Abstract CT331: “BEECH”, a phase I/II study of the AKT inhibitor AZD5363 combined with paclitaxel in patients with advanced or metastatic breast cancer: results from the dose-finding study, including quantitative assessment of circulating tumor DNA as a s
Authors: Turner Nicholas C. , Oliveira Mafalda , Armstrong Anne , Sablin Marie-Paule , Perez-Fidalgo José A. , Herebien Sarah , Garcia-Murillas Isaac , Johnson Stan , Foxley Andrew , Mahmood Adnan , Lindemann Justin P. 
Published: August 2015

Abstract
Background: The PI3K/AKT/MTOR pathway is frequently de-regulated in breast cancer. AZD5363 (AZD) is a potent selective inhibitor of AKT1-3. We report the dose-finding phase assessing the safety/tolerability of two intermittent weekly dosing schedules of AZD combined with paclitaxel (P) in HER2 negative breast cancer. The study incorporates prospective assessment of whether circulating tumour DNA (ctDNA) analysis can predict response/resistance earlier than conventional RECIST.
Design: AZD capsules were dosed p.o. in one of two schedules: “4/3” (4 days on-treatment followed by 3 days off, starting 360 mg twice daily (bd)) or “2/5” (2 days on-5 days off, starting 560 mg bd). Both schedules comprised 3 weeks P 90 mg/m2 IV on Day 1 with AZD started on Day 2, and 1 week off-treatment. Patients who stopped P were able to continue AZD alone at investigators’ discretion. Escalating doses of AZD were evaluated in cohorts of 3-6 evaluable patients treated until disease progression, unacceptable toxicity, or withdrawal of consent. A safety review committee reviewed safety data and dose limiting toxicities (DLTs) prior to dose modification. Plasma samples for ctDNA extraction were collected at baseline, weekly in cycle 1, day 1 of all subsequent cycles, and were analysed by digital PCR. Female patients aged ≥18 years with HER2 negative MBC and up to two prior chemotherapy courses for advanced cancer were recruited.
Results: 37 patients have received AZD. DLTs in 2/6 patients at 480 mg 4/3 comprised one patient with maculo-papular rash, and another with immune allergic reaction (both CTCAE grade 3). No DLT was observed in the 400 mg 4/3 cohort, which was defined as the maximum tolerated dose (MTD) in combination with P. DLTs in 2/6 patients at 640 mg 2/5 comprised one patient with prolonged neutropaenia (grade 4), and another with diarrhoea (grade 3). No DLTs were observed in 11 patients on the 560 mg 2/5 cohort. In all patients median progression free survival was 8.2 months, despite pre-treatment with taxane chemotherapy in 62% patients and a median of 2 prior lines of chemotherapy. A patient with Cowden's syndrome (PTEN germline mutation) had a partial response maintained for 18 months, including 12 months on AZD5363 alone. ctDNA assessment suggests that lack of a fall in ctDNA abundance may predict for early progression.
Conclusions: AZD5363 400mg bd 4/3 in combination with paclitaxel was determined to be well tolerated in patients with MBC, with investigation of the 2/5 schedule continuing. Two international double-blind randomised studies have commenced to assess AZD5363 400 mg bd 4/3 schedule combined with paclitaxel versus paclitaxel plus placebo in ER positive HER2 negative MBC stratified by PIK3CA mutation status (BEECH Part B), and in triple negative breast cancer (PAKT).
Citation Format: Nicholas C. Turner, Mafalda Oliveira, Anne Armstrong, Marie-Paule Sablin, José A. Perez-Fidalgo, Sarah Herebien, Isaac Garcia-Murillas, Stan Johnson, Andrew Foxley, Adnan Mahmood, Justin P. Lindemann. “BEECH”, a phase I/II study of the AKT inhibitor AZD5363 combined with paclitaxel in patients with advanced or metastatic breast cancer: results from the dose-finding study, including quantitative assessment of circulating tumor DNA as a s [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT331. doi:10.1158/1538-7445.AM2015-CT331