Study of Olaparib (± Degarelix) Given to Men With Intermediate/High Risk Prostate Cancer Before Prostatectomy

NCT02324998 | Completed Phase 1

• 2 other identifiers: CaNCaP032014-004417-86
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

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.

Conditions

Prostate Cancer

Keywords

Radical Prostatectomy; Prostate Cancer; PARP inhibition; Olaparib; Degarelix; Neoadjuvant; Pharmacodynamics; Pharmacokinetics; Biomarkers

Outcome Measures

Primary Outcomes (1)

• Determination of PARP Inhibition

  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.

  Two week olaparib therapy (alone or in combination with degarelix)

Secondary Outcomes (3)

• Incidence and Severity of Adverse Events

  Two week olaparib therapy (alone or in combination with degarelix)

• Feasibility of treatment approach

  Two week olaparib therapy (alone or in combination with degarelix)

• Clinical benefit rate

  Two week olaparib therapy (alone or in combination with degarelix)

Other Outcomes (4)

• DNA repair defect and PARP inhibition

  Two week olaparib therapy (alone or in combination with degarelix)

• Immunomodulatory effects of PARP inhibition

  Two week olaparib therapy (alone or in combination with degarelix)

• Biological effects of PARP inhibition

  Two week olaparib therapy (alone or in combination with degarelix)

Study Arms (2)

Group A

EXPERIMENTAL

Olaparib Monotherapy

Drug: Olaparib

Group B

EXPERIMENTAL

Olaparib in combination with degarelix

Drug: Olaparib; Drug: Degarelix

Interventions

Olaparib DRUG

PARP Inhibitor

Also known as: AZD2281, Lynparza

Group A; Group B

Degarelix DRUG

Gonadotrophin releasing hormone blocker

Also known as: Firmagon

Group B

Eligibility Criteria

• Age: 18 Years - 73 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• Absolute neutrophil count ≥ 1.8 x 109/L
• Haemoglobin ≥ 117g/L
• Platelet count ≥ 135 x 109/L
• WBC ≥ 3.6 x 109/L
• Peripheral blood smear with no features of MDS/AML

You may not qualify if:

• 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
• Extensive bilateral lung disease on High Resolution Computed Tomography (HRCT)
• History of pneumonitis
• Active infection including hepatitis B, hepatitis C and Human Immunodeficiency Virus. Screening for chronic conditions is not required.
• Major surgery within 4 weeks prior to entry into the trial (excluding placement of vascular access). Patients must have recovered from side effects of any major surgery. Minor surgery (not including the diagnostic prostate biopsy) within 2 weeks prior to entry into the trial.
• Patients who have received (within last 3 months of trial entry) an investigational drug within a clinical trial will not be eligible to participate.
• Concomitant use of known potent CYP3A4 inhibitors and inducers. See section 10.4.1.1 for list and consider wash out periods.

Sponsors & Collaborators

• Cambridge University Hospitals NHS Foundation Trust: lead
• AstraZeneca: collaborator

Study Sites (1)

Addenbrooke's Hospital, Cambridge University Hospitals Foundation Trust,

Cambridge, Cambridgeshire, CB2 0QQ, United Kingdom

Location

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

olaparib; acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Study Officials

• Simon C Pacey, MRCP, Ph.D

  University of Cambridge

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Cambridge Clinical Trials Unit - Cancer Theme

Study Record Dates

• First Submitted: December 19, 2014
• First Posted: December 24, 2014
• Study Start: December 1, 2016
• Primary Completion: May 1, 2019
• Study Completion: May 1, 2019
• Last Updated: August 29, 2019

Record last verified: 2019-08

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)