Phase II pharmacokinetics of oral SM-88 in heavily pretreated advanced pancreatic ductal adenocarcinoma (PC).

Abstract

277 Background: SM88 is an oral tyrosine isomer ( TI) and repurposed drugs (CYP3a4 inducer, mTOR inhibitor, oxidative stress catalyst). This regimen has reported no drug related grade 3, 4 or 5 adverse events (JCO 2013 31: e22095) and potential clinical activity in PC (JCO 2018 36: TPS 4156). PC patients have risk factors for malabsorption and a cachexia syndrome rendering some oral therapies potential unreliable. We present PK data from the completely enrolled first stage of an ongoing dose finding phase II in PC. Methods: Open label randomized TI (control – 230 mg bid vs. experimental - 430 mg bid) along with the lowest approved doses of the other agents. Samples were drawn from four patients at pre-dose and up to six h post dosing on cycle day one for two cycles after a single dose of all four components. Results: Mean age: 71.3 (59 – 80), BMI = 25.3 (21.9 – 28.8) and median three prior chemo lines, two post-pancreas surgery and one s/p RT. There was no evidence that the combination altered the expected PKs at C2. There were no serious drug related adverse events. Favorable RECIST, PERCIST or biomarker activity was documented at both TI dose levels. The PK results of the repurposed drugs were consistent with the published data for these agents, despite the combination use and lower than typical label doses; data will be provided. These results were consistent with previous animal and healthier patient PK of SM88. Conclusions: Single dose C1 and C2 TI PKs are consistent with preclinical predictions (ESMO 2016. Ann Oncol (2016) 27 (supp_6): 1605P) and those previously reported in a healthier population of cancer patients (JCO 2018 36: TPS 4156). Based on these results and PK ones from the repurposed drugs, additional data is being collected in order to define the ongoing phase II expansion cohort dose. SM-88 appears to have predictable PK even in heavily pretreated PC patient with prior radiotherapy and surgery. Clinical trial information: NCT03512756. [Table: see text]