A Pharmacokinetic/Pharmacodynamic Study of RO5185426 in Previously Treated Patients With Metastatic Melanoma

A Phase I, Randomized, Open-label, Multi-center, Multiple Dose Study to Investigate the Pharmacokinetics and Pharmacodynamics of RO5185426 Administered as 240 mg Tablets to Previously Treated BRAF V600E Positive Metastatic Melanoma Patients

This open-label study will assess the pharmacokinetics, efficacy and safety of RO5185426 administered as 240mg tablets in previously treated patients with metastatic melanoma. Patients will be randomized to receive one of four dose-levels of RO5185426 [RG7204; PLEXXIKON; PLX4032] orally twice daily on days 1 to 15 (morning dose). Starting on day 22, treatment with RO5185426 may be resumed at a dose of 960 mg twice daily and continued until disease progression. Target sample size is <100 patients.

Study Overview

• Status: Completed
• Conditions: Malignant Melanoma
• Intervention / Treatment: Drug: RO5185426; Drug: RO5185426; Drug: RO5185426; Drug: RO5185426; Drug: RO5185426

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • South Australia
    • Adelaide, South Australia, Australia, 5000
  • Victoria
    • Melbourne, Victoria, Australia, 3181
• United States
  • California
    • La Jolla, California, United States, 92093
    • San Francisco, California, United States, 94115
    • Stanford, California, United States, 94305
  • Connecticut
    • New Haven, Connecticut, United States, 06510-3289
  • Illinois
    • Chicago, Illinois, United States, 60637
    • Park Ridge, Illinois, United States, 60068
  • Iowa
    • Sioux City, Iowa, United States, 51101
  • Nebraska
    • Omaha, Nebraska, United States, 68114
  • Ohio
    • Columbus, Ohio, United States, 43219
  • Rhode Island
    • East Providence, Rhode Island, United States, 02915
  • Virginia
    • Charlottesville, Virginia, United States, 22908

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• adult patients, >/=18 years of age
• histologically confirmed metastatic melanoma, stage IIIc or IV (AJCC)
• failure of at least one prior standard of care regimen
• positive for BRAF V600E mutation (by Roche CoDx BRAF mutation assay)
• ECOG performance status 0 or 1
• adequate hematologic, renal and liver function

Exclusion Criteria:

• active CNS lesions on CT/MRI within 28 days prior to enrollment
• history of spinal cord compression o carcinomatous meningitis
• anticipated or ongoing anti-cancer therapies other than those administered in this study
• previous treatment with BRAF inhibitor (sorafenib allowed) or MEK inhibitor
• severe cardiovascular disease within 6 months prior to study
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1	Drug: RO5185426; dosage b) orally twice daily, days 1-15 (morning dose); Drug: RO5185426; dosage c) orally twice daily, days 1-15 (morning dose); Drug: RO5185426; dosage d) orally twice daily, days 1-15 (morning dose); Drug: RO5185426; 960 mg orally twice daily, from day 22 onward; Drug: RO5185426; dosage a) orally twice daily, days 1-15 (morning dose)
Experimental: 2	Drug: RO5185426; dosage b) orally twice daily, days 1-15 (morning dose); Drug: RO5185426; dosage c) orally twice daily, days 1-15 (morning dose); Drug: RO5185426; dosage d) orally twice daily, days 1-15 (morning dose); Drug: RO5185426; 960 mg orally twice daily, from day 22 onward; Drug: RO5185426; dosage a) orally twice daily, days 1-15 (morning dose)
Experimental: 3	Drug: RO5185426; dosage b) orally twice daily, days 1-15 (morning dose); Drug: RO5185426; dosage c) orally twice daily, days 1-15 (morning dose); Drug: RO5185426; dosage d) orally twice daily, days 1-15 (morning dose); Drug: RO5185426; 960 mg orally twice daily, from day 22 onward; Drug: RO5185426; dosage a) orally twice daily, days 1-15 (morning dose)
Experimental: 4	Drug: RO5185426; dosage b) orally twice daily, days 1-15 (morning dose); Drug: RO5185426; dosage c) orally twice daily, days 1-15 (morning dose); Drug: RO5185426; dosage d) orally twice daily, days 1-15 (morning dose); Drug: RO5185426; 960 mg orally twice daily, from day 22 onward; Drug: RO5185426; dosage a) orally twice daily, days 1-15 (morning dose)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 1		Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1
Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24h]) of Vemurafenib on Day 1		Pre-dose, 1, 2, 4, 5, 8, 24 hours post-dose on Day 1
Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 1		Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1
Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 1		Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1
Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 9		Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 9
Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 9		Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 9
Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 9		Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 9
Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 15		Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 15
Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24h]) of Vemurafenib on Day 15		Pre-dose, 1, 2, 4, 5, 8, 24 hours post-dose on Day 15
Area Under the Plasma Concentration-Time Curve From Time Zero to 168 Hours (AUC[0-168h]) of Vemurafenib on Day 15		Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15
Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 15		Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15
Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 15		Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15
Apparent Clearance (CL/F) of Vemurafenib on Day 15	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.	Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15
Terminal Elimination Half-Life (t1/2) of Vemurafenib on Day 15	Time measured for vemurafenib plasma concentrations to decrease by one-half (t1/2) was calculated as 0.693 divided by apparent first-order terminal elimination rate constant (0.693/kel).	Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15
Accumulation Ratio of Vemurafenib on Day 15	Accumulation ratio was calculated as, AUC(0-8) on Day 15 divided by AUC(0-8) on Day 1.	Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1 and 15

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With a Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR)	Confirmed best overall response was defined as having best objective response as CR or PR, as assessed by investigator and confirmed at least 28 days after initial response. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1). CR was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) were required to demonstrate a reduction to normal (short axis less than [<] 10 millimeters [mm]). PR was defined as a 30 percent (%) decrease in the sum of the diameters of the target lesions taking as a reference the baseline sum diameter. Percentage of participants with best overall response of confirmed CR or PR are reported.	Up to approximately 3 years (assessed at Cycle 1 Day 1, Cycle 3 Day 1, Cycle 5 Day 1, thereafter every 2 cycles and then every 4 cycles after Cycle 13)
Overall Survival (OS)	OS was defined as the time, in months, from the date of the first study drug administration to the date of death, regardless of the cause of death.	Up to approximately 3 years (assessed at Cycle 1 Day 1, Cycle 3 Day 1, Cycle 5 Day 1, thereafter every 2 cycles and then every 4 cycles after Cycle 13)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Frederick DT, Salas Fragomeni RA, Schalck A, Ferreiro-Neira I, Hoff T, Cooper ZA, Haq R, Panka DJ, Kwong LN, Davies MA, Cusack JC, Flaherty KT, Fisher DE, Mier JW, Wargo JA, Sullivan RJ. Clinical profiling of BCL-2 family members in the setting of BRAF inhibition offers a rationale for targeting de novo resistance using BH3 mimetics. PLoS One. 2014 Jul 1;9(7):e101286. doi: 10.1371/journal.pone.0101286. eCollection 2014.
• Lacouture ME, Duvic M, Hauschild A, Prieto VG, Robert C, Schadendorf D, Kim CC, McCormack CJ, Myskowski PL, Spleiss O, Trunzer K, Su F, Nelson B, Nolop KB, Grippo JF, Lee RJ, Klimek MJ, Troy JL, Joe AK. Analysis of dermatologic events in vemurafenib-treated patients with melanoma. Oncologist. 2013;18(3):314-22. doi: 10.1634/theoncologist.2012-0333. Epub 2013 Mar 1.

Study record dates

Study Major Dates

• Study Start: May 1, 2010
• Primary Completion (Actual): February 1, 2013
• Study Completion (Actual): February 1, 2013

Study Registration Dates

• First Submitted: April 12, 2010
• First Submitted That Met QC Criteria: April 19, 2010
• First Posted (Estimate): April 21, 2010

Study Record Updates

• Last Update Posted (Estimate): August 26, 2015
• Last Update Submitted That Met QC Criteria: July 29, 2015
• Last Verified: July 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma
• Other Study ID Numbers: NP25163