Clinical trial NCT01107418: A Pharmacokinetic/Pharmacodynamic Study of RO5185426 in Previously Treated Patients With Metastatic Melanoma
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Malignant Melanoma
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2010-04-21
Enrollment: 52
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility 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

Primary outcomes:
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 1
timeFrame: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24h]) of Vemurafenib on Day 1
timeFrame: Pre-dose, 1, 2, 4, 5, 8, 24 hours post-dose on Day 1
measure: Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 1
timeFrame: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1
measure: Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 1
timeFrame: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 9
timeFrame: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 9
measure: Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 9
timeFrame: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 9
measure: Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 9
timeFrame: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 9
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 15
timeFrame: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 15
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24h]) of Vemurafenib on Day 15
timeFrame: Pre-dose, 1, 2, 4, 5, 8, 24 hours post-dose on Day 15
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to 168 Hours (AUC[0-168h]) of Vemurafenib on Day 15
timeFrame: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15
measure: Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 15
timeFrame: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15
measure: Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 15
timeFrame: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15
measure: Apparent Clearance (CL/F) of Vemurafenib on Day 15
timeFrame: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15
measure: Terminal Elimination Half-Life (t1/2) of Vemurafenib on Day 15
timeFrame: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15
measure: Accumulation Ratio of Vemurafenib on Day 15
timeFrame: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1 and 15
Secondary outcomes:
measure: Percentage of Participants With a Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR)
timeFrame: 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)
measure: Overall Survival (OS)
timeFrame: 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)
Other outcomes:
Locations:
city: La Jolla
country: United States
state: California
city: San Francisco
country: United States
state: California
city: Stanford
country: United States
state: California
city: New Haven
country: United States
state: Connecticut
city: Chicago
country: United States
state: Illinois
city: Park Ridge
country: United States
state: Illinois
city: Sioux City
country: United States
state: Iowa
city: Omaha
country: United States
state: Nebraska
city: Columbus
country: United States
state: Ohio
city: East Providence
country: United States
state: Rhode Island
city: Charlottesville
country: United States
state: Virginia
city: Adelaide
country: Australia
state: South Australia
city: Melbourne
country: Australia
state: Victoria
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.