Phase I study of endoscopic ultrasound (EUS)-guided NBTXR3 delivery activated by radiotherapy (RT) for locally advanced or borderline resectable pancreatic cancer (LAPC or BRPC)

Patients with LAPC or BRPC often receive RT after chemotherapy (chemo) if no metastatic progression has occurred, and CA19-9 historically normalizes ∼20% after all therapy. While escalated dose RT (EDR) has shown promising survival in selected patients, RT dose limitations of the bowel often prevent safe EDR. To overcome this challenge, we are investigating NBTXR3, a functionalized hafnium oxide radio enhancer administered by a single intratumoral injection, locally amplifying the RT dose. The primary objective is to determine NBTXR3 recommended phase II dose (RP2D) and secondary objective is to measure anti-tumor effects. The study uses a Bayesian optimal interval design (BOIN) with two parts: dose-finding for RP2D (NBTXR3 at [level 1] 33% of gross tumor volume [GTV] or [level 2] at 42% of GTV) and cohort expansion at RP2D. In part 1, eligibility criteria included only LAPC patients with no evidence of metastatic disease after 2-6 months of chemo, part 2 allows BRPC. NBTXR3 is given once prior to RT via EUS-guided intratumoral injection. All patients receive 45 Gy in 15 fractions to GTV. Target tumor response is per RECIST v1.1 criteria. CA19-9 is measured serially. As of January 12, 2023, 12 LAPC patients (median age 61 years [range 43-81], 8 males, 4 females) received protocol therapy. The first patient (level 1) and subsequent 11 patients (level 2) had no dose limiting toxicities (DLTs). At 4 weeks post RT, 11 had stable disease (SD) locally (1 had progressive disease [PD] overall) and 1 had radiographic complete response (CR). At 3 months post RT, 11 had SD locally (1 PD overall), and 1 had surgery with negative margins and no residual viable tumor. 6 patients had elevated CA19-9 before NBTXR3/RT, 5 of these 6 (83%) had a decrease in CA19-9 subsequently, and 2 of these 6 (33%) had CA19-9 normalization eventually. 9 patients had elevated CA19-9 at diagnosis, and 5 out of 9 patients (56%) had normalization of CA19-9 after all therapy. The RP2D of NBTXR3 for LAPC is 42% of GTV. The successful CR and shift to resectability in this patient population, along with the response and CA19-9 decrease and normalization suggest promising anti-tumor efficacy of NBTXR3/RT.