ACTION-1 phase Ib/3 trial of RYZ101 in gastroenteropancreatic neuroendocrine tumors progressing after 177Lu somatostatin analogue therapy: phase 1b safety/efficacy

Daniel Halperin; Michael Morris; Gary A. Ulaner; Jonathan Strosberg; Samuel Mehr; Daneng Li; Heloisa Soares; Matt Covington; Lowell Anthony; Sandy Kotiah; Heather Jacene; Tesselaar Margot E.T.; Pamela L. Kunz; Denis Ferreira; Joanne Li; Kimberly Ma; Jessica Rearden; Susan Moran; Thomas Hope; Simron Singh

doi:10.1530/endoabs.108.C17

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Endocrine Abstracts (2024) 108 C17 | DOI: 10.1530/endoabs.108.C17

NANETS2024 17th Annual Multidisciplinary NET Medical Symposium NANETS 2024 Clinical - Chemo/SSA/Biologics (19 abstracts)

ACTION-1 phase Ib/3 trial of RYZ101 in gastroenteropancreatic neuroendocrine tumors progressing after 177Lu somatostatin analogue therapy: phase 1b safety/efficacy

Daniel Halperin ¹ , Michael Morris ² , Gary A. Ulaner ³ , Jonathan Strosberg ⁴ , Samuel Mehr ⁵ , Daneng Li ⁶ , Heloisa Soares ⁷ , Matt Covington ⁷ , Lowell Anthony ⁸ , Sandy Kotiah ⁹ , Heather Jacene ¹⁰ , Margot E.T. Tesselaar ¹¹ , Pamela L. Kunz ¹² , Denis Ferreira ¹³ , Joanne Li ¹³ , Kimberly Ma ¹³ , Jessica Rearden ¹³ , Susan Moran ¹³ , Thomas Hope ¹⁴ & Simron Singh ¹⁵

Author affiliations

¹MD Anderson Cancer Center, Houston, TX; ²Advanced Molecular Imaging and Therapy, Glen Burnie, MD; ³Hoag Family Cancer Institute, Newport Beach, CA; University of Southern California, Los Angeles, CA; ⁴Moffitt Cancer Center, Tampa, FL; ⁵Nebraska Cancer Specialists, Omaha, NE; ⁶City of Hope Comprehensive Cancer Center, Duarte, CA; ⁷Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; ⁸University of Kentucky Markey Cancer Center, Lexington, KY; ⁹Mercy Medical Center, Baltimore, MD; ¹⁰Dana Farber Cancer Institute, Boston, MA; ¹¹Netherlands Cancer Institute, Amsterdam, The Netherlands; ¹²Yale University, New Haven, CT; ¹³RayzeBio, San Diego, CA; ¹⁴University of California San Francisco, CA; ¹⁵University of Toronto, Odette Cancer Center at Sunnybrook Health Sciences Center, Toronto, ON, Canada

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+ gastroenteropancreatic neuroendocrine tumors (GEP-NETs) progressing after ¹⁷⁷Lu somatostatin analogue (SSA) therapy. Herein, we report updated results from the phase Ib portion of the trial.

Methods: The phase Ib portion of the 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. DLT was assessed for 56 days 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 patients have received at least one dose of RYZ101 at 120 kBq/kg (4 doses: 15 patients; 2 doses: 2 patients; median 8.3 MBq). Baseline 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 30 June 2023, the most frequent TEAEs were nausea (58.8%) and fatigue (52.9%). Serious adverse events (SAEs) were observed in 6 patients (none were treatment related); grade ≥3 AEs occurred in 9 patients (5 were treatment related). No AEs led to treatment discontinuation. 4 patients had TEAEs leading to dose modification, dose hold, and/or delays. The confirmed objective response rate was 29.4% (n = 5; all partial responses); 1 patient had an unconfirmed partial response. 8 patients (47.1%) had stable disease and 3 patients (17.6%) had progressive disease. Updated safety and efficacy data, including duration of response and progression-free survival, will be presented.

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. Longer-term safety and efficacy data will be presented. Part 2 (phase 3) 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 following prior ¹⁷⁷Lu-labeled SSAs.

ABSTRACT ID28436