1198P - Phase Ib portion of the ACTION-1 phase Ib/3 trial of RYZ101 in gastroenteropancreatic neuroendocrine tumors (GEP-NET) progressing after 177Lu somatostatin analogue (SSA) therapy: Safety and efficacy findings

Background

RYZ101 (²²⁵Ac-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 improved therapeutic index. ACTION-1 (NCT05477576) is a 2-part, global, randomized, controlled, open-label, phase 1b/3 trial of RYZ101 in advanced, well-differentiated SSTR+ GEP-NETs progressing after ¹⁷⁷Lu-SSA therapy. Herein, we report results from the phase Ib portion of the trial.

Methods

The phase Ib portion had a dose de-escalation/Bayesian optimal interval design with boundaries based on a dose-limiting toxicity (DLT) rate of 25%. Patients (pts) received RYZ101 IV q8w x4 cycles. Planned dose levels (n=6/level): Level 0 (starting dose) 120kBq/kg; Level –1 90kBq/kg; Level –2 60kBq/kg. DLT was assessed for 56d after the first RYZ101 dose. Treatment-emergent adverse events (TEAEs) were graded by NCI-CTCAE v5.0. Dose de-escalation decisions/safety data were overseen by a Data Review Committee. Tumor response was assessed locally by RECIST v1.1.

Results

17 pts have received at least one dose of RYZ101 at 120kBq/kg (4 doses: 6 pts; 3 doses: 2 pts; 2 doses: 8 pts; 1 dose: 1 pt; median 8.9MBq). Baseline characteristics: median age 63y; male (n=11); ECOG PS 0/1 (n=10/7); primary tumor site GI/pancreas (n=12/5). No DLTs, no dose de-escalation and no treatment-related serious AEs (SAEs) occurred. TEAEs requiring dose reductions occurred in 2 pts (G2 thrombocytopenia, n=2). G3/4 TEAEs occurred in 6 pts, 3 related to RYZ101 (lymphopenia, n=2; weight decreased, n=1). SAEs occurred in 4 pts (all unrelated). Confirmed objective response was seen in 5 evaluable pts. Updated efficacy data will be provided at the congress.

Conclusions

RYZ101 was well tolerated and a fixed dose of 10.2MBq was declared the recommended phase 3 dose. Initial data suggest promising efficacy. Part 2 (phase 3) is enrolling and will compare RYZ101 at 10.2MBq q8w for 4 cycles with standard of care in pts with advanced SSTR2+ GEP-NETs progressing following prior ¹⁷⁷Lu-labeled SSAs.

Clinical trial identification

ACTION-1 (NCT05477576).

Editorial acknowledgement

Editorial assistance for this abstract was provided by Lee Miller (Miller Medical Communications Ltd). This work was funded by the study sponsor (RayzeBio Inc).

Legal entity responsible for the study

RayzeBio Inc.

Funding

RayzeBio Inc.

Disclosure

J. Strosberg: Financial Interests, Personal, Speaker’s Bureau: Ipsen; Financial Interests, Personal, Advisory Board: Novartis, Tersera; Financial Interests, Institutional, Principal Investigator: Merck, Novartis, Alphamedix; Financial Interests, Personal, Advisory Role: Novartis. G. Ulaner: Financial Interests, Personal, Speaker’s Bureau: GE Healthcare, Lantheus; Financial Interests, Institutional, Research Grant: GE Healthcare, Lantheus, Nuclidium, Curium, RayzeBio, ImmaginAb, BriaCell, POINT; Financial Interests, Personal, Advisory Role: GE Healthcare, Lantheus, Nuclidium, POINT. H.P. Soares: Financial Interests, Personal, Advisory Board: TerSera, Ipsen, AstraZeneca, Novartis, ITM. L.B. Anthony: Financial Interests, Institutional, Principal Investigator: Rayzebio. H. Jacene: Financial Interests, Personal, Invited Speaker: Monrol, ITM; Financial Interests, Personal, Member of Board of Directors: SNMMI; Financial Interests, Personal, Royalties: Cambridge University Press; Financial Interests, Institutional, Funding: Blue Earth Diagnostics; Financial Interests, Personal, Speaker, Consultant, Advisor: Blue Earth Diagnostics, Spectrum Dynamics. D. Ferreira: Financial Interests, Personal, Full or part-time Employment: RayzeBio, Bayer; Financial Interests, Personal, Stocks or ownership: RayzeBio, Bayer, Medtronic. J. Li: Financial Interests, Personal, Full or part-time Employment: RayzeBio; Financial Interests, Personal, Stocks or ownership: RayzeBio. K. Ma: Financial Interests, Personal, Full or part-time Employment: RayzeBio; Financial Interests, Personal, Stocks or ownership: RayzeBio. J. Rearden: Financial Interests, Personal, Stocks or ownership: RayzeBio; Financial Interests, Personal, Full or part-time Employment: RayzeBio. S. Moran: Financial Interests, Personal, Full or part-time Employment: RayzeBio; Financial Interests, Personal, Stocks or ownership: RayzeBio. T. Hope: Financial Interests, Institutional, Research Funding: Clovis Oncology, Philips, GE Healthcare, Lantheus, Janssen, The Prostate Cancer Foundation, The National Cancer Institute; Financial Interests, Personal, Advisory Role: Ipsen, Bayer, BlueEarth Diagnostics, RayzeBio, Curium; Financial Interests, Personal, Stocks or ownership: RayzeBio, Curium. M. Morris: Financial Interests, Personal, Advisory Board: Gentem Health, Softhread; Financial Interests, Personal, Full or part-time Employment: AMIT; Financial Interests, Personal, Ownership Interest: AMIT, Gentem Health, Softhread; Financial Interests, Personal, Principal Investigator: AMIT; Financial Interests, Institutional, Proprietary Information: AMIT; Financial Interests, Institutional, Sponsor/Funding: AMIT. All other authors have declared no conflicts of interest.