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

Study Overview
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Brief Summary
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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.

Official Title
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A Phase I, Open-label, Excretion Balance, Pharmacokinetic and Metabolism Study After Single Oral Dose of 14C-labeled RO5185426 in Previously Treated and Untreated Patients With Metastatic Melanoma

Conditions
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Malignant Melanoma

Intervention / Treatment
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* Drug: RO5185426


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm<br> | Drug: RO5185426<br>* Continuous oral dosing b.i.d. , on Day 15 a C isotope labeled dose will be administered<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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). | 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) | 
| 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). | 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) | 
| 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. | 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) | 
| 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). | 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) | 
| 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). | 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) | 
| 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). | 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) | 
| 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. | 4+6 hours, 12 +24 hours, 36+48 hours post dose on Day 15 | 
| 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. | 4+6 hours, 12 +24 hours, 36+48 hours post dose on Day 15 | 
| 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. | 0-24 + 24-48 hours, 48-72 + 72-96 hours post dose on Day 15 | 
| 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. | 0-24 + 24-48 hours, 48-72 + 72-96 hours post dose on Day 15 | 
| 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. | 0 up to 96 hours post dose on Day 15 | 
| 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. | 0 up to 96 hours post dose on Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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) | 
| 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. | From Baseline then Day 1 of Cycle 3 thereafter, Day 1 of every other cycle (every 2 months) until death (maximum 841 days) |