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first survivin inhibitor--cancer cells not only divide too much, they die too little!
Investigational Survivin Inhibitor Shows Potential in Solid Tumors and Lymphoma
June 12, 2006 (Atlanta) — A novel investigational drug, YM155 (Astellas Pharma), that suppresses the inhibitors of apoptotic proteins is well tolerated and appears to act against several types of solid tumors, according to a team of investigators that presented its findings here at the 42nd annual meeting of the American Society of Clinical Oncology.
“This is the first survivin inhibitor that has been developed, and it was well tolerated in patients with several different types of solid tumors,” said principal investigator Andrew M. Tolcher, MD. “It exhibited provocative antitumor activity and therefore warrants a broad phase 2 evaluation.” Dr. Tolcher is the chief of staff at the Cancer Therapy and Research Center in San Antonio, Texas.
The investigators conducted the current phase 1 study with YM155 on the basis of promising preclinical activity, which included antiproliferative activity and tumor regressions. The investigators wanted to determine the maximum tolerated dose of a 168-hour continuous infusion of YM155 every 3 weeks. They also wanted to evaluate its toxicity, its pharmacokinetics, and its antitumor activity. They used a conventional dose-escalation scheme and added patients to fully characterize any toxicities at the maximum tolerated dose. They performed pharmacokinetic sampling during cycles 1 and 2.
The study involved 41 patients, 31 men and 10 women, who were a median of 61 years old. They ranged from 28 to 78 years old, with performance status ranging from 0 to 2. The investigators enrolled the patients into 4 dose cohorts:
Eight at 1.8 mg/m2/day.
Six at 3.6 mg/m2/day.
Two at 6.0 mg/m2/day.
Twenty-five at 4.8 mg/m2/day.
Among these patients, 9 had prostate cancer, 5 had non-Hodgkin's lymphoma, and 5 had colorectal cancer. The remaining 22 patients had other types of solid tumors.
Both of the patients who received the 6.0 mg/m2/day dose experienced dose-limiting toxicities consisting of renal tubular necrosis with grade 3 mucositis and increased serum creatinine, respectively. Therefore, the investigators defined the maximum tolerated dose as 4.8 mg/m2/day.
The most frequent adverse events were pyrexia, arthralgia, nausea, fatigue, and diarrhea. The most common grade 3 or 4 drug-related adverse events were: mucosal inflammation, in 2 patients (4.9%), and increased international normalized ratios, also in 2 patients (4.9%).
At the maximum tolerated dose, the median clearance was 47 L/h with a median steady-state concentration of 7.5 ng/mL and a median terminal half-life of 22 hours.
Two patients with chemotherapy-refractory, intermediate-grade non-Hodgkin's lymphoma had a marked reduction of the lymph nodes, including 1 reduction that was durable, as seen by independent reviewers. The patient went on to receive bone-marrow transplantation and was in remission when Dr. Tolcher presented this report. Two hormone-refractory prostate cancer patients also exhibited a response, as demonstrated by a drop in prostate-specific antigen of at least 50%.
“The development of this drug is interesting because most people think of cancer cells as growing too fast,” said Michael C. Heinrich, MD, in a phone interview. “However, one of the problems is that they don’t die when they’re supposed to. Breaking up the protein interactions that promote the maintenance of life is very challenging. It’s promising that there were some responses to this, and therefore we should see interest and excitement about this class of drugs.” Dr. Heinrich, who was not involved in the study, is a professor of medicine at the Oregon Health Sciences University Cancer Institute in Portland.
ASCO 42nd Annual Meeting: Abstract 3014. Presented June 5, 2006.
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