Malignant Melanoma
Conditions
Brief summary
This open-label, non-randomized study will assess the mass balance, metabolism, routes and rates of elimination as well as efficacy and safety of RO5185426 (RG7204; PLEXXIKON; PLX4032) in previously treated or untreated patients with metastatic melanoma. Patients will receive continuous twice daily oral treatment with RO5185426. On Day 15, a 14C-labeled dose will be administered. Anticipated time on study treatment is until disease progression occurs.
Interventions
DRUGRO5185426
Continuous oral dosing b.i.d. , on Day 15 a C isotope labeled dose will be administered
Sponsors
Hoffmann-La Roche
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult patients, \>/= 18 years of age * Histologically confirmed metastatic melanoma, surgically incurable and unresectable Stage IIIc or IV (AJCC) * Prior treatment for metastatic melanoma allowed; \>/= 28 days must be elapsed since previous systemic treatment prior to first administration of study drug * Positive BRAF V600E mutation result (by Roche CoDx test) * ECOG performance status 0-1 * Adequate hematologic, renal and liver function * Body Mass Index (BMI) 18 to 32 kg/m2 inclusive
Exclusion criteria
* Active CNS lesions * History of or known spinal cord compression, or carcinomatous meningitis * Anticipated or ongoing administration of any anticancer therapies other than those administered in this study * Refractory nausea or vomiting, or other medical conditions that are capable of altering the absorption, metabolism or elimination of the study drug * Known clinically significant active infection * Known HIV positivity or AIDS-related illness, active HBV, or active HCV * Previous malignancy within the past 5 years, except for basal or squamous cell carcinoma of the skin, melanoma in situ, and carcinoma in situ of the cervix * Clinically significant cardiovascular disease or incident within the 6 months prior to study drug administration * Patients who have had at least one dose of study drug (RO5185426 or comparator) in a clinical trial that includes RO5185426
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Total Dose in 14C-labeled RO5185426 and 14C-labeled Metabolite in Pooled Urine Samples | 0 up to 96 hours post dose on Day 15 | 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. |
| Percentage of Total Dose in 14C-labeled RO5185426 and 14C-labeled Metabolite in Pooled Fecal Samples | 0-24 + 24-48 hours, 48-72 + 72-96 hours post dose on Day 15 | 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. |
| Percentage of Total Integrated Radioactivity in Urine of 14C-labeled RO5185426 and 14C-labeled Metabolite | 0 up to 96 hours post dose on Day 15 | 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. |
| AUC Ratio of Blood:Plasma 14C-labeled RO5185426 | 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) | 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 RO5185426 Trough Concentrations on Days 15,16, and 17 | Pre-dose on Days 15, 16 and 17 | — |
| Maximum Plasma Concentration of 14C-labeled RO5185426 (Cmax) in Both Blood and Plasma | 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) | 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). |
| Time to Reach Cmax in Both Blood and Plasma | 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) | 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). |
| Area Under the Plasma Concentration Time Curve From Time Zero to the Last Quantifiable Sample (AUClast) of 14C-RO5185426 in Both Blood and Plasma | 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) | 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. |
| Half-life of 14C-labeled RO5185426 in Both Blood and Plasma | 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) | 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 Recovery: Percentage of Dose Excreted in Feces and Urine | 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) | 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). |
| Percentage of Total Integrated Radioactivity in Plasma of 14C-labeled RO5185426 and 14C-labeled Metabolite | 4+6 hours, 12 +24 hours, 36+48 hours post dose on Day 15 | 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. |
| Plasma 14C-labeled RO5185426 and 14C-labeled Metabolite Levels | 4+6 hours, 12 +24 hours, 36+48 hours post dose on Day 15 | 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. |
| Percentage of Total Integrated Radioactivity in Feces of 14C-labeled RO5185426 and 14C-labeled Metabolite | 0-24 + 24-48 hours, 48-72 + 72-96 hours post dose on Day 15 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From Baseline then Day 1 of Cycle 3 thereafter, Day 1 of every other cycle (every 2 months) until death (maximum 841 days) | Overall survival was defined as the time from the date of first treatment to the date of death, regardless of the cause of death. |
| Number of Participants With a Response by Confirmed Best Overall Response | 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) | 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. |
Countries
Switzerland
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 14C-labeled RO5185426 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. | 7 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Disease Progression | 5 |
Baseline characteristics
| Characteristic | 14C-labeled RO5185426 |
|---|---|
| Age, Continuous | 55.7 years STANDARD_DEVIATION 12.09 |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 7 |
| other Total, other adverse events | 7 / 7 |
| serious Total, serious adverse events | 3 / 7 |
Outcome results
Primary
14C-labeled RO5185426 Recovery: Percentage of Dose Excreted in Feces and Urine
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).
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 14C-labeled RO5185426 | 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 | 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 |
| 14C-labeled RO5185426 | 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 2.4 |
Primary
Area Under the Plasma Concentration Time Curve From Time Zero to the Last Quantifiable Sample (AUClast) of 14C-RO5185426 in Both Blood and Plasma
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 14C-labeled RO5185426 | 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 |
| 14C-labeled RO5185426 | 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 |
Primary
AUC Ratio of Blood:Plasma 14C-labeled RO5185426
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).
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 14C-labeled RO5185426 | AUC Ratio of Blood:Plasma 14C-labeled RO5185426 | 0.72 ratio | Standard Deviation 0.05 |
Primary
Half-life of 14C-labeled RO5185426 in Both Blood and Plasma
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).
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 14C-labeled RO5185426 | Half-life of 14C-labeled RO5185426 in Both Blood and Plasma | Plasma | 71.1 hour | Standard Deviation 15.4 |
| 14C-labeled RO5185426 | Half-life of 14C-labeled RO5185426 in Both Blood and Plasma | Blood | 84.4 hour | Standard Deviation 24.6 |
Primary
Maximum Plasma Concentration of 14C-labeled RO5185426 (Cmax) in Both Blood and Plasma
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).
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 14C-labeled RO5185426 | Maximum Plasma Concentration of 14C-labeled RO5185426 (Cmax) in Both Blood and Plasma | Blood | 5.25 micrograms equivalent per milliliter | Standard Deviation 1.71 |
| 14C-labeled RO5185426 | 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
Percentage of Total Dose in 14C-labeled RO5185426 and 14C-labeled Metabolite in Pooled Fecal Samples
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.
Time frame: 0-24 + 24-48 hours, 48-72 + 72-96 hours post dose on Day 15
Population: PK Analysis Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 14C-labeled RO5185426 | 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 |
| 14C-labeled RO5185426 | 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 |
| 14C-labeled RO5185426 | 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 |
| 14C-labeled RO5185426 | 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 |
| 14C-labeled RO5185426 | 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 |
| 14C-labeled RO5185426 | 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 |
| 14C-labeled RO5185426 | 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 |
| 14C-labeled RO5185426 | 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 |
Primary
Percentage of Total Dose in 14C-labeled RO5185426 and 14C-labeled Metabolite in Pooled Urine Samples
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.
Time frame: 0 up to 96 hours post dose on Day 15
Population: PK Analysis Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 14C-labeled RO5185426 | 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 0.1 |
| 14C-labeled RO5185426 | 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 |
| 14C-labeled RO5185426 | 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 0.1 |
| 14C-labeled RO5185426 | 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 |
| 14C-labeled RO5185426 | 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 |
Primary
Percentage of Total Integrated Radioactivity in Feces of 14C-labeled RO5185426 and 14C-labeled Metabolite
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.
Time frame: 0-24 + 24-48 hours, 48-72 + 72-96 hours post dose on Day 15
Population: PK Analysis Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 14C-labeled RO5185426 | 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 |
| 14C-labeled RO5185426 | 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 |
| 14C-labeled RO5185426 | 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 |
| 14C-labeled RO5185426 | 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 |
| 14C-labeled RO5185426 | 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 |
| 14C-labeled RO5185426 | 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 |
| 14C-labeled RO5185426 | 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 |
| 14C-labeled RO5185426 | 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
Percentage of Total Integrated Radioactivity in Plasma of 14C-labeled RO5185426 and 14C-labeled Metabolite
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.
Time frame: 4+6 hours, 12 +24 hours, 36+48 hours post dose on Day 15
Population: PK Analysis Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 14C-labeled RO5185426 | 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 |
| 14C-labeled RO5185426 | 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 |
| 14C-labeled RO5185426 | 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 |
| 14C-labeled RO5185426 | 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 |
| 14C-labeled RO5185426 | 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 |
| 14C-labeled RO5185426 | 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
Percentage of Total Integrated Radioactivity in Urine of 14C-labeled RO5185426 and 14C-labeled Metabolite
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.
Time frame: 0 up to 96 hours post dose on Day 15
Population: PK Analysis Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 14C-labeled RO5185426 | 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 |
| 14C-labeled RO5185426 | Percentage of Total Integrated Radioactivity in Urine of 14C-labeled RO5185426 and 14C-labeled Metabolite | RO5185426 | 32.38 percentage of total radioactivity | Standard Deviation 37.3 |
| 14C-labeled RO5185426 | 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 |
| 14C-labeled RO5185426 | 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 |
| 14C-labeled RO5185426 | 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
Plasma 14C-labeled RO5185426 and 14C-labeled Metabolite Levels
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.
Time frame: 4+6 hours, 12 +24 hours, 36+48 hours post dose on Day 15
Population: PK Analysis Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 14C-labeled RO5185426 | Plasma 14C-labeled RO5185426 and 14C-labeled Metabolite Levels | RO5185426: 4 + 6 hours | 6122 nanogram equivalent per gram | Standard Deviation 2537 |
| 14C-labeled RO5185426 | Plasma 14C-labeled RO5185426 and 14C-labeled Metabolite Levels | Mono-hydroxy Metabolite: 12 + 24 hours | 321 nanogram equivalent per gram | Standard Deviation 442 |
| 14C-labeled RO5185426 | Plasma 14C-labeled RO5185426 and 14C-labeled Metabolite Levels | Mono-hydroxy Metabolite: 36 + 48 hours | 238 nanogram equivalent per gram | Standard Deviation 249 |
| 14C-labeled RO5185426 | Plasma 14C-labeled RO5185426 and 14C-labeled Metabolite Levels | RO5185426: 12 + 24 hours | 6139 nanogram equivalent per gram | Standard Deviation 1787 |
| 14C-labeled RO5185426 | Plasma 14C-labeled RO5185426 and 14C-labeled Metabolite Levels | RO5185426: 36 + 48 hours | 4710 nanogram equivalent per gram | Standard Deviation 1544 |
| 14C-labeled RO5185426 | Plasma 14C-labeled RO5185426 and 14C-labeled Metabolite Levels | Mono-hydroxy Metabolite: 4 + 6 hours | 57 nanogram equivalent per gram | Standard Deviation 152 |
Primary
Plasma RO5185426 Trough Concentrations on Days 15,16, and 17
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 14C-labeled RO5185426 | Plasma RO5185426 Trough Concentrations on Days 15,16, and 17 | Day 15 | 61.1 micrograms per milliliter | Standard Deviation 28.1 |
| 14C-labeled RO5185426 | Plasma RO5185426 Trough Concentrations on Days 15,16, and 17 | Day 16 | 67.7 micrograms per milliliter | Standard Deviation 22.2 |
| 14C-labeled RO5185426 | Plasma RO5185426 Trough Concentrations on Days 15,16, and 17 | Day 17 | 61.5 micrograms per milliliter | Standard Deviation 13.4 |
Primary
Time to Reach Cmax in Both Blood and Plasma
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).
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 14C-labeled RO5185426 | Time to Reach Cmax in Both Blood and Plasma | Plasma | 4.1 hours |
| 14C-labeled RO5185426 | Time to Reach Cmax in Both Blood and Plasma | Blood | 4.1 hours |
Secondary
Number of Participants With a Response by Confirmed Best Overall Response
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 14C-labeled RO5185426 | Number of Participants With a Response by Confirmed Best Overall Response | 4 participants |
Secondary
Overall Survival
Overall survival was defined as the time from the date of first treatment to the date of death, regardless of the cause of death.
Time frame: 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.