The dual mTOR inhibitor AZD2014, when combined with the hormonal therapy fulvestrant, was found to be safe in patients with advanced oestrogen receptor (ER)- positive breast cancer, and some of them experienced clinical benefit from the drug combination, according to phase 1 clinical trial data presented at the AACR Annual Meeting 2015, April 18-22.

“Patients with ER-positive breast cancer respond to hormonal therapy, but over time, some eventually develop resistance to treatment and their tumours become dependent on a cell-signaling pathway called the mTOR pathway for survival,” said Manish R Patel, MD, associate director of drug development for Sarah Cannon Research Institute in Nashville, Tennessee, and director of drug development at the Florida Cancer Specialists and Research Institute in Sarasota.

“We are testing whether combining the hormonal therapy fulvestrant with the dual mTOR inhibitor AZD2014 can help overcome this resistance. AZD2014 is a new anticancer therapy and represents a potential improvement compared with other drugs that have similar mechanisms of action”, Patel added.

“In this trial, we tested two dosing schedules of AZD2014: continuous dosing, in which the drug is given every day, and intermittent dosing, in which the drug is given only two days of each week,” Patel explained.

“We compared the side-effect profiles of the two dosing schedules. The response of individual patients to treatment was also monitored.” Patel and colleagues enrolled 66 patients with metastatic ER-positive breast cancer; 43 received one of the four different dose levels of AZD2014 seven days a week, and 23 received one of the two different dose levels of AZD2014 two days a week.

All patients received fulvestrant on day one of each 28-day cycle.

Of the 49 patients with measurable disease, eight had confirmed partial responses and five had unconfirmed partial responses. Of the 66 patients, 31 had clinical benefit, which includes partial responses and stable disease.

“It was interesting to observe that AZD2014 had encouraging clinical activity whether dosed continuously or intermittently, with the two schedules having different tolerability profiles,” said Patel.

According to Patel, overall, treatment with AZD2014 was well tolerated.

Common side effects included rash, nausea, vomiting, diarrhoea, sore mouth, and fatigue.

Intermittent treatment with AZD2014 provided a more optimal safety profile than continuous dosing.

While none of the patients dosed on the intermittent schedule needed to discontinue the drug due to toxicity issues, some patients from the continuous dosing schedule discontinued due to adverse events, he explained.

Patel cautioned that this is a small phase I study that is not statistically powered to determine which schedule has the best efficacy.

This is being explored further in a phase II study called MANTA, which compares fulvestrant with or without one of the two schedules of AZD2014 as well as fulvestrant with another mTOR inhibitor, everolimus, he said.

Source: AACR