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

NCT01682772 | Unknown Phase 2 DMC

• 5 other identifiers: ICR-CTSU/2011/100302011-000601-49CRUK/C12540/A12354ISRCTN15124653ISS22810018
• Study Type: interventional
• Target: 148
• Locations: 1 country
• Sites: 2

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.

Conditions

Adenocarcinoma of the Prostate

Keywords

Olaparib; Adenocarcinoma; Prostate

Outcome Measures

Primary Outcomes (1)

• Response rate to Olaparib

  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

  Response will be evaluated 6 months post trial entry

Secondary Outcomes (9)

• Radiographic progression free survival

  Radiographic progression free survival will be evaluated 6 months post trial entry

• Progression free survival

  Progression free survival will be evaluated 6 months post trial entry

• Time to PSA Progression

  Time to PSA progression will be evaluated 6 months post trial entry

• CTC count conversion rate

  CTC count conversion rate will be evaluated 6 months post trial entry

• Duration of PSA response

  Duration of PSA response will be evaluated 6 months post trial entry

Study Arms (2)

Olaparib 400mg

EXPERIMENTAL

Oral Olaparib at a dose of 400mg twice daily, continuously on a 28 day cycle

Drug: Olaparib

Olaparib 300mg

EXPERIMENTAL

Oral Olaparib at a dose of 300mg twice daily, continuously on a 28 day cycle

Drug: Olaparib

Interventions

Olaparib DRUG

Until objective disease progression, unacceptable toxicity or patient withdrawal for whatever reason

Also known as: AZD2281

Olaparib 300mg; Olaparib 400mg

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subject capable of understanding \& complying with protocol requirements \& signed the informed consent form
• Minimum age 18 years
• Histologically confirmed adenocarcinoma of the prostate with tumour tissue available for molecular analyses
• 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
• 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
• Documented prostate cancer progression as described in the protocol.
• 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.
• Eastern Cooperative Oncology Group Performance Status of 0, 1, 2
• Life expectancy \> 12 weeks
• Able to swallow a whole tablet
• 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
• Agreeable to have all the biomarker studies including the paired fresh tumour biopsies.
• 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.
• Adequate bone marrow, hepatic \& renal function as defined in the protocol
• For Part B only, patients must have genomic defects associated with olaparib sensitivity identified by NGS by the central lab.

You may not qualify if:

• Surgery, or local prostatic intervention (excluding a prostatic biopsy) less than 28 days of Cycle 1 Day 1
• Prior treatment with a PARP inhibitor, platinum, cyclophosphamide or mitoxantrone chemotherapy
• 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
• 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
• 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
• Patients with myelodysplastic syndrome/acute myeloid leukaemia
• Patients with known symptomatic brain metastasis are not suitable for enrollment. Patients with asymptomatic, stable, treated brain metastases are eligible for study entry
• Patients with symptomatic or impending cord compression unless appropriately treated beforehand \& clinically stable \& asymptomatic
• 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
• Patients receiving any of the following classes of inhibitors of CYP3A4 (see protocol for guidelines \& wash out periods)
• Patients with gastrointestinal disorders likely to interfere with absorption of the study medication
• 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
• 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

Sponsors & Collaborators

• Institute of Cancer Research, United Kingdom: lead
• Royal Marsden NHS Foundation Trust: collaborator

Study Sites (2)

Royal Marsden NHS Foundation Trust

Sutton, Surrey, SM2 5PT, United Kingdom

Location

University College Hospital London

London, NW1 2BU, United Kingdom

Location

Related Publications (3)

• Carmichael J, Figueiredo I, Gurel B, Beije N, Yuan W, Rekowski J, Seed G, Carreira S, Bertan C, Fenor de La Maza MLD, Chandran K, Neeb A, Welti J, Gallagher L, Bogdan D, Crespo M, Riisnaes R, Ferreira A, Miranda S, Lu J, Shen MM, Hall E, Porta N, Westaby D, Guo C, Grochot R, Lord CJ, Mateo J, Sharp A, de Bono J. RNASEH2B loss and PARP inhibition in advanced prostate cancer. J Clin Invest. 2024 Jun 4;134(21):e178278. doi: 10.1172/JCI178278.

  PMID: 38833311 DERIVED

• Mateo J, Porta N, Bianchini D, McGovern U, Elliott T, Jones R, Syndikus I, Ralph C, Jain S, Varughese M, Parikh O, Crabb S, Robinson A, McLaren D, Birtle A, Tanguay J, Miranda S, Figueiredo I, Seed G, Bertan C, Flohr P, Ebbs B, Rescigno P, Fowler G, Ferreira A, Riisnaes R, Pereira R, Curcean A, Chandler R, Clarke M, Gurel B, Crespo M, Nava Rodrigues D, Sandhu S, Espinasse A, Chatfield P, Tunariu N, Yuan W, Hall E, Carreira S, de Bono JS. Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2020 Jan;21(1):162-174. doi: 10.1016/S1470-2045(19)30684-9. Epub 2019 Dec 2.

  PMID: 31806540 DERIVED

• 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.

  PMID: 26510020 DERIVED

MeSH Terms

Conditions

Adenocarcinoma

Interventions

olaparib

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms

Study Officials

• Johann de Bono

  Institute of Cancer Research, United Kingdom

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 27, 2012
• First Posted: September 11, 2012
• Study Start: July 1, 2012
• Primary Completion: March 1, 2019
• Study Completion: February 1, 2020
• Last Updated: August 15, 2019

Record last verified: 2019-08

Locations

GB (2)