Precision Promise (PrP) Bayesian platform trial for metastatic pancreatic cancer (mPDAC): Results of the first experimental arm, SM-88 as second line therapy.

Abstract

675 Background: PrP is a phase 3 Bayesian adaptive platform trial for efficiently testing multiple arms against a common control. Its design is what FDA calls a Complex Innovative Design (www.fda.gov/media/130897/download). Experimental arms in stage 1 are adaptively randomized against other arms. The maximum size of an arm’s stage 1 is 100 subjects. Strong efficacy in stage 1 leads to a fixed randomization stage 2. Stages 1 and 2 are combined for the arm’s final analysis and, if positive, would be submitted for drug registration. SM-88 (D,L-alpha-metyrosine) is a dysfunctional, racemic tyrosine mixture designed to interrupt PDAC cellular metabolism and induce oxidative stress. Methoxsalen, phenytoin and sirolimus are added to SM-88 to potentially enhance oxidative stress, and form a 4-drug oral regimen. SM-88 was selected for testing in 2nd line mPDAC using the PrP platform. Methods: Primary endpoint overall survival (OS) is analyzed based on modified intention to treat (mITT). Randomization is 7:3 to experimental and control arms. Efficacy is defined by OS hazard ratio (HR, experimental vs control). All statistical measures in PrP are Bayesian. Superiority (HR < 1) is assessed monthly and is claimed should the Bayesian probability of benefit be ≥ 98%. Futility analyses occur monthly once 50 subjects have accrued to the arm. Accrual ends for futility if Bayesian predictive power (PP) of eventual success in PrP is < 20% for all the arm’s signatures. Follow-up continues for 12 months after arm accrual stops. PrP experimental arm designs are flexible: an arm’s protocol appendix can supersede the master protocol. However, type I error is controlled at < 0.025, as shown by simulation. Results: SM-88 entered PrP in Apr 2020. As the first experimental arm in PrP, it was randomized 7:3 against control arms. Pooled controls for SM-88 were gemcitabine/nab-paclitaxel and mFOLFIRINOX at standard doses, since neither therapy was a backbone for SM-88. Between 4/2020 - 10/2021, 142 subjects were screened, 73 subjects started therapy and are included in the mITT cohort. 55 subjects were enrolled in the SM-88 arm and 18 in control arms. Median age was 65, 41% were female and 67% had ECOG-1. As per protocol, accrual stopped at its first futility analysis in Nov 2021 based on Predictive power (PP) 0.0001 (see table), which is less than the protocol bound 0.20. SM-88 toxicity was mild. Interim results at accrual stop and final results (12 month follow up) shown below. mOS was 4.1m for SM-88 vs 8.1m for control. Conclusions: Leveraging small sample sizes of SM-88 and controls, PrP efficiently and compellingly concluded SM-88 futility in 2nd line mPDAC. PrP continues to assess other therapies, utilizing time-adjusted, as well as concurrently randomized, controls. Clinical trial information: NCT04229004 . [Table: see text]