Phase I study to evaluate safety, tolerability, pharmacokinetics and anti-tumor activity of WSD0922-FU

PROJECT SUMMARY/ABSTRACT: High-grade astrocytomas (HGA) are rare incurable cancers (combined USA prevalence < 30,000) with few treatment options. Mayo Clinic is collaborating with Wayshine Biopharma to develop WSD0922-FU (WSD) (IND 145566) – a novel oral, small molecule orphan drug which potently inhibits EGFR aberrations specific to high-grade astrocytoma (HGA) (EGFR amplification, EGFRvIII mutation). Our central hypothesis is that safe and tolerable doses of WSD achieve sufficient tumor concentrations in HGA to inhibit EGFR signaling and improve efficacy in patients with EGFR-amplified / EGFRvIII HGA. This is being examined in a first-in-human phase I basket trial which is the subject of this three-year R01 submission to the FDA (“Phase I Study to Evaluate Safety, Tolerability, Pharmacokinetics and Anti-Tumor Activity of WSD0922- FU”). The investigators have broad clinical trial experience in early drug development and neuro-oncology. Early input on trial design was obtained from patient advocates to ensure study feasibility and to reduce patient burden. We expect that study completion will advance available treatments for HGA with EGFR alterations by establishing the maximum tolerated dose (MTD) for WSD, while generating critical data on central nervous system (CNS) PK (pharmacokinetics), impact on tumor EGFR signaling, preliminary efficacy and relevant genetic biomarkers of response/resistance. These data will provide robust evidence to optimize phase II/III trial design, which may lead to a new indication for WSD in HGA. The central hypothesis is evaluated in three aims: Aim 1: Evaluate the safety, tolerability and systemic PK of WSD at MTD. Patients with EGFR-amplified / EGFRvIII HGA or non-small cell lung cancer with CNS metastases will be treated with WSD in a dose escalation cohort to define the MTD and evaluate the toxicity profile of WSD. Plasma PK will be quantified by LC-MS/MS to evaluate systemic exposure. A dose expansion cohort will also include a food-effect study prior to starting continuous dosing. Plasma PK will be quantified in both the fed (WSD dosed after a high fat meal) and fasted states (WSD dosed one hour before or two hours after eating) to evaluate the effect of food on systemic PK. Aim 2: Evaluate intratumoral PK of WSD and assess its pharmacodynamic (PD) impact on EGFR pathway signaling in HGA. Patients with EGFR-amplified / EGFRvIII HGA requiring a therapeutic surgical tumor resection as part of routine clinical care will preoperatively be dosed with WSD at MTD. During surgery, tumor tissue will be collected and flash frozen. Tumor PK will be quantified by LC-MS/MS and PD impact on EGFR pathway signaling will be evaluated by functional proteomics. Aim 3: Characterize the molecular biomarkers which influence efficacy of WSD in patients with EGFR aberrant HGA. Patients with EGFR- amplified / EGFRvIII HGA will be treated continuously with WSD at MTD and monitored for treatment efficacy. Plasma PK will be quantified by LC-MS/MS to confirm sufficient exposure. DNA/RNA sequencing will be performed on archived tissue to evaluate biomarkers of response and resistance (e.g. EGFRvIII, TP53, etc.).