[OT1-03-13] A phase II, double blind, randomised, placebo-controlled study of the AKT Inhibitor AZD5363 in combination with paclitaxel in triple-negative advanced or metastatic breast cancer (TNBC) (NCT02423603).
Schmid P, Wheatley D, Baird R, Chan S, Abraham J, Tutt A, Kristeleit H, Patel G, Bathakur U, Bishop J, Harper-Wynne C, Sims E, Copson E, Perren T, Stein R, Poole C, Cartwright H, Sarker S-J, Mousa K, Turner N.
Queen Mary University of London, London, United Kingdom.
Royal Cornwall Hospital, Truro, Cornwall, United Kingdom.
Addenbrookes Hospital, Cambridge, United Kingdom.
Nottingham City Hospital, Nottingham, United Kingdom.
Velindre Cancer Centre, Cardiff, United Kingdom.
Guy's & St Thomas' Hospital, London, United Kingdom.
Queen Elizabeth Hospital, London, United Kingdom.
The Royal Sussex County Hospital, Brighton, United Kingdom.
Yeovil District Hospital, Somerset, United Kingdom.
Glan Clwyd Hospital, Denbighshire, United Kingdom.
Maidstone Hospital, Kent, United Kingdom.
Queens Hospital, Essex, United Kingdom.
Southampton General Hospital, Southampton, United Kingdom.
St James' University Hospital, Leeds, United Kingdom.
University College London Hospitals, London, United Kingdom.
University Hospital Coventry, Coventry, United Kingdom.
Royal Marsden Hospitals, London, United Kingdom.
Management of metastatic TNBC remains a challenge. Chemotherapy is the mainstay of treatment but benefits are frequently short-lived with rapid development of resistance. The PI3K/AKT/mTOR pathway has been implicated in many ways in TNBC, making inhibition of AKT an attractive therapeutic target. Based on downstream pathway activation signatures, PI3K pathway activation appears higher in TNBC compared to other molecular subtypes, despite a relatively low percentage of activating PI3K mutations. Alternative means of activating the PI3K pathway have been identified in TNBC, including loss or mutation of PTEN (up to 35%) and INPP4B (up to 30%) and/or amplification of PIK3CA, AKT2 or AKT3, resulting in increased activation of AKT. Induction of AKT by chemotherapy can be an early compensatory mechanism that can be exploited therapeutically to increase the efficacy of chemotherapy. Preclinical TNBC models with activated AKT signalling have been shown to be highly sensitive to AKT inhibitors. AZD5363 is a potent pan-AKT inhibitor with good oral bioavailability. Multiple lines of investigation have demonstrated strong synergistic effects between AKT inhibition and taxane chemotherapy in models of TNBC both in vitro and in vivo, providing rationale for the combination of AZD5363 and paclitaxel in TNBC.
PAKT is designed to test the hypothesis that inhibition of AKT will increase the anti-tumour activity of paclitaxel chemotherapy in TNBC. The study will try to characterize those patients who may benefit from this treatment to identify potential predictors of sensitivity.
PAKT is an international investigator led and sponsored, double-blind, placebo controlled, randomised phase II trial. Patients are randomised 1:1 to receive paclitaxel weekly (90mg/m2) on days 1,8, and 15 plus AZD5363 (400mgBD) or placebo (400mgBD) on days 2-5, 9-12, 15-19 (28 day treatment cycles). Patients are stratified by the number of metastatic sites and the interval from the end of adjuvant chemotherapy. Treatment is given until disease progression (RECIST 1.1), intolerable toxicity or elective withdrawal. Tumour assessments are carried out every 8 weeks.
PAKT enrols patients with histologically documented locally advanced/metastatic TNBC (ER≤Allred2, PR≤Allred2, HER2=0,1+or2+), no prior systemic therapy for advanced TNBC, ECOG PS 0-2 and measurable disease per RECIST v1.1. Patients with brain metastases, significant cardiovascular disease, motor polyneuropathy are excluded.
The primary endpoint is progression-free survival. Secondary endpoints are objective response rate, change in tumour size, clinical benefit rate, overall survival, duration of response, and patient reported outcomes. Archival tumour tissue must be available to evaluate potential biomarkers associated with therapeutic response and resistance.
PFS will be compared between treatment arms by the stratified log-rank test. HR for disease progression/death will be estimated using a stratified Cox proportional hazards model. Kaplan-Meier methodology will be used to estimate the median PFS for each arm. Approximately 140 patients will be enrolled at ≈65 sites in the UK, France, Hungary, Romania, Georgia & South Korea.
Wednesday, December 9, 2015 5:00 PM
Ongoing Clinical Trials: Ongoing Trials -- Targeted Therapies (5:00 PM-7:00 PM)
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