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MTOR Inhibitors

This is a single arm study whereby a cohort of 20 patients with early high risk prostate cancer will be treated with a 15-day course of AZD2014 (mTOR inhibitor) treatment prior to radical prostatectomy.

AZD2014

Simon C Pacey, MRCP, PhD

Patients with localised prostate cancer can be treated by radical prostatectomy (prostate gland removal surgery) or radiotherapy. Around 15% of men with prostate cancer are diagnosed with high risk disease meaning they are more likely to suffer treatment failure, disease progression and mortality. To date little progress has been made towards identifying effective treatment strategies that might delay or prevent disease recurrence in this patient population. Better identification of patients at high risk of relapse and improvements in therapy are therefore research priorities.

A protein named Mammalian Target of Rapamycin (mTOR) is known to play an important role in the development of prostate cancer. mTOR forms two protein complexes (mTORC1 and mTORC2) and sends signals helping cancer cells to grow while controlling their energy use. Blocking the function of mTOR, with an inhibitor such as AZD2014, might shut down the supply of energy supply to tumour cells leading to reduced cell growth and potentially slowing the progression of the disease.

The purpose of this study is to investigate the molecular pharmacology of AZD2014 treatment given to patients with prostate cancer prior to radical prostatectomy. The feasibility, safety and tolerability of a short course of AZD2014 will also be assessed.

Eligible patients will be required to take 50mg AZD2014 tablets twice daily for 15 days prior to radical prostatectomy.

Immunohistochemistry will be carried out on prostate tumour biopsies taken at baseline and at radical prostatectomy in order to detect phosphorylated biomarkers of mTOR signalling and determine the amount of mTORC1 and mTORC2 signalling inhibition caused by AZD2014 treatment.

On the day of radical prostatectomy, blood samples will be collected pre- and at specified times post- dose for pharmacokinetic analyses.

Additional blood samples will be collected to study any genetic changes to the DNA, RNA and circulating tumour DNA (ctDNA) which may have been caused by AZD2014 treatment.

Refer to the "outcome measures" section for further information.

Investigating the Effects of AZD2014 Therapy Given Prior to Radical Prostatectomy in Men With High Risk Prostate Cancer

A Phase 1 Window of Opportunity Study Investigating the Pharmacodynamic Biomarker Effects of AZD2014 (an mTOR1/2 Inhibitor) Given Prior to Radical Prostatectomy

On the day of radical prostatectomy surgery, participants will have up to four blood samples taken before and after their AZD2014 dose for pharmacokinetic analysis. These samples will be used to construct a concentration-time curve for AZD2014 in the blood.

Participants will be treated with AZD2014 for 15 days prior to radical prostatectomy surgery. The biological effects of AZD2014 treatment will be determined by analysis of prostate tumour biopsies and blood samples taken at baseline and following AZD2014 treatment.

The biological effects of AZD2014 on blood and prostate tumour samples will be investigated:

Histological markers of tumour cell proliferation, apoptosis and androgen receptor control of tumour metabolism will be measured.

Blood samples will be used to identify genetic changes in DNA, RNA and circulating tumor DNA caused by AZD2014 treatment.

Participants will be treated with AZD2014 for 15 days prior to radical prostatectomy surgery. To assess the amount of mTORC1 and mTORC2 inhibition caused by AZD2014 treatment, phosphorylated signalling biomarkers (namely p4EBP1, pS6 and pAKT) will be detected by immunohistochemistry and quantified. The amount of mTORC1 and mTORC2 signalling inhibition will be determined by comparison of prostate tumour biopsies taken at baseline (time of diagnosis) and following AZD2014 treatment. An intra-operative prostate biopsy will also be taken in order to evaluate variability between samples.

In order to assess the safety and feasibility of AZD2014 treatment prior to radical prostatectomy, a record will be kept of all adverse events experienced by the participants. Adverse events will be detailed by the study team when the participant attends inpatient/outpatient hospital visits and the participant will also be required to document their adverse events in a patient diary. Adverse events will be recorded for the duration of study treatment and for six weeks following treatment.

The severity of all adverse events will graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Investigating the Effects of AZD2014 Therapy Given Prior to Radical Prostatectomy in Men With High Risk Prostate Cancer	NCT02064608	Prostate Cancer	AZD2014	18 Years -	Cambridge University Hospitals NHS Foundation Trust
Investigating the Effects of AZD2014 Therapy Given Prior to Radical Prostatectomy in Men With High Risk Prostate Cancer	NCT02064608	Prostate Cancer	AZD2014	18 Years -	Cambridge University Hospitals NHS Foundation Trust

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