A Pharmacokinetic/Pharmacodynamic Study of RO5185426 in Previously Treated Patients With Metastatic Melanoma - Full Text View

Purpose

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.

Condition	Intervention	Phase
Malignant Melanoma	Drug: RO5185426	Phase 1


Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Intervention Model: Parallel Assignment Masking: None (Open Label) Primary Purpose: Treatment
Official Title:	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

Resource links provided by NLM:

MedlinePlus related topics: Melanoma

Genetic and Rare Diseases Information Center resources: Carcinoid Tumor Neuroepithelioma

U.S. FDA Resources

Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:

Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 1 [ Time Frame: 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 [ Time Frame: Pre-dose, 1, 2, 4, 5, 8, 24 hours post-dose on Day 1 ]
Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 1 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 9 ]
Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 9 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose 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.
Terminal Elimination Half-Life (t1/2) of Vemurafenib on Day 15 [ Time Frame: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose 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).
Accumulation Ratio of Vemurafenib on Day 15 [ Time Frame: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1 and 15 ]
Accumulation ratio was calculated as, AUC(0-8) on Day 15 divided by AUC(0-8) on Day 1.

Secondary Outcome Measures:

Percentage of Participants With a Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR) [ Time Frame: 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) ]
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.
Overall Survival (OS) [ Time Frame: 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) ]
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.


Enrollment:	52
Study Start Date:	May 2010
Study Completion Date:	February 2013
Primary Completion Date:	February 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: 1	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 960 mg orally twice daily, from day 22 onward
Experimental: 3	Drug: RO5185426 dosage c) orally twice daily, days 1-15 (morning dose) Drug: RO5185426 960 mg orally twice daily, from day 22 onward
Experimental: 4	Drug: RO5185426 dosage d) orally twice daily, days 1-15 (morning dose) Drug: RO5185426 960 mg orally twice daily, from day 22 onward

Eligibility


Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

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: NCT01107418

Locations


United States, California

La Jolla, California, United States, 92093

San Francisco, California, United States, 94115

Stanford, California, United States, 94305
United States, Connecticut

New Haven, Connecticut, United States, 06510-3289
United States, Illinois

Chicago, Illinois, United States, 60637

Park Ridge, Illinois, United States, 60068
United States, Iowa

Sioux City, Iowa, United States, 51101
United States, Nebraska

Omaha, Nebraska, United States, 68114
United States, Ohio

Columbus, Ohio, United States, 43219
United States, Rhode Island

East Providence, Rhode Island, United States, 02915
United States, Virginia

Charlottesville, Virginia, United States, 22908
Australia, South Australia

Adelaide, South Australia, Australia, 5000
Australia, Victoria

Melbourne, Victoria, Australia, 3181

Sponsors and Collaborators

Hoffmann-La Roche

Investigators


Study Director:	Clinical Trials	Hoffmann-La Roche

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.


Responsible Party:	Hoffmann-La Roche
ClinicalTrials.gov Identifier:	NCT01107418 History of Changes
Other Study ID Numbers:	NP25163
Study First Received:	April 12, 2010
Results First Received:	July 29, 2015
Last Updated:	July 29, 2015

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 September 21, 2017