ATCT-18: PHASE II STUDY OF MIPSAGARGIN (G-202), A PSMA-ACTIVATED PRODRUG TARGETING THE TUMOR ENDOTHELIUM, IN ADULT PATIENTS WITH RECURRENT OR PROGRESSIVE GLIOBLASTOMA

BACKGROUND: To overcome the challenges of blood-brain barrier penetration with toxic agents in patients with glioblastoma (GBM), we are investigating a soluble, cell cycle-independent prodrug targeted to the tumor vasculature. Mipsagargin is an analog of thapsigargin coupled with a PSMA-directed masking/targeting peptide that inhibits its biologic activity until proteolytic cleavage at the tumor site. PSMA is expressed selectively on some tumor types and on tumor vasculature, including tumor endothelium from human glioblastoma tissues. A Phase I study in patients with advanced solid malignancies suggests mipsagargin may induce disease stabilization in some patient populations. The primary objective of this Phase II study is evaluation of 6-month progression-free survival in patients with advanced GBM. Secondary outcomes include safety, efficacy, effects of mipsagargin on blood flow metrics, pharmacokinetics of mipsagargin in CSF and blood, and molecular response correlates. METHODS: This institutional, open label, phase II trial is ongoing in adult patients with recurrent/progressive GBM following 1-4 prior therapies (accrual goal 34 efficacy-evaluable). Mipsagargin is administered intravenously on Days 1, 2 and 3 of a 28-day treatment cycle; two dosing regimens have been evaluated: 40 mg/m² on Days 1, 2 and 3 and 40 mg/m² on Day 1 and 66.8 mg/m² on Days 2 and 3. Based on tolerability in this patient population, the lower dosing regimen was selected for further evaluation. RESULTS: To date, 13 patients have been enrolled, with nine patients evaluable for efficacy. Two patients (22%) have experienced disease stabilization. Adverse events, mostly Grade 1 or 2, attributed to mipsagargin administration include reversible creatinine elevation, fatigue, rash, nausea/vomiting, headache, infusion-related reaction, upper abdominal pain, GERD, fever, itching, and intermittent body aches. CONCLUSIONS: Preliminary results suggest mipsagargin is well-tolerated and may induce disease stabilization in patients with advanced/recurrent GBM. The study remains open to enrollment and results will be updated.