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GDC-0449 in Treating Patients With Locally Advanced or Metastatic Solid Tumors

Sponsor
Genentech, Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT00607724
Collaborator
National Cancer Institute (NCI) (NIH), Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)
68
Enrollment
7
Arms
31
Duration (Months)

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as GDC-0449, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.

PURPOSE: This phase I trial is studying the side effects and best dose of GDC-0449 in treating patients with locally advanced or metastatic solid tumors.

Condition or Disease Intervention/Treatment Phase
Phase 1

Detailed Description

OBJECTIVES:

Primary

  • To evaluate the safety and tolerability of escalating doses of systemic Hedgehog antagonist GDC-0449 in patients with locally advanced or metastatic solid tumors.

  • To estimate the maximum tolerated dose of GDC-0449 in these patients.

  • To define the dose-limiting toxicities of GDC-0449 in these patients.

  • To characterize the pharmacokinetic properties of GDC-0449 following a single dose and multiple doses.

  • To determine the recommended phase II dose and schedule of GDC-0449 for efficacy testing based on achievement of the target exposure with an acceptable safety profile.

Secondary

  • To determine whether inhibition of Hedgehog (Hh) signaling by GDC-0449 can be reliably measured in human hair follicles and to define the relationship between this pharmacodynamic (PD) effect in surrogate tissue and GDC-0449 dose and exposure.

  • To make a preliminary assessment of tumor response in patients treated with this drug.

Tertiary

  • To examine modulation of Hh target genes (other than GLI1) by GDC-0449 in hair follicles and/or tumor tissue.

OUTLINE: This is a multicenter study.

Patients receive oral systemic Hedgehog antagonist GDC-0449 once on day 1 and then once or twice daily beginning on day 8 and continuing for up to 49 weeks in the absence of disease progression or unacceptable toxicity.

Patients undergo plasma, urine, and hair sample collection and skin punch biopsies periodically for pharmacokinetic and pharmacodynamic analyses. The plasma and urine samples are analyzed separately using liquid chromatography/tandem mass spectrometry-based methods. Ex vivo plasma protein binding of GDC-0449 is assayed using an equilibrium dialysis approach. Expression levels of Gli1 and other Hedgehog target genes in hair follicle samples and/or tumor tissue are measured at the RNA level using qRT-PCR.

After completion of study therapy, patients are followed at 21 days.

Study Design

Study Type:
Interventional
Actual Enrollment :
68 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
An Open-Label, Phase I Study of Systemic Hedgehog Pathway Antagonist, GDC-0449, in Patients With Locally Advanced or Metastatic Solid Tumors That Are Refractory to Standard Therapy or For Whom No Standard Therapy Exists
Study Start Date :
Apr 1, 2007
Actual Primary Completion Date :
Nov 1, 2009
Actual Study Completion Date :
Nov 1, 2009

Arms and Interventions

Arm Intervention/Treatment
Experimental: Stage 1: GDC-0449 (150 mg)

Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 milligram (mg) on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 150 mg, orally, continuing until disease progression (deterioration of evaluable lesions and/or tumor-related symptoms defined using Response Evaluation Criteria in Solid Tumors Version 1.0 (RECIST v1.0), maximum benefit, or intolerability.

Drug: GDC-0449
Other Names:
  • Hedgehog Pathway Inhibitor

    		•
    Experimental: Stage 1: GDC-0449 (270 mg)

    Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 270 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 270 mg, orally, continuing until disease progression, maximum benefit, or intolerability.

    Drug: GDC-0449
    Other Names:
  • Hedgehog Pathway Inhibitor

    		•
    Experimental: Stage 1: GDC-0449 (540 mg)

    Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 540 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 540 mg, orally, continuing until disease progression, maximum benefit, or intolerability.

    Drug: GDC-0449
    Other Names:
  • Hedgehog Pathway Inhibitor

    		•
    Experimental: Stage 2: BCC [GDC-0449 (150 mg)]

    Participants with basal cell carcinoma (BCC) received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability.

    Drug: GDC-0449
    Other Names:
  • Hedgehog Pathway Inhibitor

    		•
    Experimental: Stage 2: BCC [GDC-0449 (270 mg)]

    Participants with BCC received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 270 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability.

    Drug: GDC-0449
    Other Names:
  • Hedgehog Pathway Inhibitor

    		•
    Experimental: Stage 2:Safety Expansion Cohort [GDC-0449 (150 mg)]

    Participants received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability.

    Drug: GDC-0449
    Other Names:
  • Hedgehog Pathway Inhibitor

    		•
    Experimental: Stage 2: New Formulation [GDC-0449 (150 mg )]

    Participants received a daily oral dose of GDC-0449 Phase II drug product hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability.

    Drug: GDC-0449
    Other Names:
  • Hedgehog Pathway Inhibitor

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Percentage of Participants With Dose-Limiting Toxicities (DLTs) [Up to Week 6]

      A DLT was defined as any Grade 3 or 4 hematologic or major organ toxicity as graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 3.0) that occurred during the first 35 days after the initiation of study drug (Days 1-35) and was attributable to GDC-0449.

    2. Maximum Observed Plasma Concentration (Cmax) After a Single Dose of GDC-0449 [-5 minutes (pre-dose) and 0.5, 1, 2, 4, 8, 24 hours post-dose on Day 1; additionally for stage 1 arms: 48 hours (Day 3), 72 hours (Day 4) post-dose and - 5 minutes (pre-dose) on Day 8]

      Phase I comprised of two stages, a dose-escalation stage with the goal of estimating the maximum tolerated dose (Stage 1), and an expanded cohort to collect additional safety, PK, and pharmacodynamic (PD) data at the proposed Phase II dose (Stage 2). Phase II represented the additional cohort initiated with 150 mg hard gelatin capsule identified from the safety, PK and PD data from Stage 1 of the trial.

    3. Cmax After Multiple Doses of GDC-0449 [-5 minutes (pre-dose), 0.5,1,2,4,8 hours post-dose on Day [D] 1; 2,3,4; -5 minutes (pre-dose) on D8,15,22,29,36,64,92,120,148,176,204,232,260,288,316,344;every 4 weeks after D345; end of treatment and study (up to 28 days after last dose), up to 2 years]

      Cmax was estimated if there were extensive PK sampling in more that 50% of the participants to form a curve.

    4. Time to Maximum Plasma Concentration (Tmax) After a Single Dose of GDC-0449 [-5 minutes (pre-dose) and 0.5, 1, 2, 4, 8, 24 hours post-dose on Day 1; additionally for stage 1 arms: 48 hours (Day 3), 72 hours (Day 4) post-dose and - 5 minutes (pre-dose) on Day 8]

      Phase I comprised of two stages, a dose-escalation stage with the goal of estimating the maximum tolerated dose (Stage 1), and an expanded cohort to collect additional safety, PK, and PD data at the proposed Phase II dose (Stage 2). Phase II represented the additional cohort initiated with 150 mg hard gelatin capsule identified from the safety, PK and PD data from Stage 1 of the trial.

    5. Tmax After Multiple Doses of GDC-0449 [-5 minutes (pre-dose), 0.5,1,2,4,8 hours post-dose on Day [D] 1; 2,3,4; -5 minutes (pre-dose) on D8,15,22,29,36,64,92,120,148,176,204,232,260,288,316,344;every 4 weeks after D345; end of treatment and study (up to 28 days after last dose), up to 2 years]

      Tmax was estimated if there were extensive PK sampling in more that 50% of the participants to form a curve.

    6. Average Plasma Concentration at Steady State (Css, Avg) After Multiple Doses of GDC-0449 [-5 minutes (pre-dose), 0.5,1,2,4,8 hours post-dose on Day [D] 1; 2,3,4; -5 minutes (pre-dose) on D8,15,22,29,36,64,92,120,148,176,204,232,260,288,316,344;every 4 weeks after D345; end of treatment and study (up to 28 days after last dose), up to 2 years]

      Steady state GDC-0449 plasma concentrations (Css) were calculated as an average of plasma concentrations from Study Day 21 (Stage 2) or Study Day 28 (Stage 1) onward.

    7. Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24) After a Single Dose of GDC-0449 [-5 minutes (pre-dose) and 0.5, 1, 2, 4, 8, 24 hours post-dose on Day 1; additionally for stage 1 arms: 48 hours (Day 3), 72 hours (Day 4) post-dose and - 5 minutes (pre-dose) on Day 8]

      AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. Phase I comprised of two stages, a dose-escalation stage with the goal of estimating the maximum tolerated dose (Stage 1), and an expanded cohort to collect additional safety, PK, and PD data at the proposed Phase II dose (Stage 2). Phase II represented the additional cohort initiated with 150 mg hard gelatin capsule identified from the safety, PK and PD data from Stage 1 of the trial.

    8. AUC0-24 After Multiple Doses of GDC-0449 [-5 minutes (pre-dose), 0.5,1,2,4,8 hours post-dose on Day [D] 1; 2,3,4; -5 minutes (pre-dose) on D8,15,22,29,36,64,92,120,148,176,204,232,260,288,316,344;every 4 weeks after D345; end of treatment and study (up to 28 days after last dose), up to 2 years]

      AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. AUC was estimated if there were extensive PK sampling in more that 50% of the participants to form a curve.

    9. Accumulation Index (AI) After Multiple Doses of GDC-0449 [-5 minutes (pre-dose), 0.5,1,2,4,8 hours post-dose on Day [D] 1; 2,3,4; -5 minutes (pre-dose) on D8,15,22,29,36,64,92,120,148,176,204,232,260,288,316,344;every 4 weeks after D345; end of treatment and study (up to 28 days after last dose), up to 2 years]

      AI was calculated using the formula [AI = AUC(0-24) on Day 15/AUC(0-24) on Day 1]. AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. AI was estimated if there were extensive PK sampling in more that 50% of the participants to form a curve.

    Secondary Outcome Measures

    1. Percentage of Participants With a Greater Than (>) 2-Fold Down-Modulation of GLI1 Expression in Skin Biopsy-Derived or Hair Follicle-Derived Messenger Ribonucleic Acid (mRNA) [Baseline up to Day 29]

      Ribonucleic acid (RNA) was extracted from biopsy specimens of noninvolved skin or hair follicles at baseline and at 7 and 21 days after the start of daily drug therapy. Control mRNA was obtained from formalin-fixed, paraffin-embedded samples of normal skin and hair follicles from participants who were not enrolled in the study.

    2. Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR): All Participants [Screening, at Week 8 thereafter every 8 weeks, up to Week 116]

      BOR was defined as the best objective response (complete or partial response determined by two consecutive investigator assessments which were at least 28 days apart) observed during the treatment period according to RECIST v1.0. CR: disappearance of all target lesions (TLs), with any pathological lymph nodes (whether target or non-target) having a reduction in short axis to less than 10 millimeters (mm). PR: at least a 30 percent (%) decrease in the sum of diameters of TLs, taking as reference the baseline (BL) sum diameters.

    3. Percentage of Participants With a BOR of CR or PR: Participants With Basal Cell Carcinoma [Screening, at Week 8 thereafter every 8 weeks, up to Week 116]

      BOR was defined as the best objective response observed during the treatment period according to RECIST v1.0. CR: disappearance of all TLs, with any pathological lymph nodes (whether target or non-target) having a reduction in short axis to less than 10 mm. PR: at least a 30% decrease in the sum of diameters of TLs, taking as reference the BL sum diameters.

    4. Duration of Objective Response: All Participants [Screening, at Week 8 thereafter every 8 weeks, up to Week 116]

      Duration of response during first line therapy is defined as the time from when response (CR or PR) was first documented to first documented disease progression or death (whichever occurs first) during first line therapy. This was only calculated for participants who achieved a best overall response of CR or PR. Participants who did not progress or die after they had a confirmed response were censored at the date of their last tumor measurement or last follow-up for progression of disease during first line therapy.

    5. Duration of Objective Response: Participants With BCC [Screening, at Week 8 thereafter every 8 weeks, up to Week 116]

      Duration of response during first line therapy is defined as the time from when response (CR or PR) was first documented to first documented disease progression or death (whichever occurs first) during first line therapy. This was only calculated for participants who achieved a best overall response of CR or PR. Participants who did not progress or die after they had a confirmed response were censored at the date of their last tumor measurement or last follow-up for progression of disease during first line therapy.

    6. Progression-Free Survival (PFS): All Participants [Screening, at Week 8 thereafter every 8 weeks, up to Week 116]

      PFS was defined as the time from first dose of GDC-0449 to documented disease progression (deterioration of evaluable lesions and/or tumor-related symptoms defined using RECIST v1.0) or death from any cause within 30 days of the last dose of GDC-0449, whichever occurred first.

    7. PFS: Participants With BCC [Screening, at Week 8 thereafter every 8 weeks, up to Week 116]

      PFS was defined as the time from first dose of GDC-0449 to documented disease progression (deterioration of evaluable lesions and/or tumor-related symptoms defined using RECIST v1.0) or death from any cause within 30 days of the last dose of GDC-0449, whichever occurred first.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    DISEASE CHARACTERISTICS:

    • Histologically confirmed locally advanced or metastatic solid tumor that is refractory to standard therapy or for which no standard therapy exists

    • Progressed after first-line and second-line therapy (if there is a second-line therapy that has been shown to provide clinical benefit)

    • Must receive standard second-line therapy if second-line therapy has been shown to provide clinical benefit

    • Evaluable disease by physical examination, imaging, and/or one of the following:

    • Two rising prostate-specific antigen (PSA) levels ≥ 2 weeks apart, with one obtained during screening (for patients with prostate cancer)

    • Two rising CA-125 levels ≥ 2 weeks apart, with one obtained during screening (for patients with ovarian cancer)

    • No CNS cancer, either primary lesions or metastatic disease, as the current malignancy

    • No pleural effusions, ascites, or leptomeningeal disease as the only manifestation of the current malignancy

    PATIENT CHARACTERISTICS:

    • ECOG performance status 0-2

    • Granulocyte count ≥ 1,500/μL

    • Platelet count ≥ 100,000/μL

    • Hemoglobin ≥ 9 g/dL

    • Serum bilirubin normal

    • Alkaline phosphatase ≤ 1.5 times upper limit of normal (ULN) (≤ 4 times ULN for patients with liver or bone metastases)

    • AST and ALT ≤ 1.5 times ULN (≤ 5 times the ULN for patients with liver metastases)

    • Serum creatinine ≤ 1.5 mg/dL

    • INR < 1.3

    • aPTT ≤ 1.5 times ULN

    • Fasting total serum cholesterol ≤ 220 mg/dL (without cholesterol-lowering drugs)

    • Not pregnant or nursing

    • Negative pregnancy test

    • Fertile patients must use effective contraception

    • Able and willing to swallow pills

    • No malabsorption syndrome or other condition that would interfere with enteral absorption

    • No history of significant atherosclerotic disease, including the following:

    • Coronary artery disease (i.e., myocardial infarction within the past year or unstable angina)

    • Documented carotid atheromas

    • No history of congestive heart failure or ventricular arrhythmia requiring medication

    • No congenital long QT syndrome

    • No baseline QTc intervals > 0.47 seconds on two of three baseline 12-lead ECGs recorded during the screening period

    • No active infection requiring intravenous antibiotics

    • No known HIV infection

    • No uncontrolled hypocalcemia, hypomagnesemia, or hypokalemia, defined as less than the lower limit of normal for the institution despite adequate electrolyte supplementation

    • No history of clinically important liver disease, including cirrhosis or viral or other hepatitis

    • No current alcohol abuse

    • No significant traumatic injury within the past 3 weeks

    • No other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the study results or renders the patient at high risk from treatment complications

    PRIOR CONCURRENT THERAPY:

    • At least 4 weeks since prior chemotherapy, investigational therapy, radiotherapy, or major surgical procedure and recovered

    • No concurrent medications with narrow therapeutic indices that are cytochrome P450 substrates (warfarin sodium [Coumadin®])

    • No concurrent medications known to prolong the QT interval, including any of the following:

    • Quinidine or other anti-arrhythmic agents

    • Haloperidol, fluoxetine, paroxetine, or sertraline

    • Pentamidine, fluoroquinolone, or macrolide antibiotics

    • No concurrent medications that may interfere with the metabolism of GDC-0449 (e.g., ketoconazole)

    • No concurrent grapefruit juice

    Contacts and Locations

    Locations

    No locations specified.

    Sponsors and Collaborators

    • Genentech, Inc.
    • National Cancer Institute (NCI)
    • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

    Investigators

    • Study Director: Clinical Trials, Hoffmann-La Roche

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Genentech, Inc.
    ClinicalTrials.gov Identifier:
    NCT00607724
    Other Study ID Numbers:
    • CDR0000585468
    • JHOC-J06131
    • GENETECH-SHH3925g
    • NCT00862771
    First Posted:
    Feb 6, 2008
    Last Update Posted:
    Oct 8, 2015
    Last Verified:
    Sep 1, 2015
    Keywords provided by Genentech, Inc.
    unspecified adult solid tumor, protocol specific
    Additional relevant MeSH terms:
    Neoplasms

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Stage 1: GDC-0449 (150 mg) Stage 1: GDC-0449 (270 mg) Stage 1: GDC-0449 (540 mg) Stage 2: Basal Cell Carcinoma [GDC-0449 (150 mg)] Stage 2: Basal Cell Carcinoma [GDC-0449 (270 mg)] Stage 2:Safety Expansion Cohort [GDC-0449 (150 mg)] Stage 2: New Formulation [GDC-0449 (150 mg )]
    Arm/Group Description Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 milligram (mg) on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 150 mg, orally, continuing until disease progression (deterioration of evaluable lesions and/or tumor-related symptoms defined using Response Evaluation Criteria in Solid Tumors Version 1.0 (RECIST v1.0), maximum benefit, or intolerability. Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 270 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 270 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 540 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 540 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants with basal cell carcinoma (BCC) received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability. Participants with BCC received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 270 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability. Participants received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability. Participants received a daily oral dose of GDC-0449 Phase II drug product hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability.
    Period Title: Stage 1: Dose Escalation
    STARTED 7 9 4 0 0 0 0
    COMPLETED 0 1 0 0 0 0 0
    NOT COMPLETED 7 8 4 0 0 0 0
    Period Title: Stage 1: Dose Escalation
    STARTED 0 0 0 6 14 12 16
    COMPLETED 0 0 0 1 5 0 5
    NOT COMPLETED 0 0 0 5 9 12 11

    Baseline Characteristics

    Arm/Group Title Stage 1: GDC-0449 (150 mg) Stage 1: GDC-0449 (270 mg) Stage 1: GDC-0449 (540 mg) Stage 2: Basal Cell Carcinoma [GDC-0449 (150 mg)] Stage 2: Basal Cell Carcinoma [GDC-0449 (270 mg)] Stage 2:Safety Expansion Cohort [GDC-0449 (150 mg)] Stage 2: New Formulation [GDC-0449 (150 mg )] Total
    Arm/Group Description Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 150 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 270 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 270 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 540 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 540 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants with BCC received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability. Participants with BCC received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 270 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability. Participants received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability. Participants received a daily oral dose of GDC-0449 Phase II drug product hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability Total of all reporting groups
    Overall Participants 7 9 4 6 14 12 16 68
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    57.6
    (10.5)
    59.9
    (12.6)
    42.3
    (15.3)
    54.2
    (15.3)
    54.7
    (11.2)
    55.3
    (14.8)
    54.6
    (11.0)
    55.0
    (12.6)
    Sex: Female, Male (Count of Participants)
    Female
    2
    28.6%
    5
    55.6%
    1
    25%
    1
    16.7%
    4
    28.6%
    5
    41.7%
    6
    37.5%
    24
    35.3%
    Male
    5
    71.4%
    4
    44.4%
    3
    75%
    5
    83.3%
    10
    71.4%
    7
    58.3%
    10
    62.5%
    44
    64.7%

    Outcome Measures

    1. Primary Outcome
    Title Percentage of Participants With Dose-Limiting Toxicities (DLTs)
    Description A DLT was defined as any Grade 3 or 4 hematologic or major organ toxicity as graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 3.0) that occurred during the first 35 days after the initiation of study drug (Days 1-35) and was attributable to GDC-0449.
    Time Frame Up to Week 6

    Outcome Measure Data

    Analysis Population Description
    Safety-evaluable population.
    Arm/Group Title Stage 1: GDC-0449 (150 mg) Stage 1: GDC-0449 (270 mg) Stage 1: GDC-0449 (540 mg) Stage 2: Basal Cell Carcinoma (GDC-0449 [150 mg]) Stage 2: Basal Cell Carcinoma (GDC-0449 [270 mg]) Stage 2:Safety Expansion Cohort (GDC-0449 [150 mg]) Stage 2: New Formulation (GDC-0449 [150 mg])
    Arm/Group Description Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 150 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 270 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 270 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 540 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 540 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants with BCC received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability. Participants with BCC received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 270 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability. Participants received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability. Participants received GDC-0449 Phase II drug product as 150-mg hard gelatin capsules daily, orally, starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability.
    Measure Participants 7 9 4 6 14 12 16
    Number [percentage of participants]
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2. Primary Outcome
    Title Maximum Observed Plasma Concentration (Cmax) After a Single Dose of GDC-0449
    Description Phase I comprised of two stages, a dose-escalation stage with the goal of estimating the maximum tolerated dose (Stage 1), and an expanded cohort to collect additional safety, PK, and pharmacodynamic (PD) data at the proposed Phase II dose (Stage 2). Phase II represented the additional cohort initiated with 150 mg hard gelatin capsule identified from the safety, PK and PD data from Stage 1 of the trial.
    Time Frame -5 minutes (pre-dose) and 0.5, 1, 2, 4, 8, 24 hours post-dose on Day 1; additionally for stage 1 arms: 48 hours (Day 3), 72 hours (Day 4) post-dose and - 5 minutes (pre-dose) on Day 8

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK)-evaluable population included participants who had at least Day 1 PK samples available.
    Arm/Group Title Stage 1: GDC-0449 (150 mg) Stage 1: GDC-0449 (270 mg) Stage 1: GDC-0449 (540 mg) Stage 2: New Formulation (GDC-0449 [150 mg])
    Arm/Group Description Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 150 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 270 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 270 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 540 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 540 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants received a daily oral dose of GDC-0449 Phase II drug product hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability.
    Measure Participants 7 9 4 16
    Phase I
    3.58
    (1.34)
    6.34
    (3.40)
    6.81
    (2.69)
    NA
    (NA)
    Phase II
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    7.2
    (3.38)
    3. Primary Outcome
    Title Cmax After Multiple Doses of GDC-0449
    Description Cmax was estimated if there were extensive PK sampling in more that 50% of the participants to form a curve.
    Time Frame -5 minutes (pre-dose), 0.5,1,2,4,8 hours post-dose on Day [D] 1; 2,3,4; -5 minutes (pre-dose) on D8,15,22,29,36,64,92,120,148,176,204,232,260,288,316,344;every 4 weeks after D345; end of treatment and study (up to 28 days after last dose), up to 2 years

    Outcome Measure Data

    Analysis Population Description
    Cmax was not reported as there were <50% participants with extensive PK sampling and the PK profiles were flat over 24 hours at steady state which did not allow estimation of Cmax.
    Arm/Group Title Stage 1+Stage 2: GDC-0449 (150 mg) Stage 1+Stage 2: GDC-0449 (270 mg) Stage 1: GDC-0449 (540 mg)
    Arm/Group Description Participants with any tumor or BCC or safety expansion cohort received single or daily oral dose of GDC-0449 hard gelatin capsules at 150 mg starting on Day 1 (Stage 1 and Stage 2) and/or Day 8 (Stage 1), until disease progression, maximum benefit, or intolerability. Participants with any tumor or BCC or safety expansion cohort received single or daily oral dose of GDC-0449 hard gelatin capsules at 270 mg starting on Day 1 (Stage 1 and Stage 2) and/or Day 8 (Stage 1), until disease progression, maximum benefit, or intolerability. Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 540 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 540 mg, orally, continuing until disease progression, maximum benefit, or intolerability.
    Measure Participants 0 0 0
    4. Primary Outcome
    Title Time to Maximum Plasma Concentration (Tmax) After a Single Dose of GDC-0449
    Description Phase I comprised of two stages, a dose-escalation stage with the goal of estimating the maximum tolerated dose (Stage 1), and an expanded cohort to collect additional safety, PK, and PD data at the proposed Phase II dose (Stage 2). Phase II represented the additional cohort initiated with 150 mg hard gelatin capsule identified from the safety, PK and PD data from Stage 1 of the trial.
    Time Frame -5 minutes (pre-dose) and 0.5, 1, 2, 4, 8, 24 hours post-dose on Day 1; additionally for stage 1 arms: 48 hours (Day 3), 72 hours (Day 4) post-dose and - 5 minutes (pre-dose) on Day 8

    Outcome Measure Data

    Analysis Population Description
    PK-evaluable population.
    Arm/Group Title Stage 1: GDC-0449 (150 mg) Stage 1: GDC-0449 (270 mg) Stage 1: GDC-0449 (540 mg) Stage 2: New Formulation (GDC-0449 [150 mg])
    Arm/Group Description Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 150 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 270 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 270 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 540 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 540 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants received a daily oral dose of GDC-0449 Phase II drug product hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability.
    Measure Participants 7 9 4 16
    Phase I
    2
    2
    2.5
    NA
    Phase II
    NA
    NA
    NA
    1
    5. Primary Outcome
    Title Tmax After Multiple Doses of GDC-0449
    Description Tmax was estimated if there were extensive PK sampling in more that 50% of the participants to form a curve.
    Time Frame -5 minutes (pre-dose), 0.5,1,2,4,8 hours post-dose on Day [D] 1; 2,3,4; -5 minutes (pre-dose) on D8,15,22,29,36,64,92,120,148,176,204,232,260,288,316,344;every 4 weeks after D345; end of treatment and study (up to 28 days after last dose), up to 2 years

    Outcome Measure Data

    Analysis Population Description
    Cmax was not reported as there were <50% participants with extensive PK sampling and the PK profiles were flat over 24 hours at steady state which did not allow estimation of Cmax, and as Tmax was related to Cmax, it was also not estimated.
    Arm/Group Title Stage 1+Stage 2: GDC-0449 (150 mg) Stage 1+Stage 2: GDC-0449 (270 mg) Stage 1: GDC-0449 (540 mg)
    Arm/Group Description Participants with any tumor or BCC or safety expansion cohort received single or daily oral dose of GDC-0449 hard gelatin capsules at 150 mg starting on Day 1 (Stage 1 and Stage 2) and/or Day 8 (Stage 1), until disease progression, maximum benefit, or intolerability. Participants with any tumor or BCC or safety expansion cohort received single or daily oral dose of GDC-0449 hard gelatin capsules at 150 mg starting on Day 1 (Stage 1 and Stage 2) and/or Day 8 (Stage 1), until disease progression, maximum benefit, or intolerability. Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 540 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 540 mg, orally, continuing until disease progression, maximum benefit, or intolerability.
    Measure Participants 0 0 0
    6. Primary Outcome
    Title Average Plasma Concentration at Steady State (Css, Avg) After Multiple Doses of GDC-0449
    Description Steady state GDC-0449 plasma concentrations (Css) were calculated as an average of plasma concentrations from Study Day 21 (Stage 2) or Study Day 28 (Stage 1) onward.
    Time Frame -5 minutes (pre-dose), 0.5,1,2,4,8 hours post-dose on Day [D] 1; 2,3,4; -5 minutes (pre-dose) on D8,15,22,29,36,64,92,120,148,176,204,232,260,288,316,344;every 4 weeks after D345; end of treatment and study (up to 28 days after last dose), up to 2 years

    Outcome Measure Data

    Analysis Population Description
    PK-evaluable population. Here "number of participants analyzed" = participants evaluable for this measure.
    Arm/Group Title Stage 1+Stage 2: GDC-0449 (150 mg) Stage 1+Stage 2: GDC-0449 (270 mg) Stage 1: GDC-0449 (540 mg) Stage 2: New Formulation (GDC-0449 [150 mg])
    Arm/Group Description Participants with any tumor or BCC or safety expansion cohort received single or daily oral dose of GDC-0449 hard gelatin capsules at 150 mg starting on Day 1 (Stage 1 and Stage 2) and/or Day 8 (Stage 1), until disease progression, maximum benefit, or intolerability. Participants with any tumor or BCC or safety expansion cohort received single or daily oral dose of GDC-0449 hard gelatin capsules at 270 mg starting on Day 1 (Stage 1 and Stage 2) and/or Day 8 (Stage 1), until disease progression, maximum benefit, or intolerability. Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 540 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 540 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants received a daily oral dose of GDC-0449 Phase II drug product hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability.
    Measure Participants 38 21 4 15
    Mean (Standard Deviation) [mcM]
    23.1
    (10.6)
    19.8
    (9.51)
    22.2
    (8.38)
    24.5
    (6.85)
    7. Primary Outcome
    Title Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24) After a Single Dose of GDC-0449
    Description AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. Phase I comprised of two stages, a dose-escalation stage with the goal of estimating the maximum tolerated dose (Stage 1), and an expanded cohort to collect additional safety, PK, and PD data at the proposed Phase II dose (Stage 2). Phase II represented the additional cohort initiated with 150 mg hard gelatin capsule identified from the safety, PK and PD data from Stage 1 of the trial.
    Time Frame -5 minutes (pre-dose) and 0.5, 1, 2, 4, 8, 24 hours post-dose on Day 1; additionally for stage 1 arms: 48 hours (Day 3), 72 hours (Day 4) post-dose and - 5 minutes (pre-dose) on Day 8

    Outcome Measure Data

    Analysis Population Description
    PK-evaluable population.
    Arm/Group Title Stage 1: GDC-0449 (150 mg) Stage 1: GDC-0449 (270 mg) Stage 1: GDC-0449 (540 mg) Stage 2: New Formulation (GDC-0449 [150 mg])
    Arm/Group Description Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 150 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 270 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 270 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 540 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 540 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants received a daily oral dose of GDC-0449 Phase II drug product hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability.
    Measure Participants 7 9 4 16
    Phase I
    2.22
    (0.966)
    4.24
    (1.95)
    4.79
    (2.22)
    NA
    (NA)
    Phase II
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    5.2
    (2.79)
    8. Primary Outcome
    Title AUC0-24 After Multiple Doses of GDC-0449
    Description AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. AUC was estimated if there were extensive PK sampling in more that 50% of the participants to form a curve.
    Time Frame -5 minutes (pre-dose), 0.5,1,2,4,8 hours post-dose on Day [D] 1; 2,3,4; -5 minutes (pre-dose) on D8,15,22,29,36,64,92,120,148,176,204,232,260,288,316,344;every 4 weeks after D345; end of treatment and study (up to 28 days after last dose), up to 2 years

    Outcome Measure Data

    Analysis Population Description
    AUC0-24 was not reported as there were <50% participants with extensive PK sampling and the PK profiles were flat over 24 hours at steady state which did not allow estimation of AUC0-24.
    Arm/Group Title Stage 1+Stage 2: GDC-0449 (150 mg) Stage 1+Stage 2: GDC-0449 (270 mg) Stage 1: GDC-0449 (540 mg)
    Arm/Group Description Participants with any tumor or BCC or safety expansion cohort received single or daily oral dose of GDC-0449 hard gelatin capsules at 150 mg starting on Day 1 (Stage 1 and Stage 2) and/or Day 8 (Stage 1), until disease progression, maximum benefit, or intolerability. Participants with any tumor or BCC or safety expansion cohort received single or daily oral dose of GDC-0449 hard gelatin capsules at 270 mg starting on Day 1 (Stage 1 and Stage 2) and/or Day 8 (Stage 1), until disease progression, maximum benefit, or intolerability. Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 540 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 540 mg, orally, continuing until disease progression, maximum benefit, or intolerability.
    Measure Participants 0 0 0
    9. Primary Outcome
    Title Accumulation Index (AI) After Multiple Doses of GDC-0449
    Description AI was calculated using the formula [AI = AUC(0-24) on Day 15/AUC(0-24) on Day 1]. AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. AI was estimated if there were extensive PK sampling in more that 50% of the participants to form a curve.
    Time Frame -5 minutes (pre-dose), 0.5,1,2,4,8 hours post-dose on Day [D] 1; 2,3,4; -5 minutes (pre-dose) on D8,15,22,29,36,64,92,120,148,176,204,232,260,288,316,344;every 4 weeks after D345; end of treatment and study (up to 28 days after last dose), up to 2 years

    Outcome Measure Data

    Analysis Population Description
    AI was not reported as there were <50% participants with extensive PK sampling and the PK profiles were flat over 24 hours at steady state which did not allow estimation of AI.
    Arm/Group Title Stage 1: GDC-0449
    Arm/Group Description Included participants with any tumor who received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg, 270 mg and 540 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 150 mg, 270 mg and 540 mg orally, continuing until disease progression, maximum benefit, or intolerability.
    Measure Participants 0
    10. Secondary Outcome
    Title Percentage of Participants With a Greater Than (>) 2-Fold Down-Modulation of GLI1 Expression in Skin Biopsy-Derived or Hair Follicle-Derived Messenger Ribonucleic Acid (mRNA)
    Description Ribonucleic acid (RNA) was extracted from biopsy specimens of noninvolved skin or hair follicles at baseline and at 7 and 21 days after the start of daily drug therapy. Control mRNA was obtained from formalin-fixed, paraffin-embedded samples of normal skin and hair follicles from participants who were not enrolled in the study.
    Time Frame Baseline up to Day 29

    Outcome Measure Data

    Analysis Population Description
    Pharmacodynamic-evaluable population included participants who had hair and/or skin samples available from Day 1 and at least one post-baseline sample while on study treatment. Here "number of participants analyzed" = participants evaluable for this measure and "n"= participants evaluable for the specific category.
    Arm/Group Title All Participants
    Arm/Group Description Included all participants from Stage 1 and Stage 2.
    Measure Participants 34
    Skin biopsy (n = 34)
    73.5
    1050%
    Hair follicle (n = 20)
    30.0
    428.6%
    11. Secondary Outcome
    Title Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR): All Participants
    Description BOR was defined as the best objective response (complete or partial response determined by two consecutive investigator assessments which were at least 28 days apart) observed during the treatment period according to RECIST v1.0. CR: disappearance of all target lesions (TLs), with any pathological lymph nodes (whether target or non-target) having a reduction in short axis to less than 10 millimeters (mm). PR: at least a 30 percent (%) decrease in the sum of diameters of TLs, taking as reference the baseline (BL) sum diameters.
    Time Frame Screening, at Week 8 thereafter every 8 weeks, up to Week 116

    Outcome Measure Data

    Analysis Population Description
    Efficacy-evaluable population were those with measurable disease at baseline and who received at least 1 dose of GDC-0449 and either had a post-baseline tumor assessment or progressed before any tumor assessment.
    Arm/Group Title Stage 1: GDC-0449 (150 mg) Stage 1: GDC-0449 (270 mg) Stage 1: GDC-0449 (540 mg) Stage 2: Basal Cell Carcinoma (GDC-0449 [150 mg]) Stage 2: Basal Cell Carcinoma (GDC-0449 [270 mg]) Stage 2:Safety Expansion Cohort (GDC-0449 [150 mg]) Stage 2: New Formulation (GDC-0449 [150 mg])
    Arm/Group Description Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 150 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 270 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 270 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 540 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 540 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants with BCC received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability. Participants with BCC received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 270 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability. Participants received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability. Participants received a daily oral dose of GDC-0449 Phase II drug product hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability.
    Measure Participants 7 9 4 6 14 10 16
    Number [percentage of participants]
    14.3
    204.3%
    11.1
    123.3%
    0.0
    0%
    66.7
    1111.7%
    42.9
    306.4%
    0.0
    0%
    37.5
    234.4%
    12. Secondary Outcome
    Title Percentage of Participants With a BOR of CR or PR: Participants With Basal Cell Carcinoma
    Description BOR was defined as the best objective response observed during the treatment period according to RECIST v1.0. CR: disappearance of all TLs, with any pathological lymph nodes (whether target or non-target) having a reduction in short axis to less than 10 mm. PR: at least a 30% decrease in the sum of diameters of TLs, taking as reference the BL sum diameters.
    Time Frame Screening, at Week 8 thereafter every 8 weeks, up to Week 116

    Outcome Measure Data

    Analysis Population Description
    Efficacy-evaluable population; only participants with BCC were included in the analysis.
    Arm/Group Title Stage 1: GDC-0449 (150 mg) Stage 1: GDC-0449 (270 mg) Stage 1: GDC-0449 (540 mg) Stage 2: Basal Cell Carcinoma (GDC-0449 [150 mg]) Stage 2: Basal Cell Carcinoma (GDC-0449 [270 mg]) Stage 2: New Formulation (GDC-0449 [150 mg])
    Arm/Group Description Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 150 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 270 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 270 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 540 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 540 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants with BCC received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability. Participants with BCC received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 270 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability. Participants received a daily oral dose of GDC-0449 Phase II drug product hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability.
    Measure Participants 1 1 1 6 14 10
    Number [percentage of participants]
    100.0
    1428.6%
    100.0
    1111.1%
    0.0
    0%
    66.7
    1111.7%
    42.9
    306.4%
    60.0
    500%
    13. Secondary Outcome
    Title Duration of Objective Response: All Participants
    Description Duration of response during first line therapy is defined as the time from when response (CR or PR) was first documented to first documented disease progression or death (whichever occurs first) during first line therapy. This was only calculated for participants who achieved a best overall response of CR or PR. Participants who did not progress or die after they had a confirmed response were censored at the date of their last tumor measurement or last follow-up for progression of disease during first line therapy.
    Time Frame Screening, at Week 8 thereafter every 8 weeks, up to Week 116

    Outcome Measure Data

    Analysis Population Description
    Efficacy-evaluable population; only participants who achieved a best overall response of CR or PR were included in the analysis.
    Arm/Group Title Stage 1: GDC-0449 (150 mg) Stage 1: GDC-0449 (270 mg) Stage 1: GDC-0449 (540 mg) Stage 2: Basal Cell Carcinoma (GDC-0449 [150 mg]) Stage 2: Basal Cell Carcinoma (GDC-0449 [270 mg]) Stage 2:Safety Expansion Cohort (GDC-0449 [150 mg]) Stage 2: New Formulation (GDC-0449 [150 mg])
    Arm/Group Description Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 150 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 270 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 270 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 540 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 540 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants with BCC received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability. Participants with BCC received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 270 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability. Participants received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability. Participants received a daily oral dose of GDC-0449 Phase II drug product hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability.
    Measure Participants 1 1 0 4 6 0 6
    Median (95% Confidence Interval) [months]
    9.2
    NA
    6.1
    NA
    8.3
    14. Secondary Outcome
    Title Duration of Objective Response: Participants With BCC
    Description Duration of response during first line therapy is defined as the time from when response (CR or PR) was first documented to first documented disease progression or death (whichever occurs first) during first line therapy. This was only calculated for participants who achieved a best overall response of CR or PR. Participants who did not progress or die after they had a confirmed response were censored at the date of their last tumor measurement or last follow-up for progression of disease during first line therapy.
    Time Frame Screening, at Week 8 thereafter every 8 weeks, up to Week 116

    Outcome Measure Data

    Analysis Population Description
    Efficacy-evaluable participants; only participants with BCC who achieved a best overall response of CR or PR were included in the analysis.
    Arm/Group Title Stage 1+Stage 2: GDC-0449 (150 mg) Stage 1+Stage 2: GDC-0449 (270 mg) Stage 1: GDC-0449 (540 mg)
    Arm/Group Description Participants with any tumor or BCC or safety expansion cohort received single or daily oral dose of GDC-0449 hard gelatin capsules at 150 mg starting on Day 1 (Stage 1 and Stage 2) and/or Day 8 (Stage 1), until disease progression, maximum benefit, or intolerability. Participants with any tumor or BCC or safety expansion cohort received single or daily oral dose of GDC-0449 hard gelatin capsules at 270 mg starting on Day 1 (Stage 1 and Stage 2) and/or Day 8 (Stage 1), until disease progression, maximum benefit, or intolerability. Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 540 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 540 mg, orally, continuing until disease progression, maximum benefit, or intolerability.
    Measure Participants 11 7 0
    Median (Full Range) [months]
    8.3
    NA
    15. Secondary Outcome
    Title Progression-Free Survival (PFS): All Participants
    Description PFS was defined as the time from first dose of GDC-0449 to documented disease progression (deterioration of evaluable lesions and/or tumor-related symptoms defined using RECIST v1.0) or death from any cause within 30 days of the last dose of GDC-0449, whichever occurred first.
    Time Frame Screening, at Week 8 thereafter every 8 weeks, up to Week 116

    Outcome Measure Data

    Analysis Population Description
    Efficacy-evaluable population. Number of participants censored for Stage 1 150 mg, 270 mg, and 540 mg were 1, 2, and 1 subjects, respectively and for Stage 2 BCC 150 mg, 270 mg, Stage 2 Safety Expansion Cohort 150 mg, and Stage 2 New Formulation 150 mg were 2, 6, 1, and 6 subjects, respectively.
    Arm/Group Title Stage 1: GDC-0449 (150 mg) Stage 1: GDC-0449 (270 mg) Stage 1: GDC-0449 (540 mg) Stage 2: Basal Cell Carcinoma (GDC-0449 [150 mg]) Stage 2: Basal Cell Carcinoma (GDC-0449 [270 mg]) Stage 2:Safety Expansion Cohort (GDC-0449 [150 mg]) Stage 2: New Formulation (GDC-0449 [150 mg])
    Arm/Group Description Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 150 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 270 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 270 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 540 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 540 mg, orally, continuing until disease progression, maximum benefit, or intolerability. Participants with BCC received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability. Participants with BCC received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 270 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability. Participants received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability. Participants received a daily oral dose of GDC-0449 Phase II drug product hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability.
    Measure Participants 7 9 4 6 14 10 16
    Median (95% Confidence Interval) [months]
    2.0
    1.6
    2.1
    9.6
    12.7
    1.8
    7.1
    16. Secondary Outcome
    Title PFS: Participants With BCC
    Description PFS was defined as the time from first dose of GDC-0449 to documented disease progression (deterioration of evaluable lesions and/or tumor-related symptoms defined using RECIST v1.0) or death from any cause within 30 days of the last dose of GDC-0449, whichever occurred first.
    Time Frame Screening, at Week 8 thereafter every 8 weeks, up to Week 116

    Outcome Measure Data

    Analysis Population Description
    Efficacy-evaluable population; only participants with BCC were included in the analysis. Number of participants censored for Stage 1+Stage 2 150 mg, and Stage 1+Stage 2 270 mg were 8 and 7 subjects, respectively, and no subject censored from Stage 1 540 mg group.
    Arm/Group Title Stage 1+Stage 2: GDC-0449 (150 mg) Stage 1+Stage 2: GDC-0449 (270 mg) Stage 1: GDC-0449 (540 mg)
    Arm/Group Description Participants with any tumor or BCC or safety expansion cohort received single or daily oral dose of GDC-0449 hard gelatin capsules at 150 mg starting on Day 1 (Stage 1 and Stage 2) and/or Day 8 (Stage 1), until disease progression, maximum benefit, or intolerability. Participants with any tumor or BCC or safety expansion cohort received single or daily oral dose of GDC-0449 hard gelatin capsules at 270 mg starting on Day 1 (Stage 1 and Stage 2) and/or Day 8 (Stage 1), until disease progression, maximum benefit, or intolerability. Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 540 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 540 mg, orally, continuing until disease progression, maximum benefit, or intolerability.
    Measure Participants 17 15 1
    Median (95% Confidence Interval) [months]
    10.8
    12.7
    1.2

    Adverse Events

    Time Frame From Screening up to 28 days after the last dose of GDC-0449 (Week 116).
    Adverse Event Reporting Description
    Arm/Group Title Stage 1: GDC-0449 (150 mg) Stage 1: GDC-0449 (270 mg) Stage 1: GDC-0449 (540 mg) Stage 2: Basal Cell Carcinoma [GDC-0449 (150 mg)] Stage 2: Basal Cell Carcinoma [GDC-0449 (270 mg)] Stage 2:Safety Expansion Cohort [GDC-0449 (150 mg)] Stage 2: New Formulation [GDC-0449 (150 mg )]
    Arm/Group Description Participants received single dose of GDC-0449 hard gelatin capsules at 150 mg on Day 1, thereafter Day 8 received daily until disease progression, maximum benefit, or intolerability. Stage 1: GDC-0449 (270 mg) Participants received single dose of GDC-0449 hard gelatin capsules at 270 mg on Day 1, thereafter Day 8 received daily dose until disease progression, maximum benefit, or intolerability. Participants received single dose of GDC-0449 hard gelatin capsules at 540 mg on Day 1, thereafter Day 8 received daily dose until disease progression, maximum benefit, or intolerability. Participants with basal cell carcinoma (BCC) received daily dose of GDC-0449 hard gelatin capsules at 150 mg on Day 1 until disease progression, maximum benefit, or intolerability. Participants with basal cell carcinoma (BCC) received daily dose of GDC-0449 hard gelatin capsules at 270 mg on Day 1 until disease progression, maximum benefit, or intolerability. Participants with tolerable safety, pharmacokinetic and pharmacodynamic data from Stage 1 received daily dose of GDC-0449 hard gelatin capsules at 150 mg on Day 1 until disease progression, maximum benefit, or intolerability. Participants received a daily oral dose of GDC-0449 Phase II drug product hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability.
    All Cause Mortality
    Stage 1: GDC-0449 (150 mg) Stage 1: GDC-0449 (270 mg) Stage 1: GDC-0449 (540 mg) Stage 2: Basal Cell Carcinoma [GDC-0449 (150 mg)] Stage 2: Basal Cell Carcinoma [GDC-0449 (270 mg)] Stage 2:Safety Expansion Cohort [GDC-0449 (150 mg)] Stage 2: New Formulation [GDC-0449 (150 mg )]
    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 / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Stage 1: GDC-0449 (150 mg) Stage 1: GDC-0449 (270 mg) Stage 1: GDC-0449 (540 mg) Stage 2: Basal Cell Carcinoma [GDC-0449 (150 mg)] Stage 2: Basal Cell Carcinoma [GDC-0449 (270 mg)] Stage 2:Safety Expansion Cohort [GDC-0449 (150 mg)] Stage 2: New Formulation [GDC-0449 (150 mg )]
    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 3/7 (42.9%) 2/9 (22.2%) 1/4 (25%) 2/6 (33.3%) 4/14 (28.6%) 4/12 (33.3%) 4/16 (25%)
    Cardiac disorders
    Atrial fibrillation 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Gastrointestinal disorders
    Abdominal pain 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 2/12 (16.7%) 0/16 (0%)
    Duodenal ulcer 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Impaired gastric emptying 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Intestinal obstruction 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Vomiting 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    General disorders
    Pain 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Infections and infestations
    Infection 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Pneumonia 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Pyelonephritis 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Injury, poisoning and procedural complications
    Transfusion reaction 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Metabolism and nutrition disorders
    Hyponatraemia 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Hyperkalaemia 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Dehydration 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pancreatic carcinoma metastatic 1/7 (14.3%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Adenocarcinoma pancreas 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Pancreatic carcinoma 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Chondrosarcoma 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Basal cell carcinoma 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Nervous system disorders
    Presyncope 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Psychiatric disorders
    Paranoia 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Confusional state 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Vascular disorders
    Haemorrhage 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Other (Not Including Serious) Adverse Events
    Stage 1: GDC-0449 (150 mg) Stage 1: GDC-0449 (270 mg) Stage 1: GDC-0449 (540 mg) Stage 2: Basal Cell Carcinoma [GDC-0449 (150 mg)] Stage 2: Basal Cell Carcinoma [GDC-0449 (270 mg)] Stage 2:Safety Expansion Cohort [GDC-0449 (150 mg)] Stage 2: New Formulation [GDC-0449 (150 mg )]
    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 7/7 (100%) 9/9 (100%) 4/4 (100%) 6/6 (100%) 14/14 (100%) 12/12 (100%) 16/16 (100%)
    Blood and lymphatic system disorders
    Anaemia 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 2/6 (33.3%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Leukopenia 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Lymph node pain 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Lymphopenia 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Neutropenia 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Thrombocytopenia 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Cardiac disorders
    Sinus tachycardia 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Cardiac flutter 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Palpitations 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Pericardial effusion 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Sinus bradycardia 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Tachycardia 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Ear and labyrinth disorders
    Tinnitus 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Auricular swelling 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Cerumen impaction 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Dysacusis 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Ear canal stenosis 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Ear haemorrhage 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Ear pain 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Hyperacusis 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Hypoacusis 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Eye disorders
    Vision blurred 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 2/16 (12.5%)
    Lacrimation increased 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Vitreous floaters 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Arcus lipoides 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Conjunctival hyperaemia 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Dry eye 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Eye discharge 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Keratitis 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Ocular hyperaemia 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Photophobia 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Photopsia 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Pterygium 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Visual acuity reduced 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Gastrointestinal disorders
    Nausea 1/7 (14.3%) 5/9 (55.6%) 1/4 (25%) 2/6 (33.3%) 5/14 (35.7%) 4/12 (33.3%) 5/16 (31.3%)
    Diarrhoea 1/7 (14.3%) 2/9 (22.2%) 1/4 (25%) 3/6 (50%) 4/14 (28.6%) 1/12 (8.3%) 6/16 (37.5%)
    Constipation 1/7 (14.3%) 1/9 (11.1%) 1/4 (25%) 3/6 (50%) 2/14 (14.3%) 2/12 (16.7%) 2/16 (12.5%)
    Vomiting 1/7 (14.3%) 2/9 (22.2%) 1/4 (25%) 0/6 (0%) 2/14 (14.3%) 3/12 (25%) 2/16 (12.5%)
    Abdominal pain 0/7 (0%) 2/9 (22.2%) 0/4 (0%) 1/6 (16.7%) 1/14 (7.1%) 3/12 (25%) 2/16 (12.5%)
    Abdominal pain upper 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 3/14 (21.4%) 0/12 (0%) 3/16 (18.8%)
    Dyspepsia 0/7 (0%) 2/9 (22.2%) 0/4 (0%) 0/6 (0%) 3/14 (21.4%) 2/12 (16.7%) 1/16 (6.3%)
    Abdominal distension 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 4/14 (28.6%) 1/12 (8.3%) 2/16 (12.5%)
    Dysphagia 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 3/14 (21.4%) 0/12 (0%) 1/16 (6.3%)
    Dry mouth 1/7 (14.3%) 1/9 (11.1%) 0/4 (0%) 2/6 (33.3%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Gastrooesophageal reflux disease 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 1/12 (8.3%) 2/16 (12.5%)
    Flatulence 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 1/12 (8.3%) 2/16 (12.5%)
    Abdominal discomfort 1/7 (14.3%) 2/9 (22.2%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Abdominal pain lower 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 1/12 (8.3%) 1/16 (6.3%)
    Oral pain 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 1/16 (6.3%)
    Ascites 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Frequent bowel movements 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 2/14 (14.3%) 0/12 (0%) 0/16 (0%)
    Abdominal rigidity 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Cheilitis 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Duodenal ulcer 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Dyschezia 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Eructation 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Faecal incontinence 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Gastric disorder 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Glossodynia 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Haemorrhoidal haemorrhage 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Haemorrhoids 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Hyperchlorhydria 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Hypoaesthesia oral 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Inguinal hernia 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Lip ulceration 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Mouth ulceration 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Mucous stools 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Oesophageal stenosis 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Oesophagitis 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Oral cavity fistula 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Oral mucosal blistering 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Tongue ulceration 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Tooth loss 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    General disorders
    Fatigue 1/7 (14.3%) 4/9 (44.4%) 0/4 (0%) 4/6 (66.7%) 8/14 (57.1%) 6/12 (50%) 5/16 (31.3%)
    Pyrexia 1/7 (14.3%) 0/9 (0%) 1/4 (25%) 1/6 (16.7%) 3/14 (21.4%) 2/12 (16.7%) 0/16 (0%)
    Pain 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 3/14 (21.4%) 1/12 (8.3%) 2/16 (12.5%)
    Chest pain 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 3/14 (21.4%) 0/12 (0%) 2/16 (12.5%)
    Oedema peripheral 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 1/12 (8.3%) 3/16 (18.8%)
    Oedema 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 1/14 (7.1%) 1/12 (8.3%) 1/16 (6.3%)
    Chest discomfort 0/7 (0%) 2/9 (22.2%) 0/4 (0%) 0/6 (0%) 2/14 (14.3%) 0/12 (0%) 0/16 (0%)
    Chills 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 3/14 (21.4%) 0/12 (0%) 1/16 (6.3%)
    Facial pain 0/7 (0%) 1/9 (11.1%) 1/4 (25%) 0/6 (0%) 2/14 (14.3%) 0/12 (0%) 0/16 (0%)
    Influenza like illness 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 2/14 (14.3%) 0/12 (0%) 1/16 (6.3%)
    Gait disturbance 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Asthenia 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Axillary pain 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Catheter site pain 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Catheter site related reaction 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Feeling cold 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Feeling hot 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Feeling jittery 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Puncture site haemorrhage 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Sensation of foreign body 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Unevaluable event 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Immune system disorders
    Drug hypersensitivity 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Seasonal allergy 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Infections and infestations
    Upper respiratory tract infection 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 1/6 (16.7%) 3/14 (21.4%) 2/12 (16.7%) 2/16 (12.5%)
    Rhinitis 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 1/6 (16.7%) 3/14 (21.4%) 0/12 (0%) 2/16 (12.5%)
    Influenza 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 2/14 (14.3%) 1/12 (8.3%) 0/16 (0%)
    Sinusitis 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 2/6 (33.3%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Nasopharyngitis 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 2/14 (14.3%) 0/12 (0%) 0/16 (0%)
    Bronchitis 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Diverticulitis 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Eye infection 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 1/16 (6.3%)
    Folliculitis 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 1/16 (6.3%)
    Gastroenteritis viral 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 1/12 (8.3%) 0/16 (0%)
    Oral candidiasis 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Pneumonia 0/7 (0%) 0/9 (0%) 1/4 (25%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Wound infection staphylococcal 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 2/14 (14.3%) 0/12 (0%) 0/16 (0%)
    Wound infection 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 2/14 (14.3%) 0/12 (0%) 0/16 (0%)
    Abscess limb 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Candidiasis 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Catheter site infection 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Cystitis 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Gastroenteritis 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Infected cyst 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Lobar pneumonia 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Localised infection 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Onychomycosis 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Oral fungal infection 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Oral herpes 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Postoperative wound infection 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Rash pustular 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Skin infection 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Urinary tract infection 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Injury, poisoning and procedural complications
    Contusion 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 2/14 (14.3%) 0/12 (0%) 0/16 (0%)
    Excoriation 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Laceration 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Wound secretion 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 2/14 (14.3%) 0/12 (0%) 0/16 (0%)
    Corneal abrasion 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Humerus fracture 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Muscle rupture 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Spinal compression fracture 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Tooth fracture 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Wound complication 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Investigations
    Weight decreased 0/7 (0%) 3/9 (33.3%) 1/4 (25%) 2/6 (33.3%) 4/14 (28.6%) 2/12 (16.7%) 6/16 (37.5%)
    Blood alkaline phosphatase increased 0/7 (0%) 0/9 (0%) 1/4 (25%) 1/6 (16.7%) 0/14 (0%) 1/12 (8.3%) 1/16 (6.3%)
    Blood chloride decreased 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 1/14 (7.1%) 1/12 (8.3%) 0/16 (0%)
    Lymphocyte count decreased 0/7 (0%) 0/9 (0%) 1/4 (25%) 1/6 (16.7%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Alanine aminotransferase increased 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Aspartate aminotransferase increased 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Blood lactate dehydrogenase increased 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Blood urea increased 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Weight increased 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 1/12 (8.3%) 1/16 (6.3%)
    Blood bilirubin increased 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Blood creatinine increased 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Blood potassium increased 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Blood triglycerides increased 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Blood urine 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Blood urine present 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Brain natriuretic peptide increased 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Carbohydrate antigen 19-9 increased 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Electrocardiogram change 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Haemoglobin decreased 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Metamyelocyte percentage increased 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Myelocyte percentage increased 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Neutrophil count decreased 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Metabolism and nutrition disorders
    Decreased appetite 0/7 (0%) 4/9 (44.4%) 2/4 (50%) 1/6 (16.7%) 4/14 (28.6%) 5/12 (41.7%) 3/16 (18.8%)
    Hyponatraemia 3/7 (42.9%) 1/9 (11.1%) 0/4 (0%) 2/6 (33.3%) 2/14 (14.3%) 1/12 (8.3%) 0/16 (0%)
    Hypokalaemia 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 2/14 (14.3%) 2/12 (16.7%) 3/16 (18.8%)
    Hypomagnesaemia 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 2/6 (33.3%) 2/14 (14.3%) 1/12 (8.3%) 1/16 (6.3%)
    Dehydration 0/7 (0%) 0/9 (0%) 1/4 (25%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 2/16 (12.5%)
    Hyperglycaemia 0/7 (0%) 0/9 (0%) 0/4 (0%) 2/6 (33.3%) 1/14 (7.1%) 1/12 (8.3%) 0/16 (0%)
    Hypoalbuminaemia 0/7 (0%) 0/9 (0%) 0/4 (0%) 2/6 (33.3%) 0/14 (0%) 1/12 (8.3%) 1/16 (6.3%)
    Hypercholesterolaemia 0/7 (0%) 0/9 (0%) 1/4 (25%) 1/6 (16.7%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Hyperkalaemia 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Hypoglycaemia 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Electrolyte imbalance 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Fluid retention 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Gout 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Hypercalcaemia 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Hypertriglyceridaemia 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Hypocalcaemia 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Salt craving 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Type 2 diabetes mellitus 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Musculoskeletal and connective tissue disorders
    Muscle spasms 2/7 (28.6%) 2/9 (22.2%) 1/4 (25%) 4/6 (66.7%) 12/14 (85.7%) 0/12 (0%) 11/16 (68.8%)
    Back pain 1/7 (14.3%) 2/9 (22.2%) 1/4 (25%) 2/6 (33.3%) 1/14 (7.1%) 2/12 (16.7%) 4/16 (25%)
    Musculoskeletal chest pain 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 1/6 (16.7%) 3/14 (21.4%) 1/12 (8.3%) 2/16 (12.5%)
    Arthralgia 1/7 (14.3%) 1/9 (11.1%) 0/4 (0%) 1/6 (16.7%) 1/14 (7.1%) 1/12 (8.3%) 2/16 (12.5%)
    Pain in extremity 0/7 (0%) 3/9 (33.3%) 0/4 (0%) 0/6 (0%) 2/14 (14.3%) 0/12 (0%) 2/16 (12.5%)
    Musculoskeletal pain 1/7 (14.3%) 3/9 (33.3%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 1/12 (8.3%) 0/16 (0%)
    Flank pain 0/7 (0%) 0/9 (0%) 0/4 (0%) 2/6 (33.3%) 0/14 (0%) 1/12 (8.3%) 2/16 (12.5%)
    Myalgia 0/7 (0%) 2/9 (22.2%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Muscle tightness 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 2/14 (14.3%) 0/12 (0%) 1/16 (6.3%)
    Muscle twitching 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 2/14 (14.3%) 0/12 (0%) 0/16 (0%)
    Neck pain 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 2/14 (14.3%) 0/12 (0%) 0/16 (0%)
    Joint swelling 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Musculoskeletal discomfort 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Pain in jaw 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Arthritis 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Groin pain 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Intervertebral disc protrusion 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Joint range of motion decreased 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Joint stiffness 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Musculoskeletal stiffness 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Osteopenia 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bowen's disease 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Neoplasm malignant 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Seborrhoeic keratosis 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Skin neoplasm bleeding 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Skin papilloma 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Tumour associated fever 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Nervous system disorders
    Dysgeusia 1/7 (14.3%) 3/9 (33.3%) 1/4 (25%) 5/6 (83.3%) 8/14 (57.1%) 2/12 (16.7%) 8/16 (50%)
    Hypoaesthesia 0/7 (0%) 0/9 (0%) 3/4 (75%) 1/6 (16.7%) 0/14 (0%) 1/12 (8.3%) 2/16 (12.5%)
    Headache 0/7 (0%) 1/9 (11.1%) 1/4 (25%) 1/6 (16.7%) 2/14 (14.3%) 0/12 (0%) 1/16 (6.3%)
    Dizziness 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 2/14 (14.3%) 1/12 (8.3%) 1/16 (6.3%)
    Paraesthesia 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 2/14 (14.3%) 0/12 (0%) 1/16 (6.3%)
    Sinus headache 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 2/14 (14.3%) 0/12 (0%) 0/16 (0%)
    Somnolence 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Ageusia 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 2/16 (12.5%)
    Anosmia 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Neuropathy peripheral 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 1/12 (8.3%) 0/16 (0%)
    Tremor 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Amimia 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Burning sensation 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Carotid artery stenosis 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Cognitive disorder 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Dyskinesia 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Hyperaesthesia 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Hypogeusia 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Memory impairment 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Neuralgia 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Paresis cranial nerve 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Parosmia 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Phantom pain 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Sensory disturbance 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Tongue paralysis 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Trigeminal neuralgia 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Viith nerve paralysis 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Psychiatric disorders
    Anxiety 1/7 (14.3%) 2/9 (22.2%) 0/4 (0%) 1/6 (16.7%) 1/14 (7.1%) 1/12 (8.3%) 4/16 (25%)
    Insomnia 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 1/6 (16.7%) 3/14 (21.4%) 0/12 (0%) 4/16 (25%)
    Depression 1/7 (14.3%) 1/9 (11.1%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 1/12 (8.3%) 1/16 (6.3%)
    Abnormal dreams 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Hallucination 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Sleep disorder 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Stress 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Renal and urinary disorders
    Urinary hesitation 0/7 (0%) 0/9 (0%) 2/4 (50%) 2/6 (33.3%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Dysuria 0/7 (0%) 2/9 (22.2%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Haematuria 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 1/12 (8.3%) 0/16 (0%)
    Chromaturia 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Hydronephrosis 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Pollakiuria 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Proteinuria 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Renal pain 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Urinary retention 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Urine flow decreased 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Reproductive system and breast disorders
    Amenorrhoea 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Breast swelling 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Menstruation irregular 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Respiratory, thoracic and mediastinal disorders
    Cough 1/7 (14.3%) 2/9 (22.2%) 1/4 (25%) 2/6 (33.3%) 5/14 (35.7%) 2/12 (16.7%) 2/16 (12.5%)
    Dyspnoea 2/7 (28.6%) 1/9 (11.1%) 0/4 (0%) 2/6 (33.3%) 2/14 (14.3%) 3/12 (25%) 3/16 (18.8%)
    Productive cough 1/7 (14.3%) 1/9 (11.1%) 0/4 (0%) 2/6 (33.3%) 1/14 (7.1%) 1/12 (8.3%) 1/16 (6.3%)
    Dyspnoea exertional 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 1/14 (7.1%) 2/12 (16.7%) 0/16 (0%)
    Oropharyngeal pain 0/7 (0%) 1/9 (11.1%) 1/4 (25%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 1/16 (6.3%)
    Rhinorrhoea 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 1/6 (16.7%) 1/14 (7.1%) 1/12 (8.3%) 0/16 (0%)
    Dysphonia 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 2/14 (14.3%) 0/12 (0%) 1/16 (6.3%)
    Respiratory tract congestion 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 2/14 (14.3%) 0/12 (0%) 0/16 (0%)
    Wheezing 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 1/14 (7.1%) 0/12 (0%) 1/16 (6.3%)
    Pleuritic pain 0/7 (0%) 0/9 (0%) 0/4 (0%) 2/6 (33.3%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Sinus congestion 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Throat irritation 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Aspiration 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Atelectasis 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Epistaxis 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Haemoptysis 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Hydrothorax 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Nasal congestion 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Oropharyngeal swelling 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Pleural effusion 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Pleurisy 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Sputum increased 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    upper respiratory tract congestion 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Upper-airway cough syndrome 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Skin and subcutaneous tissue disorders
    Alopecia 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 3/6 (50%) 10/14 (71.4%) 1/12 (8.3%) 9/16 (56.3%)
    Pruritus 1/7 (14.3%) 2/9 (22.2%) 1/4 (25%) 2/6 (33.3%) 1/14 (7.1%) 0/12 (0%) 2/16 (12.5%)
    Erythema 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 4/14 (28.6%) 0/12 (0%) 1/16 (6.3%)
    Dry skin 0/7 (0%) 0/9 (0%) 0/4 (0%) 2/6 (33.3%) 1/14 (7.1%) 0/12 (0%) 2/16 (12.5%)
    Rash 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 3/14 (21.4%) 0/12 (0%) 1/16 (6.3%)
    Skin exfoliation 0/7 (0%) 2/9 (22.2%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Acne 0/7 (0%) 0/9 (0%) 1/4 (25%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Decubitus ulcer 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Dermatitis acneiform 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Hyperhidrosis 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 1/16 (6.3%)
    Madarosis 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Night sweats 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Skin discolouration 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Skin ulcer 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Actinic elastosis 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Campbell de morgan spots 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    hair colour changes 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Nail ridging 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Onychoclasis 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Pain of skin 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Photosensitivity reaction 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Pruritus generalised 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Psoriasis 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 1/12 (8.3%) 0/16 (0%)
    Rash macular 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Rash maculo-papular 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Rash pruritic 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Skin lesion 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Skin tightness 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Swelling face 0/7 (0%) 1/9 (11.1%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Urticaria 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 1/14 (7.1%) 0/12 (0%) 0/16 (0%)
    Vascular disorders
    Flushing 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 3/14 (21.4%) 0/12 (0%) 1/16 (6.3%)
    Hypertension 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 1/14 (7.1%) 1/12 (8.3%) 1/16 (6.3%)
    Hypotension 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 2/12 (16.7%) 2/16 (12.5%)
    Deep vein thrombosis 1/7 (14.3%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Hot flush 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)
    Orthostatic hypotension 0/7 (0%) 0/9 (0%) 0/4 (0%) 1/6 (16.7%) 0/14 (0%) 0/12 (0%) 0/16 (0%)
    Raynaud's phenomenon 0/7 (0%) 0/9 (0%) 0/4 (0%) 0/6 (0%) 0/14 (0%) 0/12 (0%) 1/16 (6.3%)

    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-LaRoche
    Phone 800-821-8590
    Email genentech@druginfo.com
    Responsible Party:
    Genentech, Inc.
    ClinicalTrials.gov Identifier:
    NCT00607724
    Other Study ID Numbers:
    • CDR0000585468
    • JHOC-J06131
    • GENETECH-SHH3925g
    • NCT00862771
    First Posted:
    Feb 6, 2008
    Last Update Posted:
    Oct 8, 2015
    Last Verified:
    Sep 1, 2015