Plexxikon Announces First Patient Dosed in Phase 3 Trial of PLX4032 (RG7204) for Metastatic Melanoma
Berkeley, CA—January 8, 2010
Plexxikon Inc. announces that enrollment has been initiated and the first patient has been dosed in a pivotal Phase 3 trial of PLX4032 (RG7204) in patients with metastatic melanoma. PLX4032 is a novel, oral and highly targeted drug that is designed to inhibit the BRAF cancer-causing mutation that occurs in about 50 percent of melanomas and about eight percent of all solid tumors. The randomized, controlled, Phase 3 “BRAF Inhibitor in Melanoma” (BRIM3) trial in previously untreated patients is part of the planned registration program for PLX4032. The initiation of the Phase 3 trial has triggered a significant milestone payment to Plexxikon from Roche, its co-development partner, under their 2006 collaboration agreement. Plexxikon also is entitled to receive additional payments for further milestone achievements as well as royalties on sales of PLX4032. A Phase 2 trial (BRIM2) in previously treated melanoma patients was initiated in September 2009, with enrollment ongoing.
“With some tumor shrinkage in nearly all mutation-positive melanoma patients, and 70 percent of patients achieving at least 30 percent tumor shrinkage in our most recent clinical study, PLX4032 has shown meaningful anti-tumor activity. The Phase 3 trial, with a primary endpoint of overall survival, will provide an assessment of clinical benefit of PLX4032 in a randomized, controlled study design, which should further build our registration program for this drug,” stated K. Peter Hirth, Ph.D., chief executive officer of Plexxikon. “We are hopeful that this accelerated development program will enable us to bring this new personalized medicine to melanoma patients as quickly as possible. PLX4032 represents the first drug in Plexxikon’s promising franchise of oncology drug candidates.”
BRIM3 is a Phase 3 trial expected to enroll approximately 700 previously untreated melanoma patients who will be randomized one-to-one with PLX4032 at a dose of 960 mg BID or dacarbazine (DTIC), a comparator drug approved for the treatment of metastatic melanoma. Patients will be monitored throughout the study for safety and efficacy endpoints. The primary endpoint of this trial is overall survival. Secondary endpoints include duration of response, progression-free survival and best overall response rate (BORR). The BRIM3 trial is a multicenter study being conducted at approximately 100 sites, including sites in the United States, Australia, Europe and Canada, with sites continuing to open through Q2 2010.
BRIM2 is a Phase 2 trial expected to enroll approximately 100 patients and is a single-arm study in previously treated melanoma patients. This trial is enrolling patients at 13 sites in the U.S. and Australia.
Patients enrolling in both BRIM3 and BRIM2 are being selected using an investigational companion diagnostic test that detects the BRAF mutation. This diagnostic is being co-developed in parallel with PLX4032 by Roche Molecular Systems, Inc. and Plexxikon. Patients interested in enrolling in the BRIM2 or BRIM3 trials may find additional information at the Roche Clinical Trials Registry (http://www.roche-trials.com/), at email@example.com, by visiting www.clinicaltrials.gov, or by contacting the Roche/Genentech Call Center at 888-662-6728.
Phase 1 Data Support Advanced Clinical Development Program for PLX4032
Promising data from the Phase 1 extension cohort in mutation-positive melanoma patients were recently presented at the September 2009 ECCO/ESMO conference, and provided support for the initiation of the pivotal Phase 2 and Phase 3 trials in melanoma. These data showed some tumor shrinkage in nearly all patients treated with PLX4032, and 70 percent of patients achieving at least 30% tumor shrinkage by RECIST criteria. Patients in the Phase 1 melanoma extension cohort were treated with PLX4032 at a dose of 960 mg twice daily (BID), which was well tolerated. Drug-related adverse events were predominantly mild in severity, including rash, joint pain, photosensitivity and fatigue. Skin squamous cell carcinoma (keratoacanthoma subtype) was observed in 20 percent of patients and removed by excision while treatment with PLX4032 was continued.
Plexxikon conducted the Phase 1 dose escalation cohort and an extension cohort in mutation-positive melanoma patients. The company has also completed enrollment in a second extension cohort of mutation-positive colorectal cancer patients. Roche, and its wholly-owned subsidiary, Genentech, are conducting all future clinical trials of PLX4032, including BRIM2 and BRIM3.
BRAF Mutation in Melanoma and Other Cancers
The BRAF mutation has been shown, both in preclinical studies and PLX4032 clinical studies, to be a key driver of cancer, particularly in melanoma. This mutation is present in approximately 50 percent of melanoma skin cancers. Overall, about eight percent of all solid tumors carry this mutation, including melanoma, colorectal, thyroid, biliary tract, prostate, ovarian, lung and glioma cancers. The BRAF mutation represents a unique target for cancer therapy since the mutation occurs only in tumor cells and not in normal cells. The high degree of selectivity of PLX4032 for this target has enabled sufficient dose levels to achieve over 90 percent inhibition required for tumor shrinkage.
Melanoma is the most serious type of skin cancer. More than 50,000 people in the U.S. and 160,000 people worldwide are diagnosed with melanoma each year. The median progression-free survival for a patient with metastatic melanoma is less than 60 days, and the median overall survival for these patients is less than 12 months.
About PLX4032 (RG7204)—A Personalized Medicine for Cancer Treatment
PLX4032 is a novel, oral small molecule for melanoma and other cancers harboring the BRAF mutation. Plexxikon utilized its structure-guided chemistry platform to discover PLX4032, and initiated clinical development in 2006. PLX4032 is now being co-developed under a 2006 license and collaboration agreement between Plexxikon and Roche. A DNA-based companion diagnostic to identify patients whose tumors carry the BRAF mutation is being co-developed by Plexxikon and Roche Molecular Systems, Inc. in parallel with the development of PLX4032.
Plexxikon is a leader in the structure-guided discovery and development of novel small molecule pharmaceuticals to treat human disease. The company’s clinical stage programs include PLX4032 for melanoma and colorectal cancer, PLX5568 for polycystic kidney disease, PLX204 for diabetes and PLX3397 for metastatic disease and rheumatoid arthritis. Among the company’s preclinical development programs, candidates are being developed for rheumatoid arthritis, multiple sclerosis and other autoimmune diseases as well as for other cancers.
Plexxikon’s proprietary Scaffold-Based Drug Discovery™ platform integrates multiple state-of-the-art technologies, including structural screening as one key component that provides a significant competitive advantage over other drug discovery approaches. To date, the company has discovered a portfolio of clinical and preclinical stage compounds being developed to address significant unmet medical needs in cardio-renal disease, CNS disorders, inflammatory and neuro-inflammatory diseases and oncology.