CANCAP02: A study into the pharmacodynamic biomarker effects of vistusertib (AZD2014), an mTORC1/2 inhibitor, given prior to radical prostatectomy (RP)
| Autor: | Vincent J. Gnanapragasam, Javier Garcia Corbacho, Elisabeth Oelmann, Sanjeev Kumar, Sara Stearn, Simon Pacey, Richard D. Baird, Ola Bratt, Wanfeng Zhao, Susan Ingle, Nimish Shah, Anne Y. Warren, Mirela Hategan, Elizabeth A. Harrington, Wendi Qian, Barry R. Davies, Leanne K Bell, William Dott |
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| Rok vydání: | 2017 |
| Předmět: |
Oncology
Cancer Research medicine.medical_specialty medicine.diagnostic_test business.industry Prostatectomy medicine.medical_treatment Pharmacology medicine.disease Prostate cancer Tolerability Internal medicine Pharmacodynamics Biopsy Clinical endpoint Medicine Biomarker (medicine) business Adverse effect |
| Zdroj: | Journal of Clinical Oncology. 35:97-97 |
| ISSN: | 1527-7755 0732-183X |
| Popis: | 97 Background: Additional systemic therapy given to unselected patients (pts) around RP has yet to improved pt survival. Further trials should use appropriate pt selection, i.e. men at highest risk of relapse, ideally biomarker stratified. Using novel drugs prior to RP allows direct study of effects in primary prostate cancer (PC) that may guide design of future trials. Altered PI3K/AKT/mTOR pathway signalling is associated with aggressive PC hence we have undertaken a study vistusertib, an oral, dual mTORC1/mTORC2 inhibitor prior to RP. Methods: Primary endpoint was to measure mTOR1/2 inhibition by immunohistochemistry (IHC). Secondary endpoints were feasibility, safety, tolerability and determining plasma concentrations of vistusertib. Exploratory objectives included measurement of anti-cancer effects. Men, due for RP, with high volume or aggressive PC consented and received vistusertib, 50mg bd, for 15 days prior to RP. Diagnostic biopsy and RP tissue were collected for IHC. Adverse events (AE) were graded according to CTCAE v4. Plasma was collected to determine vistusertib concentrations. Results: 21 men, median age 62 (range 50 – 69) included 11 intermediate and 10 high risk PC. 18/21 were evaluable for primary endpoint. On day of RP mean plasma vistusertib concentration at RP was 648 ng/mL (range 386-852) and 6-8 hr post dose 484 ng/mL (range 211-660). Majority of related AEs were Grade (Gr) 1, the most common being rash, thrombocytopenia, oral mucositis, diarrhoea, lymphopenia and fatigue. Six pts experienced Gr3 AEs (3 pt lymphopenia, 1 pt each rash, mucositis and ALT rise). Two pts discontinued due to AEs (mucositis, thrombocytopenia) and one withdrew consent. Surgery was delayed in one pt (Gr 1 thrombocytopenia). IHC confirmed at RP: 4EBP1 was reduced in 100% pt (75% no staining post vistusertib) and pS6 was reduced in 67%, not changed in 25% and increased in 8%. A fall in PSA occurred in 4/18 pts. Conclusions: 2 weeks of AZD2014 can be given prior to RP. Active plasma concentrations were achieved. mTOR pathway inhibition was confirmed on IHC and a PSA fall occurred in 22% of pt. Analysis is ongoing, to be informed by concomitant studies in a PTEN null PC model. Clinical trial information: NCT02064608. |
| Databáze: | OpenAIRE |
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