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Ph II Study to Evaluate Olaparib With Abiraterone in Treating Metastatic Castration Resistant Prostate Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by AstraZeneca
Sponsor:
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT01972217
First received: October 24, 2013
Last updated: October 3, 2014
Last verified: October 2014
  Purpose

This is a 2-part study in patients with metastatic CRPC. Part A is an open-label safety run-in study to assess the safety, tolerability and pharmacokinetics (PK) of olaparib when given in addition to abiraterone 1000 mg once daily. Part B is a randomised, double-blind, placebo controlled comparison of the efficacy, safety and tolerability of the dose of olaparib selected from Part A when given in addition to abiraterone, versus placebo given in addition to abiraterone. Abiraterone is indicated in combination with prednisone or prednisolone for the treatment of patients with metastatic CRPC. Prednisone or prednisolone 5 mg twice daily (bid) will be administered with the abiraterone in this study.


Condition Intervention Phase
Metastatic Castration-resistant Prostate Cancer
Drug: Olaparib
Drug: Placebo
Drug: Abiraterone
Drug: Prednisone or prednisolone
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Randomised, Double-Blind, Placebo-Controlled, Multicentre Phase II Study to Compare the Efficacy, Safety and Tolerability of Olaparib Versus Placebo When Given in Addition to Abiraterone Treatment in Patients With Metastatic Castrate-Resistant Prostate Cancer Who Have Received Prior Chemotherapy Containing Docetaxel

Resource links provided by NLM:


Further study details as provided by AstraZeneca:

Primary Outcome Measures:
  • Part A. • To evaluate the safety, tolerability of daily olaparib when given in addition to abiraterone and prednisolone. [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
    The parameters describing the safety and tolerability of olaparib will include: - The percentage of patients with DLTs; -The percentage of patients with adverse events by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) (version 4.03) grade; - The percentage of patients with serious adverse events; - The percentage of patients who discontinue olaparib due to adverse events or serious adverse events. Adverse events will be assessed by graded Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Clinical chemistry and haematology laboratory tests, and vital signs will also be measured. The number of adverse events that constitute dose limiting toxicities will be derived and used to select a dose to evaluate further in Part B of the study.

  • Part B. Radiologic Progression-Free Survival (rPFS). [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    rPFS will be assessed from randomization, every 12 weeks, until disease progression or death. Progression-free survival is defined as the time from randomisation until the date of objective disease progression according to RECIST 1.1 (for soft tissue disease) and/or PCWG-2 criteria (for bone disease), or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomised therapy or receives another anti-cancer therapy prior to progression.


Secondary Outcome Measures:
  • Part A: Olaparib and abiraterone PK parameters: AUCss. Cmax ss, tmax ss, Cmin ss. [ Time Frame: Up to 14 days. ] [ Designated as safety issue: No ]
    Treatment ratios for abiraterone steady state Cmax and AUC (in combination : alone) and olaparib steady state Cmax and AUC (in combination : alone) will be calculated to assess the drug -drug interaction potential between olaparib and abiraterone.

  • Part B: Overall survival (OS). [ Time Frame: 37 months. ] [ Designated as safety issue: No ]
    Overall survival is defined as the time from the date of randomisation until death due to any cause.

  • Part B: The time to second progression (PFS2) [ Time Frame: 37 months. ] [ Designated as safety issue: No ]
    PFS2. Progression defined by local standard clinical practice. May involve any of: objective radiological progression, symptomatic progression, PSA or death.

  • Part B: Response to treatment as shown by Overall Response Rates (ORR), changes in PSA levels, change in CTC levels over time and measurement of time to requiring further prostate cancer treatment [ Time Frame: 37 months ] [ Designated as safety issue: No ]
    Malignant soft tissue response and overall radiological response [malignant soft tissue response by RECIST 1.1 and overall radiological response by RECIST 1.1 and PCWG-2]).

  • Part B: To evaluate the safety, tolerability of daily olaparib when given in addition to abiraterone and prednisolone [ Time Frame: 37 months ] [ Designated as safety issue: Yes ]

    The parameters describing the safety and tolerability of olaparib will include:

    • The percentage of patients with adverse events by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) (version 4.03) grade;
    • The percentage of patients with serious adverse events;
    • The percentage of patients who discontinue olaparib due to adverse events or serious adverse events;

    Assessment of AEs graded by CTCAE v4.0. Clinical chemistry and haematological laboratory tests and vital signs also evaluated.


  • Part B: ERG expression/fusion status [ Time Frame: 37 months ] [ Designated as safety issue: No ]
    Where possible patient ERG expression/fusion will be assessed and association between this and treatment efficacy will be examined.


Other Outcome Measures:
  • Change in HRQL [ Time Frame: 37 months ] [ Designated as safety issue: No ]
    Assessed using FACT-P.

  • Change in pain and other prostate cancer related symptoms [ Time Frame: 37 months ] [ Designated as safety issue: No ]
    Assessed using FACT-P and BPI-SF.

  • Health state utility index [ Time Frame: 37 months ] [ Designated as safety issue: No ]
    Assessed Using EQ-5D-5L health state utility index.


Estimated Enrollment: 158
Study Start Date: April 2014
Estimated Study Completion Date: July 2017
Estimated Primary Completion Date: July 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Olaparib
200 mg or 300 mg bid
Drug: Olaparib
Olaparib bid
Other Name: PARP inhibition
Drug: Abiraterone
Abiraterone 1000 mg
Other Name: Abiraterone
Drug: Prednisone or prednisolone
Prednisone or prednisolone 5 mg bid will be co-administered with the abiraterone in this study.
Placebo Comparator: Placebo
placebo to match olaparib bid
Drug: Placebo
Placebo bid
Other Name: Placebo to PARP inhibition
Drug: Abiraterone
Abiraterone 1000 mg
Other Name: Abiraterone
Drug: Prednisone or prednisolone
Prednisone or prednisolone 5 mg bid will be co-administered with the abiraterone in this study.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Provision of signed and dated written informed consent prior to any study specific procedures.
  • Male aged 18 years and older.
  • Histologically or cytologically proven diagnosis of prostate cancer.
  • Candidate for abiraterone therapy with documented evidence of metastatic castration-resistant prostate cancer. Metastatic status is defined as at least one documented metastatic lesion on either bone scan or CT/MRI scan. Castration resistant prostate cancer is defined as rising PSA or other signs of disease progression despite treatment with androgen deprivation therapy and the presence of a castrate level of testosterone (≤50 ng/dL).
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 with no deterioration over the previous 2 weeks.
  • Patients must have a life expectancy ≥12 weeks.
  • Patients are willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations, and completing PRO instruments.
  • Patients must be on a stable concomitant medication regimen, defined as no changes in medication or in dose within 2 weeks prior to start of olaparib dosing, except for bisphosphonates, denosumab and corticosteroids, which should be stable for at least 4 weeks prior to start of olaparib dosing.
  • For the randomised phase only, patients must have received chemotherapy in the form of docetaxel treatment for metastatic castration-resistant prostate cancer. Note: patients who discontinued docetaxel for toxicity reasons and without completing the full course will still be eligible to enter this study provided they received at least 2 cycles of chemotherapy.

Provide informed consent for the pharmacogenetic sampling and analyses.

Exclusion Criteria:

  • Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff, its agents and/or staff at the study site).
  • Previous treatment in the present study.
  • Treatment with any of the following:

    • Previous exposure to any 2nd generation anti-hormonal including abiraterone and enzalutamide
    • More than 2 prior courses of chemotherapy for metastatic prostate cancer
    • Previous use of immunotherapy or radium-223 for the treatment of metastatic prostate cancer
    • Any investigational agents or study drugs from a previous clinical study within 30 days of the first dose of study treatment;
    • Any previous exposure to a CYP17 (17α-hydroxylase/C17,20-lyase) inhibitor;
    • Substrates of CYP2D6 with a narrow therapeutic index (eg, thioridazine);
    • Potent inhibitors or inducers of CYP3A4 within 2 weeks before the first dose of study treatment (3 weeks for St John's Wort).
    • Any previous treatment with a PARP inhibitor, including olaparib.
  • With the exception of alopecia or toxicities related to the use of gonadotropinreleasing hormone agonists, any unresolved toxicities from prior therapy greater than CTCAE Grade 2 at the time of starting study treatment.
  • Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring steroids for at least 4 weeks prior to start of study treatment.
  • As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
  • Any of the following cardiac criteria:

    • Mean resting QTc >470 msec obtained from 3 ECGs
    • Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG eg, complete left bundle branch block, third degree heart block
    • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval.
  • Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer or other solid tumours including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for ≥5 years.
  • Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:

    • Absolute neutrophil count (ANC) <1.5 x 109/L
    • Platelet count <100 x 109/L
    • Haemoglobin (Hb) <100 g/L
    • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 x upper limit of normal (ULN) if no demonstrable liver metastases or >5 x ULN in the presence of liver metastases
    • Total bilirubin >1.5 x ULN if no liver metastases or >3 x ULN in the presence of liver metastases (except in the case of Gilbert's disease)
    • Creatinine >1.5 x ULN concurrent with creatinine clearance <50 mL/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is >1.5 x ULN
    • If bone metastases are present and liver function is otherwise considered adequate by the Investigator then elevated alkaline phosphatase (ALP) will not exclude the patient.
  • 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 or abiraterone.
  • History of hypersensitivity to active or inactive excipients of olaparib or abiraterone or drugs with a similar chemical structure or class to olaparib or abiraterone.
  • Patients with myelodysplastic syndrome/acute myeloid leukaemia.
  • Current disease or condition known to interfere with absorption, distribution, metabolism, or excretion of drugs, at the Investigator's discretion.
  • Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.
  • Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.

Exclusion from the genetic research may be for any of the exclusion criteria specified in the main study or any of the following:

  • Previous allogeneic bone marrow transplant.
  • Non-leukocyte depleted whole blood transfusion within 120 days of the date of the pharmacogenetic sample collection.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01972217

Contacts
Contact: Clinical Trial Transparency ClinicalTrialTransparency@astrazeneca.com
Contact: Michala Worrell +44 (0) 1530 519421 michala.worrell@quintiles.com

  Show 50 Study Locations
Sponsors and Collaborators
AstraZeneca
  More Information

No publications provided

Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT01972217     History of Changes
Other Study ID Numbers: D081DC00008, UVA97934
Study First Received: October 24, 2013
Last Updated: October 3, 2014
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
Belgium: Federal Agency for Medicinal Products and Health Products
Netherlands: Dutch Health Care Inspectorate
Netherlands: Medicines Evaluation Board (MEB)
Czech Republic: State Institute for Drug Control
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
France: National Agency for the Safety of Medicine and Health Products
Italy: Italian Medicines Agency
Spain: Spanish Agency for Medicines and Health Products
United States: Food and Drug Administration
Canada: Health Canada Policy, Communications & Regulatory Affairs Directorate
Russia: Ministry of Health of the Russian Federation

Keywords provided by AstraZeneca:
Olaparib
castration-resistant, metastatic prostate cancer
Prior Docetaxel Chemotherapy

Additional relevant MeSH terms:
Prostatic Neoplasms
Genital Neoplasms, Male
Neoplasms
Neoplasms by Site
Prostatic Diseases
Urogenital Neoplasms
Genital Diseases, Male
Methylprednisolone
Methylprednisolone acetate
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone acetate
Prednisolone hemisuccinate
Prednisolone phosphate
Prednisone
Anti-Inflammatory Agents
Antiemetics
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Autonomic Agents
Central Nervous System Agents
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Neuroprotective Agents
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Protective Agents

ClinicalTrials.gov processed this record on October 29, 2014