50.0
    833.3%
    42.9
    612.9%
    25.0
    312.5%
    100.0
    2000%
    58.3
    485.8%
    3. Primary Outcome
    Title Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of Cobimetinib
    Description A prior dose level was defined as an MTD/MAD if at a certain dose level, there were greater than or equal to (>=) 2 out of 6 participants who had Dose Limiting Toxicities (DLTs).
    Time Frame Cycle 1 Day 1 up to Cycle 1 Day 28 (cycle length=28 days)

    Outcome Measure Data

    Analysis Population Description
    The safety evaluable population was defined as all participants who received at least one dose of study drug.
    Arm/Group Title Cobimetinib (Tablet) Population Cobimetinib (Suspension) Population
    Arm/Group Description Participants received Cobimetinib (Tablet) formulation Participants received Cobimetinib (Suspension) formulation
    Measure Participants 18 38
    Number [mg/kg]
    0.8
    1
    4. Primary Outcome
    Title Percentage of Participants With Objective Response (Complete Response (CR) or Partial Response (PR)) as Determined by the Investigator Using Modified International Neuroblastoma Response Criteria (mINRC) for Participants With Neuroblastoma (Phase I)
    Description Tumor assessment was performed using mINRC for Participants with Neuroblastoma.
    Time Frame Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)

    Outcome Measure Data

    Analysis Population Description
    The safety evaluable population was defined as all participants who received at least one dose of study drug. Participants enrolled into phase I (Dose-Escalation) cohorts independent of their tumor type. As the same criteria were not used to assess response in all tumor types, the efficacy analyses were broken down by tumor type.
    Arm/Group Title Neuroblastoma
    Arm/Group Description Participants with Neuroblastoma.
    Measure Participants 1
    Number [Percentage of Participants]
    0
    0%
    5. Primary Outcome
    Title Percentage of Participants With Objective Response (CR or PR) as Determined by the Investigator Using RANO Criteria for Participants With High-Grade Glioma (HGG) (Phase I) and RECIST v1.1 for Participants With Low-Grade Glioma (LGG) (Phase I and II)
    Description Tumor assessment was performed using Response Assessment in Neuro-Oncology (RANO) criteria for participants with HGG and Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) for participants with LGG. While the data for LGG in the phase II cohort is presented separately in other parts of the record, it was also considered useful to combine the data for LGG from phase I and phase II, which was done here.
    Time Frame Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)

    Outcome Measure Data

    Analysis Population Description
    The safety evaluable population was defined as all participants who received at least one dose of study drug. Participants enrolled into phase I (Dose-Escalation) cohorts independent of their tumor type. For phase II, only one tumor type cohort was opened (LGG). As the same criteria were not used to assess response in all tumor types, the efficacy analyses were broken down by tumor type.
    Arm/Group Title High Grade Glioma Low Grade Glioma
    Arm/Group Description Participants with High Grade Glioma. Participants with Low Grade Glioma.
    Measure Participants 5 32
    Number [Percentage of Participants]
    0
    0%
    9.4
    156.7%
    6. Primary Outcome
    Title Percentage of Participants With Objective Response (CR or PR) as Determined by the Investigator Using RECIST v1.1 Criteria for Participants With All Other Tumours (Phase I)
    Description Tumor assessment was performed using RECIST v1.1 for Participants with All Other Tumours.
    Time Frame Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)

    Outcome Measure Data

    Analysis Population Description
    The safety evaluable population was defined as all participants who received at least one dose of study drug. Participants enrolled into phase I (Dose-Escalation) cohorts independent of their tumor type. As the same criteria were not used to assess response in all tumor types, the efficacy analyses were broken down by tumor type.
    Arm/Group Title Dnet In Noonan's Syndrome Tumor With RAS/RAF/MEK/ERK Pathway Activation Malignant Peripheral Nerve Sheath Tumor Metastatic Mediastinal Yolksac Tumor With RAS/RAF/MEK/ERK Pathway Activation Non-Rhabdomyosarcoma Soft Tissue Sarcoma Plexiform Neurofibroma Rhabdoid Tumor/ATRT
    Arm/Group Description Participants with Dnet In Noonan's Syndrome Tumor With RAS/RAF/MEK/ERK Pathway Activation. Participants with Malignant Peripheral Nerve Sheath Tumor. Participants with Metastatic Mediastinal Yolksac Tumor With RAS/RAF/MEK/ERK Pathway Activation. Participants with Non-Rhabdomyosarcoma Soft Tissue Sarcoma. Participants with Plexiform Neurofibroma. Participants with Rhabdoid Tumor/ATRT.
    Measure Participants 1 2 1 1 12 1
    Number [Percentage of Participants]
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    7. Primary Outcome
    Title Percentage of Participants With Objective Response (CR or PR) as Determined by the Investigator Using RANO Criteria for Participants With LGG (Phase II)
    Description Tumor assessment will be performed using RANO criteria for LGG.
    Time Frame Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)

    Outcome Measure Data

    Analysis Population Description
    The safety evaluable population was defined as all participants who received at least one dose of study drug. For phase II, only one tumor type cohort was opened (LGG).
    Arm/Group Title Low Grade Glioma
    Arm/Group Description Participants with Low Grade Glioma.
    Measure Participants 12
    Number [Percentage of Participants]
    8.3
    138.3%
    8. Primary Outcome
    Title Progression-Free Survival (PFS) as Determined by the Investigator Using mINRC for Participants With Neuroblastoma (Phase I)
    Description Tumor assessment was performed using mINRC for Participants with Neuroblastoma.
    Time Frame From the time of cobimetinib study drug initiation to the first documented disease progression, or death due to any cause, whichever occurs first (up to 5 years, 2 months)

    Outcome Measure Data

    Analysis Population Description
    The safety evaluable population was defined as all participants who received at least one dose of study drug. Participants enrolled into phase I (Dose-Escalation) cohorts independent of their tumor type. As the same criteria were not used to assess response in all tumor types, the efficacy analyses were broken down by tumor type.
    Arm/Group Title Neuroblastoma
    Arm/Group Description Participants with Neuroblastoma.
    Measure Participants 1
    Median (95% Confidence Interval) [Months]
    1.3
    9. Primary Outcome
    Title PFS as Determined by the Investigator Using RANO Criteria for Participants With HGG (Phase I) and RECIST v1.1 for Partcipants With LGG (Phase I and II)
    Description Tumor assessment was performed using RANO for participants with HGG and RECIST v1.1 for participants with LGG. While the data for LGG in the phase II cohort is presented separately in other parts of the record, it was also considered useful to combine the data for LGG from phase I and phase II, which was done here.
    Time Frame From the time of cobimetinib study drug initiation to the first documented disease progression, or death due to any cause, whichever occurs first (up to 5 years, 2 months)

    Outcome Measure Data

    Analysis Population Description
    The safety evaluable population was defined as all participants who received at least one dose of study drug. Participants enrolled into phase I (Dose-Escalation) cohorts independent of their tumor type. For phase II, only one tumor type cohort was opened (LGG). As the same criteria were not used to assess response in all tumor types, the efficacy analyses were broken down by tumor type.
    Arm/Group Title High Grade Glioma Low Grade Glioma
    Arm/Group Description Participants with High Grade Glioma. Participants with Low Grade Glioma.
    Measure Participants 5 32
    Median (95% Confidence Interval) [Months]
    1.0
    22.0
    10. Primary Outcome
    Title PFS as Determined by the Investigator Using RECIST v1.1 Criteria for Participants With All Other Tumours (Phase I)
    Description Tumor assessment was performed using RECIST v1.1 for Participants with All Other Tumours.
    Time Frame From the time of cobimetinib study drug initiation to the first documented disease progression, or death due to any cause, whichever occurs first (up to 5 years, 2 months)

    Outcome Measure Data

    Analysis Population Description
    The safety evaluable population was defined as all participants who received at least one dose of study drug. Participants enrolled into phase I (Dose-Escalation) cohorts independent of their tumor type. As the same criteria were not used to assess response in all tumor types, the efficacy analyses were broken down by tumor type.
    Arm/Group Title Dnet In Noonan's Syndrome Tumor With RAS/RAF/MEK/ERK Pathway Activation Malignant Peripheral Nerve Sheath Tumor Metastatic Mediastinal Yolksac Tumor With RAS/RAF/MEK/ERK Pathway Activation Non-Rhabdomyosarcoma Soft Tissue Sarcoma Plexiform Neurofibroma Rhabdoid Tumor/ATRT
    Arm/Group Description Participants with Dnet In Noonan's Syndrome Tumor With RAS/RAF/MEK/ERK Pathway Activation. Participants with Malignant Peripheral Nerve Sheath Tumor. Participants with Metastatic Mediastinal Yolksac Tumor With RAS/RAF/MEK/ERK Pathway Activation. Participants with Non-Rhabdomyosarcoma Soft Tissue Sarcoma. Participants with Plexiform Neurofibroma. Participants with Rhabdoid Tumor/ATRT.
    Measure Participants 1 2 1 1 12 1
    Median (95% Confidence Interval) [Months]
    NA
    4.1
    1.1
    3.4
    NA
    0.5
    11. Primary Outcome
    Title PFS as Determined by the Investigator Using RANO Criteria for Participants With LGG (Phase II)
    Description Tumor assessment was performed using RANO criteria for Participants with LGG.
    Time Frame From the time of cobimetinib study drug initiation to the first documented disease progression, or death due to any cause, whichever occurs first (up to 5 years, 2 months)

    Outcome Measure Data

    Analysis Population Description
    The safety evaluable population was defined as all participants who received at least one dose of study drug. For phase II, only one tumor type cohort was opened (LGG).
    Arm/Group Title Low Grade Glioma
    Arm/Group Description Participants with Low Grade Glioma.
    Measure Participants 12
    Median (95% Confidence Interval) [Months]
    18.4
    12. Secondary Outcome
    Title Recommended Phase II Dose (RP2D) of Cobimetinib
    Description A prior dose level was defined as an RP2D if at a certain dose level, there were greater than or equal to (≥) 2 out of 6 participants who had Dose Limiting Toxicities (DLTs).
    Time Frame Cycle 1 Day 1 up to Cycle 1 Day 28 (cycle length=28 days)

    Outcome Measure Data

    Analysis Population Description
    The safety evaluable population was defined as all participants who received at least one dose of study drug.
    Arm/Group Title Cobimetinib (Suspension) Population
    Arm/Group Description Participants received Cobimetinib (Suspension) formulation
    Measure Participants 38
    Number [mg/kg]
    1
    13. Secondary Outcome
    Title Duration of Response (DOR) as Determined by the Investigator Using RECIST v1.1 for Participants With LGG (Phase I and II)
    Description Tumor assessment was performed using RECIST v1.1 criteria for participants with LGG. While the data for LGG in the phase II cohort is presented separately in other parts of the record, it was also considered useful to combine the data for LGG from phase I and phase II, which was done here.
    Time Frame From first occurrence of objective response to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)

    Outcome Measure Data

    Analysis Population Description
    The safety evaluable population was defined as all participants who received at least one dose of study drug. Participants enrolled into phase I (Dose-Escalation) cohorts independent of their tumor type. For phase II, only one tumor type cohort was opened (LGG). As the same criteria were not used to assess response in all tumor types, the efficacy analyses were broken down by tumor type.
    Arm/Group Title Low Grade Glioma
    Arm/Group Description Participants with Low Grade Glioma
    Measure Participants 3
    Median (95% Confidence Interval) [Months]
    NA
    14. Secondary Outcome
    Title DOR as Determined by the Investigator RANO Criteria for Participants With LGG (Phase II)
    Description Tumor assessment was performed using RANO criteria for Participants with LGG.
    Time Frame From first occurrence of objective response to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)

    Outcome Measure Data

    Analysis Population Description
    The safety evaluable population was defined as all participants who received at least one dose of study drug. For phase II, only one tumor type cohort was opened (LGG).
    Arm/Group Title Low Grade Glioma
    Arm/Group Description Participants with Low Grade Glioma
    Measure Participants 1
    Median (95% Confidence Interval) [Months]
    NA
    15. Secondary Outcome
    Title Overall Survival (OS) for Participants With Neuroblastoma (Phase I)
    Description OS was defined as the time from initiation of study drug to death from any cause.
    Time Frame Baseline until death due to any cause (up to 5 years, 2 months)

    Outcome Measure Data

    Analysis Population Description
    The safety evaluable population was defined as all participants who received at least one dose of study drug. Participants enrolled into phase I (Dose-Escalation) cohorts independent of their tumor type. As the same criteria were not used to assess response in all tumor types, the efficacy analyses were broken down by tumor type.
    Arm/Group Title Neuroblastoma
    Arm/Group Description Participants with Neuroblastoma.
    Measure Participants 1
    Median (95% Confidence Interval) [Months]
    4.6
    16. Secondary Outcome
    Title OS for Participants With High-Grade Glioma (HGG) (Phase I) and Low-Grade Glioma (LGG) (Phase I and II)
    Description OS was defined as the time from initiation of study drug to death from any cause. While the data for LGG in the phase II cohort is presented separately in other parts of the record, it was also considered useful to combine the data for LGG from phase I and phase II, which was done here.
    Time Frame Baseline until death due to any cause (up to 5 years, 2 months)

    Outcome Measure Data

    Analysis Population Description
    The safety evaluable population was defined as all participants who received at least one dose of study drug. Participants enrolled into phase I (Dose-Escalation) cohorts independent of their tumor type. For phase II, only one tumor type cohort was opened (LGG). As the same criteria were not used to assess response in all tumor types, the efficacy analyses were broken down by tumor type.
    Arm/Group Title High Grade Glioma Low Grade Glioma
    Arm/Group Description Participants with High Grade Glioma. Participants with Low Grade Glioma.
    Measure Participants 5 32
    Median (95% Confidence Interval) [Months]
    1.4
    NA
    17. Secondary Outcome
    Title OS for Participants With All Other Tumours (Phase I)
    Description OS was defined as the time from initiation of study drug to death from any cause.
    Time Frame Baseline until death due to any cause (up to 5 years, 2 months)

    Outcome Measure Data

    Analysis Population Description
    The safety evaluable population was defined as all participants who received at least one dose of study drug. Participants enrolled into phase I (Dose-Escalation) cohorts independent of their tumor type. As the same criteria were not used to assess response in all tumor types, the efficacy analyses were broken down by tumor type.
    Arm/Group Title Dnet In Noonan's Syndrome Tumor With RAS/RAF/MEK/ERK Pathway Activation Malignant Peripheral Nerve Sheath Tumor Metastatic Mediastinal Yolksac Tumor With RAS/RAF/MEK/ERK Pathway Activation Non-Rhabdomyosarcoma Soft Tissue Sarcoma Plexiform Neurofibroma Rhabdoid Tumor/ATRT
    Arm/Group Description Participants with Dnet In Noonan's Syndrome Tumor With RAS/RAF/MEK/ERK Pathway Activation. Participants with Malignant Peripheral Nerve Sheath Tumor. Participants with Metastatic Mediastinal Yolksac Tumor With RAS/RAF/MEK/ERK Pathway Activation. Participants with Non-Rhabdomyosarcoma Soft Tissue Sarcoma. Participants with Plexiform Neurofibroma. Participants with Rhabdoid Tumor/ATRT.
    Measure Participants 1 2 1 1 12 1
    Median (95% Confidence Interval) [Months]
    NA
    5.5
    1.1
    6.3
    NA
    5.1
    18. Secondary Outcome
    Title Maximum Plasma Concentration Observed (Cmax) of Cobimetinib
    Description Plasma samples for determination of Cobimetinib concentration were collected prior to dosing and at 2, 4, 6 and 24 hours after dosing on Days 1 and 21 of Cycle 1. The sampling will allow determination of Cmax.
    Time Frame Pre-dose, 2, 4, 6, and 24 hours post-dose on Cycle 1 Days 1 and 21 (predose=within 4 hours prior to dose; cycle length=28 days)

    Outcome Measure Data

    Analysis Population Description
    The PK population was defined as all participants who received at least 1 dose of Cobimetinib and had evaluable PK data. Only participants for whom data were collected are included in the analysis.
    Arm/Group Title Phase I (Tablet) Cobimetinib (0.6 mg/kg) Phase I (Tablet) Cobimetinib (0.8 mg/kg) Phase I (Tablet) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (0.6 mg/kg) Phase I (Suspension) Cobimetinib (0.8 mg/kg) Phase I (Suspension) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (1.33 mg/kg) Phase II (Suspension) Cobimetinib (1 mg/kg)
    Arm/Group Description Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 1.33 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Expansion: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.
    Measure Participants 6 6 6 6 7 8 5 12
    Cycle 1 Day 1
    62.0
    (82.3)
    88.3
    (102)
    144
    (58.6)
    51.5
    (73.4)
    67.4
    (165)
    136
    (80.3)
    111
    (37.0)
    44.0
    (69.8)
    Cycle 1 Day 21
    51.1
    (74.0)
    181
    (134)
    193
    (35.0)
    105
    (84.5)
    156
    (91.2)
    179
    (113)
    172
    (60.3)
    116
    (42)
    19. Secondary Outcome
    Title Time to Cmax (Tmax) of Cobimetinib
    Description Plasma samples for determination of Cobimetinib concentration were collected prior to dosing and at 2, 4, 6 and 24 hours after dosing on Days 1 and 21 of Cycle 1. The sampling will allow determination of Tmax.
    Time Frame Pre-dose, 2, 4, 6, and 24 hours post-dose on Cycle 1 Days 1 and 21 (pre-dose=within 4 hours prior to dose; cycle length=28 days)

    Outcome Measure Data

    Analysis Population Description
    The PK population was defined as all participants who received at least 1 dose of Cobimetinib and had evaluable PK data. Only participants for whom data were collected are included in the analysis.
    Arm/Group Title Phase I (Tablet) Cobimetinib (0.6 mg/kg) Phase I (Tablet) Cobimetinib (0.8 mg/kg) Phase I (Tablet) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (0.6 mg/kg) Phase I (Suspension) Cobimetinib (0.8 mg/kg) Phase I (Suspension) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (1.33 mg/kg) Phase II (Suspension) Cobimetinib (1 mg/kg)
    Arm/Group Description Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 1.33 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Expansion: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.
    Measure Participants 6 6 6 6 7 8 5 12
    Cycle 1 Day 1
    4
    2
    3
    4
    4
    2
    5
    4
    Cycle 1 Day 21
    4
    4
    2
    4
    2
    3
    4
    2
    20. Secondary Outcome
    Title Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of Cobimetinib
    Description Plasma samples for determination of Cobimetinib concentration were collected prior to dosing and at 2, 4, 6 and 24 hours after dosing on Days 1 and 21 of Cycle 1. The sampling will allow determination of AUC0-24.
    Time Frame Pre-dose, 2, 4, 6, and 24 hours post-dose on Cycle 1 Days 1 and 21 (pre-dose=within 4 hours prior to dose; cycle length=28 days)

    Outcome Measure Data

    Analysis Population Description
    The PK population was defined as all participants who received at least 1 dose of Cobimetinib and had evaluable PK data. Only participants for whom data were collected are included in the analysis.
    Arm/Group Title Phase I (Tablet) Cobimetinib (0.6 mg/kg) Phase I (Tablet) Cobimetinib (0.8 mg/kg) Phase I (Tablet) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (0.6 mg/kg) Phase I (Suspension) Cobimetinib (0.8 mg/kg) Phase I (Suspension) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (1.33 mg/kg) Phase II (Suspension) Cobimetinib (1 mg/kg)
    Arm/Group Description Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 1.33 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Expansion: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.
    Measure Participants 6 6 6 6 7 8 5 12
    Cycle 1 Day 1
    865
    (83.0)
    1006
    (100)
    1432
    (50.0)
    743
    (67.4)
    1111
    (144)
    1627
    (74.0)
    1567
    (33.1)
    589
    (79.5)
    Cycle 1 Day 21
    836
    (83.5)
    2802
    (111)
    2382
    (38.4)
    1624
    (80.4)
    1805
    (109)
    2562
    (104)
    2511
    (104)
    1402
    (59)
    21. Secondary Outcome
    Title Apparent Clearance (CL/F) of Cobimetinib
    Description Plasma samples for determination of Cobimetinib concentration were collected prior to dosing and at 2, 4, 6 and 24 hours after dosing on Days 1 and 21 of Cycle 1, and within 4 hours prior to dosing on Day 1 of Cycle 2.
    Time Frame Pre-dose, 2, 4, 6, and 24 hours post-dose on Cycle 1 Days 1 and 21; pre-dose on Cycle 2 Day 1 (pre-dose=within 4 hours prior to dose; cycle length=28 days)

    Outcome Measure Data

    Analysis Population Description
    Please note that for this Outcome Measure, the Apparent Clearance of Cobimetinib could not be calculated/estimated as PK samples were collected only up to 24hr post dosing.
    Arm/Group Title Phase I (Tablet) Cobimetinib (0.6 mg/kg) Phase I (Tablet) Cobimetinib (0.8 mg/kg) Phase I (Tablet) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (0.6 mg/kg) Phase I (Suspension) Cobimetinib (0.8 mg/kg) Phase I (Suspension) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (1.33 mg/kg) Phase II (Suspension) Cobimetinib (1 mg/kg)
    Arm/Group Description Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 1.33 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Expansion: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.
    Measure Participants 6 6 6 6 7 8 5 12
    Geometric Mean (Geometric Coefficient of Variation) [L/hr]
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)

    Adverse Events

    Time Frame Baseline up until 30 days after the last dose of study drug (up to 5 years, 2 months)
    Adverse Event Reporting Description
    Arm/Group Title Phase I (Tablet) Cobimetinib (0.6 mg/kg) Phase I (Tablet) Cobimetinib (0.8 mg/kg) Phase I (Tablet) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (0.6 mg/kg) Phase I (Suspension) Cobimetinib (0.8 mg/kg) Phase I (Suspension) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (1.33 mg/kg) Phase II (Suspension) Cobimetinib (1 mg/kg)
    Arm/Group Description Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Escalation: Participants received 1.33 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. Dose-Expansion: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.
    All Cause Mortality
    Phase I (Tablet) Cobimetinib (0.6 mg/kg) Phase I (Tablet) Cobimetinib (0.8 mg/kg) Phase I (Tablet) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (0.6 mg/kg) Phase I (Suspension) Cobimetinib (0.8 mg/kg) Phase I (Suspension) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (1.33 mg/kg) Phase II (Suspension) Cobimetinib (1 mg/kg)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events 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 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/5 (0%) 0/12 (0%)
    Serious Adverse Events
    Phase I (Tablet) Cobimetinib (0.6 mg/kg) Phase I (Tablet) Cobimetinib (0.8 mg/kg) Phase I (Tablet) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (0.6 mg/kg) Phase I (Suspension) Cobimetinib (0.8 mg/kg) Phase I (Suspension) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (1.33 mg/kg) Phase II (Suspension) Cobimetinib (1 mg/kg)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events 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 2/6 (33.3%) 2/6 (33.3%) 2/6 (33.3%) 2/6 (33.3%) 1/7 (14.3%) 2/8 (25%) 2/5 (40%) 5/12 (41.7%)
    Cardiac disorders
    Cardiac ventricular thrombosis 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Pericardial effusion 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Eye disorders
    Chorioretinopathy 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/12 (0%) 0
    Gastrointestinal disorders
    Abdominal pain 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/12 (0%) 0
    Vomiting 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    General disorders
    Pyrexia 0/6 (0%) 0 1/6 (16.7%) 2 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/12 (0%) 0
    Infections and infestations
    Catheter site infection 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/12 (0%) 0
    Gastroenteritis 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Infection 0/6 (0%) 0 1/6 (16.7%) 2 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Paronychia 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/12 (0%) 0
    Pneumonia 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/12 (0%) 0
    Skin infection 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/12 (0%) 0
    Upper respiratory tract infection 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Vascular device infection 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/12 (0%) 0
    Injury, poisoning and procedural complications
    Femoral neck fracture 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Investigations
    Blood creatine phosphokinase increased 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Musculoskeletal and connective tissue disorders
    Pain in extremity 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/12 (0%) 0
    Nervous system disorders
    Encephalopathy 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Headache 1/6 (16.7%) 2 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Hydrocephalus 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Neuralgia 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/12 (0%) 0
    Seizure 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Somnolence 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Other (Not Including Serious) Adverse Events
    Phase I (Tablet) Cobimetinib (0.6 mg/kg) Phase I (Tablet) Cobimetinib (0.8 mg/kg) Phase I (Tablet) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (0.6 mg/kg) Phase I (Suspension) Cobimetinib (0.8 mg/kg) Phase I (Suspension) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (1.33 mg/kg) Phase II (Suspension) Cobimetinib (1 mg/kg)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events 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 6/6 (100%) 6/6 (100%) 6/6 (100%) 6/6 (100%) 7/7 (100%) 8/8 (100%) 5/5 (100%) 12/12 (100%)
    Blood and lymphatic system disorders
    Anaemia 0/6 (0%) 0 2/6 (33.3%) 7 0/6 (0%) 0 1/6 (16.7%) 3 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 3/12 (25%) 6
    Leukopenia 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Lymphadenopathy 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Thrombocytopenia 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Cardiac disorders
    Sinus tachycardia 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 2 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Congenital, familial and genetic disorders
    Iris hamartoma 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 1/6 (16.7%) 1 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Ear and labyrinth disorders
    Ear pain 0/6 (0%) 0 1/6 (16.7%) 1 1/6 (16.7%) 1 1/6 (16.7%) 1 0/7 (0%) 0 2/8 (25%) 3 0/5 (0%) 0 2/12 (16.7%) 2
    Endocrine disorders
    Precocious puberty 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Eye disorders
    Chorioretinopathy 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/12 (0%) 0
    Conjunctivitis allergic 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/12 (0%) 0
    Corneal neovascularisation 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Detachment of retinal pigment epithelium 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/12 (0%) 0
    Dry eye 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/12 (0%) 0
    Eye disorder 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/12 (0%) 0
    Eye pain 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/12 (0%) 0
    Eyelid ptosis 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/12 (0%) 0
    Eyelid skin dryness 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Miosis 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/12 (0%) 0
    Ocular hyperaemia 1/6 (16.7%) 2 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Ocular hypertension 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Optic atrophy 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Optic disc disorder 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Punctate keratitis 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 1/12 (8.3%) 1
    Retinal detachment 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Retinal disorder 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Serous retinal detachment 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 2 0/12 (0%) 0
    Vision blurred 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Visual acuity reduced transiently 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Visual field defect 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Visual impairment 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Gastrointestinal disorders
    Abdominal distension 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Abdominal pain 2/6 (33.3%) 2 3/6 (50%) 3 2/6 (33.3%) 2 1/6 (16.7%) 1 2/7 (28.6%) 2 1/8 (12.5%) 1 2/5 (40%) 2 3/12 (25%) 7
    Abdominal pain upper 0/6 (0%) 0 1/6 (16.7%) 1 1/6 (16.7%) 1 0/6 (0%) 0 1/7 (14.3%) 1 0/8 (0%) 0 1/5 (20%) 4 1/12 (8.3%) 2
    Anal haemorrhage 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Anorectal discomfort 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Aphthous ulcer 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Constipation 3/6 (50%) 3 2/6 (33.3%) 3 3/6 (50%) 5 0/6 (0%) 0 0/7 (0%) 0 2/8 (25%) 3 1/5 (20%) 1 3/12 (25%) 3
    Dental caries 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Diarrhoea 3/6 (50%) 5 4/6 (66.7%) 17 5/6 (83.3%) 8 4/6 (66.7%) 6 2/7 (28.6%) 3 4/8 (50%) 6 4/5 (80%) 10 4/12 (33.3%) 11
    Dry mouth 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Dyspepsia 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Dysphagia 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/12 (0%) 0
    Faeces hard 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Gastritis 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/12 (0%) 0
    Gastrooesophageal reflux disease 1/6 (16.7%) 1 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Glossodynia 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 2 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Haematochezia 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Lip haemorrhage 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Lip ulceration 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Mouth ulceration 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/12 (0%) 0
    Nausea 2/6 (33.3%) 2 1/6 (16.7%) 1 3/6 (50%) 3 0/6 (0%) 0 2/7 (28.6%) 7 3/8 (37.5%) 5 0/5 (0%) 0 2/12 (16.7%) 2
    Oesophagitis 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/12 (0%) 0
    Proctalgia 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Stomatitis 1/6 (16.7%) 2 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/8 (0%) 0 1/5 (20%) 1 0/12 (0%) 0
    Tongue ulceration 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 2 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Tooth impacted 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Toothache 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Vomiting 1/6 (16.7%) 1 2/6 (33.3%) 4 4/6 (66.7%) 9 2/6 (33.3%) 2 2/7 (28.6%) 9 4/8 (50%) 7 2/5 (40%) 2 7/12 (58.3%) 14
    General disorders
    Asthenia 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 2
    Chest pain 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 2 0/5 (0%) 0 0/12 (0%) 0
    Extravasation 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/12 (0%) 0
    Fatigue 2/6 (33.3%) 2 2/6 (33.3%) 2 3/6 (50%) 5 2/6 (33.3%) 2 2/7 (28.6%) 3 3/8 (37.5%) 3 1/5 (20%) 1 2/12 (16.7%) 2
    Gait disturbance 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Inflammation 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/12 (0%) 0
    Localised oedema 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/12 (0%) 0
    Malaise 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/12 (0%) 0
    Mucosal inflammation 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/12 (0%) 0
    Nodule 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Oedema peripheral 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Pyrexia 2/6 (33.3%) 2 1/6 (16.7%) 2 1/6 (16.7%) 3 1/6 (16.7%) 1 1/7 (14.3%) 1 2/8 (25%) 2 2/5 (40%) 3 3/12 (25%) 5
    Xerosis 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Immune system disorders
    Hypersensitivity 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Infections and infestations
    Anorectal infection 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Bronchitis 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    COVID-19 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Catheter site infection 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 1/12 (8.3%) 1
    Conjunctivitis 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/12 (0%) 0
    Ear infection 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 1/8 (12.5%) 1 0/5 (0%) 0 0/12 (0%) 0
    Folliculitis 1/6 (16.7%) 2 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 1/7 (14.3%) 1 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Fungal skin infection 1/6 (16.7%) 1 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    H1N1 influenza 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Hand-foot-and-mouth disease 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/12 (0%) 0
    Hordeolum 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Impetigo 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 2 0/5 (0%) 0 0/12 (0%) 0
    Influenza 1/6 (16.7%) 1 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 1/12 (8.3%) 1
    Localised infection 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Nail infection 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Nasopharyngitis 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 1/7 (14.3%) 1 0/8 (0%) 0 0/5 (0%) 0 2/12 (16.7%) 2
    Oral candidiasis 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Oral herpes 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/12 (0%) 0
    Otitis media 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/12 (0%) 0
    Paronychia 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 2/6 (33.3%) 2 1/7 (14.3%) 1 1/8 (12.5%) 1 1/5 (20%) 1 2/12 (16.7%) 2
    Pharyngitis 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 2 0/5 (0%) 0 1/12 (8.3%) 1
    Rash pustular 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 1/12 (8.3%) 1
    Respiratory tract infection 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 2/12 (16.7%) 2
    Rhinitis 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/12 (0%) 0
    Rhinovirus infection 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Scarlet fever 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Skin infection 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 1/5 (20%) 2 0/12 (0%) 0
    Staphylococcal infection 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/12 (0%) 0
    Suspected COVID-19 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Tonsillitis 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Upper respiratory tract infection 0/6 (0%) 0 1/6 (16.7%) 1 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 2/12 (16.7%) 2
    Urinary tract infection 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 5 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 2 0/12 (0%) 0
    Varicella 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 1/8 (12.5%) 1 0/5 (0%) 0 1/12 (8.3%) 1
    Viral infection 1/6 (16.7%) 1 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/12 (0%) 0
    Viral tonsillitis 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Viral upper respiratory tract infection 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/12 (0%) 0
    Injury, poisoning and procedural complications
    Abdominal injury 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Arthropod bite 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Contusion 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 3 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/12 (0%) 0
    Face injury 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Fall 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 4 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 1/5 (20%) 1 1/12 (8.3%) 1
    Foot fracture 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Foreign body in ear 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Hand fracture 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Head injury 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 5 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Ligament sprain 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/12 (0%) 0
    Limb injury 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 3 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Skin abrasion 0/6 (0%) 0 1/6 (16.7%) 1 1/6 (16.7%) 2 0/6 (0%) 0 1/7 (14.3%) 1 1/8 (12.5%) 1 0/5 (0%) 0 1/12 (8.3%) 1
    Skin laceration 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/12 (0%) 0
    Skin wound 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Thermal burn 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Tooth fracture 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Wrist fracture 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 1/12 (8.3%) 1
    Investigations
    Alanine aminotransferase increased 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 2/5 (40%) 3 0/12 (0%) 0
    Anion gap increased 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 3
    Aspartate aminotransferase increased 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 2 1/12 (8.3%) 1
    Blood alkaline phosphatase increased 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 2
    Blood bicarbonate decreased 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 2
    Blood chloride increased 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 3
    Blood cholesterol increased 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Blood creatine phosphokinase increased 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 3 1/6 (16.7%) 1 2/7 (28.6%) 3 1/8 (12.5%) 1 0/5 (0%) 0 4/12 (33.3%) 8
    Blood creatinine decreased 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Blood creatinine increased 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 1/7 (14.3%) 1 1/8 (12.5%) 1 0/5 (0%) 0 0/12 (0%) 0
    Body temperature decreased 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Body temperature increased 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Cortisol decreased 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Ejection fraction decreased 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 1/8 (12.5%) 3 1/5 (20%) 1 0/12 (0%) 0
    Electrocardiogram QT prolonged 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 2 0/12 (0%) 0
    Gamma-glutamyltransferase increased 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Intraocular pressure increased 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 1/6 (16.7%) 1 1/7 (14.3%) 1 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Lymphocyte count decreased 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 4 1/7 (14.3%) 1 1/8 (12.5%) 1 0/5 (0%) 0 2/12 (16.7%) 4
    Lymphocyte count increased 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Mean cell volume increased 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Neutrophil count decreased 0/6 (0%) 0 1/6 (16.7%) 7 0/6 (0%) 0 0/6 (0%) 0 2/7 (28.6%) 3 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 5
    Neutrophil count increased 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 1/12 (8.3%) 1
    Oxygen saturation decreased 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Platelet count decreased 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Platelet count increased 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 2
    Protein total decreased 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 3
    Transaminases increased 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 2 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Weight decreased 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/12 (0%) 0
    Weight increased 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 2/12 (16.7%) 2
    White blood cell count decreased 0/6 (0%) 0 1/6 (16.7%) 9 0/6 (0%) 0 0/6 (0%) 0 2/7 (28.6%) 3 0/8 (0%) 0 0/5 (0%) 0 2/12 (16.7%) 8
    White blood cell count increased 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/12 (0%) 0
    Metabolism and nutrition disorders
    Decreased appetite 1/6 (16.7%) 1 1/6 (16.7%) 1 2/6 (33.3%) 2 0/6 (0%) 0 2/7 (28.6%) 2 2/8 (25%) 2 1/5 (20%) 1 1/12 (8.3%) 1
    Dehydration 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Glucose tolerance impaired 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Hyperglycaemia 0/6 (0%) 0 1/6 (16.7%) 3 0/6 (0%) 0 1/6 (16.7%) 1 1/7 (14.3%) 1 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Hyperkalaemia 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Hypernatraemia 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Hyperuricaemia 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 2
    Hypoalbuminaemia 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Hypoglycaemia 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Hypokalaemia 0/6 (0%) 0 1/6 (16.7%) 4 0/6 (0%) 0 2/6 (33.3%) 6 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/12 (0%) 0
    Hypomagnesaemia 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 1/6 (16.7%) 5 2/7 (28.6%) 2 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Hyponatraemia 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 5 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Hypophosphataemia 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 1/7 (14.3%) 1 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 4 1/6 (16.7%) 1 0/7 (0%) 0 2/8 (25%) 2 0/5 (0%) 0 0/12 (0%) 0
    Back pain 0/6 (0%) 0 0/6 (0%) 0 2/6 (33.3%) 6 0/6 (0%) 0 1/7 (14.3%) 1 2/8 (25%) 2 0/5 (0%) 0 0/12 (0%) 0
    Flank pain 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Groin pain 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Joint swelling 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Muscle spasms 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/12 (0%) 0
    Myalgia 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/12 (0%) 0
    Neck pain 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 2 0/6 (0%) 0 2/7 (28.6%) 2 1/8 (12.5%) 1 0/5 (0%) 0 0/12 (0%) 0
    Pain in extremity 0/6 (0%) 0 1/6 (16.7%) 1 2/6 (33.3%) 6 0/6 (0%) 0 2/7 (28.6%) 3 0/8 (0%) 0 1/5 (20%) 1 0/12 (0%) 0
    Pain in jaw 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Spinal deformity 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hair follicle tumour benign 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Skin papilloma 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Nervous system disorders
    Dizziness 1/6 (16.7%) 1 0/6 (0%) 0 1/6 (16.7%) 2 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/12 (0%) 0
    Headache 3/6 (50%) 5 3/6 (50%) 4 2/6 (33.3%) 2 2/6 (33.3%) 4 3/7 (42.9%) 8 4/8 (50%) 4 3/5 (60%) 5 7/12 (58.3%) 11
    Lethargy 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Neuralgia 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Paraesthesia 0/6 (0%) 0 1/6 (16.7%) 1 1/6 (16.7%) 4 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Sciatica 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Tremor 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 2/8 (25%) 2 0/5 (0%) 0 0/12 (0%) 0
    Psychiatric disorders
    Anxiety 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 2 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/12 (0%) 0
    Behaviour disorder 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Bradyphrenia 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Inappropriate affect 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 2
    Insomnia 1/6 (16.7%) 1 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 1/5 (20%) 1 0/12 (0%) 0
    Renal and urinary disorders
    Acute kidney injury 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 2
    Dysuria 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Micturition urgency 0/6 (0%) 0 1/6 (16.7%) 1 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Pollakiuria 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 2 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Polyuria 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/12 (0%) 0
    Urinary hesitation 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Urinary incontinence 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 2 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Urinary retention 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 0/12 (0%) 0
    Urinary tract pain 0/6 (0%) 0 1/6 (16.7%) 2 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Reproductive system and breast disorders
    Balanoposthitis 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Scrotal ulcer 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Vulvovaginal pain 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Respiratory, thoracic and mediastinal disorders
    Cough 2/6 (33.3%) 3 2/6 (33.3%) 4 1/6 (16.7%) 1 2/6 (33.3%) 2 1/7 (14.3%) 1 1/8 (12.5%) 1 0/5 (0%) 0 3/12 (25%) 5
    Dyspnoea 1/6 (16.7%) 3 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 2/8 (25%) 2 0/5 (0%) 0 0/12 (0%) 0
    Epistaxis 1/6 (16.7%) 3 1/6 (16.7%) 1 1/6 (16.7%) 2 1/6 (16.7%) 1 1/7 (14.3%) 1 0/8 (0%) 0 1/5 (20%) 1 4/12 (33.3%) 5
    Nasal congestion 0/6 (0%) 0 1/6 (16.7%) 2 0/6 (0%) 0 2/6 (33.3%) 2 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Oropharyngeal pain 1/6 (16.7%) 1 1/6 (16.7%) 1 1/6 (16.7%) 2 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 1/12 (8.3%) 1
    Pleural effusion 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Pneumonia aspiration 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Rhinorrhoea 1/6 (16.7%) 1 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Sputum decreased 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Skin and subcutaneous tissue disorders
    Acne 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/8 (0%) 0 1/5 (20%) 1 0/12 (0%) 0
    Alopecia 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/12 (0%) 0
    Dandruff 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 2
    Dermatitis acneiform 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 1/6 (16.7%) 1 1/7 (14.3%) 1 1/8 (12.5%) 1 3/5 (60%) 3 1/12 (8.3%) 1
    Dermatitis atopic 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 1/12 (8.3%) 1
    Dermatitis contact 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/12 (0%) 0
    Dry skin 2/6 (33.3%) 6 1/6 (16.7%) 2 2/6 (33.3%) 2 0/6 (0%) 0 3/7 (42.9%) 3 2/8 (25%) 2 1/5 (20%) 2 1/12 (8.3%) 1
    Eczema 0/6 (0%) 0 1/6 (16.7%) 1 1/6 (16.7%) 1 1/6 (16.7%) 1 1/7 (14.3%) 1 1/8 (12.5%) 1 0/5 (0%) 0 2/12 (16.7%) 2
    Eczema asteatotic 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/12 (0%) 0
    Erythema 1/6 (16.7%) 2 1/6 (16.7%) 1 0/6 (0%) 0 1/6 (16.7%) 1 1/7 (14.3%) 1 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Hand dermatitis 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/12 (0%) 0
    Hirsutism 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Hyperhidrosis 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Hyperkeratosis 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Ingrowing nail 1/6 (16.7%) 2 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Miliaria 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Onychomadesis 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 1/6 (16.7%) 1 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Papule 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Photosensitivity reaction 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Pityriasis alba 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Pruritus 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 1/6 (16.7%) 1 0/7 (0%) 0 1/8 (12.5%) 1 1/5 (20%) 1 0/12 (0%) 0
    Purpura 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 2
    Rash 0/6 (0%) 0 2/6 (33.3%) 5 1/6 (16.7%) 2 1/6 (16.7%) 1 2/7 (28.6%) 2 1/8 (12.5%) 1 1/5 (20%) 1 2/12 (16.7%) 2
    Rash erythematous 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Rash macular 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Rash maculo-papular 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 1/6 (16.7%) 1 0/7 (0%) 0 1/8 (12.5%) 5 0/5 (0%) 0 1/12 (8.3%) 1
    Rash papular 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/8 (12.5%) 1 0/5 (0%) 0 1/12 (8.3%) 2
    Seborrhoea 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Skin fissures 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 1/5 (20%) 1 0/12 (0%) 0
    Skin lesion 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Skin mass 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Skin ulcer 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 1/7 (14.3%) 1 0/8 (0%) 0 0/5 (0%) 0 0/12 (0%) 0
    Telangiectasia 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Xeroderma 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1
    Vascular disorders
    Hypertension 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/8 (0%) 0 0/5 (0%) 0 1/12 (8.3%) 1

    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:
    NCT02639546
    Other Study ID Numbers:
    • GO29665
    • 2014-004685-25
    First Posted:
    Dec 24, 2015
    Last Update Posted:
    Mar 31, 2022
    Last Verified:
    Mar 1, 2022