A Study Into the Pharmacodynamic Biomarker Effects of Olaparib (a PARP Inhibitor) ± Degarelix (a GnRH Antagonist) Given Prior to Radical Prostatectomy
Overview
- Phase
- Phase 1
- Intervention
- Degarelix
- Conditions
- Prostate Cancer
- Sponsor
- Cambridge University Hospitals NHS Foundation Trust
- Enrollment
- 20
- Locations
- 1
- Primary Endpoint
- Determination of PARP Inhibition
- Status
- Completed
- Last Updated
- 6 years ago
Overview
Brief Summary
Despite recent advances in the treatment of Castrate-Resistant Prostate Cancer (CRPC), there remains an unmet medical need to identify and optimise additional treatment for those patients with early prostate cancer who are at greatest risk of relapse following first-line treatment with curative intent.
This is a phase I study investigating the feasibility and tolerability of a short course of neoadjuvant treatment with olaparib, either as a monotherapy or in combination with degarelix) given in the window-of-opportunity prior to radical prostatectomy in men with early, localised intermediate-/high- risk prostate cancer. Our primary objective is to determine the pharmacodynamic biomarker effects of olaparib (a PARP inhibitor) in this patient population.
Participants will receive either single agent olaparib or olaparib in combination with degarelix (androgen deprivation) for two weeks prior to routine radical prostatectomy. We will use immunohistochemistry to quantify changes in the levels of biomarkers of PARP inhibition, e.g. PAR, gamma H2AX, pH2A(s129) and Rad51 foci, using tumour samples taken at baseline and at the time of radical prostatectomy. An intra-operative prostate biopsy will permit us to examine biomarker variability between the samples.
The incidence and severity of Adverse Events will be documented and we will assess the number of trial participants who undergo surgery on schedule. We will assess preliminary evidence of tumour response, e.g. pathological changes and Prostate Specific Antigen (PSA). We also intend to investigate changes to the ctDNA profile by comparing blood samples collected throughout the study.
Investigators
CCTU- Cancer Theme
Cambridge Clinical Trials Unit - Cancer Theme
Cambridge University Hospitals NHS Foundation Trust
Eligibility Criteria
Inclusion Criteria
- •To be included in the trial the patient must:
- •Have given written informed consent to participate\*
- •Men aged 18 years or over
- •Patients suitable for radical prostatectomy
- •ECOG performance status of 0 or 1
- •Access to archived diagnostic tissue or consent to undergo repeat biopsy, if necessary
- •Diagnosis of High risk or Intermediate risk prostate cancer, defined as:
- •High risk disease: one or more of stage T2c - 3a, or PSA level \>20ng/mL, or Gleason score ≥ 8
- •Intermediate risk disease: two or more of: Stage T2 (any), PSA \> 10, Gleason of ≥ 7
- •Adequate bone marrow reserve and organ function (measured within 28 days prior to planned first olaparib administration) as demonstrated by the following values:
Exclusion Criteria
- •The presence of any of the following will preclude patient inclusion:
- •Contraindication to olaparib or degarelix
- •History of hypersensitivity to active or inactive excipients of olaparib
- •Patients with known hypersensitivity to the degarelix active substance or mannitol must not receive degarelix.
- •Current refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of olaparib
- •As judged by the Investigator, any patient considered a poor medical risk due to a serious uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection including but not limited to:
- •Uncontrolled ventricular arrhythmia
- •Recent myocardial infarction (within three months)
- •Unstable spinal cord compression
- •Superior vena cava syndrome
Arms & Interventions
Group B
Olaparib in combination with degarelix
Intervention: Degarelix
Group A
Olaparib Monotherapy
Intervention: Olaparib
Group B
Olaparib in combination with degarelix
Intervention: Olaparib
Outcomes
Primary Outcomes
Determination of PARP Inhibition
Time Frame: Two week olaparib therapy (alone or in combination with degarelix)
Measure the degree of PARP inhibition by comparison of tumour samples taken from men with early prostate cancer at baseline and following treatment with olaparib (either alone or in combination with degarelix). Inhibition of PARP will be measured by the change in IHC levels of biomarkers such as PAR, gamma H2AX, pH2A(s129), Rad51 foci, FancD2 foci and ATM/ATR/CHK1/2.
Secondary Outcomes
- Feasibility of treatment approach(Two week olaparib therapy (alone or in combination with degarelix))
- Incidence and Severity of Adverse Events(Two week olaparib therapy (alone or in combination with degarelix))
- Clinical benefit rate(Two week olaparib therapy (alone or in combination with degarelix))