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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT01164891
First received: July 16, 2010
Last updated: January 11, 2016
Last verified: January 2016
  Purpose
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.

Condition Intervention Phase
Malignant Melanoma
Drug: RO5185426
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • Plasma RO5185426 Trough Concentrations on Days 15,16, and 17 [ Time Frame: Pre-dose on Days 15, 16 and 17 ] [ Designated as safety issue: No ]
  • Maximum Plasma Concentration of 14C-labeled RO5185426 (Cmax) in Both Blood and Plasma [ 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) ] [ Designated as safety issue: No ]
    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 [ 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) ] [ Designated as safety issue: No ]
    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 [ 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) ] [ Designated as safety issue: No ]
    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 [ 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) ] [ Designated as safety issue: No ]
    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).

  • AUC Ratio of Blood:Plasma 14C-labeled RO5185426 [ 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) ] [ Designated as safety issue: No ]
    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 [ 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) ] [ Designated as safety issue: No ]
    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 [ Time Frame: 4+6 hours, 12 +24 hours, 36+48 hours post dose on Day 15 ] [ Designated as safety issue: No ]
    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 [ Time Frame: 4+6 hours, 12 +24 hours, 36+48 hours post dose on Day 15 ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0-24 + 24-48 hours, 48-72 + 72-96 hours post dose on Day 15 ] [ Designated as safety issue: No ]
    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.

  • Percentage of Total Dose in 14C-labeled RO5185426 and 14C-labeled Metabolite in Pooled Fecal Samples [ Time Frame: 0-24 + 24-48 hours, 48-72 + 72-96 hours post dose on Day 15 ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0 up to 96 hours post dose on Day 15 ] [ Designated as safety issue: No ]
    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.

  • Percentage of Total Dose in 14C-labeled RO5185426 and 14C-labeled Metabolite in Pooled Urine Samples [ Time Frame: 0 up to 96 hours post dose on Day 15 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Number of Participants With a Response by Confirmed Best Overall Response [ 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) ] [ Designated as safety issue: No ]
    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.

  • Overall Survival [ 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) ] [ Designated as safety issue: No ]
    Overall survival was defined as the time from the date of first treatment to the date of death, regardless of the cause of death.


Enrollment: 7
Study Start Date: July 2010
Study Completion Date: December 2012
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Single Arm Drug: RO5185426
Continuous oral dosing b.i.d. , on Day 15 a C isotope labeled dose will be administered

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01164891

Locations
Switzerland
Zürich, Switzerland, 8091
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01164891     History of Changes
Other Study ID Numbers: NP25158 
Study First Received: July 16, 2010
Results First Received: July 29, 2015
Last Updated: January 11, 2016
Health Authority: Switzerland: Swissmedic

Additional relevant MeSH terms:
Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas

ClinicalTrials.gov processed this record on August 25, 2016