Phase II trial of olaparib in patients with advanced castration resistant prostate cancer

Phase 2

Completed

Conditions: Topic: National Cancer Research Network
Subtopic: Prostate Cancer
Disease: Prostate
Cancer
Malignant neoplasm of prostate

Registration Number: ISRCTN15124653

Lead Sponsor: The Institute for Cancer Research (UK)

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Completed

Sex: Male

Target Recruitment: 89

Inclusion Criteria

1. The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document
2. Age >= 18 years
3. Histologically confirmed adenocarcinoma of the prostate with tumour tissue available for molecular analyses. If archival tissue for biomarker analysis is not available then the patient must be willing to have a further biopsy to obtain tumour tissue for histological diagnosis.
4. At least one but no more than two previous taxanebased chemotherapy regimens. If docetaxel chemotherapy is used more than once, this will be considered as one regime. Patients may have had prior exposure to cabazitaxel treatment.
5. At least 28 days since the completion of prior therapy, including major surgery, chemotherapy and other investigational agents. Additionally, clinically relevant sequelae should have resolved to grade 1 or less prior to recommencing treatment. For hormonal treatment and radiotherapy refer to the guidelines below:
5.1. At least 28 days since the completion of prior flutamide treatment. Patients whose Prostate-specific antigen (PSA) did not decline in response to anti-androgens given as a second line or later intervention will only require a 14 days washout prior to Cycle 1, Day 1.
5.2. At least 42 days since the completion of prior bicalutamide (Casodex) and nilutimide (Nilandron) treatment. Patients whose PSA did not decline for 3 or 4 months in response to antiandrogens given as second line or later intervention will require only a 14 day washout period prior to Cycle 1 Day1.
5.3. At least 14 days from any radiotherapy with the exception of a single fraction of radiotherapy for the purposes of palliation (confined to one field) is permitted.
6. Documented prostate cancer progression as assessed by the investigator with one of the following:
6.1. PSA progression defined by a minimum of three rising PSA levels with an interval of >= 1 week between each determination. The PSA value at the Screening visit should be >= 2 µg/L (2 ng/ml); patients on systemic glucorticoids for control of symptoms must have documented PSA progression by PCWG22 while on systemic glucocorticoids prior to commencing Cycle1 Day1 of treatment.
6.2. Radiographic progression of soft tissue disease by modified RECIST criteria or of bone metastasis with two or more documented new bone lesions on a bone scan with or without PSA progression.
7. Surgically or medically castrated, with testosterone levels of < 50 ng/dL (< 2.0 nM). If the patient is being treated with LHRH agonists (patient who have not undergone orchiectomy), this therapy must have been initiated at least 4 weeks prior to Cycle 1 Day 1 and must be continued throughout the study.
8. Eastern Cooperative Oncology Group (ECOG) Performance Status of <= 2 (Karnofsky Performance Status = 50%)
9. Life expectancy > 12 weeks
10. Patient must be able to swallow a whole tablet
11. Patient and the patient?s partner of childbearing potential, must agree to use medically accepted methods of contraception (eg, barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 3 months after the last dose of study drug.
12. Agreeable to have all the biomarker studies including the paired fresh tumour biopsies
13. Subjects must have a circulating tumour cell (CTC) count of >= 5 cells/7.5mls blood at screening
14. Subjects must have adequate bone marrow, hepatic and renal function documented

Exclusion Criteria

1. Surgery, or local prostatic intervention (excluding a prostatic biopsy) less than 28 days of Cycle 1 Day 1
2. Less than 28 days from any active anticancer therapy or investigational agents. For hormonal treatment and radiotherapy refer to the guidelines outlined in the inclusion criteria
3. Prior treatment with a PARP inhibitor, platinum, cyclophosphamide or mitoxantrone chemotherapy
4. Uncontrolled intercurrent illness including, but not limited to, active infection, symptomatic congestive heart failure (New York Heart Association Class III or IV heart disease), unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension or psychiatric illness/social situations that would limit compliance with study requirements
5. Any acute toxicities due to prior chemotherapy and / or radiotherapy that have not resolved to a National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.02 grade 1 with the exception of chemotherapy induced alopecia and grade 2 peripheral neuropathy. 6. Malignancy within the previous 2 years with a > 30% probability of recurrence within 12 months with the exception of non-melanoma skin cancer, in-situ or superficial bladder cancer
7. Patients with myelodysplastic syndrome/acute myeloid leukaemia
8. Patients with known symptomatic brain metastasis are not suitable for enrolment. Patients with asymptomatic, stable, treated brain metastases are eligible for study entry
9. Patients with symptomatic or impending cord compression unless appropriately treated beforehand and clinically stable and asymptomatic
10. Patients who experience a seizures within 6 months of study treatment or who are currently being treated with cytochrome P450 enzyme inducing antiepileptic drugs for seizures (use of antiepileptic drugs to control pain is allowed in patients not suffering from seizures unless drug is excluded due to CYP3A4 induction phenytoin, carbamazepine, phenobarbital
11. Patients receiving any of the following classes of inhibitors of CYP3A4; -Azole antifungals -Macrolide antibiotics -Protease inhibitors 12. Patients with gastrointestinal disorders likely to interfere with absorption of the study medication
13. Initiating bisphosphonate therapy or adjusting bisphosphonate dose/regimen within 30 days prior to Cycle 1 Day 1. Patients on a stable bisphosphonate regimen are eligible and may continue.
14. Presence of a condition or situation, which, in the investigator?s opinion, may put the patient at significant risk, may confound the study results, or may interfere significantly with patient?s participation in the study
15. The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Response will be defined on the basis of the following outcomes, if any of these occur patients will be considered to have responded: <br>1. Objective response by modified Response Evaluation Criteria In Solid Tumors (RECIST)<br>2. Prostate-specific antigen (PSA) decline of =50% according to the Prostate Cancer Working Group 2 and <br>3. Conversion of circulating tumour cell count (CTC) from =5 cells/7.5ml blood at baseline to <5 cells/7.5ml blood confirmed by at least 2 readings 4 weeks apart

Secondary Outcome Measures

Name	Time	Method
1. Radiological progression free survival<br>2. Time to radiological progression<br>3. Progression free survival<br>4. Overall survival<br>5. Time to PSA progression<br>6. Proportion of patients with conversion of circulating tumour cell count from =5 cells/7.5ml blood at baseline to <5/7.5ml blood nadir<br>7. Duration of PSA response and objective response if applicable<br>8. Safety and tolerability of Olaparib