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TOPARP: A Phase II Trial of Olaparib in Patients With Advanced Castration Resistant Prostate Cancer (TOPARP)

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ClinicalTrials.gov Identifier: NCT01682772
Recruitment Status : Active, not recruiting
First Posted : September 11, 2012
Last Update Posted : August 15, 2019
Sponsor:
Collaborator:
Royal Marsden NHS Foundation Trust
Information provided by (Responsible Party):
Institute of Cancer Research, United Kingdom

Tracking Information
First Submitted Date  ICMJE July 27, 2012
First Posted Date  ICMJE September 11, 2012
Last Update Posted Date August 15, 2019
Actual Study Start Date  ICMJE July 2012
Actual Primary Completion Date March 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 10, 2012)
Response rate to Olaparib [ Time Frame: Response will be evaluated 6 months post trial entry ]
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
  • PSA decline of ≥50% according to the Prostate Cancer Working Group 2
  • Conversion of circulating tumour cell count from ≥5 cells/7.5ml blood at baseline to <5 cells/7.5ml blood confirmed by at least two readings 4 weeks apart
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT01682772 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 10, 2012)
  • Radiographic progression free survival [ Time Frame: Radiographic progression free survival will be evaluated 6 months post trial entry ]
    rPFS will be defined by either RECIST progression and/or progression on bone scan. It will be measured from the date of trial entry to the first occurence of radiographic progression or death from any cause
  • Progression free survival [ Time Frame: Progression free survival will be evaluated 6 months post trial entry ]
    PFS will be measured from date of trial entry until radiographic progression, unequivocal clinical progression or death
  • Time to PSA Progression [ Time Frame: Time to PSA progression will be evaluated 6 months post trial entry ]
    For patients who have achieved ≥50% decrease from the cycle 1 day 1 (baseline), the PSA progression date is defined as the date that a ≥25% increase and an absolute increase of ≥2ng.mL above the nadir is documented. This must be confirmed by a second consecutive value. For patients without a PSA decrease of this magnitude or no decrease at all, PSA progression date is defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the baseline is documented. This must also be confirmed by a second consecutive value.
  • CTC count conversion rate [ Time Frame: CTC count conversion rate will be evaluated 6 months post trial entry ]
    Proportion of patients with conversion of CTC count from ≥5/7.5ml blood at baseline to <5/7.5ml blood nadir
  • Duration of PSA response [ Time Frame: Duration of PSA response will be evaluated 6 months post trial entry ]
    Duration of PSA response is calculated from the time the PSA value first declines by at least 50% of the cycle 1 day 1 (baseline) value (must be confirmed by a second value) until the time there is an increase of 25% of PSA nadir, provided the absolute increase is at least 2 ng/mL. The increase must be confirmed by a second consecutive measurement.
  • Number of participants with grade 3 or 4 adverse events as a measure of safety and tolerability. [ Time Frame: Will be evaluated 1) when the first 5 and 10 participants have completed the 1st cycle of treatment and, 2) at 6 months post trial entry. ]
    The proportion of patients with grade 3/4 adverse events will be described along with other descriptive measures of safety and tolerability and evaluated by the IDMC
  • Time to radiographic progression [ Time Frame: Will be evaluated 6 months post trial entry ]
    Time to radiographic progression (progression defined by either RECIST progression and /or progression on bone scan) will be measured from the date of trial entry to the first occurrence of radiographic progression. Death from prostate cancer or any other cause without prior radiographic evidence of progression will not count as an event.
  • Overall survival [ Time Frame: Will be evaluated 6 months post trial entry ]
    OS will be measured from the date of trial entry to the date of death (whatever the cause). Survival time of living patients will be censored on the last date a patient is known to be alive or lost to follow-up
  • PSA objective response [ Time Frame: Will be evaluated 6 months post trial entry ]
    PSA response and PSA progression are defined according to the consensus guidelines of the Prostate Cancer Clinical Trials Working Group 2.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE TOPARP: A Phase II Trial of Olaparib in Patients With Advanced Castration Resistant Prostate Cancer
Official Title  ICMJE A Phase II Trial of Olaparib in Patients With Advanced Castration Resistant Prostate Cancer (TOPARP)
Brief Summary

This is an open-label, single arm, two part adaptive design phase II trial of Olaparib in patients with advanced castration resistant prostate cancer.

The trial aims to evaluate the the anti-tumour activity of Olaparib in metastatic castration resistant prostate cancer, identify molecular signatures of tumour cells in responding and non-responding patients, and to identify predictive biomarkers of Olaparib response.

Detailed Description Patients with advanced castration resistant prostate cancer will receive single agent Olaparib at a dose of 400mg twice daily, continuously on a 28 day cycle. Olaparib will be administered until objective disease progression or unacceptable toxicity or patient withdrawal for whatever reason
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Adenocarcinoma of the Prostate
Intervention  ICMJE Drug: Olaparib
Until objective disease progression, unacceptable toxicity or patient withdrawal for whatever reason
Other Name: AZD2281
Study Arms  ICMJE
  • Experimental: Olaparib 400mg
    Oral Olaparib at a dose of 400mg twice daily, continuously on a 28 day cycle
    Intervention: Drug: Olaparib
  • Experimental: Olaparib 300mg
    Oral Olaparib at a dose of 300mg twice daily, continuously on a 28 day cycle
    Intervention: Drug: Olaparib
Publications * Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, Nava Rodrigues D, Robinson D, Omlin A, Tunariu N, Boysen G, Porta N, Flohr P, Gillman A, Figueiredo I, Paulding C, Seed G, Jain S, Ralph C, Protheroe A, Hussain S, Jones R, Elliott T, McGovern U, Bianchini D, Goodall J, Zafeiriou Z, Williamson CT, Ferraldeschi R, Riisnaes R, Ebbs B, Fowler G, Roda D, Yuan W, Wu YM, Cao X, Brough R, Pemberton H, A'Hern R, Swain A, Kunju LP, Eeles R, Attard G, Lord CJ, Ashworth A, Rubin MA, Knudsen KE, Feng FY, Chinnaiyan AM, Hall E, de Bono JS. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N Engl J Med. 2015 Oct 29;373(18):1697-708. doi: 10.1056/NEJMoa1506859.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: August 13, 2019)
148
Original Estimated Enrollment  ICMJE
 (submitted: September 10, 2012)
89
Estimated Study Completion Date  ICMJE February 2020
Actual Primary Completion Date March 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Subject capable of understanding & complying with protocol requirements & signed the informed consent form
  2. Minimum age 18 years
  3. Histologically confirmed adenocarcinoma of the prostate with tumour tissue available for molecular 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 & other investigational agents. Clinically relevant sequelae should have resolved to grade 1 or less prior to recommencing treatment. For hormonal treatment & radiotherapy refer to the protocol guidelines
  6. Documented prostate cancer progression as described in the protocol.
  7. Surgically or medically castrated, with testosterone levels of < 50 ng/dL (< 2.0 nM). If the patient is being treated with LHRH agonists this must have been initiated at least 4 weeks prior to Cycle 1 Day 1 & must be continued throughout the study.
  8. Eastern Cooperative Oncology Group Performance Status of 0, 1, 2
  9. Life expectancy > 12 weeks
  10. Able to swallow a whole tablet
  11. Patient & the patient's partner of childbearing potential, must agree to use medically accepted methods of contraception during the course of the study & 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. CTC count of 5 cells/7.5mls blood or more at screening. Note: For Part B, CTC count >5 cells/7.5mls blood is not mandatory if patient has measurable disease by modified RECIST and a lesion >2cm and PSA greater than or equal to 2ng/ml at screening.
  14. Adequate bone marrow, hepatic & renal function as defined in the protocol
  15. For Part B only, patients must have genomic defects associated with olaparib sensitivity identified by NGS by the central lab.

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 & 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 & / or radiotherapy that have not resolved to a NCI-CTCAE v4.02 grade 0 or 1 with the exception of chemotherapy induced alopecia & 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 enrollment. Patients with asymptomatic, stable, treated brain metastases are eligible for study entry
  9. Patients with symptomatic or impending cord compression unless appropriately treated beforehand & clinically stable & asymptomatic
  10. Patients who have experienced a seizure or seizures within 6 months of study treatment or who are currently being treated with cytochrome P450 enzyme inducing anti-epileptic drugs for seizures
  11. Patients receiving any of the following classes of inhibitors of CYP3A4 (see protocol for guidelines & wash out periods)
  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 & may continue
  14. Presence of a condition or situation, which, may put the patient at significant risk, confound the study results, or interfere significantly with participation in the study
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01682772
Other Study ID Numbers  ICMJE ICR-CTSU/2011/10030
2011-000601-49 ( EudraCT Number )
CRUK/C12540/A12354 ( Other Grant/Funding Number: Cancer Research UK )
ISRCTN15124653 ( Registry Identifier: Randomised Controlled Trials )
ISS22810018 ( Other Grant/Funding Number: Astra Zeneca )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Institute of Cancer Research, United Kingdom
Study Sponsor  ICMJE Institute of Cancer Research, United Kingdom
Collaborators  ICMJE Royal Marsden NHS Foundation Trust
Investigators  ICMJE
Principal Investigator: Johann de Bono Institute of Cancer Research, United Kingdom
PRS Account Institute of Cancer Research, United Kingdom
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP