Abstract CT027: Safety, pharmacokinetics (PK) & pharmacodynamics (PD) of idasanutlin (idasa), combined with abiraterone (abi)/prednisolone (pred) or enzalutamide (enza) in castrate resistant prostate cancer (CRPC)

Abstract

Abstract Introduction MDM2 inhibitor idasa aims to treat cancers retaining functional TP53, inactivated by binding of negative regulator, MDM2. Many CRPCs retain functional TP53. Pre-clinical data suggest addition of MDM2 inhibition to androgen deprivation enhances tumour regression & survival in xenografts. This phase 1b study explored safety, PK & PD of idasa with abi or enza to define optimum biological dose & combination. Methods Patients (pts) received oral (PO) idasa in a 3+3 dose escalation design with PO abi 1000mg once daily (OD) & PO pred 5mg twice daily (BD) (Part A) or PO enza 160mg OD (Part B) in 28 day cycles (C). In the first two cohorts (Part A), pts received a single dose of idasa on day (D) -7. Two different formulations for idasa were explored (microprecipitated bulk powder (MBP) and spray-dried powder (SDP)). Toxicity was assessed by CTCAE v4.03. Plasma idasa/M4 metabolite & plasma abi was measured (Part A). In Part B idasa/M4 metabolite & enza PK were examined. Macrophage inhibitory cytokine 1 (MIC-1) was measured to assess target modulation. Biochemical response was assessed monthly & radiological response 8 weekly. Results 24 pts were enrolled. In part A, 3 pts were treated in cohort 1 with idasa MBP 200mg, D -7 and D1-5, OD, q28; 2 pts experienced a suspected unexpected serious adverse reaction (SUSAR) (pulmonary embolism and myocardial infarction). The dose of idasa was de-escalated for cohort-1 (idasa MBP 200mg, D-7, D1-3, OD); no DLTs were reported (n=3). 3 pts treated in cohort 1* (idasa MBP 200mg, D1-5, OD) & 3 pts in cohort 2 (idasa MBP 400mg, D1-5, OD) had no DLTs. The formulation of idasa was switched to SDP (cohort 3) & a further 3 pts were treated at a dose equivalent to mono-agent MTD (MBP 500mg = SDP 250mg, D1-5, OD) & 1 DLT (grade 4 thrombocytopenia) was reported. A further 3 pts treated at this dose reported no DLTs. 4 additional SUSARs in 3 pts have been reported to date (grade 3 (G3) depression, G3 thromboembolic events, G3 vomiting and prolonged G4 thrombocytopenia/neutropenia). 4 serious adverse reactions (SAR)s have also been reported (G2 decreased platelet count, G3 atrial fibrillation, G3 lung infection & G4 decreased platelet count). In Part B pts received idasa SDP 250mg, D1-5, OD and no DLTs were reported. Dose escalation beyond this mono-agent MTD of idasa was not permitted. Idasa had a dose-proportional PK profile. There was no clinically significant PK interaction with abi, although idasa exposure was reduced when combined with enza (known strong CYP3A inducer). MIC-1 was induced by idasa & abi, but less so by idasa & enza. 7 pts remain on combination & 4 remain on hormonal monotherapy. Efficacy data are immature. Conclusions Idasa can be safely given with abi to achieve exposure comparable with previous data & sufficient to activate p53. Idasa can also be given with enza albeit with reduction in exposure to idasa and less robust p53 activation. Citation Format: Patricia Roxburgh, Dawn Currie, Paula Morrison, Caroline Kelly, Fiona Thomson, Carol McCormick, Alan Bilsland, Robert H. Jones, Amy Quinton, Elaine McCartney, Lorraine Barwell, Rob J. Jones. Safety, pharmacokinetics (PK) & pharmacodynamics (PD) of idasanutlin (idasa), combined with abiraterone (abi)/prednisolone (pred) or enzalutamide (enza) in castrate resistant prostate cancer (CRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT027.