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A Combination Clinical Study of PLX3397 and Pembrolizumab To Treat Advanced Melanoma and Other Solid Tumors

Sponsor
Daiichi Sankyo, Inc. (Industry)
Overall Status
Terminated
CT.gov ID
NCT02452424
Collaborator
Plexxikon (Industry), Merck Sharp & Dohme LLC (Industry)
78
Enrollment
12
Locations
2
Arms
39.4
Actual Duration (Months)
6.5
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The goal of this clinical research study is to learn how PLX3397 and pembrolizumab work together to affect cancer cells.

PLX3397 is designed to target the receptor for CSF1 (CSF1R). Pembrolizumab is designed to block the interaction between the receptor PD-1 and molecules that bind PD-1. In this study, PLX3397 and pembrolizumab are being given together in order to study their combined effects on patients' immune responses to their tumors. Tumor-specific immune responses have been shown to kill cancer cells and/or to stop tumors from growing.

Part 1 of the study (dose-escalation phase) will establish the safest dose of PLX3397 to be given in combination with pembrolizumab. Part 2 of the study (expansion phase) will include an evaluation of efficacy of this combination in the following tumor types:

  • Advanced melanoma: prior anti-PD-1/PD-L1 therapy but never responded

  • Advanced melanoma: prior anti-PD-1/PD-L1 therapy and responded but later progressed as defined by irRECIST while on therapy

  • Non-small cell lung cancer

  • Ovarian cancer

  • Gastrointestinal Stromal Tumor (GIST)

  • Squamous cell cancer of the head and neck

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

Study Design

Study Type:
Interventional
Actual Enrollment :
78 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase 1/2a Study of Double-Immune Suppression Blockade By Combining a CSF1R Inhibitor (PLX3397) With An Anti-PD-1 Antibody (Pembrolizumab) To Treat Advanced Melanoma And Other Solid Tumors
Actual Study Start Date :
Jul 2, 2015
Actual Primary Completion Date :
Aug 17, 2018
Actual Study Completion Date :
Oct 12, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: PLX3397 and Pembrolizumab (Part 1)

Open-label, sequential PLX3397 dose escalation with a fixed dose of pembrolizumab in approximately 24 patients with advanced solid tumors. (Enrollment complete- 33 enrolled)

Drug: PLX3397
PLX3397 capsules, 200 mg
Other Names:
  • Pexidartinib

    • Biological: Pembrolizumab
    Pembrolizumab, 200 mg, IV
    Other Names:
  • Keytruda, MK-3475, SCH 900475

    		•
    Experimental: PLX3397 and Pembrolizumab (Part 2)

    Extension cohort at the RP2D of PLX3397 in combination with pembrolizumab in approximately 376 patients with advanced solid tumors (Enrollment Complete- 45 enrolled)

    Drug: PLX3397
    PLX3397 capsules, 200 mg
    Other Names:
  • Pexidartinib

    • Biological: Pembrolizumab
    Pembrolizumab, 200 mg, IV
    Other Names:
  • Keytruda, MK-3475, SCH 900475

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Treatment-emergent Adverse Events (TEAEs) in Participants Regardless of Causality While Taking PLX3397 in Combination With Pembrolizumab [1 year (Dose Escalation); 2 years (Dose Expansion)]

      Treatment-emergent Adverse Events (TEAEs) in participants regardless of causality while taking PLX3397 in combination with pembrolizumab are reported

    Secondary Outcome Measures

    1. Summary of the Percentage of Participants With Objective Response Rate Assessed by RECIST v1.1 During Pembrolizumab and PLX3397 [1 year (Dose Escalation); 2 years (Dose Expansion)]

      Objective response rate was defined as the proportion of subjects who achieved a best disease response of either Complete or Partial (CR or PR) based on the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed generally by MRI, CT, or PET-CT and are summarized as: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions. Participants who discontinued study therapy due to clinical progression, radiographic progression, or death without the required tumor assessments were considered to be non-responders in the Objective Response Rate (ORR) calculation. The efficacy analysis included all subjects with baseline tumor measurements who received at least 1 dose of study drug.

    Eligibility Criteria

    Criteria

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

    A subject must satisfy all of the following criteria to be considered for inclusion in the study:

    • Subjects with histologically or cytologically-confirmed diagnosis of cancer that is recurrent, metastatic, or persistent, who have relapsed from or are refractory to treatment and who also meet the following corresponding requirements for the cohort or phase of the study into which they will enroll:

    • Dose-escalation Phase: Subjects with advanced solid tumors (any tumor type) considered to have no standard-of care treatment for their malignancy with a curative intent, either as initial therapy or after progressing to prior therapies; subjects who have been treated previously with a CSF1R inhibitor or an anti PD1/PDL1 inhibitor may enroll.

    • Expansion Phase: Subjects with 1 of the tumor types who have relapsed from or are refractory to standard treatment. Subjects with non-small-cell lung cancer (non-squamous; EGFR, ALK wild type), advanced melanoma, ovarian cancer, unresectable RCC with component of clear-cell histology and/or component of sarcomatoid histology, glioblastoma or gliosarcoma, gastrointestinal stromal tumor.

    • Subjects with melanoma must have a histologically confirmed diagnosis of stage III disease not amenable to local therapy. Melanoma subjects may have received any number of prior lines of therapy for metastatic disease and must have measurable disease per RECISTv1.1. Subjects with melanoma who have received prior treatment with a BRAF/MEK inhibitor are acceptable candidates.

    • Expansion cohorts: Subjects must have relapsed or been refractory to standard treatment. NSCLC, SCCHN, and Melanoma must show primary progression with antiPD1/anti-PDL1 therapy. They must have tumor accessible for sequential biopsy (core needle biopsy or excision required) and be willing to provide on study tumor tissue biopsy. Subjects for whom newly obtained samples cannot be obtained (e.g. inaccessible or patient safety concern) may submit an archived specimen onlyupon agreement from the Sponsor.

    • ECOG performance status 0 or 1.

    • Women of childbearing potential must have a negative serum pregnancy test within 72 hours prior to initiation of dosing.

    • Women of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Women of non-child bearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥1 year.

    • Fertile men must agree to use an effective method of birth control starting with the first dose of study treatment through 120 days after the last dose of study treatment.

    • Adequate organ function as demonstrated by laboratory values.

    Exclusion Criteria:

    A subject who meets any of the following criteria will be disqualified from entering the study:

    • Disease that is suitable for local therapy administered with curative intent.

    • Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment.

    • Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 28 days prior to the first dose of study treatment.

    • Has had monoclonal antibody within 28 days of first dose of study treatment or has not recovered from AEs due to agents administered more than 28 days earlier.

    • Has had chemotherapy, targeted small molecule therapy, or radiation therapy within 14 days prior to first dose of study treatment or who has not recovered from AEs due to a previously administered agent.

    • Note: Subjects with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to this criterion and may qualify for the study.

    • Note: If a subject received major surgery, he or she must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.

    • Has received transfusion of blood products (including platelets or red blood cells [RBC]) or administration of colony stimulating factors (including granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, or recombinant erythropoietin) within 28 days prior to Day 1.

    • Evidence of interstitial lung disease or active, noninfectious pneumonitis.

    • Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, in situ cervical cancer and isolated elevation of prostate-specific antigen. Subjects with a completely treated prior malignancy with no evidence of disease for ≥ 2 years are eligible.

    • For Dose escalation cohort: patients with liver metastases, inclusion of patients with liver metastases in subsequent cohorts will be based upon clinical data.

    • For Expansion cohort subjects who have previously received an anti-PD-1, anti-PD-L1, or anti#PD-L2 agent or has previously participated in pembrolizumab clinical trials are excluded, except the following tumor types Melanoma, NSCLC and SCCHN (who must show primary progression to anti-PD1/anti-PDL1 therapy).

    • Radiation therapy within 14 days of first dose of study treatment.- remove since it's repetitive

    • Has active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy is not considered a form of systemic treatment.

    • Has an active infection requiring systemic therapy.

    • Has known central nervous system metastases and/or carcinomatous meningitis.

    o Note: Subjects with previously treated brain metastases may participate if they meet the following criteria: 1) are stable for at least 28 days prior to the first dose of study treatment and if all neurologic symptoms returned to baseline); 2) have no evidence of new or enlarging brain metastases; and 3) have not been using steroids for at least 7 days prior to first dose of study treatment. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability.

    • Uncontrolled intercurrent illness.

    • Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant small bowel resection that would preclude adequate absorption.

    • QT interval corrected using Fridericia's formula (QTc) ≥ 450 msec (males) or ≥ 470 msec (females) at Screening.

    • Congenital long QT syndrome or patients taking concomitant medications known to prolong the QT interval.

    • Major surgery within 28 days prior to first dose of study treatment.

    • Has received a live vaccine administered within 30 days prior to first dose of study treatment.

    • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.

    • Active and clinically significant bacterial, fungal or viral infection, including hepatitis B virus (HBV), hepatitis C virus (HCV), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome related illness (HIV testing is not required), including subjects who have an active infection requiring systemic therapy.

    • Any of the following within 48 weeks (~1 year) prior to first dose of study treatment: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack.

    • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of study treatment.

    • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

    • Has had prior exposure to PLX3397.

    • Has had hypersensitivity (≥Grade 3) reaction to pembrolizumab and/or any of its excipients.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 HonorHealth Research Institute Scottsdale Arizona United States 85258
    2 Marin Cancer Care Greenbrae California United States 94904
    3 Ronald Reagan UCLA Medical Center Los Angeles California United States 90095
    4 Massachusetts General Hospital Boston Massachusetts United States 02114
    5 Beth Israel Deaconess Medical Center Boston Massachusetts United States 02115
    6 Dana-Farber Cancer Institute Boston Massachusetts United States 02215
    7 Karmanos Cancer Institute Detroit Michigan United States 48201
    8 Washington University St. Louis Siteman Cancer Center Saint Louis Missouri United States 63130
    9 Memorial Sloan Kettering Cancer Center New York New York United States 10065
    10 Medical University Health Hollings Cancer Center Charleston South Carolina United States 29425
    11 Vanderbilt Ingram Cancer Center Nashville Tennessee United States 37212
    12 South Texas Accelerated Research Therapeutics San Antonio Texas United States 78229

    Sponsors and Collaborators

    • Daiichi Sankyo, Inc.
    • Plexxikon
    • Merck Sharp & Dohme LLC

    Investigators

    None specified.

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Daiichi Sankyo, Inc.
    ClinicalTrials.gov Identifier:
    NCT02452424
    Other Study ID Numbers:
    • PLX108-14
    • KEYNOTE-103
    First Posted:
    May 22, 2015
    Last Update Posted:
    Mar 5, 2020
    Last Verified:
    Feb 1, 2020
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Melanoma
    Squamous Cell Carcinoma of Head and Neck
    Gastrointestinal Stromal Tumors
    Pembrolizumab

    Study Results

    Participant Flow

    Recruitment Details Dose Escalation: 33 participants who met the inclusion and none of the exclusion criteria were enrolled and received study drug. Dose Expansion: 45 participants with melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, squamous cell carcinoma of the head and neck (SCCHN), and gastrointestinal stromal tumor (GIST) were enrolled.
    Pre-assignment Detail Dose Escalation: Up to 42 participants with advanced solid tumors (any type) were to be enrolled sequentially in up to 7 cohorts (3+3 design). Dose Expansion: Up to 483 participants were planned with the sample size for each tumor type based on a truncated sequential probability ratio test (max sample size 28 to 48 participants per tumor type).
    Arm/Group Title Dose Escalation: 400 mg/Day Dose Escalation: 600 mg/Day Dose Escalation: 600 mg/Day (Liver Metastases Dose Escalation: 600 mg/Day (no Liver Metastases) Dose Escalation: 800 mg/Day (Liver Metastases) Dose Escalation: 800 mg/Day (no Liver Metastases) Dose Expansion: Melanoma Dose Expansion: NSCLC Dose Expansion: Ovarian Cancer Dose Expansion: SCCHN Dose Expansion: GIST
    Arm/Group Description Participants received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 400 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 200 mg in the evening). Participants received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with liver metastases received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with no liver metastases received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with liver metastases received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 800 mg/day (administered twice daily [BID] as a split dose of 400 mg in the morning and 400 mg in the evening). Participants with no liver metastases received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 800 mg/day (administered twice daily [BID] as a split dose of 400 mg in the morning and 400 mg in the evening). Participants with melanoma received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with NSCLC received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with ovarian cancer received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with SCCHN received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with GIST received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening).
    Period Title: Overall Study
    STARTED 4 3 7 9 4 6 13 8 15 3 6
    COMPLETED 2 0 0 1 2 5 3 4 9 1 4
    NOT COMPLETED 2 3 7 8 2 1 10 4 6 2 2

    Baseline Characteristics

    Arm/Group Title Dose Escalation: 400 mg/Day Dose Escalation: 600 mg/Day Dose Escalation: 600 mg/Day (Liver Metastases Dose Escalation: 600 mg/Day (no Liver Metastases) Dose Escalation: 800 mg/Day (Liver Metastases) Dose Escalation: 800 mg/Day (no Liver Metastases) Dose Expansion: Melanoma Dose Expansion: NSCLC Dose Expansion: Ovarian Cancer Dose Expansion: SCCHN Dose Expansion: GIST Total
    Arm/Group Description Participants received pembrolizumab 200 mg IV every 3 weeks in combination with of PLX3397 at 400 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 200 mg in the evening).. Participants received pembrolizumab 200 mg IV every 3 weeks in combination with of PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with liver metastases received pembrolizumab 200 mg IV every 3 weeks in combination with of PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with no liver metastases received pembrolizumab 200 mg IV every 3 weeks in combination with of PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with liver metastases received pembrolizumab 200 mg IV every 3 weeks in combination with of PLX3397 at 800 mg/day (administered twice daily [BID] as a split dose of 400 mg in the morning and 400 mg in the evening). Participants with no liver metastases received pembrolizumab 200 mg IV every 3 weeks in combination with of PLX3397 at 800 mg/day (administered twice daily [BID] as a split dose of 400 mg in the morning and 400 mg in the evening).. Participants with melanoma received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with NSCLC received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with ovarian cancer received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with SCCHN received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with GIST received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Total of all reporting groups
    Overall Participants 4 3 7 9 4 6 13 8 15 3 6 78
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    1
    25%
    2
    66.7%
    6
    85.7%
    7
    77.8%
    0
    0%
    3
    50%
    9
    69.2%
    6
    75%
    10
    66.7%
    2
    66.7%
    4
    66.7%
    50
    64.1%
    >=65 years
    3
    75%
    1
    33.3%
    1
    14.3%
    2
    22.2%
    4
    100%
    3
    50%
    4
    30.8%
    2
    25%
    5
    33.3%
    1
    33.3%
    2
    33.3%
    28
    35.9%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    64.5
    (8.6)
    54.7
    (10.2)
    51.1
    (17.0)
    55.9
    (10.9)
    72.0
    (5.3)
    61.7
    (8.7)
    61.8
    (8.3)
    57.0
    (11.3)
    60.4
    (12.5)
    52.7
    (16.3)
    59.7
    (8.8)
    59.3
    (11.5)
    Sex: Female, Male (Count of Participants)
    Female
    2
    50%
    1
    33.3%
    3
    42.9%
    3
    33.3%
    2
    50%
    4
    66.7%
    4
    30.8%
    5
    62.5%
    15
    100%
    0
    0%
    2
    33.3%
    41
    52.6%
    Male
    2
    50%
    2
    66.7%
    4
    57.1%
    6
    66.7%
    2
    50%
    2
    33.3%
    9
    69.2%
    3
    37.5%
    0
    0%
    3
    100%
    4
    66.7%
    37
    47.4%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    12.5%
    1
    6.7%
    0
    0%
    0
    0%
    2
    2.6%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    1
    25%
    0
    0%
    0
    0%
    1
    11.1%
    0
    0%
    1
    16.7%
    0
    0%
    1
    12.5%
    0
    0%
    0
    0%
    1
    16.7%
    5
    6.4%
    White
    3
    75%
    3
    100%
    6
    85.7%
    8
    88.9%
    3
    75%
    5
    83.3%
    12
    92.3%
    6
    75%
    14
    93.3%
    3
    100%
    5
    83.3%
    68
    87.2%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    0
    0%
    1
    14.3%
    0
    0%
    1
    25%
    0
    0%
    1
    7.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    3
    3.8%
    Region of Enrollment (participants) [Number]
    United States
    4
    100%
    3
    100%
    7
    100%
    9
    100%
    4
    100%
    6
    100%
    13
    100%
    8
    100%
    15
    100%
    3
    100%
    6
    100%
    78
    100%

    Outcome Measures

    1. Primary Outcome
    Title Treatment-emergent Adverse Events (TEAEs) in Participants Regardless of Causality While Taking PLX3397 in Combination With Pembrolizumab
    Description Treatment-emergent Adverse Events (TEAEs) in participants regardless of causality while taking PLX3397 in combination with pembrolizumab are reported
    Time Frame 1 year (Dose Escalation); 2 years (Dose Expansion)

    Outcome Measure Data

    Analysis Population Description
    Safety events were assessed in the Safety Population.
    Arm/Group Title Dose Escalation: 400 mg/Day Dose Escalation: 600 mg/Day Dose Escalation: 600 mg/Day (Liver Metastases Dose Escalation: 600 mg/Day (no Liver Metastases) Dose Escalation: 800 mg/Day (Liver Metastases) Dose Escalation: 800 mg/Day (no Liver Metastases) Dose Expansion: Melanoma Dose Expansion: NSCLC Dose Expansion: Ovarian Cancer Dose Expansion: SCCHN Dose Expansion: GIST
    Arm/Group Description Participants received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 400 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 200 mg in the evening). Participants received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with liver metastases received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with no liver metastases received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with liver metastases received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 800 mg/day (administered twice daily [BID] as a split dose of 400 mg in the morning and 400 mg in the evening). Participants with no liver metastases received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 800 mg/day (administered twice daily [BID] as a split dose of 400 mg in the morning and 400 mg in the evening). Participants with melanoma received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with NSCLC received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with ovarian cancer received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with SCCHN received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with GIST received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening).
    Measure Participants 4 3 7 9 4 6 13 8 15 3 6
    Count of Participants [Participants]
    4
    100%
    3
    100%
    7
    100%
    9
    100%
    4
    100%
    6
    100%
    12
    92.3%
    8
    100%
    15
    100%
    3
    100%
    6
    100%
    2. Secondary Outcome
    Title Summary of the Percentage of Participants With Objective Response Rate Assessed by RECIST v1.1 During Pembrolizumab and PLX3397
    Description Objective response rate was defined as the proportion of subjects who achieved a best disease response of either Complete or Partial (CR or PR) based on the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed generally by MRI, CT, or PET-CT and are summarized as: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions. Participants who discontinued study therapy due to clinical progression, radiographic progression, or death without the required tumor assessments were considered to be non-responders in the Objective Response Rate (ORR) calculation. The efficacy analysis included all subjects with baseline tumor measurements who received at least 1 dose of study drug.
    Time Frame 1 year (Dose Escalation); 2 years (Dose Expansion)

    Outcome Measure Data

    Analysis Population Description
    Overall best response was assessed in the Efficacy Analysis Set.
    Arm/Group Title Dose Escalation: 400 mg/Day Dose Escalation: 600 mg/Day Dose Escalation: 600 mg/Day (Liver Metastases Dose Escalation: 600 mg/Day (no Liver Metastases) Dose Escalation: 800 mg/Day (Liver Metastases) Dose Escalation: 800 mg/Day (no Liver Metastases) Dose Expansion: Melanoma Dose Expansion: NSCLC Dose Expansion: Ovarian Cancer Dose Expansion: SCCHN Dose Expansion: GIST
    Arm/Group Description Participants received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 400 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 200 mg in the evening). Participants received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with liver metastases received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with no liver metastases received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with liver metastases received pembrolizumab 200 mg IV every 3 weeks in combination with of PLX3397 at 800 mg/day (administered twice daily [BID] as a split dose of 400 mg in the morning and 400 mg in the evening). Participants with no liver metastases received pembrolizumab 200 mg IV every 3 weeks in combination with of PLX3397 at 800 mg/day (administered twice daily [BID] as a split dose of 400 mg in the morning and 400 mg in the evening). Participants with melanoma received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with NSCLC received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with ovarian cancer received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with SCCHN received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with GIST received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening).
    Measure Participants 4 3 7 9 4 6 13 8 15 3 6
    Complete response
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Partial response
    0
    0%
    0
    0%
    1
    14.3%
    0
    0%
    0
    0%
    1
    16.7%
    2
    15.4%
    0
    0%
    1
    6.7%
    0
    0%
    0
    0%
    Progressive disease
    2
    50%
    1
    33.3%
    3
    42.9%
    7
    77.8%
    1
    25%
    2
    33.3%
    4
    30.8%
    3
    37.5%
    9
    60%
    2
    66.7%
    3
    50%
    Stable disease
    2
    50%
    2
    66.7%
    1
    14.3%
    1
    11.1%
    1
    25%
    2
    33.3%
    3
    23.1%
    2
    25%
    1
    6.7%
    0
    0%
    3
    50%
    Not evaluable
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Not assessed for response
    0
    0%
    0
    0%
    2
    28.6%
    1
    11.1%
    2
    50%
    1
    16.7%
    4
    30.8%
    3
    37.5%
    4
    26.7%
    1
    33.3%
    0
    0%

    Adverse Events

    Time Frame Adverse event data were collected for each subject from after the first dose was administered to 30 days after the last dose, through study completion at Cycle 16 (up to approximately 100 weeks)
    Adverse Event Reporting Description Adverse events that emerge (or worsen) after the first dose of study drug and within 30 days after the last dose.
    Arm/Group Title Dose Escalation: 400 mg/Day Dose Escalation: 600 mg/Day Dose Escalation: 600 mg/Day (Liver Metastases Dose Escalation: 600 mg/Day (no Liver Metastases) Dose Escalation: 800 mg/Day (Liver Metastases) Dose Escalation: 800 mg/Day (no Liver Metastases) Dose Expansion: Melanoma Dose Expansion: NSCLC Dose Expansion: Ovarian Cancer Dose Expansion: SCCHN Dose Expansion: GIST
    Arm/Group Description Participants received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 400 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 200 mg in the evening). Participants received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with liver metastases received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with no liver metastases received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with liver metastases received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 800 mg/day (administered twice daily [BID] as a split dose of 400 mg in the morning and 400 mg in the evening). Participants with no liver metastases received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 800 mg/day (administered twice daily [BID] as a split dose of 400 mg in the morning and 400 mg in the evening). Participants with melanoma received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with NSCLC received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with ovarian cancer received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with SCCHN received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening). Participants with GIST received pembrolizumab 200 mg IV every 3 weeks in combination with PLX3397 at 600 mg/day (administered twice daily [BID] as a split dose of 200 mg in the morning and 400 mg in the evening).
    All Cause Mortality
    Dose Escalation: 400 mg/Day Dose Escalation: 600 mg/Day Dose Escalation: 600 mg/Day (Liver Metastases Dose Escalation: 600 mg/Day (no Liver Metastases) Dose Escalation: 800 mg/Day (Liver Metastases) Dose Escalation: 800 mg/Day (no Liver Metastases) Dose Expansion: Melanoma Dose Expansion: NSCLC Dose Expansion: Ovarian Cancer Dose Expansion: SCCHN Dose Expansion: GIST
    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 Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/4 (50%) 2/3 (66.7%) 2/7 (28.6%) 6/9 (66.7%) 2/4 (50%) 0/6 (0%) 5/13 (38.5%) 1/8 (12.5%) 3/15 (20%) 1/3 (33.3%) 0/6 (0%)
    Serious Adverse Events
    Dose Escalation: 400 mg/Day Dose Escalation: 600 mg/Day Dose Escalation: 600 mg/Day (Liver Metastases Dose Escalation: 600 mg/Day (no Liver Metastases) Dose Escalation: 800 mg/Day (Liver Metastases) Dose Escalation: 800 mg/Day (no Liver Metastases) Dose Expansion: Melanoma Dose Expansion: NSCLC Dose Expansion: Ovarian Cancer Dose Expansion: SCCHN Dose Expansion: GIST
    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 Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/4 (50%) 1/3 (33.3%) 3/7 (42.9%) 3/9 (33.3%) 2/4 (50%) 3/6 (50%) 3/13 (23.1%) 3/8 (37.5%) 5/15 (33.3%) 1/3 (33.3%) 0/6 (0%)
    Blood and lymphatic system disorders
    Febrile neutropenia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Splenic infarction 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Cardiac disorders
    Pericardial effusion 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Gastrointestinal disorders
    Abdominal pain lower 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Diarrhoea 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Faecaloma 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Gastrointestinal haemorrhage 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Lower gastrointestinal haemorrhage 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Obstruction gastric 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Rectal haemorrhage 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Small intestinal obstruction 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 2/15 (13.3%) 0/3 (0%) 0/6 (0%)
    General disorders
    Generalised oedema 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Pyrexia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 2/6 (33.3%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Hepatobiliary disorders
    Drug-induced liver injury 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Immune system disorders
    Drug hypersensitivity 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Infections and infestations
    Parotitis 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Urinary tract infection 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Urosepsis 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Injury, poisoning and procedural complications
    Radiation oesophagitis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 1/3 (33.3%) 0/6 (0%)
    Investigations
    Alanine aminotransferase increased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Aspartate aminotransferase increased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Hepatic enzyme increased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Liver function test abnormal 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Transaminases increased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 2/15 (13.3%) 0/3 (0%) 0/6 (0%)
    Metabolism and nutrition disorders
    Dehydration 0/4 (0%) 0/3 (0%) 2/7 (28.6%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Tumour pain 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Nervous system disorders
    Haemorrhage intracranial 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Hydrocephalus 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Migraine with aura 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Presyncope 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Psychiatric disorders
    Completed suicide 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Renal and urinary disorders
    Haematuria 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Respiratory, thoracic and mediastinal disorders
    Aspiration 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Dyspnoea 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 1/4 (25%) 1/6 (16.7%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Dyspnoea exertional 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 1/3 (33.3%) 0/6 (0%)
    Haemoptysis 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Pleuritic pain 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Pneumonitis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 1/3 (33.3%) 0/6 (0%)
    Pneumothorax 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 1/3 (33.3%) 0/6 (0%)
    Vascular disorders
    Hypotension 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Other (Not Including Serious) Adverse Events
    Dose Escalation: 400 mg/Day Dose Escalation: 600 mg/Day Dose Escalation: 600 mg/Day (Liver Metastases Dose Escalation: 600 mg/Day (no Liver Metastases) Dose Escalation: 800 mg/Day (Liver Metastases) Dose Escalation: 800 mg/Day (no Liver Metastases) Dose Expansion: Melanoma Dose Expansion: NSCLC Dose Expansion: Ovarian Cancer Dose Expansion: SCCHN Dose Expansion: GIST
    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 Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 4/4 (100%) 3/3 (100%) 7/7 (100%) 9/9 (100%) 4/4 (100%) 6/6 (100%) 12/13 (92.3%) 8/8 (100%) 15/15 (100%) 3/3 (100%) 6/6 (100%)
    Blood and lymphatic system disorders
    Anemia (All grades) 1/4 (25%) 0/3 (0%) 1/7 (14.3%) 2/9 (22.2%) 0/4 (0%) 0/6 (0%) 5/13 (38.5%) 1/8 (12.5%) 6/15 (40%) 2/3 (66.7%) 2/6 (33.3%)
    Febrile neutropenia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Increased tendency to bruise 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Leukocytosis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Leukopenia (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 1/3 (33.3%) 0/6 (0%)
    Lymphadenopathy (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 2/13 (15.4%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Lymphopenia (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 1/9 (11.1%) 1/4 (25%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Neutropenia (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 1/6 (16.7%)
    Pancytopenia (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Splenic infarction (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Thrombocytopenia (All grades) 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 2/9 (22.2%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 2/15 (13.3%) 0/3 (0%) 0/6 (0%)
    Cardiac disorders
    Atrial fibrillation (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Atrial tachycardia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Bradycardia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Pericardial effusion 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 2/15 (13.3%) 0/3 (0%) 0/6 (0%)
    Sinus bradycardia (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Tachycardia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 1/15 (6.7%) 1/3 (33.3%) 0/6 (0%)
    Ventricular arrhythmia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 2/6 (33.3%)
    Ear and labyrinth disorders
    Ear discomfort (All grades) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Ear pain 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 1/3 (33.3%) 0/6 (0%)
    Tinnitus 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 2/8 (25%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Endocrine disorders
    Adrenal insufficiency (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Hyperthyroidism (All grades) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 1/4 (25%) 2/6 (33.3%) 1/13 (7.7%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Hypothyroidism 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 1/3 (33.3%) 0/6 (0%)
    Inappropriate antidiuretic hormone secretion 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Eye disorders
    Conjunctival haemorrhage (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Dry eye 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Eye irritation 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Eye oedema 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Eye swelling 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Eyelid oedema 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Lacrimation increased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 1/6 (16.7%)
    Periorbital oedema 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 1/6 (16.7%)
    Uveitis (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Vision blurred (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 2/13 (15.4%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Visual impairment 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Vitreous floaters 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Gastrointestinal disorders
    Abdominal discomfort (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Abdominal distension 0/4 (0%) 1/3 (33.3%) 1/7 (14.3%) 1/9 (11.1%) 0/4 (0%) 1/6 (16.7%) 2/13 (15.4%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Abdominal pain (All grades) 1/4 (25%) 1/3 (33.3%) 2/7 (28.6%) 2/9 (22.2%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 5/15 (33.3%) 1/3 (33.3%) 2/6 (33.3%)
    Abdominal pain lower (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Abdominal pain upper 1/4 (25%) 0/3 (0%) 0/7 (0%) 2/9 (22.2%) 1/4 (25%) 1/6 (16.7%) 2/13 (15.4%) 0/8 (0%) 2/15 (13.3%) 0/3 (0%) 0/6 (0%)
    Ascites 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Breath odor 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Chapped lips 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Constipation (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 2/9 (22.2%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 2/8 (25%) 3/15 (20%) 1/3 (33.3%) 1/6 (16.7%)
    Defaecation urgency 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Diarrhoea (All grades) 1/4 (25%) 0/3 (0%) 0/7 (0%) 4/9 (44.4%) 0/4 (0%) 2/6 (33.3%) 5/13 (38.5%) 2/8 (25%) 5/15 (33.3%) 0/3 (0%) 2/6 (33.3%)
    Diverticulum 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Dry mouth (All grades) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 2/13 (15.4%) 1/8 (12.5%) 1/15 (6.7%) 2/3 (66.7%) 1/6 (16.7%)
    Dyspepsia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 2/13 (15.4%) 2/8 (25%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Dysphagia (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 2/3 (66.7%) 0/6 (0%)
    Faecal incontinence 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Faecaloma 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Faeces hard 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Flatulence 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Gastrointestinal haemorrhage 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Gastrointestinal sounds abnormal 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Gastrooesophageal reflux disease 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 3/15 (20%) 1/3 (33.3%) 0/6 (0%)
    Glossodynia (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Haemorrhoids 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Hypoaesthesia oral 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Lip dry 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Lip swelling 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Lower gastrointestinal hemorrhage (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Nausea (All grades) 0/4 (0%) 0/3 (0%) 3/7 (42.9%) 3/9 (33.3%) 3/4 (75%) 1/6 (16.7%) 4/13 (30.8%) 4/8 (50%) 5/15 (33.3%) 3/3 (100%) 2/6 (33.3%)
    Obstruction gastric (All grades) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Oesophageal pain 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 1/3 (33.3%) 0/6 (0%)
    Oral pain 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 2/13 (15.4%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Paraesthesia oral (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Rectal haemorrhage (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Retching (All grades) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Salivary gland enlargement 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Small intestinal obstruction 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 2/15 (13.3%) 0/3 (0%) 0/6 (0%)
    Stomatitis (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 2/13 (15.4%) 1/8 (12.5%) 1/15 (6.7%) 1/3 (33.3%) 0/6 (0%)
    Tongue discolouration 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Vomiting (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 2/9 (22.2%) 1/4 (25%) 2/6 (33.3%) 3/13 (23.1%) 5/8 (62.5%) 3/15 (20%) 1/3 (33.3%) 1/6 (16.7%)
    General disorders
    Adverse drug reaction 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Asthenia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 2/13 (15.4%) 2/8 (25%) 0/15 (0%) 2/3 (66.7%) 0/6 (0%)
    Axillary pain 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Chest discomfort 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Chest pain (All grades) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Chills (All grades) 1/4 (25%) 0/3 (0%) 1/7 (14.3%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 3/13 (23.1%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Decreased activity 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Device occlusion (All grades) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Discomfort 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Early satiety 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 2/13 (15.4%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Face oedema 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 1/6 (16.7%)
    Facial pain (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Fatigue (All grades) 1/4 (25%) 0/3 (0%) 2/7 (28.6%) 5/9 (55.6%) 1/4 (25%) 1/6 (16.7%) 6/13 (46.2%) 3/8 (37.5%) 9/15 (60%) 3/3 (100%) 3/6 (50%)
    Gait disturbance 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 2/8 (25%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Generalized oedema (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Influenza-like illness (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 2/15 (13.3%) 0/3 (0%) 0/6 (0%)
    Localised oedema 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Malaise (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 2/8 (25%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Non-cardiac chest pain 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 2/8 (25%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Oedema peripheral (All grades) 2/4 (50%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 2/13 (15.4%) 2/8 (25%) 2/15 (13.3%) 0/3 (0%) 0/6 (0%)
    Pain (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 3/8 (37.5%) 2/15 (13.3%) 0/3 (0%) 0/6 (0%)
    Peripheral swelling (All grades) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 1/13 (7.7%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Pyrexia (All grades) 1/4 (25%) 0/3 (0%) 4/7 (57.1%) 2/9 (22.2%) 1/4 (25%) 3/6 (50%) 1/13 (7.7%) 2/8 (25%) 8/15 (53.3%) 1/3 (33.3%) 0/6 (0%)
    Hepatobiliary disorders
    Bile duct obstruction (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Drug-induced liver injury (All grades) 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Hepatic function abnormal 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Hepatic pain (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Hepatic steatosis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Hyperbilirubinemia (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Immune system disorders
    Drug hypersensitivity 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Infections and infestations
    Bacteremia (All grades) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Bacterial infection (All grades) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Cystitis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Fungal infection (All grades) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Fungal skin infection (All grades) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Furuncle (All grades) 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Mastitis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Nasopharyngitis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 1/6 (16.7%)
    Oral candidiasis (All grades) 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 1/15 (6.7%) 1/3 (33.3%) 0/6 (0%)
    Oral herpes (All grades) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Parotitis (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Pneumonia (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 2/8 (25%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Rash pustular 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Rectal abscess (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Root canal infection (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Tooth abscess 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 1/6 (16.7%)
    Upper respiratory tract infection 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 2/13 (15.4%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 1/6 (16.7%)
    Urinary tract infection (All grades) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 2/13 (15.4%) 1/8 (12.5%) 2/15 (13.3%) 0/3 (0%) 0/6 (0%)
    Urinary tract infection bacterial (All grades) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Urosepsis (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Injury, poisoning and procedural complications
    Arthropod bite (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Contusion (All grades) 1/4 (25%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Excoriation 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Fall (All grades) 2/4 (50%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Foot fracture 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Infusion-related reaction (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Laceration (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Procedure pain 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 2/13 (15.4%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Radiation oesophagitis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 1/3 (33.3%) 0/6 (0%)
    Tooth fracture 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Investigations
    Alanine aminotransferase increased (All grades) 0/4 (0%) 2/3 (66.7%) 1/7 (14.3%) 1/9 (11.1%) 1/4 (25%) 3/6 (50%) 5/13 (38.5%) 3/8 (37.5%) 9/15 (60%) 1/3 (33.3%) 4/6 (66.7%)
    Aspartate aminotransferase increased (All grades) 1/4 (25%) 2/3 (66.7%) 2/7 (28.6%) 4/9 (44.4%) 2/4 (50%) 3/6 (50%) 6/13 (46.2%) 3/8 (37.5%) 8/15 (53.3%) 1/3 (33.3%) 4/6 (66.7%)
    Blood alkaline phosphatase increased (All grades) 1/4 (25%) 2/3 (66.7%) 1/7 (14.3%) 3/9 (33.3%) 1/4 (25%) 2/6 (33.3%) 4/13 (30.8%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 2/6 (33.3%)
    Blood bilirubin increased (All grades) 1/4 (25%) 1/3 (33.3%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Blood creatinine increased (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 2/15 (13.3%) 0/3 (0%) 1/6 (16.7%)
    Blood creatinine phosphokinase increased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Blood glucose increased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Blood lactate dehydrogenase increased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 1/6 (16.7%)
    Blood potassium increased (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Blood thyroid stimulating hormone increased (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Breath sounds abnormal (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 1/13 (7.7%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Electrocardiogram PR prolongation 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Electrocardiogram T wave abnormal 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Gamma-glutamyltransferase increased (All grades) 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 4/13 (30.8%) 1/8 (12.5%) 3/15 (20%) 0/3 (0%) 1/6 (16.7%)
    Haemoglobin decreased (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 1/9 (11.1%) 0/4 (0%) 1/6 (16.7%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Heart rate irregular 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Hepatic enzyme increased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Lipase increased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Liver function test abnormal (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Mean cell haemoglobin decreased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Mean cell volume decreased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Neutrophil count decreased (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 2/13 (15.4%) 0/8 (0%) 2/15 (13.3%) 0/3 (0%) 0/6 (0%)
    Nutritional condition abnormal 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Palpatory finding abnormal 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Platelet count decreased (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 2/13 (15.4%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Prothrombin time prolonged (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Thyroxine free decreased (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Transaminase increased (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 3/15 (20%) 0/3 (0%) 0/6 (0%)
    Troponin increased (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Weight decreased (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 1/6 (16.7%) 1/13 (7.7%) 1/8 (12.5%) 0/15 (0%) 2/3 (66.7%) 0/6 (0%)
    White blood cell count decreased (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 2/9 (22.2%) 0/4 (0%) 2/6 (33.3%) 3/13 (23.1%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 2/6 (33.3%)
    Metabolism and nutrition disorders
    Cachexia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 1/3 (33.3%) 0/6 (0%)
    Decreased appetite (All grades) 1/4 (25%) 0/3 (0%) 3/7 (42.9%) 3/9 (33.3%) 1/4 (25%) 2/6 (33.3%) 4/13 (30.8%) 3/8 (37.5%) 6/15 (40%) 1/3 (33.3%) 1/6 (16.7%)
    Dehydration (All grades) 1/4 (25%) 0/3 (0%) 2/7 (28.6%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 3/13 (23.1%) 1/8 (12.5%) 3/15 (20%) 2/3 (66.7%) 0/6 (0%)
    Hyperglycaemia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 2/13 (15.4%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 3/6 (50%)
    Hyperkalaemia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Hypernatraemia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 1/6 (16.7%)
    Hypokalaemia (All grades) 1/4 (25%) 1/3 (33.3%) 1/7 (14.3%) 1/9 (11.1%) 2/4 (50%) 0/6 (0%) 2/13 (15.4%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Hypomagnaesemia (All grades) 1/4 (25%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 3/15 (20%) 0/3 (0%) 0/6 (0%)
    Hyponatraemia (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 1/4 (25%) 1/6 (16.7%) 2/13 (15.4%) 0/8 (0%) 2/15 (13.3%) 2/3 (66.7%) 0/6 (0%)
    Hypophagia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Hypophosphataemia (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 2/6 (33.3%)
    Malnutrition 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Polydipsia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Vitamin D deficiency (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Musculoskeletal and connective tissue disorders
    Arthralgia (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 2/9 (22.2%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 1/8 (12.5%) 2/15 (13.3%) 0/3 (0%) 0/6 (0%)
    Back pain (All grades) 2/4 (50%) 0/3 (0%) 1/7 (14.3%) 1/9 (11.1%) 0/4 (0%) 1/6 (16.7%) 2/13 (15.4%) 2/8 (25%) 4/15 (26.7%) 0/3 (0%) 0/6 (0%)
    Flank pain (All grades) 1/4 (25%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 1/4 (25%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Groin pain (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Intervertebral disc displacement 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Joint stiffness 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Joint swelling 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Limb discomfort 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Muscle atrophy 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Muscle oedema 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Muscular Stiffness (All Grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Muscular weakness (All grades) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Musculoskeletal chest pain (All grades) 0/4 (0%) 0/3 (0%) 2/7 (28.6%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Musculoskeletal pain 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Musculoskeletal pain (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 2/6 (33.3%) 0/13 (0%) 2/8 (25%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Myalgia (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 4/13 (30.8%) 1/8 (12.5%) 2/15 (13.3%) 0/3 (0%) 0/6 (0%)
    Neck pain (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 1/6 (16.7%) 2/13 (15.4%) 2/8 (25%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Pain in extremity (All grades) 1/4 (25%) 0/3 (0%) 0/7 (0%) 2/9 (22.2%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 1/6 (16.7%)
    Pain in jaw 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Spondylolisthesis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Tenosynovitis stenosans 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain (All grades) 1/4 (25%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Tumour pain (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Nervous system disorders
    Cerebral infarction (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Cognitive disorder (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Dizziness (All grades) 1/4 (25%) 0/3 (0%) 2/7 (28.6%) 3/9 (33.3%) 0/4 (0%) 0/6 (0%) 5/13 (38.5%) 1/8 (12.5%) 2/15 (13.3%) 1/3 (33.3%) 0/6 (0%)
    Dysarthria (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Dysgeusia (All grades) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 1/4 (25%) 1/6 (16.7%) 3/13 (23.1%) 1/8 (12.5%) 1/15 (6.7%) 1/3 (33.3%) 0/6 (0%)
    Encephalopathy (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Haemorrhage intracranial (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Headache (All grades) 1/4 (25%) 0/3 (0%) 0/7 (0%) 2/9 (22.2%) 0/4 (0%) 0/6 (0%) 3/13 (23.1%) 2/8 (25%) 1/15 (6.7%) 1/3 (33.3%) 0/6 (0%)
    Hydrocephalus (All grades) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Hypoaesthesia (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Migraine with aura (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Neuralgia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Neuropathy peripheral 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Paraesthesia (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Peripheral sensory neuropathy 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Presyncope (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Syncope (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Psychiatric disorders
    Anxiety (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Completed suicide 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Confusional state (All grades) 1/4 (25%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Hallucination (All grades) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Insomnia (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 2/13 (15.4%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Mental status changes (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Restlessness 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Renal and urinary disorders
    Acute kidney injury 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 2/15 (13.3%) 0/3 (0%) 0/6 (0%)
    Chromaturia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Dysuria 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 2/13 (15.4%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Haematuria (All grades) 1/4 (25%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 1/6 (16.7%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 1/6 (16.7%)
    Pollakiuria 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Proteinuria (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 2/6 (33.3%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Urinary retention 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 2/13 (15.4%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Urinary tract pain 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Urine abnormality 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Reproductive system and breast disorders
    Benign prostatic hyperplasia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Menstruation irregular 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Penile discharge (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Perineal pain (All grades) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Respiratory, thoracic and mediastinal disorders
    Alveolar lung disease 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Aspiration 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Atelectasis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Cough (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 3/9 (33.3%) 0/4 (0%) 3/6 (50%) 4/13 (30.8%) 5/8 (62.5%) 5/15 (33.3%) 1/3 (33.3%) 0/6 (0%)
    Dysphonia (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 1/3 (33.3%) 0/6 (0%)
    Dyspnoea (All grades) 0/4 (0%) 1/3 (33.3%) 1/7 (14.3%) 4/9 (44.4%) 1/4 (25%) 2/6 (33.3%) 2/13 (15.4%) 4/8 (50%) 2/15 (13.3%) 0/3 (0%) 0/6 (0%)
    Dyspnoea at rest 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Dyspnoea exertional (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 2/13 (15.4%) 2/8 (25%) 1/15 (6.7%) 1/3 (33.3%) 0/6 (0%)
    Epistaxis (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Haemoptysis (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 1/3 (33.3%) 0/6 (0%)
    Hypoxia (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 1/3 (33.3%) 0/6 (0%)
    Lung disorder 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Nasal congestion 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Nasal discharge discolouration 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Oropharyngeal pain (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 2/13 (15.4%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Paranasal sinus hypersecretion 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Pharyngeal erythema (All grade) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Pleural effusion (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/13 (0%) 1/8 (12.5%) 4/15 (26.7%) 1/3 (33.3%) 0/6 (0%)
    Pleuritic pain (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Pneumonia aspiration 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Pneumonitis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 2/3 (66.7%) 0/6 (0%)
    Pneumothorax 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 1/3 (33.3%) 0/6 (0%)
    Productive cough 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 2/13 (15.4%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Pulmonary embolism (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Rales 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Respiratory tract congestion 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Rhinorrhea (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Sinus congestion 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Sneezing 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Tachypnoea 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Throat irritation 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Upper respiratory tract congestion 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Upper-airway cough syndrome 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Skin and subcutaneous tissue disorders
    Acne 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Alopecia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Blister 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Cold sweat (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Dry skin 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 2/13 (15.4%) 1/8 (12.5%) 1/15 (6.7%) 0/3 (0%) 1/6 (16.7%)
    Erythema (All grades) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 3/8 (37.5%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Hair colour changes (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 2/6 (33.3%) 2/13 (15.4%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Hyperhidrosis (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 2/13 (15.4%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Ingrowing nail 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Night sweats (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Palmar-plantar erythrodysaesthesia syndrome 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 1/6 (16.7%)
    Photosensitivity reaction 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 1/6 (16.7%)
    Pruritus (All grades) 0/4 (0%) 0/3 (0%) 3/7 (42.9%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 3/13 (23.1%) 5/8 (62.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Pruritus generalised 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Rash (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 1/4 (25%) 2/6 (33.3%) 2/13 (15.4%) 3/8 (37.5%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Rash erythematous (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Rash generalized (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Rash macular 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 2/13 (15.4%) 2/8 (25%) 2/15 (13.3%) 0/3 (0%) 1/6 (16.7%)
    Rash maculo-papular (All grades) 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 2/9 (22.2%) 1/4 (25%) 1/6 (16.7%) 4/13 (30.8%) 2/8 (25%) 8/15 (53.3%) 0/3 (0%) 3/6 (50%)
    Rash pruritic 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 1/15 (6.7%) 1/3 (33.3%) 0/6 (0%)
    Skin discolouration (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 1/3 (33.3%) 0/6 (0%)
    Skin exfoliation 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Skin hyperpigmentation (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Skin hypopigmentation (All grades) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 1/6 (16.7%)
    Skin lesion (All grades) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 3/13 (23.1%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Swelling face 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 1/8 (12.5%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)
    Vitiligo 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Vascular disorders
    Flushing 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 1/8 (12.5%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Haematoma 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Hot flush 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/13 (0%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 1/6 (16.7%)
    Hyperaemia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/13 (7.7%) 0/8 (0%) 0/15 (0%) 0/3 (0%) 0/6 (0%)
    Hypertension (All grades) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 2/13 (15.4%) 0/8 (0%) 3/15 (20%) 0/3 (0%) 2/6 (33.3%)
    Hypotension (All grades) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 2/13 (15.4%) 0/8 (0%) 1/15 (6.7%) 0/3 (0%) 0/6 (0%)

    Limitations/Caveats

    Enrollment for this study was terminated early for insufficient evidence of clinical efficacy. Some of the planned statistical analyses described in the protocol and Statistical Analysis Plan (SAP) were not performed.

    More Information

    Certain Agreements

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

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Medical Director
    Organization Daiichi Sankyo Inc.
    Phone 908-992-6400
    Email CTRinfo@dsi.com
    Responsible Party:
    Daiichi Sankyo, Inc.
    ClinicalTrials.gov Identifier:
    NCT02452424
    Other Study ID Numbers:
    • PLX108-14
    • KEYNOTE-103
    First Posted:
    May 22, 2015
    Last Update Posted:
    Mar 5, 2020
    Last Verified:
    Feb 1, 2020