ETCTN 10366: A Phase 1 Study of DNA-PK Inhibitor Peposertib in Combination with Hypofractionated Radiotherapy for the Treatment of Locally Advanced Pancreatic Adenocarcinoma.

4168 Background: Optimal therapy for patients with locally advanced pancreatic adenocarcinoma (LAPC) is unknown, though consensus guidelines suggest induction chemotherapy followed by radiation as an option for treatment. In preclinical work, synergy was observed with the addition of DNA-PK inhibitor peposertib to radiation in pancreatic cancer cell lines and xenograft models. This phase 1 dose escalation trial (NCT04172532) evaluated the safety and tolerability of peposertib in combination with hypofractionated radiotherapy in patients with LAPC following induction chemotherapy. Methods: Patients with LAPC following 4-6 months of induction chemotherapy with FOLFIRINOX or gemcitabine/nab-paclitaxel were eligible. Patients received stereotactic body radiotherapy (SBRT) in 5 fractions delivered every other day, in combination with peposertib daily for 14 days during the SBRT period. The peposertib dose was escalated according to a 3+3 design, and the SBRT dose was escalated from 33Gy to 40Gy in an additional dose level after the highest peposertib dose was deemed safe. The dose limiting toxicity (DLT) window extended for 30 days following the last treatment. Plasma pharmacokinetics were assessed for the combination. Following study treatment, patients were allowed to proceed with additional therapy as per standard guidelines. Results: A total of 18 patients with locally advanced pancreatic adenocarcinoma were enrolled across 7 ETCTN sites in dose escalation. No dose limiting toxicities were observed across the 4 dose levels: 1) 100 mg, 2) 200 mg, 3) 300 mg peposertib daily x 14 days in combination with SBRT 6.6 Gy x 5 fractions, and 4) peposertib 300 mg daily x 14 days with SBRT at the higher dose of 8 Gy x 5 fractions. As no DLT was observed in 6 total patients treated at the top dose level (4), this was determined the recommended phase 2 dose. Most common treatment emergent adverse events across all dose levels included nausea, fatigue, abdominal pain, and diarrhea, most of which were grade 1 or 2 in severity. A total of 4 grade 3 adverse events were observed, and included lymphocyte count decrease (2), fatigue and anemia. Two grade 5 events were documented in study participants treated at dose level 3, one attributed to complications of a Whipple procedure, and the second attributed to disease progression following hospitalization for sepsis associated with a PICC line infection. Both events were deemed unrelated to study treatment. PK evaluation is ongoing and will be reported. Conclusions: Peposertib 300 mg daily x 14 days in combination with SBRT at a dose of 8 Gy x 5 fractions is the recommended phase 2 dose. A randomized phase 2 study is now enrolling to further assess the efficacy of the combination in patients with LAPC. Clinical trial information: NCT04172532 .