New Drug Shows Benefit in NET Carcinoid Syndrome

Zosia Chustecka

October 06, 2015

VIENNA ― The first drug developed specifically for patients with carcinoid syndrome has shown clinical benefit in a phase 3 trial.

The trial was presented in a late-breaking abstract here at European Cancer Congress (ECC) 2015.

Carcinoid syndrome develops in patients with metastatic neuroendocrine tumors (NETs) and results from the overproduction of serotonin by these tumors. Symptoms include debilitating diarrhea, facial flushing, and abdominal pain and can result in serious consequences, such as heart valve damage.

"Carcinoid syndrome has a significant impact on the lives of patients who already have been battling metastatic cancer," Maryann Wahmann, founder and president of the Neuroendocrine Cancer Awareness Network, said in a statement. "These patients can live for many years with their cancer, yet the symptoms of carcinoid syndrome are what frequently limit their lives and restrict their activities every single day. So there is a tremendous need for effective new treatment options."

The new drug, telotristat etiprate (under development by Lexicon), inhibits tryptophan hydroxylase, an enzyme that triggers the excess serotonin production within metastatic NET cells that leads to carcinoid syndrome. Although existing treatments for carcinoid syndrome reduce the release of serotonin outside tumor cells, telotristat etiprate works at the source to reduce serotonin production within the tumor cells, the company explains.

Telotristat etiprate has received Fast Track and Orphan Drug designation from the US Food and Drug Administration.

The drug was tested in a pivotal phase 3 trial, known as TELESTAR. The trial was conducted in 135 patients with carcinoid syndrome that was not adequately controlled on treatment with long- acting somatostatin analogues (SSA), which is the current standard of care.

Patients continued with their SSA therapy and were randomly assigned to receive either telotristat etiprate (250 mg or 500 mg orally, each taken 3 times daily) or placebo during a 12-week period.

The primary end point of the study was the reduction from baseline in the average number of daily bowel movements.

The results show that at both doses tested, the new drug significantly reduced the average number of daily bowel movements during the 12-week study period (P < .001).

In the placebo group (n = 35), patients had an average of 5.25 bowel movements daily at baseline; this was reduced by 17%, to an average of 4.34 daily, at week 12.

In the group taking telotristat 250 mg (n = 36), the average number of bowel movements at baseline was 5.95; this was reduced by 29%, to 4.24 daily, at week 12.

In the patients taking the higher dose of 500 mg, the average number of daily bowel movements fell from 5.94 at baseline to 3.83 at week 12, a reduction of 35%.

Patients taking the drug showed a reduction in urinary 5-HIAA, the main metabolite of serotonin, which shows that the drug was targeting serotonin overproduction, commented lead author Matthew H. Kulke, MD, director of the program in neuroendocrine and carcinoid tumors and senior physician, Dana Farber Cancer Institute, and associate professor of medicine, Harvard Medical School, both in Boston.

Dr Kulke reported that telotristat also reduced the frequency of flushing episodes and the intensity of abdominal pain compared with placebo, but these differences did not reach statistical significance. About 39% of patients had these symptoms at baseline, he noted.

Serious adverse events were uncommon and were similar for all the treatment groups, Dr Kulke reported. He commented specifically on nausea and depression as adverse events of interest, and said that reports of these symptoms were mild or moderate and did not lead to discontinuation.

Nausea was reported by 11.1% of patients receiving placebo, by 13.3% by those receiving telotristat 250 mg, and by 28.9% by those receiving telotristat 500 mg.

Depression was reported by 6.7% with placebo, by 2.2% with the lower dose, and by 17.7% with the higher dose. Depressed mood was reported by 0, 2.2% and 4.4% respectively.

Telotristat has a favorable safety profile, he commented, and concluded: "We believe this is a promising new treatment approach."

He noted that 87% of patients in the study continued with open-label treatment with the higher dose of the drug, telotrsistat 500 mg tid.

The drug was specifically designed not to cross the blood-brain barrier, which is important because reducing serotonin levels in the brain results in depression, explained discussant for the study David Cunningham, MD, FRCP, consultant medical oncologist at the Royal Marsden Hospital, Sutton, and director of clinical research at the Institute of Cancer Research, United Kingdom.

Dr Cunningham commented that the reduction in bowel movements was significant when compared with placebo but that the reduction was "relatively modest," he said. He added that the drug had no significant effect on reducing flushing and abdominal pain.

He emphasized that the chronic diarrhea associated with carcinoid syndrome can be debilitating ― it can be severe and unpredictable, and it can prevent patients from going about their daily activities and going to new places. He said that quality-of-life data were needed to show what effect this new drug had on patients' lives. "We need careful health economic evaluation of this treatment approach," he concluded.

The TELESTAR study was funded by Lexicon.

European Cancer Congress (ECC) 2015: Abstract 37LBA. Presented September 29, 2015.

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