ACTION-1 phase Ib/3 trial of RYZ101 in somatostatin receptor subtype 2–expressing (SSTR2+) gastroenteropancreatic neuroendocrine tumors (GEP-NET) progressing after 177Lu somatostatin analogue (SSA) therapy: Initial safety analysis.

Abstract

4132 Background: RYZ101 (225Ac-DOTATATE) is a first-in-class, highly potent alpha-emitting radiopharmaceutical in development for treating SSTR2+ solid tumors. Alpha-particles (as emitted by 225Ac) have a shorter path length (40–100 μm) and higher linear energy transfer (80–100 keV/μm) than beta-particles, causing more frequent double-strand DNA breaks and potentially higher cancer cell kill rates and less damage to healthy tissues. ACTION-1 (NCT05477576) is a 2-part, global, randomized, controlled, open-label, phase 1b/3 trial of RYZ101 in patients (pts) with advanced well-differentiated SSTR+ GEP-NETs progressing after 177Lu-SSA therapy. Part 1 (phase 1b) aims to determine safety, pharmacokinetics, and recommended phase 3 dose (RP3D) of RYZ101. Methods: Part 1 is an uncontrolled dose de-escalation study with a Bayesian optimal interval design. Escalation (0.197) and de-escalation (0.298) boundaries based on a target dose-limiting toxicity (DLT) rate of 25% were applied. Pts received RYZ101 IV every 8w for up to 4 cycles. Planned dose levels (n=6/level): Level 0 (starting dose), 120 kBq/kg (3.2 µCi/kg); if necessary, Level –1, 90 kBq/kg (2.4 µCi/kg); Level –2, 60 kBq/kg (1.6 µCi/kg). No dose escalation above starting dose was permitted. DLT was assessed for 56d after the first RYZ101 treatment. Treatment-emergent adverse events (TEAEs) were graded by NCI-CTCAE v5.0. Dose de-escalation decisions and safety data review were overseen by a Data Review Committee. Data cut-off: 26 Oct 2022. Results: At data cut-off, 9 pts had received RYZ101 at 120 kBq/kg (median dose 8.9 MBq); 7 pts were DLT-evaluable. No DLTs occurred and no dose de-escalation steps were implemented. Baseline characteristics: median age 70y; male (n=6)/female (n=3); ECOG PS 0 (n=4)/1 (n=5); median disease duration 6.9y; primary tumor site GI (n=6)/pancreas (n=3). A safety summary is shown. No treatment-related serious AEs were observed. TEAE requiring dose reductions occurred in 2 pts (Grade 2 platelet count decreased, n=1; Grade 2 thrombocytopenia, n=1). Grade 3 or 4 TEAEs occurred in 3 pts (lymphocyte count decreased, n=2; skin infection, n=1; weight decreased, n=1). One serious adverse event (skin infection) was unrelated to treatment. Conclusions: RYZ101 was well tolerated at 120 kBq/kg, which was declared the RP3D. Part 2 (Phase 3) will commence after Part 1 and will compare RYZ101 at the RP3D with standard of care in pts with advanced SSTR2+ GEP-NETs with disease progression following prior 177Lu-labeled SSAs. Clinical trial information: NCT05477576 . [Table: see text]