Roche
Other Designation: PLX4032, PLX4720, RG7204, RO5185426
Description: PLX4720,
a BRAF(V600E) inhibitor, is one af a series of a novel selective potent
inhibitor of oncogenic B-Raf, including PLX4720, among others.
Current as of: January 10, 2010 |
BRaf (B-Raf)
• Braf(V600E) |
Trial participants are classified by B-Raf V600E mutation status using
a diagnostic test to identify patients with this mutation, being
co-developed by Plexxikon and Roche, under a separate agreement.
The relationship between PK, pharmacodynamics (pERK, Ki67, FDG-PET),
tumor histology, and clinical activity was investigated in 6 patients
with metastatic melanoma harboring BRAFV600E mutations treated with
PLX4032 daily at several dose levels. Tumor biopsies obtained at
baseline and on day 15 were assessed histologically and by
semi-quantitative IHC analysis for pERK and Ki67. The first 4 patients
were treated with a crystalline formulation of PLX4032; and the last 2
patients with a different formulation with increased bioavailability.
Plasma PK parameters were collected at frequent time points on days 1,
8 and 15. FDG-PET was performed on days 1 and 15 on last 2 patients. In
the first 4 patients there were no histologic changes with treatment
and disease progressed in all. In all these patients Ki67 positive
nuclei decreased and pERK levels decreased in 3 of the 4, from a median
60 before treatment to a median of 11 post treatment. Mean PLX4032
AUC0-24 hours was in the range for preclinical tumor stasis but below
the threshold for shrinkage. In the last 2 patients a striking tumor
necrosis and tumor melanosis was observed in the post treatment samples
resulting in 1 durable confirmed PR, and disease stabilized in the
other patient but progressed in cycle 2. The percentage of Ki67
positive nuclei declined substantially, from 30% and 50% before
treatment to 5% and 3% after treatment, as did the levels of pERK in
the patient with PR from 70 to 2. Mean PLX4032 AUC0-24 hours was well
above the preclinical threshold. A decreased FDG uptake on day 15 was
noted in both patients. Clinical activity of PLX4032 treatment
correlates with drug exposure levels as measured by AUC0-24 hours and
was associated with histologic changes in BRAFV600E-positive melanoma
on day 15. Reduction of pERK, along with evidence of reduced
proliferation and FDG uptake was observed Puzanov I, etal, ASCO09, Abs.
9021). |
