ACTION-1 is investigating RYZ101 versus standard-of-care therapy in patients with SSTR-positive gastroenteropancreatic neuroendocrine tumors after 177Lu-SSA therapy.
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The first of 210 patients with an SSTR-positive gastroenteropancreatic neuroendocrine tumor (GEP-NET), has been dosed with the novel targeted radiopharmaceutical, RYZ101, in the phase 1/b/3 ACTION-1 study (NCT05477576).1
RYZ101, a first-in-class, highly potent, α-emitting radiopharmaceutical therapy, is currently being developed for the treatment of SSTR-positive solid tumors, including GEP-NETs, and small cell lung cancer (SCLC). In a preclinical study of SCLC xenograft models, RYZ101 achieved significant reductions in tumor growth and extended survival. The agent also demonstrated the ability to elicit deeper responses in models with a higher SSTR2 level.2
“Patients with GEP-NETs have very limited options upon progression after Lutetium-177 labelled somatostatin analogue therapy,” said Thomas Hope, MD, vice chair, Clinical Operations and Strategy in the Department of Radiology, University of California, San Francisco, in a press release. “With existing results using Actinium-225 DOTATATE suggesting clinical benefit, we are excited to be moving this therapy forward in the ACTION-1 study.”
Trial Name: Phase 1b/3 Global, Randomized, Controlled, Open-label Trial Comparing Treatment With RYZ101 to Standard of Care Therapy in Subjects With Inoperable, Advanced, SSTR+, Well-differentiated GEP-NETs That Have Progressed Following Prior 177Lu-SSA Therapy
ClinicalTrials.gov Identifier: NCT05477576
Sponsor: RayzeBio, Inc.
Recruitment Contact: RayzeBio Clinical Trials, +1 619 657 0057, clinicaltrials@rayzebio.com
Completion Date: July 2028
ACTION-1, is a global, randomized, controlled, open-label trial aiming to determine how RYZ101 compares with standard-of-care (SoC) for the inoperable, advanced, SSTR-positive, well-differentiated GEP-NET population. Those enrolled in the study will be randomized 1:1 to receive RYZ101 or 1 of the SoC therapies; everolimus (Afinitor), sunitinib (Sutent), octreotide (Sandostatin), or lanreotide (Somatuline).
During part 1, the uncontrolled dose de-escalation phase, investigators will confirm the safety and determine the recommended phase 3 dose of RYZ101 by following a Bayesian optimal interval design. Patients enrolled into the experimental arm will be in cohort of 6, receiving up to 4 infusions of the investigational agent, every 8 weeks. Treatment with RYZ101 will be de-escalated if the initial dose is not tolerated. Investigators will assess up 3 dose levels of the drug.
In the comparator arm patients will receive either an oral everolimus 10 mg-dose, daily or oral sunitinib at 37.5 mg daily, high-dose octreotide LAR 60 mg every 4 weeks by injection, or lanreotide at a high-dose frequency of 120 mg given every 2 weeks by injection.
Patients eligible for enrollment in the study are those with histologically confirmed grade 1/2 well-differentiated, inoperable, advanced GEP-NETs, an ECOG performance status of 0 to 2, life expectancy of 12 weeks or longer, a PET scan showing SSTR positivity, and adequate renal function, hematologic function, and laboratory results at baseline. Patients cannot be pregnant and must use contraception during the study.
Those with GEP-NETs who have hypersensitivity to 225Actinium, 68Gallium, 64Copper, octreotate, or any of the excipients of DOTATATE imaging agents are not eligible for enrollment in ACTION-1. The study also excludes patients who received prior treatment with alkylating agents, radioembolization, surgery, chemoembolization, or radiofrequency ablation within 12 weeks of dosing in the study, and anti-cancer agents too close to dosing in the study. In addition, patients with hypertension, and other conditions that may interfere with treatment are excluded from the study.
The study is recruiting patients who meet the enrollment criteria at study sites in California, Maryland, and Nebraska. Additional study sites will be in Texas, Utah, and Florida, but have not yet begun recruiting patients.
“We are very encouraged by the continued interest in and potential of RYZ101. I look forward to working with the GEP-NET community to advance RYZ101 in this important therapeutic indication. RYZ101 was well tolerated in the phase 1b trial, and we look forward to providing updates on efficacy from the Phase 1b trial even as we continue to enroll patients in the phase 3 trial,” said Susan Moran, MD, MSCE, chief medical officer, RayzeBio, in a press release.
REFERENCES:
1. RayzeBio announces first patient dosed in phase 3 ACTION-1 Study, evaluating RYZ101 (Actinium-225 DOTATATE) in neuroendocrine tumors. News release. May 31, 2023. Accessed May 31, 2023. https://tinyurl.com/57j9m8ue
2. Han G, Hwang E, Lin F, et al. Abstract 5042: Anti-tumor activity of RYZ101 (Ac-225 DOTATATE) in somatostatin receptor-expressing preclinical models of small-cell lung cancer. Cancer Res. 2023; 83 (suppl 7): 5042. doi: 10.1158/1538-7445.AM2023-5042
3. Study of RYZ101 compared with soc in pts with inoperable sstr+ well-differentiated GEP-NET that has progressed following 177Lu-SSA therapy (ACTION-1). ClincialTrials.gov. Updated May 26, 203. Accessed June 2, 2023. https://clinicaltrials.gov/ct2/show/NCT05477576
