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The Tyrosine Kinase Inhibitor Optimization and Selectivity Study (TOPS) isthe first Phase III, randomized, controlled clinical trial designed toevaluate the potential benefits of an 800 mg starting dose across all riskcategories of newly diagnosed, previously untreated patients with Philadelphiachromosome-positive chronic myeloid leukemia (Ph+ CML).
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Numerically, more patients achieved a major molecular response (MMR) withthe 800 mg dose than the 400 mg dose (46.4% vs. 40.1%); however, thedifference between the two arms -- the primary endpoint of the study -- wasnot statistically significant. This trend of improved MMR rate at 12 months inthe 800 mg vs. 400 mg arms was most pronounced in the subset of patients withthe highest risk for disease progression (41.1% vs. 26.2%). Further, patientsin the 800 mg arm achieved MMR significantly faster than those who startedtreatment with Gleevec at 400 mg(1). Achievement of a MMR is an important goalof therapy for CML.
"TOPS reaffirms Gleevec as the standard of care for newly diagnosed CMLpatients," said Jorge Cortes, MD, Professor of Medicine and Deputy Chair ofLeukemia at the University of Texas MD Anderson Cancer Center in Houston. "Wesee a strong trend for rapid response with the 800 mg dose. As with trialslike IRIS, further follow up will be needed to assess what this rapid earlyresponse will mean in terms of long-term benefit."
TOPS also showed that patients with lower blood levels of Gleevec at onemonth had a lower molecular response at a year, an observation made inprevious studies(2). Cumulatively, these data suggest that maintainingadequate blood levels may help attain better clinical responses(2).
These findings, from the first analysis of the TOPS data set, will bepresented on Saturday, June 14, at the 2008 Congress of the EuropeanHematology Association (EHA) in Copenhagen.
"Our robust clinical program with Gleevec continues to provide meaningfulinsights into the treatment of Ph+ CML and other types of cancer," said DianeYoung, MD, Head of Global Medical Affairs at Novartis Oncology. "Novartiscontinues to invest in trials like ENESTnd, which is comparing Tasigna toGleevec in the first-line setting, to build on this knowledge and furtherenhance treatment outcomes for patients."
ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials ofnewly diagnosed Ph+ CML patients) is designed to study the efficacy and safetyof Tasigna(R) (nilotinib) capsules vs. Gleevec in newly diagnosed patients inthe chronic phase. ENESTnd is currently underway and will enroll approximately771 patients at 220 centers worldwide. Tasigna is currently approved for thetreatment of Ph+ CML in the chronic or accelerated phase in patients resistantto, or intolerant of, Gleevec.
Chronic myeloid leukemia (CML) is a cancer of the blood and bone marrow inwhich the body produces cancerous white blood cells. Almost all patients withCML have an abnormality known as the Philadelphia chromosome, which produces aprotein called Bcr-Abl that causes malignant white blood cells to proliferate.Gleevec, the first therapy to inhibit the activity of Bcr-Abl, revolutionizedthe treatment of Ph+ CML and is now the standard of care for this disease.
Study details
TOPS is a Phase III, international, open label, randomized, multi-centerclinical trial that included 103 study sites from 19 countries. The 476patients with newly diagnosed, previously untreated Ph+ CML in chronic phasewere randomized to receive Gleevec at either 800 mg/day or the standard
