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)
| Autor: | Anthony M. Joshua, Lucille Sebastian, Ruban Thanigasalam, Martin R. Stockler, Tahlia Scheinberg, Henry H. Woo, Lisa G. Horvath, Kate L. Mahon, Margaret M. Centenera, Lisa M. Butler, James G. Kench, Nariman Ahmadi, Phillip D. Stricker |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Oncology Prostate biopsy medicine.medical_treatment Aminopyridines Apoptosis prostatic neoplasms Prostate cancer Prostate Randomized Controlled Trials as Topic medicine.diagnostic_test Caspase 3 Prostatectomy Cell Cycle General Medicine Neoadjuvant Therapy Prostate-specific antigen medicine.anatomical_structure Research Design Kallikreins Adult medicine.medical_specialty Adolescent Antineoplastic Agents Disease-Free Survival Clinical Trials Phase II as Topic Breast cancer Internal medicine window of opportunity trial medicine Humans ribociclib Cell Proliferation business.industry Cyclin-Dependent Kinase 4 Cancer Cyclin-Dependent Kinase 6 Prostate-Specific Antigen medicine.disease E2F Transcription Factors Clinical trial neoadjuvant trial translational research Purines business |
| Zdroj: | BMJ Open |
| ISSN: | 2044-6055 |
| Popis: | IntroductionDespite 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 analysisThe 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 disseminationThe 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 supplyNovartis.Protocol version2.0, 30 May 2019Trial registration numberAustralian New Zealand Clinical Trials Registry (ACTRN12618000354280). |
| Databáze: | OpenAIRE |
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