Pharmacodynamics effects of CDK4/6 inhibitor LEE011 (ribociclib) in high-risk, localised prostate cancer: a study protocol for a randomised controlled phase II trial (LEEP study: LEE011 in high-risk, localised Prostate cancer)
Introduction Despite the development of new therapies for advanced prostate cancer, it remains the most common cause of cancer and the second leading cause of cancer death in men. It is critical to develop novel agents for the treatment of prostate cancer, particularly those that target aspects of a...
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BMJ Publishing Group
2020-01-01
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| Series: | BMJ Open |
| Online Access: | https://bmjopen.bmj.com/content/10/1/e033667.full |
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| author | Lisa M Butler Anthony M Joshua Tahlia Scheinberg James Kench Martin Stockler Kate L Mahon Lucille Sebastian Phillip Stricker H Woo Ruban Thanigasalam Nariman Ahmadi Margaret M Centenera Lisa G Horvath |
| author_facet | Lisa M Butler Anthony M Joshua Tahlia Scheinberg James Kench Martin Stockler Kate L Mahon Lucille Sebastian Phillip Stricker H Woo Ruban Thanigasalam Nariman Ahmadi Margaret M Centenera Lisa G Horvath |
| author_sort | Lisa M Butler |
| collection | DOAJ |
| description | Introduction Despite the development of new therapies for advanced prostate cancer, it remains the most common cause of cancer and the second leading cause of cancer death in men. It is critical to develop novel agents for the treatment of prostate cancer, particularly those that target aspects of androgen receptor (AR) signalling or prostate biology other than inhibition of androgen synthesis or AR binding. Neoadjuvant pharmacodynamic studies allow for a rational approach to the decisions regarding which targeted therapies should progress to phase II/III trials. CDK4/6 inhibitors have evidence of efficacy in breast cancer, and have been shown to have activity in preclinical models of hormone sensitive and castrate resistant prostate cancer. The LEEP trial aims to assess the pharmacodynamic effects of LEE011 (ribociclib), an orally bioavailable and highly selective CDK4/6 inhibitor, in men undergoing radical prostatectomy for high-risk, localised prostate cancer.Methods and analysis The multicentre randomised, controlled 4:1 two-arm, phase II, open label pharmacodynamic study will recruit 47 men with high risk, localised prostate cancer who are planned to undergo radical prostatectomy. Participants who are randomised to receive the study treatment will be treated with LEE011 400 mg daily for 21 days for one cycle. The primary endpoint is the frequency of a 50% reduction in Ki-67 proliferation index from the pretreatment prostate biopsy compared to that present in prostate cancer tissue from radical prostatectomy. Secondary and tertiary endpoints include pharmacodynamic assessment of CDK4/6 cell cycle progression via E2F levels, apoptotic cell death by cleaved caspase-3, changes in serum and tumour levels of Prostate Specific Antigen (PSA), pathological regression, safety via incidence of adverse events and exploratory biomarker analysis.Ethics and dissemination The protocol was approved by a central ethics review committee (St Vincent’s Hospital HREC) for all participating sites (HREC/17/SVH/294). Results will be disseminated in peer-reviewed journals and at scientific conferences.Drug supply Novartis.Protocol version 2.0, 30 May 2019Trial registration number Australian New Zealand Clinical Trials Registry (ACTRN12618000354280). |
| format | Article |
| id | doaj-art-8ba64206d4ee4d468c56577ef46fa9f8 |
| institution | OA Journals |
| issn | 2044-6055 |
| language | English |
| publishDate | 2020-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | BMJ Open |
| spelling | doaj-art-8ba64206d4ee4d468c56577ef46fa9f82025-08-20T02:21:04ZengBMJ Publishing GroupBMJ Open2044-60552020-01-0110110.1136/bmjopen-2019-033667Pharmacodynamics effects of CDK4/6 inhibitor LEE011 (ribociclib) in high-risk, localised prostate cancer: a study protocol for a randomised controlled phase II trial (LEEP study: LEE011 in high-risk, localised Prostate cancer)Lisa M Butler0Anthony M Joshua1Tahlia Scheinberg2James Kench3Martin Stockler4Kate L Mahon5Lucille Sebastian6Phillip Stricker7H Woo8Ruban Thanigasalam9Nariman Ahmadi10Margaret M Centenera11Lisa G Horvath12Prostate Cancer Research Group, South Australian Health and Medical Research Institute, Adelaide, South Australia, AustraliaCancer Research, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia3 Department of Medicine, The University of Sydney, Sydney, New South Wales, AustraliaSchool of Medicine, The University of Sydney, Sydney, New South Wales, AustraliaSchool of Medicine, The University of Sydney, Sydney, New South Wales, AustraliaMedical Oncology, Chris O`Brien Lifehouse, Camperdown, New South Wales, AustraliaNHMRC Clinical Trials Centre, University of Sydney, Camperdown, New South Wales, AustraliaCancer Research, Garvan Institute of Medical Research, Darlinghurst, New South Wales, AustraliaSchool of Medicine, The University of Sydney, Sydney, New South Wales, AustraliaSchool of Medicine, The University of Sydney, Sydney, New South Wales, AustraliaUrology, Chris O`Brien Lifehouse, Camperdown, NSW, AustraliaProstate Cancer Research Group, South Australian Health and Medical Research Institute, Adelaide, South Australia, AustraliaMedical Oncology, Chris O`Brien Lifehouse, Camperdown, New South Wales, AustraliaIntroduction Despite the development of new therapies for advanced prostate cancer, it remains the most common cause of cancer and the second leading cause of cancer death in men. It is critical to develop novel agents for the treatment of prostate cancer, particularly those that target aspects of androgen receptor (AR) signalling or prostate biology other than inhibition of androgen synthesis or AR binding. Neoadjuvant pharmacodynamic studies allow for a rational approach to the decisions regarding which targeted therapies should progress to phase II/III trials. CDK4/6 inhibitors have evidence of efficacy in breast cancer, and have been shown to have activity in preclinical models of hormone sensitive and castrate resistant prostate cancer. The LEEP trial aims to assess the pharmacodynamic effects of LEE011 (ribociclib), an orally bioavailable and highly selective CDK4/6 inhibitor, in men undergoing radical prostatectomy for high-risk, localised prostate cancer.Methods and analysis The multicentre randomised, controlled 4:1 two-arm, phase II, open label pharmacodynamic study will recruit 47 men with high risk, localised prostate cancer who are planned to undergo radical prostatectomy. Participants who are randomised to receive the study treatment will be treated with LEE011 400 mg daily for 21 days for one cycle. The primary endpoint is the frequency of a 50% reduction in Ki-67 proliferation index from the pretreatment prostate biopsy compared to that present in prostate cancer tissue from radical prostatectomy. Secondary and tertiary endpoints include pharmacodynamic assessment of CDK4/6 cell cycle progression via E2F levels, apoptotic cell death by cleaved caspase-3, changes in serum and tumour levels of Prostate Specific Antigen (PSA), pathological regression, safety via incidence of adverse events and exploratory biomarker analysis.Ethics and dissemination The protocol was approved by a central ethics review committee (St Vincent’s Hospital HREC) for all participating sites (HREC/17/SVH/294). Results will be disseminated in peer-reviewed journals and at scientific conferences.Drug supply Novartis.Protocol version 2.0, 30 May 2019Trial registration number Australian New Zealand Clinical Trials Registry (ACTRN12618000354280).https://bmjopen.bmj.com/content/10/1/e033667.full |
| spellingShingle | Lisa M Butler Anthony M Joshua Tahlia Scheinberg James Kench Martin Stockler Kate L Mahon Lucille Sebastian Phillip Stricker H Woo Ruban Thanigasalam Nariman Ahmadi Margaret M Centenera Lisa G Horvath Pharmacodynamics effects of CDK4/6 inhibitor LEE011 (ribociclib) in high-risk, localised prostate cancer: a study protocol for a randomised controlled phase II trial (LEEP study: LEE011 in high-risk, localised Prostate cancer) BMJ Open |
| title | Pharmacodynamics effects of CDK4/6 inhibitor LEE011 (ribociclib) in high-risk, localised prostate cancer: a study protocol for a randomised controlled phase II trial (LEEP study: LEE011 in high-risk, localised Prostate cancer) |
| title_full | Pharmacodynamics effects of CDK4/6 inhibitor LEE011 (ribociclib) in high-risk, localised prostate cancer: a study protocol for a randomised controlled phase II trial (LEEP study: LEE011 in high-risk, localised Prostate cancer) |
| title_fullStr | Pharmacodynamics effects of CDK4/6 inhibitor LEE011 (ribociclib) in high-risk, localised prostate cancer: a study protocol for a randomised controlled phase II trial (LEEP study: LEE011 in high-risk, localised Prostate cancer) |
| title_full_unstemmed | Pharmacodynamics effects of CDK4/6 inhibitor LEE011 (ribociclib) in high-risk, localised prostate cancer: a study protocol for a randomised controlled phase II trial (LEEP study: LEE011 in high-risk, localised Prostate cancer) |
| title_short | Pharmacodynamics effects of CDK4/6 inhibitor LEE011 (ribociclib) in high-risk, localised prostate cancer: a study protocol for a randomised controlled phase II trial (LEEP study: LEE011 in high-risk, localised Prostate cancer) |
| title_sort | pharmacodynamics effects of cdk4 6 inhibitor lee011 ribociclib in high risk localised prostate cancer a study protocol for a randomised controlled phase ii trial leep study lee011 in high risk localised prostate cancer |
| url | https://bmjopen.bmj.com/content/10/1/e033667.full |
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