Plexxikon Inc. announces that enrollment has been initiated and the first patient has been treated in the first of two pivotal trials of PLX4032 (RG7204) in patients with metastatic melanoma. PLX4032 is a novel, oral and highly selective drug that targets the BRAFV600E cancer-causingmutation occurring in about 50 percent of melanomas and about eight percent of all solid tumors. This single arm Phase 2 B-Raf Inhibitor in Melanoma (BRIM2) trial for previously-treated metastatic melanoma patients, along with a randomized, controlled Phase 3 trial (BRIM3) expected to start by the end of 2009 in first-line patients, are part of the planned registration program for PLX4032. The initiation of the Phase 2 trial has triggered a significant milestone payment to Plexxikon from Roche. Plexxikon is entitled to receive additional payments for milestone achievements as well as royalties on sales of PLX4032. Plexxikon and Roche are co-developing PLX4032 under their 2006 license and collaboration agreement.
The Phase 2 trial (Study #NP22657) is an open label, single arm study in which approximately 100 metastatic melanoma patients who test positive for the BRAFV600E cancer-causingmutation will be treated with PLX4032 at a dose of 960 mg twice-daily (BID). Eligible patients for this trial must have progressed after at least one prior treatment. Patients will be monitored throughout the study for safety and efficacy endpoints. The primary endpoint of this trial is Best Overall Response Rate (BORR) as indicated by tumor regression measured by RECIST (Response Evaluation Criteria in Solid Tumors) criteria. Secondary endpoints include progression-free survival (PFS), symptom improvement and overall survival.
The Phase 2 trial will be conducted at 13 sites in the United States and Australia, and enrollment is expected to be complete by the end of 2009. Patients interested in enrolling in the Phase 2 trial may find additional information at the Roche Clinical Trials Registry (http://www.roche-trials.com/), by visiting www.clinicaltrials.gov, or by contacting the Roche Call Center at 973-235-5000. Roche is conducting all future clinical trials of PLX4032, including these Phase 2 and 3 clinical trials.
Plexxikon has conducted the Phase 1 dose escalation study, and has completed an extension study in exclusively mutation-positive metastatic melanoma patients. Enrollment for a second extension study of mutation-positive colorectal cancer patients is expected to complete by year end.
“Since presenting our positive clinical data at both ASCO and ECCO this year, we have had overwhelming interest in PLX4032 from physicians and patients worldwide. We are looking forward to advancing PLX4032 with the hope of registering this drug as soon as possible in order to make this medicine available to the many metastatic melanoma patients who may benefit,” stated K. Peter Hirth, Ph.D., chief executive officer of Plexxikon. “The data generated from the melanoma extension study clearly demonstrate single agent activity with PLX4032, which is unprecedented for melanoma. Additionally, the high degree of selectivity of PLX4032 has enabled us to dose to near complete target inhibition while such treatment has been well tolerated by most patients.”
Melanoma Extension Study Confirms Safety & Tumor Regression Seen in Phase 1 Dose Escalation
In an extension study of melanoma patients with the BRAFV600E mutation, 31 patients have been enrolled, most with advanced metastatic disease (Stage M1c), and treated with PLX4032 at 960 mg BID. Among the 27 evaluable patients to date, results confirm the preliminary safety and efficacy seen in the previous Phase 1 dose escalation study:
- PLX4032 was well tolerated at 960 mg BID, now confirmed as the maximum tolerated dose
- Complete response in 1 patient treated for 3 cycles
- Partial responses of greater than 30% tumor regression by RECIST criteria have been observed in 18 patients, with 15 patients showing responses of greater than 50%
- Minor responses in 6 patients showed tumor regression between 10% and 30%
A median PFS has not been achieved since it is too early in the study to report. These data were presented earlier this month at the ECCO 15 / ESMO 34 2009 Conference in Berlin, Germany.
Drug-related adverse events were predominantly mild in severity and included rash, joint pain, photosensitivity and fatigue. Serious adverse events were observed in some patients after chronic treatment, including seven patients with cutaneous squamous cell carcinoma (keratoacanthoma subtype) that were treated by excision, while treatment with PLX4032 was continued. A risk management plan is in place for baseline evaluation of the skin and monitoring of all patients while on study.