Healthcare Industry News: Prothrombin Time
News Release - July 20, 2007
Journal of Clinical Oncology Publishes Data on ZOLINZA(TM) (vorinostat), Merck's Treatment for Advanced Cutaneous T-cell LymphomaWHITEHOUSE STATION, N.J.--(HSMN NewsFeed)--Results from a clinical study conducted with patients who were diagnosed with advanced, refractory cutaneous T-cell lymphoma (CTCL) showed nearly a third of patients responded to treatment with ZOLINZA(TM) (vorinostat), as measured by objective response rate, according to data published in this week's Journal of Clinical Oncology. ZOLINZA, Merck's most recent anticancer treatment, is approved for the treatment of cutaneous manifestations in patients with CTCL who have progressive, persistent or recurrent disease on or following two systemic therapies. CTCL is a cancer of the T-cells, a type of white blood cell, which affects the skin and is a form of non-Hodgkin's lymphoma.
In the open-label, single-arm study, 30 percent of all patients (22 of 74, 95% CI (19.7 to 41.5%)) with CTCL achieved an objective response to daily oral treatment with ZOLINZA as did 30 percent of patients with Stage IIB or higher disease (18 of 61, 95% CI (18.5 to 42.6%)). Objective response rate, the primary endpoint of the study, was defined as at least four weeks of either a complete response (defined as no evidence of disease) or a partial response (defined as greater than or equal to 50 percent decrease in a skin assessment score compared to baseline). One patient with Stage IIB CTCL achieved a complete clinical response with ZOLINZA.
"The findings from this clinical study are quite encouraging, particularly given that the effect of ZOLINZA was evaluated based on stringent criteria to determine objective response," said Elise Olsen, M.D., director, Cutaneous Lymphoma Treatment and Research Center at Duke University Medical Center, and lead author of the study. "Furthermore, the effect of ZOLINZA was consistent in the overall patient population and among patients in later stage (IIB or higher) disease."
Study assessed other efficacy measures
Other findings from the study showed the median time to objective response was less than two months (55 days) in all patients, however, in rare cases, it took up to six months for patients to achieve an objective response to ZOLINZA. The median duration of response was not reached since the majority of responses continued at the time of analysis, but was estimated to exceed six months in all patients; and the median time to progression approached five months (148 days) in all patients treated with ZOLINZA.
The most common side effects observed in the study were diarrhea (49 percent), fatigue (46 percent), nausea (43 percent), anorexia (26 percent), dysgeusia (24 percent) and thrombocytopenia (22 percent).
About the study
The clinical study was an open-label, non-randomized trial that included 74 patients with CTCL who had previously failed at least two prior systemic therapies. Patients were given ZOLINZA 400 mg once daily until disease progression or intolerable toxicity, with modifications to the dose, as needed.
The median age of patients in the study was 60 years. Fifty-one percent of the patients were male and 49 percent were female. Eighteen percent of patients had Stage IB or IIA CTCL and 82 percent had Stage IIB and higher CTCL. The median number of prior systemic therapies was three. Extent of skin disease was quantitatively assessed by investigators using a modified Severity Weighted Assessment Tool.
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 thromboembolic events. 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 therapy 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.
Based on reports of dehydration as a serious drug-related adverse event in clinical trials, patients should be instructed to drink at least two L/Day of fluids for adequate hydration. Hyperglycemia has been observed in patients receiving ZOLINZA. Serum glucose should be monitored, especially in diabetic or potentially diabetic patients. Adjustment of diet and/or therapy for increased glucose may be necessary. QTc prolongation has been observed. Monitor electrolytes and ECGs at baseline and periodically during treatment. Hypokalemia or hypomagnesemia should be corrected prior to administration of ZOLINZA.
The most common serious adverse events, regardless of causality, in the 86 CTCL patients in two clinical studies were pulmonary embolism reported in 4.7 percent (4/86) of patients, squamous cell carcinoma reported in 3.5 percent (3/86) of patients and anemia reported in 2.3 percent (2/86) of patients. 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).
Prolongation of Prothrombin Time (PT) and International Normalized Ratio (INR) were observed in patients receiving ZOLINZA concomitantly with coumarin-derivative anticoagulants. Physicians should carefully monitor PT and INR in patients concurrently administered ZOLINZA and coumarin derivatives. Severe thrombocytopenia and gastrointestinal bleeding have been reported with concomitant use of ZOLINZA and other HDAC inhibitors (e.g., valproic acid). Monitor platelet count every two weeks for the first two months.
ZOLINZA was not evaluated in patients with hepatic impairment. As ZOLINZA is predominately eliminated through metabolism, patients with hepatic impairment should be treated with caution.
Dosing and administration for ZOLINZA
The recommended dose of ZOLINZA is 400 mg orally once daily with food. If the patient is intolerant to therapy, the dose may be reduced to 300 mg orally once daily with food. The dose may be further reduced to 300 mg once daily with food for five consecutive days each week. Treatment with ZOLINZA may be continued as long as there is no evidence of progressive disease or unacceptable toxicity. ZOLINZA capsules should not be opened or crushed.
ZOLINZA was approved in October 2006 by the U.S. Food and Drug Administration for the treatment of the cutaneous manifestations in patients with CTCL who have progressive, persistent or recurrent disease on or following two systemic therapies. ZOLINZA is accessible to patients through Merck's Accessing Coverage Today (ACT) program. ACT is a three-part program specifically designed to assist patients in obtaining ZOLINZA, help with insurance reimbursement issues, and provide support for those qualified individuals lacking insurance coverage for ZOLINZA. Patients without insurance coverage may be eligible for Merck's Patient Assistant Program, which allows them to receive ZOLINZA free of charge. Merck also is contributing to co-pay assistance foundations that provide co-pay assistance to qualified individuals. To enroll in the ACT program, patients need to call 1-866-363-6379 once they receive a prescription for ZOLINZA.
CTCL - a type of lymphoma cancer
CTCL, a type of non-Hodgkin's lymphoma, is a form of cancer in T-cells, a type of white blood cell. Normal T-cells function by regulating the body's immune system in its job of fighting infections and other foreign antigens. In CTCL, the malignant T-cells are drawn to the skin, where some are deposited. Patients usually develop CTCL after age 50, but it may present at any age. CTCL affects up to 20,000 patients in the United States, with another 1,500 new cases reported each year.
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.
Merck & Co., Inc., is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.
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