Oral SM-88 plus MPS, an effective yet less toxic treatment option in second-line advanced pancreatic cancer? Final phase II/III study results.
Authors: Noel Marcus Smith , Wong Steve , Picozzi Vincent J. , Staszewski Harry , Kim Dae Won , Hartley Marion L. , Loushin Maria , Stanicky Shabnam , Lau Justin , Kim Semmie , Van Tornout Jan , Philip Philip Agop , Chung Vincent , Ocean Allyson J. , wang-gillam Andrea 
Published: January 2022

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Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) has a poor prognosis in refractory patients (pts). SM-88 Regimen, which comprises oral SM-88 (racemetyrosine, TYME Inc) plus 10mg methoxsalen, 50mg phenytoin, and 0.5mg sirolimus (MPS), has previously shown clinical activity in mPDAC. Methods: We report on the final results (primary objective, ORR) of our multicenter, prospective open-label phase II/III RCT (TYME-88-Panc Part 1, NCT03512756) of SM-88 Regimen in pts with mPDAC who had received at least one prior line of therapy. Subjects received either 230 mg BID or 460 mg BID PO SM-88; oral MPS QD was given at the same dose in both arms. Results: The last subject was enrolled on Mar 12, 2019. As of Sep 1, 2021, 49 subjects were randomized to either 460 (n = 26) or 920mg (n = 23) SM-88 plus MPS daily (ITT population); 37 were deemed evaluable after completing at least one 28-day cycle of treatment (min 23 days on treatment). The study population was heterogeneous: a majority (32/37 = 86.5%) had failed at least 2 prior lines of chemotherapy. Twenty pts (54.1%) had received FOLFIRINOX in the first line and 16 pts (43.2%), a gemcitabine-based regimen. For evaluable pts, the overall disease control rate (DCR) was 27.0%: 10/37 subjects reached RECIST v1.1-verified stable disease (SD); 3 of the 10 had RECIST-confirmed SD. For the 49 ITT pts, mOS was 3.4 months (mo). For the 37 evaluable pts, mOS was 3.9 mo, and mPFS was 1.9 mo. mOS, mPFS, and DCR did not differ significantly by SM-88 dose. mOS and mPFS trended toward improvement in subjects with fewer prior lines of treatment: for pts in the second line (n = 5), mOS was 8.1 mo (95% CI: 3.0 – no UL), and mPFS was 3.8 mo (95% CI: 0.9 – no UL). Although not confirmatory, exploratory analyses showed that circulating tumor cells decreased on SM-88 Regimen. SM-88 Regimen was well tolerated: only one pt of the 48 ever dosed (2.1%) experienced related SAEs on treatment (Grade 3 abdominal pain, Grade 4 hypotension), which were eventually resolved. Enrollment criteria specified ECOG < = 2 at study entry; these scores were maintained or improved for most pts (24/37 = 64.9%) while on treatment. Overall health and quality of life (QOL) scores via EORTC QLQ-C30 were maintained, trending toward superiority for pts on 920 mg vs. 460 mg (p = ns). Conclusions: This final analysis confirmed that SM-88 Regimen was well tolerated, with pts attaining an overall DCR of 27%. Of note, for the small subset of pts treated in the second line, the mOS and mPFS were on par with results achieved in other published randomized PhIII second-line trials for mPDAC. Moreover, SM-88 Regimen exhibited far fewer Grade 3 and 4 AEs than other commonly used cytotoxic regimens in the second line. The 27% DCR, 8.1 mo mOS, and 3.8 mo mPFS in the second line, with minimal toxicity and preserved QOL, resulted in the active investigation of SM-88 Regimen in a large, ongoing second-line trial in mPDAC (NCT04229004). Clinical trial information: NCT03512756.