New data on ZOLINZA (vorinostat) in combination with Bortezomib

Results from two Phase 1 studies of ZOLINZA (vorinostat), Merck's oral histone deacetylase (HDAC) inhibitor, administered in combination with bortezomib, showed early anti-tumor activity in patients with relapsed and/or refractory multiple myeloma, including those previously treated with and no longer responding to bortezomib.

Results of these studies, which were designed primarily to determine the maximum tolerated dose of the combination regimen, were presented today at the 50th Annual Meeting of the American Society of Hematology (Abstract #871). ZOLINZA is approved in the United States for treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent or recurrent disease on or following two systemic therapies. The findings presented today are investigational.

"Based on these data, Merck has moved rapidly into late-stage clinical development to further evaluate ZOLINZA in combination with bortezomib for advanced multiple myeloma," said Jose Garcia-Vargas, M.D., senior director, Clinical Oncology, Merck Research Laboratories. "This action affirms our belief in the potential of ZOLINZA and our commitment to improve the lives of patients living with this devastating disease."

Merck has initiated global, multi-center trials investigating ZOLINZA in combination with bortezomib in patients with relapsed and/or refractory multiple myeloma. These trials, part of the VANTAGE ( Vorinosta t Clinical Trials in Hematologic and Solid Malignancies) program, include a Phase 3 randomized, double-blind, placebo-controlled trial and an open-label Phase 2b trial, both of which are now recruiting patients.

"Patients with advanced multiple myeloma eventually relapse and that makes identification of new drugs a greater imperative," said Sundar Jagannath, M.D., lead investigator of the Phase 3 study and chief, Multiple Myeloma Program, St. Vincent's Comprehensive Cancer Center in New York City. "These trials will help us better understand the potential of ZOLINZA combined with bortezomib in myeloma treatment, and we are grateful to the patients who will participate."

The first Phase 1 trial, led by Donna Weber, M.D., University of Texas, M.D. Anderson Cancer Center, was a multi-center open-label, escalating-dose study of 34 patients with relapsed/refractory multiple myeloma, 33 of whom were available for evaluation of response. Patients were administered oral ZOLINZA 200 mg bid or 400 mg daily for 14 days and bortezomib 0.7 or 0.9 mg/m 2 I.V. on days 1, 4, 8, 11 and 15 or bortezomib 0.9, 1.1 or 1.3 mg/m 2 I.V. on days 1, 4, 8 and 11. Cycles were repeated every 21 days for < 8 cycles until progressive disease or intolerable toxicity. Patients who did not experience disease progression and continued to meet eligibility criteria after the first 8 cycles, were allowed to continue with the combination regimen at the same dose and schedule.

The study's primary objective, determining the maximum tolerated dose (MTD), was not achieved because two or more dose-limiting toxicities (DLTs) did not occur at any dose level. However, the maximum administered dose was ZOLINZA 400 mg daily for 14 days plus 1.3 mg/m 2 bortezomib. In the assessment of activity as measured by European Blood and Marrow Transplantation Group (EBMT) criteria, 54 percent of patients experienced either a partial response (36 percent, n=12) or a minimal response (18 percent, n=6). Thirty-nine percent (n=13) demonstrated stable disease and six percent (n=2) experienced progressive disease. Among seven evaluable patients who were previously treated with and were refractory to bortezomib, a response rate of 4/7 (57 percent) was observed: two had a partial response, two had a minimal response and three had stable disease. Two patients at differing dose levels experienced a DLT (transient AST elevation and thrombocytopenia). The most common adverse events (>20 percent) were nausea (n=21), diarrhea (n=20), thrombocytopenia (n=17), vomiting (n=17), fatigue (n=14), constipation (n=8) and increased lacrimation (excess secretion of tears, n=8).

The second Phase 1 study, led by Ashraf Badros, M.D., University of Maryland, and sponsored by the National Cancer Institute under a Clinical Trials Agreement with Merck for vorinostat and a Cooperative Research and Development Agreement with Millennium for bortezomib, enrolled 23 patients with relapsed or refractory multiple myeloma, 21 of whom were available for objective response evaluation. Patients received ZOLINZA (100 mg bid, 200 mg bid, 400 mg daily or 500 mg daily) on days 4-11 in combination with bortezomib (1.0 or 1.3 mg/m 2 I.V.) on days 1, 4, 8 and 11. Cycles were repeated every 21 days for < 8 cycles. If no response was observed at cycle 2, dexamethasone 20 mg was added on days 4-8.

MTD, the primary objective, was achieved at ZOLINZA 400 mg daily on days 4-11 and bortezomib 1.3 mg/m 2 I.V. on days 1, 4, 8 and 11. Assessment of clinical activity, a secondary objective, showed 10 percent (n=2) achieved a very good partial response, 33 percent (n=7) achieved a partial response, 48 percent (n=10) showed stable disease and 10 percent (n=2) experienced progressive disease to the combination regimen. Among eight evaluable patients who were previously treated with and were refractory to bortezomib, a response rate of 3/8 (38 percent) was observed: three had a partial response and four had stable disease. Dexamethasone was added at cycle 2 for six patients with progressive disease, at cycle 4 in five patients, and at cycle 6 in two patients. Two patients in the 500 mg group experienced DLTs (fatigue and prolonged QT interval). Pharmacokinetics of ZOLINZA were not altered by the addition of bortezomib. The main side effects observed were hematologic; Grade 3/4 side effects included anemia (n=6), neutropenia (n=5), thrombocytopenia (n=19), diarrhea (n=4), fatigue (n=6), prolonged QTc (n=1), hyponatremia (n=4) and hypokalemia (n=4).

VANTAGE 088: The randomized, placebo-controlled Phase 3 trial will enroll 742 patients at more than 35 centers across the United States, Latin America, Europe, Asia/Pacific, Middle East and Africa. Eligible patients must be 18 years or older, have a diagnosis of multiple myeloma, and have received at least one but no more than three prior treatment regimens. Patients who have previously received bortezomib therapy must have experienced a complete, partial or minimal response and not be considered refractory to bortezomib. The study will compare progression-free survival in patients taking bortezomib with either ZOLINZA or placebo. Overall survival, time to progression, objective response and tolerability also will be assessed.

VANTAGE 095: The open-label Phase 2b study is anticipated to enroll 142 patients at more than 13 sites in North America, Europe, Asia, and Middle East. To qualify, patients must be at least 18 years or older, have a diagnosis of multiple myeloma, and have had at least two prior courses of treatment. In addition, patients must be refractory to bortezomib taken alone or in combination with other anti-myeloma therapies and have been exposed to prior immunologic therapies, such as thalidomide or lenalidomide. The study will assess the objective response rate as well as progression-free survival, overall survival, time to disease progression and tolerability.