| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Castration Resistant Prostate Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Prostate cancer that has spread and that is resistant to hormonal treatment |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Male diseases of the urinary and reproductive systems [C12] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10036910 |
| E.1.2 | Term | Prostate cancer NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
|
| E.2.2 | Secondary objectives of the trial |
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. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 < 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 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 and screening PSA ≥ 2 μg/L (2 ng/ml)
14.Subjects must have adequate bone marrow, hepatic and renal function documented within 7 days of registration, defined as:
•Haemoglobin ≥10g/dL independent of transfusions for 14 days if related to anaemia due to advanced prostate cancer. If not, subjects should be independant of tranfusions for 28 days
•White blood cells >3x109/L
•Absolute neutrophil count ≥1.5x109/L
•Platelets ≥100 x109/L
•Total bilirubin ≤ 1.5 x upper limit of normal (ULN) except for patients with known Gilbert’s syndrome
•Aspartate transaminase (AST) (SGOT) and alanine transaminase (ALT) (SGPT) ≤2.5 x ULN or ≤5 x ULN in the presence of liver metastases
•Serum creatinine ≤1.5 x ULN or a calculated creatinine clearance >40mL/min for patients with creatinine levels above institutional normal. For GFR estimation, the Cockcroft and Gault equation should be used:
GFR=CrCl(ml/min)=(140 - age)×wt(kg)/(serum creatinine × 72)
•Albumin >25 g/l
15. For Part B only - Subjects must have genomic defects associated with olaparib sensitivity as identified by next generation sequencing (anticipated to be approximately 30% of patients) confirmed by the central laboratory or, if there is a next generation sequencing result report from an external laboratory, the patient could be enrolled prior to confirmation of these results by the central laboratory following approval by the Chief Investigator (in such cases the tumour sample will still be tested at the central laboratory) |
|
| E.4 | Principal 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
|
|
| E.5 End points |
| E.5.1 | 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)
|
|
| E.5.1.1 | 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.
|
|
| E.5.2 | 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. |
|
| E.5.2.1 | 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.
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The date of last data capture for the last subject. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 4 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 4 |
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