A phase 2, open-label, single-arm monotherapy trial of Sulfasalazine in patients with PancrEatic AdenocaRcinoma: Statistical analysis plan for the SPEAR study

BackgroundPancreatic ductal adenocarcinoma (PDAC) is associated with an extremely poor prognosis, with a 5-year survival rate of less than 9% (1). The SPEAR study is a Phase II, single-arm, open-label, signal-seeking trial evaluating the clinical activity of sulfasalazine, a repurposed anti-inflammatory agent, in patients with advanced or metastatic PDAC who have progressed on one prior line of systemic therapy. This document extends the published study protocol by pre-specifying the planned statistical analyses, including post hoc analyses following early trial termination for futility. Design and SettingSingle-arm, multi-centre Phase II trial conducted in two sequential cohorts (Cohort 1: n=17; Cohort 2: n=17-22), with inclusion contingent on remaining on study until at least Cycle 2 Day 1 (C2D1). Sulfasalazine was administered using a pharmacokinetically guided dose-escalation strategy, with escalation speed informed by acetylator status to minimise toxicity. Interim analyses were planned to assess early signals of efficacy and safety, with predefined stopping rules. OutcomesThe primary outcome is the proportion of patients achieving progression-free survival (PFS) at 6 months. Secondary outcomes include objective tumour response rate, median PFS, overall survival (OS) at 12 months, median OS, time to progression, safety, and dose intensity. Tertiary outcomes include exploratory biomarkers such as tumour markers (CA 19-9, CEA), peripheral blood glutathione, and serum collagen degradation products. Planned AnalysesAll analyses will be conducted using R (version 4.0.0 or above) or SAS Enterprise Guide (version 8.3 or above), with a two-sided alpha of 0.05. Binary outcomes, including the primary outcome, will be summarised as proportions with 95% confidence intervals. Time-to-event outcomes will be analysed using Kaplan-Meier methods, and continuous outcomes will be summarised using appropriate descriptive statistics. Post hoc exploratory analyses will examine factors associated with recruitment, clinical suitability, and early treatment discontinuation. These include evaluating the relationship between line of therapy and time on study and assessing whether baseline HRQoL or inflammatory biomarkers may better inform future eligibility criteria. Additional analyses will explore associations between baseline characteristics and overall survival or early discontinuation using regression and survival methods. All post hoc analyses will be clearly identified and interpreted as hypothesis-generating.