“Many patients with ovarian cancer accumulate a lot of fluid in their abdomen, which is drained prior to chemotherapy. In an earlier study, we isolated cancer cells from the drained fluid from some patients and found that those whose cancer cells had elevated levels of a protein called pS6K developed resistance to chemotherapy,” said Udai Banerji, MD, PhD, a reader in Molecular Cancer Pharmacology at The Institute of Cancer Research in London and The Royal Marsden NHS Foundation Trust, also in London, United Kingdom.
“AZD2014 is a dual mTOR inhibitor that can reverse the effects of pS6K. We first conducted preclinical studies to test whether combining AZD2014 with paclitaxel might help overcome resistance to treatment, and then initiated a phase I clinical trial to test this combination in patients with heavily pretreated ovarian cancer and NSCLC,” Banerji explained.
“Our study is a classic example of a bedside-to-bench and back-to-bedside story. We are excited that our study could possibly change the way advanced squamous NSCLC and ovarian cancer are treated,” Banerji said.
Banerji and colleagues tested AZD2014 and paclitaxel individually and in combination in ovarian, lung, and breast cancer cell lines and found that combining the two drugs increased cancer cell death, when compared with the outcomes from testing the drugs individually. They further confirmed these findings using two animal models of lung and ovarian cancer, respectively, in which tumor volume reductions were accompanied by a reduction in the pS6K protein levels, providing proof of principle.
The investigators presented the results of the phase I dose-escalation clinical trial that recommended the phase II dose of the combination at 80 mg/m2 of paclitaxel weekly and 50mg twice a day of AZD2014, including data on toxicity and preliminary efficacy.
In the investigator-initiated phase I trial, 21 patients with solid tumors were enrolled. Patients received one of the escalating doses of AZD2014 twice a day, either two times or three times a week, overlapped with a fixed dose of paclitaxel given weekly. Radiological response was measured by RECIST, and clinical benefit, defined as progression at 14 weeks or later, was assessed.
Of the 10 evaluable patients with ovarian cancer, seven had partial responses. Of the two evaluable patients with squamous NSCLC in the dose expansion section of the study, both had partial responses. “An expansion cohort in squamous lung cancer is currently ongoing to follow up these encouraging findings,” Banerji said.
Side effects included fatigue, diarrhea, and nausea, but none of these were serious (grade 3 or 4) at the recommended phase II dose, Banerji noted.
“We will be launching a randomized phase II trial in the United Kingdom to test the combination in patients with advanced ovarian cancer, and we will be recruiting patients to an open-label phase Ib multicenter trial to test the combination in patients with squamous NSCLC,” said Banerji.
This study was funded by AstraZeneca, the Experimental Cancer Medicine Centre (ECMC) and the NIHR Biomedical Research Centre at The Royal Marsden and The Institute of Cancer Research. Dr Banerji has received research funding from AstraZeneca.
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