Women with HER2-positive early-stage breast cancer receiving adjuvant treatment with PB272 (neratinib) may experience severe diarrhea as a side effect, but other agents can control this, according to a new study.
The Phase 2 CONTROL trial (NCT02400476) showed that a combination of loperamide, loperamide and budesonide, or loperamide plus colestipol prophylaxis, reduces diarrhea’s incidence, severity and duration. Los Angeles-based Puma Biotechnology presented the study, “Effects of adding budesonide or colestipol to loperamide prophylaxis on neratinib-associated diarrhea in patients with HER2+ early-stage breast cancer: the CONTROL trial,” earlier this month at the American Association for Cancer Research (AACR) 2017 Annual Meeting in Washington, D.C.
PB272, developed by Puma, is an experimental oral drug for the treatment of breast cancer and other solid tumors. A 2010 report on a Phase 2 clinical trial showed that PB272 by itself benefits HER+ metastatic breast cancer patients.
The Phase 3 ExteNET trial (NCT00878709) investigated the effect of PB272 as an adjuvant treatment in women with HER2+ early-stage breast cancer who had previously received Herceptin as an adjuvant. Results showed that 95.4 percent of patients had diarrhea in general, and that 39.8 percent had grade 3 or higher diarrhea.
The CONTROL trial is a Phase 2 study investigating whether using loperamide prophylaxis, with or without other agents, may reduce PB272-associated diarrhea. For this reason, the trial enrolled patients with HER2+ early-stage breast cancer who had completed Herceptin-based adjuvant therapy and received daily PB272 for one year.
Patients received loperamide 16 mg on the first day, 12 mg on the second and third days, and then 6-8 mg on days 4 to 56. The protocol was later changed, and patients received 12 mg on days 1-14 and 8 mg on days 15-56.
The trial included two additional patient groups. One received loperamide and budesonide (an anti-inflammatory corticosteroid that is believed to reduce diarrhea) and the other received loperamide plus colestipol (a bile acid sequestrant that is expected to reduce diarrhea as well). Results showed that the incidence of grade 3 diarrhea was 30.7 percent among those who received loperamide prophylaxis, 23.4 percent among those on loperamide plus budesonide, and 11.5 percent among those who received the combination of loperamide plus colestipol.
While patients on the ExteNET trial reported persistent diarrhea during the treatment period, patients on the CONTROL trial reported early but not recurring diarrhea.
“We are pleased to see the reductions in the incidence of severe [PB272]-related diarrhea in the CONTROL trial when using the loperamide, loperamide plus budesonide or loperamide plus colestipol regimens,” Puma President and CEO Alan Auerbach said in a news release. “The severe diarrhea appears to become more acute, whereby it does not typically recur after the first month. We are also very encouraged by the improvements in tolerability that have been seen to date in the budesonide and the colestipol cohorts. This is a marked improvement in tolerability over what was seen in the ExteNET trial and we look forward to continuing to monitor this in the loperamide plus colestipol cohort.”
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