Advanced Castration Resistant Prostate Cancer MedDRA version: 18.0 Level: LLT Classification code 10036910 Term: Prostate cancer NOS System Organ Class: 100000004864
Conditions
Interventions
Product Name: olaparib
Product Code: AZD2281
Pharmaceutical Form: Tablet
INN or Proposed INN: Olaparib
CAS Number: 761133-22-0
Current Sponsor code: AZD2281
Other descriptive name: n/a
Concentration u
Sponsors
The Institute of Cancer Research
Royal Marsden NHS Foundation Trust
Eligibility
Sex/Gender
Male
Inclusion criteria
Inclusion criteria: 1.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 archival tumour tissue available for molecular analyses. If the patient does not have a prior histological diagnosis then the planned baseline fresh biopsy may be used for both the purpose of confirming the histological diagnosis prior to trial entry and for subsequent biomarker analyses 4.At least one but no more than two previous taxane-based 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: •At least 28 days since the completion of prior flutamide treatment. Patients whose PSA did not decline in response to antiandrogens given as a second line or later intervention will only require a 14 days washout prior to Cycle 1, Day 1 •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 •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: •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 •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 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 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 CTC count of =5 cells/7.5mls blood at screening confirmed by the central laboratory. For part B of the study, the minimum CTC count at screening is not mandatory if the patient has measurable disease according to modified RECIST1.1 >2 cms in size at screening a
Exclusion criteria
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 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 anti-epileptic drugs for seizures (use of anti-epileptic 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of this study is to evaluate the activity of olaparib in patients with advanced prostate cancer who have progressed following one or two chemotherapy regimens including docetaxel.;Secondary Objective: The secondary objectives are to evaluate: • Radiological progression-free survival (rPFS) • Time to radiological progression • Progression free survival (PFS) • Overall survival • Time to PSA progression • Duration of PSA response (decline of =50%) •Percentage of change in PSA from baseline to 12 weeks (or earlier if discontinued therapy) and maximum PSA decline while on treatment. • The utility of CTCs as an early indication of benefit from PARP inhibitor therapy • Further characterise the safety profile of olaparib in advanced CRPC patients •TOPARP-B only - drug exposure (pharmacokinetics) with the two dose levels of 300mg or 400mg of the tablet formulation and correlation of drug exposure with safety events and antitumour activity. •TOPARP-B only – evaluation of the two dose levels and recommendation of dose to investigate further.;Primary end point(s): Response rate: Response will be defined on the basis of the following outcomes; if any of these occur patients will be considered to have responded; •Objective response by modified RECIST 1.1 (Appendix E) or •Conversion of circulating tumour cell count (CTC) from =5/7.5 ml blood at baseline to <5/7.5 ml blood nadir confirmed by at least two readings 4 weeks apart or •PSA decline of =50% (according to the PCWG2) (Appendix B) ;Timepoint(s) of evaluation of this end point: Patients will be evaluated at each of the clinical visits for safety and tolerability end points. Response end points will be evaluated at cycle 4, 7, 11 and every 3rd cycle thereafter. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): •Radiological progression-free survival (rPFS) • Time to radiological progression • Progression free survival (PFS) • Overall survival • Time to PSA progression • Duration of PSA response (decline of =50%) • Percentage of change in PSA from baseline to 12 weeks (or earlier if discontinued therapy) and maximum PSA decline while on treatment • Proportion of patients with conversion of CTC count to <5/7.5ml blood nadir • Safety and tolerability profile of olaparib in patients with metastatic CRPC • For TOPARP-B only - Cmax and AUC after first dose and at steady state for the 400mg and 300mg BID dose levels.;Timepoint(s) of evaluation of this end point: Patients will be evaluated at each of the clinical visits for safety and tolerability end points. Response end points will be evaluated at cycle 4, 7, 11 and every 3rd cycle thereafter. | — |
Countries
United Kingdom
Contacts
Public ContactTOPARP Trial Manager
Institute of Cancer Research CTSU
Outcome results
None listed