Trial Outcomes & Findings for A Pharmacokinetic and Metabolism Study of 14C-labeled RO5185426 on Patients With Metastatic Melanoma (NCT NCT01164891)

NCT ID: NCT01164891

Last Updated: 2023-04-05

Results Overview

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 7 participants
• Primary outcome timeframe: Pre-dose on Days 15, 16 and 17
• Results posted on: 2023-04-05

Participant Flow

Participant milestones

Measure	14C-labeled RO5185426 Participants received non-labeled RO5185426 film-coated tablets 960 milligrams (mg) orally two times daily (BID) from Day 1 to Day 14. On Day 15, participants received a single dose of 960 mg RO5185426 with a maximum of 2.56 millibecquerel (69.2 microcurie) of 14C RO5185426. After Day 15, participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID until the development of progressive disease, unacceptable toxicity, consent withdrawal, death, lost to follow-up or any other criteria for removal as determined by the investigator.
Overall Study STARTED	7
Overall Study COMPLETED	1
Overall Study NOT COMPLETED	6

Reasons for withdrawal

Measure	14C-labeled RO5185426 Participants received non-labeled RO5185426 film-coated tablets 960 milligrams (mg) orally two times daily (BID) from Day 1 to Day 14. On Day 15, participants received a single dose of 960 mg RO5185426 with a maximum of 2.56 millibecquerel (69.2 microcurie) of 14C RO5185426. After Day 15, participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID until the development of progressive disease, unacceptable toxicity, consent withdrawal, death, lost to follow-up or any other criteria for removal as determined by the investigator.
Overall Study Disease Progression	5
Overall Study Adverse Event	1

Baseline Characteristics

A Pharmacokinetic and Metabolism Study of 14C-labeled RO5185426 on Patients With Metastatic Melanoma

Baseline characteristics by cohort

Measure	14C-labeled RO5185426 n=7 Participants Participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID from Day 1 to Day 14. On Day 15, participants received a single dose of 960 mg RO5185426 with a maximum of 2.56 millibecquerel (69.2 microcurie) of 14C RO5185426. After Day 15, participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID until the development of progressive disease, unacceptable toxicity, consent withdrawal, death, lost to follow-up or any other criteria for removal as determined by the investigator.
Age, Continuous	55.7 years STANDARD_DEVIATION 12.09 • n=5 Participants
Sex: Female, Male Female	4 Participants n=5 Participants
Sex: Female, Male Male	3 Participants n=5 Participants

PRIMARY outcome

Timeframe: Pre-dose on Days 15, 16 and 17

Population: Pharmacokinetic (PK) Analysis Population: participants from whom the level of radioactivity recovered from excreta (urine and feces) was ≤ 1% of the radioactivity in the administered dose between any two successive 48-hour interval assessments.

Outcome measures

Measure	14C-labeled RO5185426 n=7 Participants Participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID from Day 1 to Day 14. On Day 15, participants received a single dose of 960 mg RO5185426 with a maximum of 2.56 millibecquerel (69.2 microcurie) of 14C RO5185426. After Day 15, participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID until the development of progressive disease, unacceptable toxicity, consent withdrawal, death, lost to follow-up or any other criteria for removal as determined by the investigator.
Plasma RO5185426 Trough Concentrations on Days 15,16, and 17 Day 15	61.1 micrograms per milliliter Standard Deviation 28.1
Plasma RO5185426 Trough Concentrations on Days 15,16, and 17 Day 16	67.7 micrograms per milliliter Standard Deviation 22.2
Plasma RO5185426 Trough Concentrations on Days 15,16, and 17 Day 17	61.5 micrograms per milliliter Standard Deviation 13.4

PRIMARY outcome

Timeframe: 0 hour (prior to evening dose) on Day 14; 0 hour (pre dose), 1, 2, 4, 6, 12, 24, 36, 48, 72, 96, 168, 216, 312 hours post dose on Day 15, and then every 96 hour until recovery criteria met (maximum: 432 hours)

Population: PK Analysis Population. Number of participants analyzed = participants with measurable data for this outcome.

Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments). 14C-labeled RO5185426 given was equivalent to ≤1 millisieverts (mSv).

Outcome measures

Measure	14C-labeled RO5185426 n=5 Participants Participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID from Day 1 to Day 14. On Day 15, participants received a single dose of 960 mg RO5185426 with a maximum of 2.56 millibecquerel (69.2 microcurie) of 14C RO5185426. After Day 15, participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID until the development of progressive disease, unacceptable toxicity, consent withdrawal, death, lost to follow-up or any other criteria for removal as determined by the investigator.
Maximum Plasma Concentration of 14C-labeled RO5185426 (Cmax) in Both Blood and Plasma Blood	5.25 micrograms equivalent per milliliter Standard Deviation 1.71
Maximum Plasma Concentration of 14C-labeled RO5185426 (Cmax) in Both Blood and Plasma Plasma	7.83 micrograms equivalent per milliliter Standard Deviation 2.28

PRIMARY outcome

Timeframe: 0 hour (prior to evening dose) on Day 14; 0 hour (pre dose), 1, 2, 4, 6, 12, 24, 36, 48, 72, 96, 168, 216, 312 hours post dose on Day 15, and then every 96 hour until recovery criteria met (maximum: 432 hours)

Population: PK Analysis Population. Number of participants analyzed = participants with measurable data for this outcome.

Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments).

Outcome measures

Measure	14C-labeled RO5185426 n=5 Participants Participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID from Day 1 to Day 14. On Day 15, participants received a single dose of 960 mg RO5185426 with a maximum of 2.56 millibecquerel (69.2 microcurie) of 14C RO5185426. After Day 15, participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID until the development of progressive disease, unacceptable toxicity, consent withdrawal, death, lost to follow-up or any other criteria for removal as determined by the investigator.
Time to Reach Cmax in Both Blood and Plasma Blood	4.1 hours Interval 4.0 to 12.0
Time to Reach Cmax in Both Blood and Plasma Plasma	4.1 hours Interval 4.0 to 12.0

PRIMARY outcome

Timeframe: 0 hour (prior to evening dose) on Day 14; 0 hour (pre dose), 1, 2, 4, 6, 12, 24, 36, 48, 72, 96, 168, 216, 312 hours post dose on Day 15, and then every 96 hour until recovery criteria met (maximum: 432 hours)

Population: PK Analysis Population. Number of participants analyzed = participants with measurable data for this outcome.

Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments). 14C-labeled RO5185426 given was equivalent to ≤1mSv.

Outcome measures

Measure	14C-labeled RO5185426 n=5 Participants Participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID from Day 1 to Day 14. On Day 15, participants received a single dose of 960 mg RO5185426 with a maximum of 2.56 millibecquerel (69.2 microcurie) of 14C RO5185426. After Day 15, participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID until the development of progressive disease, unacceptable toxicity, consent withdrawal, death, lost to follow-up or any other criteria for removal as determined by the investigator.
Area Under the Plasma Concentration Time Curve From Time Zero to the Last Quantifiable Sample (AUClast) of 14C-RO5185426 in Both Blood and Plasma Blood	456.0 (micrograms equivalent/milliliter)*hour Standard Deviation 85.4
Area Under the Plasma Concentration Time Curve From Time Zero to the Last Quantifiable Sample (AUClast) of 14C-RO5185426 in Both Blood and Plasma Plasma	633.0 (micrograms equivalent/milliliter)*hour Standard Deviation 123.0

PRIMARY outcome

Timeframe: 0 hour (prior to evening dose) on Day 14; 0 hour (pre dose), 1, 2, 4, 6, 12, 24, 36, 48, 72, 96, 168, 216, 312 hours post dose on Day 15, and then every 96 hour until recovery criteria met (maximum: 432 hours)

Population: PK Analysis Population. Number of participants analyzed = participants with measurable data for this outcome.

Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments).

Outcome measures

Measure	14C-labeled RO5185426 n=5 Participants Participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID from Day 1 to Day 14. On Day 15, participants received a single dose of 960 mg RO5185426 with a maximum of 2.56 millibecquerel (69.2 microcurie) of 14C RO5185426. After Day 15, participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID until the development of progressive disease, unacceptable toxicity, consent withdrawal, death, lost to follow-up or any other criteria for removal as determined by the investigator.
Half-life of 14C-labeled RO5185426 in Both Blood and Plasma Blood	84.4 hour Standard Deviation 24.6
Half-life of 14C-labeled RO5185426 in Both Blood and Plasma Plasma	71.1 hour Standard Deviation 15.4

PRIMARY outcome

Timeframe: 0 hour (prior to evening dose) on Day 14; 0 hour (pre dose), 1, 2, 4, 6, 12, 24, 36, 48, 72, 96, 168, 216, 312 hours post dose on Day 15, and then every 96 hour until recovery criteria met (maximum: 432 hours)

Population: PK Analysis Population. Number of participants analysed = participants with measurable data for this outcome.

Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments).

Outcome measures

Measure

14C-labeled RO5185426 n=5 Participants Participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID from Day 1 to Day 14. On Day 15, participants received a single dose of 960 mg RO5185426 with a maximum of 2.56 millibecquerel (69.2 microcurie) of 14C RO5185426. After Day 15, participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID until the development of progressive disease, unacceptable toxicity, consent withdrawal, death, lost to follow-up or any other criteria for removal as determined by the investigator.

AUC Ratio of Blood:Plasma 14C-labeled RO5185426

0.72 ratio Standard Deviation 0.05

PRIMARY outcome

Timeframe: Urine:0 hour (pre dose),in quantitative fraction(0-6,6-12,12-24 hours) post dose on Day 15,during 24 hour interval thereafter;Feces:From Day 14 upto pre dose on Day 15,during 24 hour interval post dose until recovery criterion;(maximum:432 hours for both)

Population: PK Analysis Population. One participant was excluded in the analysis because of contamination of urine sample with feces.

Urinary and fecal samples were analyze for the percentage dose recovered as total radioactivity. The radioactivity was determined on a Packard liquid scintillation counter. Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments).

Outcome measures

Measure	14C-labeled RO5185426 n=6 Participants Participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID from Day 1 to Day 14. On Day 15, participants received a single dose of 960 mg RO5185426 with a maximum of 2.56 millibecquerel (69.2 microcurie) of 14C RO5185426. After Day 15, participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID until the development of progressive disease, unacceptable toxicity, consent withdrawal, death, lost to follow-up or any other criteria for removal as determined by the investigator.
14C-labeled RO5185426 Recovery: Percentage of Dose Excreted in Feces and Urine Percent Dose Total Recovery (Feces and Urine)	95.02 percentage of dose recovered Standard Deviation 2.40
14C-labeled RO5185426 Recovery: Percentage of Dose Excreted in Feces and Urine Percent Dose Recovery in Feces	94.05 percentage of dose recovered Standard Deviation 2.66
14C-labeled RO5185426 Recovery: Percentage of Dose Excreted in Feces and Urine Percent Dose Recovery in Urine	0.97 percentage of dose recovered Standard Deviation 0.43

PRIMARY outcome

Timeframe: 4+6 hours, 12 +24 hours, 36+48 hours post dose on Day 15

Population: PK Analysis Population.

Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments). Plasma samples were pooled over three time intervals for this analysis based on available radioactive counts (4 + 6 hours, 12 + 24 hours, and 36 + 48 hours). Radioactivity was measured in terms of region of interest by high performance liquid chromatography. The radiolabelled components in each chromatogram were evaluated to determine retention times and peak area values. Data for 14C-labeled RO5185426 and 14C-labeled metabolite (mono-hydroxy) are reported.

Outcome measures

Measure	14C-labeled RO5185426 n=7 Participants Participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID from Day 1 to Day 14. On Day 15, participants received a single dose of 960 mg RO5185426 with a maximum of 2.56 millibecquerel (69.2 microcurie) of 14C RO5185426. After Day 15, participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID until the development of progressive disease, unacceptable toxicity, consent withdrawal, death, lost to follow-up or any other criteria for removal as determined by the investigator.
Percentage of Total Integrated Radioactivity in Plasma of 14C-labeled RO5185426 and 14C-labeled Metabolite RO5185426: 4 + 6 hours	99.46 percentage of total radioactivity Standard Deviation 1.42
Percentage of Total Integrated Radioactivity in Plasma of 14C-labeled RO5185426 and 14C-labeled Metabolite RO5185426: 12 + 24 hours	95.93 percentage of total radioactivity Standard Deviation 5.49
Percentage of Total Integrated Radioactivity in Plasma of 14C-labeled RO5185426 and 14C-labeled Metabolite RO5185426: 36 + 48 hours	96.03 percentage of total radioactivity Standard Deviation 3.76
Percentage of Total Integrated Radioactivity in Plasma of 14C-labeled RO5185426 and 14C-labeled Metabolite Mono-hydroxy Metabolite: 4 + 6 hours	0.54 percentage of total radioactivity Standard Deviation 1.42
Percentage of Total Integrated Radioactivity in Plasma of 14C-labeled RO5185426 and 14C-labeled Metabolite Mono-hydroxy Metabolite: 12 + 24 hours	4.07 percentage of total radioactivity Standard Deviation 5.49
Percentage of Total Integrated Radioactivity in Plasma of 14C-labeled RO5185426 and 14C-labeled Metabolite Mono-hydroxy Metabolite: 36 + 48 hours	3.97 percentage of total radioactivity Standard Deviation 3.76

PRIMARY outcome

Timeframe: 4+6 hours, 12 +24 hours, 36+48 hours post dose on Day 15

Population: PK Analysis Population.

Collection of samples for radioactivity continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48 hour interval assessments). Plasma samples were pooled over three time intervals for this analysis based on available radioactive counts (4 + 6 hours, 12 + 24 hours, and 36 + 48 hours). The concentrations were measured in nanogram equivalent per gram which was calculated based on ratio of dosed radioactivity and the last dose of RO5185426. The concentration values represented the drug portion of the last dose. Data for 14C-labeled RO5185426 and 14C-labeled metabolite (mono-hydroxy) are reported.

Outcome measures

Measure	14C-labeled RO5185426 n=7 Participants Participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID from Day 1 to Day 14. On Day 15, participants received a single dose of 960 mg RO5185426 with a maximum of 2.56 millibecquerel (69.2 microcurie) of 14C RO5185426. After Day 15, participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID until the development of progressive disease, unacceptable toxicity, consent withdrawal, death, lost to follow-up or any other criteria for removal as determined by the investigator.
Plasma 14C-labeled RO5185426 and 14C-labeled Metabolite Levels RO5185426: 4 + 6 hours	6122 nanogram equivalent per gram Standard Deviation 2537
Plasma 14C-labeled RO5185426 and 14C-labeled Metabolite Levels RO5185426: 12 + 24 hours	6139 nanogram equivalent per gram Standard Deviation 1787
Plasma 14C-labeled RO5185426 and 14C-labeled Metabolite Levels RO5185426: 36 + 48 hours	4710 nanogram equivalent per gram Standard Deviation 1544
Plasma 14C-labeled RO5185426 and 14C-labeled Metabolite Levels Mono-hydroxy Metabolite: 4 + 6 hours	57 nanogram equivalent per gram Standard Deviation 152
Plasma 14C-labeled RO5185426 and 14C-labeled Metabolite Levels Mono-hydroxy Metabolite: 12 + 24 hours	321 nanogram equivalent per gram Standard Deviation 442
Plasma 14C-labeled RO5185426 and 14C-labeled Metabolite Levels Mono-hydroxy Metabolite: 36 + 48 hours	238 nanogram equivalent per gram Standard Deviation 249

PRIMARY outcome

Timeframe: 0-24 + 24-48 hours, 48-72 + 72-96 hours post dose on Day 15

Population: PK Analysis Population.

Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments). Fecal samples were pooled over two time intervals for this analysis (0-24 + 24-48 hours, 48-72 + 72-96 hours). Radioactivity was measured in terms of region of interest by high performance liquid chromatography. The radiolabelled components in each chromatogram were evaluated to determine retention times and peak area values. Data for 14C-labeled RO5185426 and 14C-labeled metabolites (glucosylation, mono-hydroxy, and glucuronide) are reported.

Outcome measures

Measure	14C-labeled RO5185426 n=7 Participants Participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID from Day 1 to Day 14. On Day 15, participants received a single dose of 960 mg RO5185426 with a maximum of 2.56 millibecquerel (69.2 microcurie) of 14C RO5185426. After Day 15, participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID until the development of progressive disease, unacceptable toxicity, consent withdrawal, death, lost to follow-up or any other criteria for removal as determined by the investigator.
Percentage of Total Integrated Radioactivity in Feces of 14C-labeled RO5185426 and 14C-labeled Metabolite RO5185426: 0-24 + 24-48 hours	94.19 percentage of total radioactivity Standard Deviation 5.75
Percentage of Total Integrated Radioactivity in Feces of 14C-labeled RO5185426 and 14C-labeled Metabolite RO5185426: 48-72 + 72-96 hours	55.52 percentage of total radioactivity Standard Deviation 20.12
Percentage of Total Integrated Radioactivity in Feces of 14C-labeled RO5185426 and 14C-labeled Metabolite Glucosylation: 0-24 + 24-48 hours	2.58 percentage of total radioactivity Standard Deviation 3.06
Percentage of Total Integrated Radioactivity in Feces of 14C-labeled RO5185426 and 14C-labeled Metabolite Glucosylation: 48-72 + 72-96 hours	18.83 percentage of total radioactivity Standard Deviation 6.71
Percentage of Total Integrated Radioactivity in Feces of 14C-labeled RO5185426 and 14C-labeled Metabolite Mono-hydroxy: 0-24 + 24-48 hours	0.15 percentage of total radioactivity Standard Deviation 0.41
Percentage of Total Integrated Radioactivity in Feces of 14C-labeled RO5185426 and 14C-labeled Metabolite Mono-hydroxy: 48-72 + 72-96 hours	13.71 percentage of total radioactivity Standard Deviation 9.07
Percentage of Total Integrated Radioactivity in Feces of 14C-labeled RO5185426 and 14C-labeled Metabolite Glucuronide: 0-24 + 24-48 hours	3.08 percentage of total radioactivity Standard Deviation 4.01
Percentage of Total Integrated Radioactivity in Feces of 14C-labeled RO5185426 and 14C-labeled Metabolite Glucuronide: 48-72 + 72-96 hours	11.94 percentage of total radioactivity Standard Deviation 12.13

PRIMARY outcome

Timeframe: 0-24 + 24-48 hours, 48-72 + 72-96 hours post dose on Day 15

Population: PK Analysis Population.

Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments). Fecal samples were pooled over 2 time intervals (0-24 + 24-48 hours, 48-72 + 72-96 hours) for measurement of 14C-labeled RO5185426 and 14C-labeled metabolites (glucosylation, mono-hydroxy, glucuronide) levels.

Outcome measures

Measure	14C-labeled RO5185426 n=7 Participants Participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID from Day 1 to Day 14. On Day 15, participants received a single dose of 960 mg RO5185426 with a maximum of 2.56 millibecquerel (69.2 microcurie) of 14C RO5185426. After Day 15, participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID until the development of progressive disease, unacceptable toxicity, consent withdrawal, death, lost to follow-up or any other criteria for removal as determined by the investigator.
Percentage of Total Dose in 14C-labeled RO5185426 and 14C-labeled Metabolite in Pooled Fecal Samples RO5185426: 0-24 + 24-48 hours	37.49 percentage of total dose administered Standard Deviation 21.59
Percentage of Total Dose in 14C-labeled RO5185426 and 14C-labeled Metabolite in Pooled Fecal Samples RO5185426: 48-72 + 72-96 hours	17.10 percentage of total dose administered Standard Deviation 11.45
Percentage of Total Dose in 14C-labeled RO5185426 and 14C-labeled Metabolite in Pooled Fecal Samples Glucosylation: 0-24 + 24-48 hours	0.97 percentage of total dose administered Standard Deviation 1.08
Percentage of Total Dose in 14C-labeled RO5185426 and 14C-labeled Metabolite in Pooled Fecal Samples Glucosylation: 48-72 + 72-96 hours	5.04 percentage of total dose administered Standard Deviation 2.91
Percentage of Total Dose in 14C-labeled RO5185426 and 14C-labeled Metabolite in Pooled Fecal Samples Mono-hydroxy: 0-24 + 24-48 hours	0.11 percentage of total dose administered Standard Deviation 0.29
Percentage of Total Dose in 14C-labeled RO5185426 and 14C-labeled Metabolite in Pooled Fecal Samples Mono-hydroxy: 48-72 + 72-96 hours	3.30 percentage of total dose administered Standard Deviation 2.23
Percentage of Total Dose in 14C-labeled RO5185426 and 14C-labeled Metabolite in Pooled Fecal Samples Glucuronide: 0-24 + 24-48 hours	1.19 percentage of total dose administered Standard Deviation 1.42
Percentage of Total Dose in 14C-labeled RO5185426 and 14C-labeled Metabolite in Pooled Fecal Samples Glucuronide: 48-72 + 72-96 hours	2.86 percentage of total dose administered Standard Deviation 3.13

PRIMARY outcome

Timeframe: 0 up to 96 hours post dose on Day 15

Population: PK Analysis Population.

Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments). Urine samples were pooled over period of 96 hours (pool of 0-6 + 6-12 + 12-24 + 24-48 + 48-72 + 72-96 hour samples), Radioactivity was measured in terms of region of interest by high performance liquid chromatography. The radiolabelled components in each chromatogram were evaluated to determine retention times and peak area values. Data for 14C-labeled RO5185426 and 14C-labeled metabolites (2 unknown metabolites, glucosylation, mono-hydroxy) are reported.

Outcome measures

Measure	14C-labeled RO5185426 n=7 Participants Participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID from Day 1 to Day 14. On Day 15, participants received a single dose of 960 mg RO5185426 with a maximum of 2.56 millibecquerel (69.2 microcurie) of 14C RO5185426. After Day 15, participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID until the development of progressive disease, unacceptable toxicity, consent withdrawal, death, lost to follow-up or any other criteria for removal as determined by the investigator.
Percentage of Total Integrated Radioactivity in Urine of 14C-labeled RO5185426 and 14C-labeled Metabolite RO5185426	32.38 percentage of total radioactivity Standard Deviation 37.30
Percentage of Total Integrated Radioactivity in Urine of 14C-labeled RO5185426 and 14C-labeled Metabolite Unknown Metabolite 1	4.56 percentage of total radioactivity Standard Deviation 12.05
Percentage of Total Integrated Radioactivity in Urine of 14C-labeled RO5185426 and 14C-labeled Metabolite Unknown Metabolite 2	25.44 percentage of total radioactivity Standard Deviation 35.51
Percentage of Total Integrated Radioactivity in Urine of 14C-labeled RO5185426 and 14C-labeled Metabolite Glucosylation	30.22 percentage of total radioactivity Standard Deviation 28.79
Percentage of Total Integrated Radioactivity in Urine of 14C-labeled RO5185426 and 14C-labeled Metabolite Mono-hydroxy	7.41 percentage of total radioactivity Standard Deviation 12.87

PRIMARY outcome

Timeframe: 0 up to 96 hours post dose on Day 15

Population: PK Analysis Population.

Collection of samples continued until the recovery criterion was met (radioactivity recovered from urine and feces ≤ 1 % of the radioactivity in the administered dose between any two successive 48-hour interval assessments). Urine samples were pooled over period of 96 hours (pool of 0-6 + 6-12 + 12-24 + 24-48 + 48-72 + 72-96 hour samples). Data for parent drug (RO5185426) and metabolites (2 unknown metabolites, glucosylation, mono-hydroxy) are reported.

Outcome measures

Measure	14C-labeled RO5185426 n=7 Participants Participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID from Day 1 to Day 14. On Day 15, participants received a single dose of 960 mg RO5185426 with a maximum of 2.56 millibecquerel (69.2 microcurie) of 14C RO5185426. After Day 15, participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID until the development of progressive disease, unacceptable toxicity, consent withdrawal, death, lost to follow-up or any other criteria for removal as determined by the investigator.
Percentage of Total Dose in 14C-labeled RO5185426 and 14C-labeled Metabolite in Pooled Urine Samples Glucosylation	0.24 percentage of total dose administered Standard Deviation 0.26
Percentage of Total Dose in 14C-labeled RO5185426 and 14C-labeled Metabolite in Pooled Urine Samples RO5185426	1.03 percentage of total dose administered Standard Deviation 2.33
Percentage of Total Dose in 14C-labeled RO5185426 and 14C-labeled Metabolite in Pooled Urine Samples Unknown Metabolite 1	0.04 percentage of total dose administered Standard Deviation 0.10
Percentage of Total Dose in 14C-labeled RO5185426 and 14C-labeled Metabolite in Pooled Urine Samples Unknown Metabolite 2	0.17 percentage of total dose administered Standard Deviation 0.21
Percentage of Total Dose in 14C-labeled RO5185426 and 14C-labeled Metabolite in Pooled Urine Samples Mono-hydroxy	0.05 percentage of total dose administered Standard Deviation 0.10

SECONDARY outcome

Timeframe: From Baseline then Day 1 of Cycle 3 thereafter, Day 1 of every other cycle (every 2 months) until disease progression, withdrawal from study or death (maximum 841 days)

Population: Safety population included all participants who received at least 1 dose of study drug.

Best overall response (according to Response Evaluation Criteria In Solid Tumors 1.1 criteria) was defined as best response recorded from start of treatment until disease progression which included complete response (CR) or partial response (PR) that had been confirmed by second tumor assessment no less than (<) 4 weeks after criteria for response were first met. Confirmed CR: disappearance of all target and non-target lesions; no new lesions, and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 millimeters (mm). Confirmed PR: at least 30% decrease in sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. Disease progression: at least 20% increase in sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesions.

Outcome measures

Measure

14C-labeled RO5185426 n=7 Participants Participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID from Day 1 to Day 14. On Day 15, participants received a single dose of 960 mg RO5185426 with a maximum of 2.56 millibecquerel (69.2 microcurie) of 14C RO5185426. After Day 15, participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID until the development of progressive disease, unacceptable toxicity, consent withdrawal, death, lost to follow-up or any other criteria for removal as determined by the investigator.

Number of Participants With a Response by Confirmed Best Overall Response

4 participants

SECONDARY outcome

Timeframe: From Baseline then Day 1 of Cycle 3 thereafter, Day 1 of every other cycle (every 2 months) until death (maximum 841 days)

Population: The data was not collected, as planned, due to small number of participants enrolled in the study.

Overall survival was defined as the time from the date of first treatment to the date of death, regardless of the cause of death.

Outcome measures

Outcome data not reported

Adverse Events

14C-labeled RO5185426

Serious events: 3 serious events

Other events: 7 other events

Deaths: 1 deaths

Serious adverse events

Measure	14C-labeled RO5185426 n=7 participants at risk Participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID from Day 1 to Day 14. On Day 15, participants received a single dose of 960 mg RO5185426 with a maximum of 2.56 millibecquerel (69.2 microcurie) of 14C RO5185426. After Day 15, participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID until the development of progressive disease, unacceptable toxicity, consent withdrawal, death, lost to follow-up or any other criteria for removal as determined by the investigator.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Keratoacanthoma	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant Melanoma	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous Cell Carcinoma	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous Cell Carcinoma of Skin	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.

Other adverse events

Measure	14C-labeled RO5185426 n=7 participants at risk Participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID from Day 1 to Day 14. On Day 15, participants received a single dose of 960 mg RO5185426 with a maximum of 2.56 millibecquerel (69.2 microcurie) of 14C RO5185426. After Day 15, participants received non-labeled RO5185426 film-coated tablets 960 mg orally BID until the development of progressive disease, unacceptable toxicity, consent withdrawal, death, lost to follow-up or any other criteria for removal as determined by the investigator.
Blood and lymphatic system disorders Anemia	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Eye disorders Conjunctivital Hyperaemia	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Gastrointestinal disorders Abdominal Distension	28.6% 2/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Gastrointestinal disorders Abdominal Pain	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Gastrointestinal disorders Abdominal Pain Upper	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Gastrointestinal disorders Diarrhoea	28.6% 2/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Gastrointestinal disorders Dry Mouth	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Gastrointestinal disorders Gastrooesophageal Reflux Disease	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Gastrointestinal disorders Lip Swelling	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Gastrointestinal disorders Parotid Gland Enlargement	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Gastrointestinal disorders Tongue Coated	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
General disorders Fatigue	85.7% 6/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
General disorders Oedema Peripheral	28.6% 2/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
General disorders Pain	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
General disorders Pyrexia	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Infections and infestations Device Related Infection	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Infections and infestations Erythema Induratum	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Injury, poisoning and procedural complications Sunburn	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Injury, poisoning and procedural complications Thermal Burn	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Investigations Alanine Aminotransferase Increased	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Investigations Blood Potassium Decreased	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Investigations Gamma-Glutamyltransferase Increased	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Investigations Weight Decreased	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Metabolism and nutrition disorders Decreased Appetite	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Arthralgia	71.4% 5/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Back Pain	28.6% 2/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Bursitis	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Joint Swelling	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Muscular Weakness	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Myalgia	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Sensation of Heaviness	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Papilloma	57.1% 4/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Nervous system disorders Burning sensation	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Nervous system disorders Dizziness	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Nervous system disorders Headache	42.9% 3/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Nervous system disorders Hypoaesthesia	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Psychiatric disorders Restlessness	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Dysphonia	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Oropharyngeal Pain	28.6% 2/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Rhinitis Allergic	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Skin and subcutaneous tissue disorders Alopecia	28.6% 2/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Skin and subcutaneous tissue disorders Dermatitis Atopic	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Skin and subcutaneous tissue disorders Eczema	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Skin and subcutaneous tissue disorders Erythema	28.6% 2/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Skin and subcutaneous tissue disorders Hyperkeratosis	71.4% 5/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Skin and subcutaneous tissue disorders Onychoclasis	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Skin and subcutaneous tissue disorders Papule	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Skin and subcutaneous tissue disorders Photosensitivity Reaction	42.9% 3/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Skin and subcutaneous tissue disorders Pruritus	28.6% 2/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Skin and subcutaneous tissue disorders Pruritus Generalised	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Skin and subcutaneous tissue disorders Rash	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Skin and subcutaneous tissue disorders Rash Follicular	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Skin and subcutaneous tissue disorders Rash Generalised	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Skin and subcutaneous tissue disorders Rash Macular	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Skin and subcutaneous tissue disorders Rash Maculo-Papular	57.1% 4/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Skin and subcutaneous tissue disorders Seborrhoeic Dermatitis	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Skin and subcutaneous tissue disorders Skin Exfoliation	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Skin and subcutaneous tissue disorders Skin Induration	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.
Vascular disorders Hypotension	14.3% 1/7 • Baseline up to 28 days after last dose (up to 869 days) Safety population included all participants who received at least 1 dose of study drug.

Additional Information

Medical Communications

Hoffmann-LaRoche

Phone: 800 821-8590

Email: genentech@druginfo.com

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER