ATLANTA, GA, December 8, 2007 -- Results from two investigational Phase I trials of ZOLINZA® (vorinostat) in combination with bortezomib provide preliminary anti-tumor activity in patients with relapsed and/or refractory multiple myeloma. Data from one study showed that 10 of 21 (48 percent) evaluable patients had a partial or minimal response from the ZOLINZA and bortezomib combination treatment. Data from a second study, sponsored by the United States National Cancer Institute under a Clinical Trials Agreement with Merck & Co., Inc., demonstrated 10 of 23 (43 percent) evaluable patients had a partial response or greater from the combination treatment. These data were presented today at the 49th Annual Meeting of the American Society of Hematology (Abstracts #1168 and #1172).
These trials are the first to evaluate the safety and efficacy of ZOLINZA as part of a combination regimen in patients with relapsed and/or refractory multiple myeloma. The primary objective of both trials was to determine the maximum tolerated dose (MTD) of ZOLINZA in combination with bortezomib in these patients. Bortezomib is regarded as a standard treatment option against multiple myeloma; the use of ZOLINZA in this patient population is investigational.
“With more than 50,000 men and women living with multiple myeloma, continued research is imperative, as patients eventually relapse after completing therapy,” said Jose Garcia-Vargas, M.D., senior director, Clinical Oncology, Merck Research Laboratories. “These data provide a preliminary evaluation of the combination of vorinostat with bortezomib in patients with advanced multiple myeloma, including those who've previously received bortezomib therapy. Larger clinical studies are needed to confirm these results.”
Study results
In the multicenter open-label, escalating-dose Phase I trial, a total of 24 patients with relapsed or refractory multiple myeloma were administered oral ZOLINZA 200 mg bid or 400 mg daily for 14 days in combination with bortezomib 0.7 or 0.9 mg/m2 I.V. on days 4, 8, 11 and 15 or in combination with bortezomib 0.9, 1.1, or 1.3 mg/m2 I.V. on days 1, 4, 8 and 11. Cycles were repeated every 21 days for a maximum of 8 cycles until progressive disease or intolerable toxicity. The primary objective was to determine MTD; secondary objectives included assessment of activity (using EBMT criteria) and safety and tolerability of the combination regimen. The median age of patients in the study was 61 years (45-76) and the median number of prior anti-cancer therapies was 3 (range of 1-14), with 25 percent (n=6) of patients previously treated with bortezomib.
Although the MTD has not yet been determined, of the 21 evaluable patients who received the combination regimen, as assessed using EBMT criteria, 48 percent had a partial (n=5) or minimal (n=5) response. Among the six patients previously treated with bortezomib, two achieved a partial response and three had a minimal response. Two patients experienced dose-limiting toxicities (transient AST elevation and thrombocytopenia). The most common drug-related adverse events among all patients were nausea (n=14), thrombocytopenia (n=13), diarrhea (n=12), vomiting (n=12), fatigue (n=10) anemia (n=6) and neutropenia (n=6). Accrual continues to determine the MTD.
In the second Phase I study lead by Dr. Ashraf Badros, University of Maryland, and sponsored by the Division of Cancer Treatment and Diagnosis, National Cancer Institute, 23 patients with relapsed or refractory multiple myeloma were administered oral ZOLINZA (100 mg bid, 200 mg bid, 400 mg daily or 500 mg daily) on days 4-11 over a 21-day period in combination with bortezomib (1.0 or 1.3 mg/m2 I.V. on days 1, 4, 8 and 11). Cycles were repeated every 21 days for a maximum of 8 cycles. If no response was observed at Cycle 2, dexamethasone 20 mg was added on days 4-8. The primary objective was to determine the MTD and pharmacokinetic and pharmacodynamic activity of the combination regimen. Patients also were evaluated for response and tolerability.
The median age of patients in the study was 54 years (39-78) and the median number of prior therapies was 7 (range of 3-13), with 19 patients previously treated with bortezomib.
Results of the study showed that the MTD for the combination regimen was achieved at ZOLINZA 400 mg daily for 8 days plus bortezomib 1.3 mg/ m2 days 1, 4, 8 and 11 respectively. Forty-three percent of patients had a partial response or greater (1 VGPR and 9 PR) following treatment with the ZOLINZA and bortezomib combination regimen, assessed using the International uniform response criteria for multiple myeloma. Among the 19 patients previously treated with bortezomib, one achieved a very good partial response and six had a partial response. Two patients experienced dose-limiting toxicities (fatigue and prolonged QT interval). Some of the non-hematological toxicities grade 2 and higher included fatigue (n=9), nausea (n=6), vomiting (n=3), diarrhea (n=3), pneumonia (n=3, bacterial and RSV), shingles (n=2) and atrial fibrillation (n=1).
“Based on these initial results presented for the first time, Merck is evaluating plans to accelerate testing of ZOLINZA in combination with bortezomib in the randomized clinical trial setting to further define the clinical activity in relapsed or refractory multiple myeloma," said Dr. Garcia-Vargas.
About ZOLINZA
ZOLINZA is the first histone deacetylase (HDAC) inhibitor approved by the U.S. Food & Drug Administration (FDA) for the 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.
ZOLINZA works by inhibiting the enzymatic activity of HDAC1, HDAC2, HDAC3 (Class I) and HDAC 6 (Class II) at nanomolar concentrations (IC50 < 86nM). In some cancer cells, excess amounts of the enzyme HDAC prevent the activation of genes that control normal cell activity. Based on in vitro studies, ZOLINZA is believed to decrease the activity of HDAC, allowing for the activation of genes that may help to slow or stop the growth of cancer cells. The exact mechanism of the anticancer effect of ZOLINZA has not been fully characterized.
Important safety information about ZOLINZA
As pulmonary embolism and deep vein thrombosis have been reported as adverse reactions, physicians should be alert to the signs and symptoms of these events, particularly in patients with a prior history of thrombocytopenia. Treatment with ZOLINZA can cause dose-related thrombocytopenia and anemia. If platelet counts and/or hemoglobin are reduced during treatment with ZOLINZA, the dose should be modified or discontinued. Gastrointestinal disturbances, including nausea, vomiting and diarrhea, have been reported and may require the use of antiemetic and antidiarrheal medications. Fluid and electrolytes should be replaced to prevent dehydration. Pre-existing nausea, vomiting and diarrhea should be adequately controlled before beginning therapy with ZOLINZA.
Hyperglycemia has been observed in patients receiving ZOLINZA. Serum glucose should be monitored, especially in diabetic or potentially diabetic patients receiving ZOLINZA. Adjustment of diet and/or glucose therapy may be necessary. QTc prolongation has been observed. Monitor electrolytes and ECGs at baseline and periodically during treatment. Administer with caution in patients who have or may develop QTc prolongation. Hypokalemia or hypomagnesemia should be corrected prior to administration with ZOLINZA.
The most common adverse events observed in clinical trials with ZOLINZA for CTCL, regardless of causality, were fatigue (52 percent), diarrhea (52 percent), nausea (41 percent), dysgeusia (28 percent), thrombocytopenia (26 percent), anorexia (24 percent), decreased weight (21 percent) and muscle spasm (20 percent).
About Merck Oncology
Merck Oncology focuses on all aspects of cancer care – prevention, treatment, and supportive care. Through strong internal research capabilities, selective alliances and acquisitions, and enabling technologies such as the Molecular Profiling platform of Rosetta, Merck Oncology is looking to lead in the discovery, development and delivery of targeted anticancer therapies customized for patient subpopulations. Merck Oncology conducts research at sites in Boston, Seattle, West Point, Japan and Italy.
About Merck
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