Phase 1b portion of the ACTION-1 phase 1b/3 trial of RYZ101 in gastroenteropancreatic neuroendocrine tumors (GEP-NET) progressing after ¹⁷⁷ Lu somatostatin analogue (SSA) therapy: Safety and efficacy findings.

661 Background: RYZ101 ( 225 Ac-DOTATATE) is an alpha-emitting radiopharmaceutical in development for SSTR2+ solid tumors. Alpha-particles have a shorter path length/higher linear energy transfer than beta-particles, causing more frequent double-strand DNA breaks and potentially improving the therapeutic index. ACTION-1 (NCT05477576) is a two-part, global, randomized, controlled, open-label, phase 1b/3 trial of RYZ101 in advanced, well-differentiated SSTR+ GEP-NETs progressing after 177 Lu-SSA therapy. Herein, we report updated results from the phase 1b portion of the trial. Methods: The phase 1b portion of the ACTION-1 trial had a dose de-escalation/Bayesian optimal interval design with boundaries based on a dose-limiting toxicity (DLT) rate of 25%. Patients received RYZ101 IV every 8 weeks for 4 cycles. Planned dose levels (n=6/level): Level 0 (starting dose) 120 kBq/kg; Level 1 90 kBq/kg; Level 2 60 kBq/kg. DLTs were assessed for 56 days after the first RYZ101 dose. Treatment-emergent adverse events (TEAEs) were graded by NCI-CTCAE v5.0. A Data Review Committee oversaw dose de-escalation decisions/safety data. Tumor response was assessed locally by RECIST v1.1. Results: Seventeen patients received at least one dose of RYZ101 at 120 kBq/kg (4 doses: 15 patients; 2 doses: 2 patients; median 8.3 MBq). Baseline patient characteristics: median age 63 years; male (n=11); ECOG PS 0/1 (n=10/7); primary tumor site GI/pancreas (n=12/5). As of 14 December 2023, the most frequent TEAEs were anemia (58.8%), nausea (58.8%), and fatigue (52.9%). Serious adverse events (SAEs) were observed in 6 patients (35.3%, none were treatment-related); grade ≥3 TEAEs occurred in 9 patients (5 were treatment-related, 29.4%). No TEAEs led to treatment discontinuation. Four patients had TEAEs leading to dose modification, dose hold, and/or dose delays. There was one grade 5 TEAE of hepatic failure that was deemed unrelated to the study drug. The confirmed objective response rate was 29.4% (n=5; 1 complete response, 4 partial responses). One additional patient had an unconfirmed partial response at the time of data cutoff, which was subsequently confirmed. Seven patients (41.2%) had stable disease and 3 (17.6%) had progressive disease. The median duration of response was not estimable (95% CI 9.26 months, not estimable), and the median progression-free survival was not estimable (95% CI 12.16 months, not estimable). Conclusions: RYZ101 was well tolerated, and a fixed dose of 10.2 MBq was declared the recommended phase 3 dose. Initial data suggest promising efficacy and a manageable safety profile. Part 2 (phase 3) of the ACTION-1 trial is enrolling and will compare RYZ101 at 10.2 MBq every 8 weeks for 4 cycles with standard of care in patients with advanced SSTR2+ GEP-NETs progressing after 177 Lu-labeled SSAs. Clinical trial information: NCT05477576 .