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Investigating the Effects of AZD2014 Therapy Given Prior to Radical Prostatectomy in Men With High Risk Prostate Cancer (CaNCaP02)

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ClinicalTrials.gov Identifier: NCT02064608
Recruitment Status : Completed
First Posted : February 17, 2014
Last Update Posted : July 17, 2019
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
CCTU- Cancer Theme, Cambridge University Hospitals NHS Foundation Trust

Tracking Information
First Submitted Date  ICMJE February 14, 2014
First Posted Date  ICMJE February 17, 2014
Last Update Posted Date July 17, 2019
Study Start Date  ICMJE October 2014
Actual Primary Completion Date December 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 17, 2014)
To measure the amount of inhibition (percentage change from baseline) in mTORC1 and mTORC2 signalling in tumour samples from men with early, high-risk prostate cancer after AZD2014 treatment [ Time Frame: 2 weeks ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: February 14, 2014)
To measure the amount of inhibition (percentage chance from baseline) in mTORC1 and mTORC2 signalling in tumour samples from men with early, high-risk prostate cancer after AZD2014 treatment [ Time Frame: 2 weeks ]
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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 17, 2014)
  • To determine the incidence of adverse events due to AZD2014 given prior to radical prostatectomy [ Time Frame: 8 weeks unless further observation is clinically indicated ]
    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.
  • To determine the severity of adverse events due to AZD2014 prior to radical prostatectomy [ Time Frame: 8 weeks unless further observation is clinically indicated ]
    The severity of all adverse events will graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 14, 2014)
To determine the incidence and severity of adverse events due to AZD2014 given prior to radical prostatectomy [ Time Frame: 8 weeks unless further observation is clinically indicated ]
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. Adverse events will be classified and graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.
Current Other Pre-specified Outcome Measures
 (submitted: February 17, 2014)
  • To determine blood plasma concentration and pharmacokinetics of AZD2014. [ Time Frame: Following 15 days AZD2014 treatment ]
    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.
  • To measure the biological effects of AZD2014 treatment [ Time Frame: Following 15 days AZD2014 treatment ]
    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.
  • Exploratory endpoints [ Time Frame: Following 15 days 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.
Original Other Pre-specified Outcome Measures
 (submitted: February 14, 2014)
  • To determine blood plasma concentration and pharmacokinetics of AZD2014. [ Time Frame: Following 15 days AZD2014 treatment ]
    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.
  • To measure the biological effects of AZD2014 treatment [ Time Frame: Following 15 days AZD2014 treatment ]
    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. To assess the biological effects of AZD2014 treatment on the prostate tumour, histological markers of tumour cell proliferation and apoptosis will be measured. Altered androgen receptor control of tumour metabolism will also be investigated. Blood samples taken throughout the study will be used to investigate genetic changes in DNA, RNA and circulating tumor DNA caused by AZD2014 treatment. Any preliminary evidence of predictive biomarkers and the clinical benefit rate will also be assessed.
 
Descriptive Information
Brief Title  ICMJE Investigating the Effects of AZD2014 Therapy Given Prior to Radical Prostatectomy in Men With High Risk Prostate Cancer
Official Title  ICMJE A Phase 1 Window of Opportunity Study Investigating the Pharmacodynamic Biomarker Effects of AZD2014 (an mTOR1/2 Inhibitor) Given Prior to Radical Prostatectomy
Brief Summary

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.

Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Prostate Cancer
Intervention  ICMJE Drug: AZD2014
mTOR inhibitor
Other Name: AZ12729279
Study Arms  ICMJE Experimental: AZD2014
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.
Intervention: Drug: AZD2014
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 6, 2017)
23
Original Estimated Enrollment  ICMJE
 (submitted: February 14, 2014)
20
Actual Study Completion Date  ICMJE June 2018
Actual Primary Completion Date December 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Men aged 18 years old or older
  • ECOG performance status of 0 or 1
  • Clinical diagnosis of Intermediate (one or more of stage T2, or PSA >10ng/mL, or Gleason score of at least 7) or High Risk Prostate Cancer (one or more of stage T2c, or PSA >20ng/mL, or Gleason score of at least 8)
  • Patient suitable for radical prostatectomy, following discussion at specialist MDT and subsequent review by surgical team
  • Willing to use barrier contraceptive method, e.g. condom & spermicide
  • Adequate bone marrow reserve or organ function (as specified in the study protocol)
  • Normal chest radiograph and oxygen saturations, OR normal CT thorax

Exclusion Criteria:

  • Contraindication to AZD2014 (as specified in the study protocol)
  • Patients who have experienced any of the following procedures in the past 12 months: coronary artery bypass graft; angioplasty; vascular stent; myocardial infarction; angina pectoris; congestive heart failure (New York Heart Association grade of 2 or above); ventricular arrhythmias requiring continuous therapy; supraventricular arrhythmias including atrial fibrillation, which are uncontrolled; haemorrhagic or thrombotic stroke including transient ischaemic attacks or any other CNS bleeding.
  • Previous chemotherapy, biological therapy, radiation therapy, androgens, thalidomide, immunotherapy, other anticancer agents and/or investigational agents within 28 days of starting study treatment.
  • Major surgery within 4 weeks prior to study entry (excluding placement of vascular access), or minor surgery within 2 weeks of entry into the study
  • Potent or moderate inhibitors and inducers of CYP2C8 if taken within the stated wash-out period: Gemfibrozil, trimethoprim, glitazones, montelukast, deferasirox and quercetin (1-week minimum wash out period)
  • Any haematopoietic growth factors, e.g. G-CSF, GM-CSF, within 4 weeks prior to receiving study drug
  • As judged by the Investigator, any evidence of severe or uncontrolled systemic disease (as specified in the study protocol)
  • Abnormal ECHO or MUGA at baseline
  • Mean resting QTc of 470msec or above (as per local reading)
  • Concomitant medications known to prolong QT interval, or with factors that increase the risk of QTc prolongation, or risk of arrythmic events (examples specified in study protocol). History of Torsades de Pointes.
  • Patients with Diabetes Type I or uncontrolled Type II as judged by the investigator
  • Judgement by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements.
  • Unable to provide informed consent
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02064608
Other Study ID Numbers  ICMJE CANCAP02
2014-000214-56 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party CCTU- Cancer Theme, Cambridge University Hospitals NHS Foundation Trust
Study Sponsor  ICMJE Cambridge University Hospitals NHS Foundation Trust
Collaborators  ICMJE AstraZeneca
Investigators  ICMJE
Principal Investigator: Simon C Pacey, MRCP, PhD Cambridge University Hospitals NHS Foundation Trust
PRS Account Cambridge University Hospitals NHS Foundation Trust
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP