RYZ101 for Neuroendocrine Tumors

(ACTION-1 Trial)

Recruiting at 115 trial locations

Overseen By RayzeBio Clinical Trials

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: RayzeBio, Inc.

Must not be taking: High-dose glucocorticoids

Disqualifiers: Cardiovascular disease, Resistant hypertension, Uncontrolled diabetes, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

288 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called RYZ101 (also known as 225Ac-DOTATATE) for individuals with advanced neuroendocrine tumors that cannot be surgically removed. The trial aims to determine if RYZ101 is safe and effective compared to standard treatments for tumors that have continued to grow despite previous therapy. Suitable candidates have tumors related to the stomach or pancreas that have worsened even after specific radiation therapy. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants access to a potentially groundbreaking treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on high-dose glucocorticoids (a type of steroid), you must stop them 14 days before starting the study treatment.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that RYZ101 was well-tolerated in earlier studies. One study found that a dose of 10.2 MBq of RYZ101 was safe for further testing, with no major side effects reported at this dose. This finding is encouraging for those considering participation in a trial with RYZ101, as it suggests the treatment is safe for more testing in future trials. However, long-term safety information is still being collected, and more details will become available as additional studies are completed. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about RYZ101 for neuroendocrine tumors because it employs a novel approach using a radiolabeled somatostatin analog (SSA). Unlike standard treatments like everolimus, sunitinib, octreotide, or lanreotide, RYZ101 is linked with Actinium-225, which delivers targeted radiation directly to the tumor cells. This targeted approach could potentially minimize damage to surrounding healthy tissues while effectively attacking the tumor, offering a promising new avenue for treatment.

What evidence suggests that RYZ101 might be an effective treatment for neuroendocrine tumors?

Research has shown that RYZ101, which participants in this trial may receive, may help treat neuroendocrine tumors. Early lab studies demonstrated that RYZ101 slowed tumor growth, particularly in tumors with more somatostatin receptors. Initial human studies found that some patients' cancer did not worsen. Research on a similar treatment, 225Ac-DOTATATE, showed that it helped patients with neuroendocrine tumors live longer. These findings suggest that RYZ101 could be effective for patients whose tumors have continued to grow after other treatments. ^{6 7 8 9 10}

Who Is on the Research Team?

Ye Yuan, MD

Principal Investigator

RayzeBio Sr. Medical Director

Are You a Good Fit for This Trial?

This trial is for adults with advanced, inoperable GEP-NETs that express somatostatin receptors and have progressed after treatment with 177Lu-SSA therapy. Participants must have a life expectancy of at least 12 weeks, stable symptoms controlled by SSAs, adequate kidney and blood function, and agree to use effective contraception.

Inclusion Criteria

My tumor is a low to intermediate grade and cannot be removed by surgery.

I am a man who will use protection and avoid fathering a child while on the study drug and for 3 months after.

My kidneys are working well.

Exclusion Criteria

I haven't taken high-dose steroids for my condition in the last 14 days.

I haven't had cancer, except for specific types, in the last 3 years.

I do not have serious heart disease, uncontrollable high blood pressure, or diabetes.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1b Treatment

Uncontrolled dose de-escalation study to confirm the safety and determine the RP3D of RYZ101

8 weeks

Multiple visits for dose administration and monitoring

Phase 3 Treatment

Comparison of RYZ101 with investigator-selected standard of care therapy

Up to 80 months

Regular visits for treatment and assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 80 months

What Are the Treatments Tested in This Trial?

Interventions

• RYZ101

Trial Overview The study tests RYZ101's safety and dosage compared to standard care therapies like Everolimus or Sunitinib in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). It has two parts: determining the safe dose of RYZ101 and comparing its effectiveness against other treatments.

How Is the Trial Designed?

Group I: Phase 1b - RYZ101 Experimental Treatment 1 Intervention

Part 1 is an uncontrolled dose de-escalation study to confirm the safety and determine the RP3D of RYZ101 based on Bayesian optimal interval design.

Group II: Phase 3 - Standard of Care Active Control 4 Interventions

Investigator's choice of standard of care between everolimus, sunitinib, octreotide, or lanreotide.

Group III: Phase 3 - RYZ101 Active Control 1 Intervention

Actinium 225 radiolabeled somatostatin analog (SSA) for injection

Who Is Running the Clinical Trial?

RayzeBio, Inc.

Lead Sponsor

Trials

6

Recruited

540+

Published Research Related to This Trial

In a study of 60 patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs), DOTATATE Y-90 therapy demonstrated a clinical partial response in 72% of patients and a median progression-free survival of 17 months, indicating its effectiveness in managing this type of cancer.

While DOTATATE Y-90 therapy was generally safe, with a low risk of myelotoxicity, there were cases of renal toxicity in 8% of patients, highlighting the need for careful kidney monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of radionuclide treatment DOTATATE Y-90 in patients with progressive metastatic gastroenteropancreatic neuroendocrine carcinomas (GEP-NETs): a phase II study. Cwikla, JB., Sankowski, A., Seklecka, N., et al.[2022]

In a study of 11 patients with grade 1/2 metastatic neuroendocrine tumors treated with [225Ac]Ac-DOTATATE, the therapy demonstrated a high disease control rate of 89%, with 44.4% of patients showing a partial response and 44.4% having stable disease.

The treatment was found to be stable and safe, with only mild toxicities reported (grade 2 renal and hematotoxicity), and a median progression-free survival of 12 months, indicating its potential effectiveness for patients who were refractory to previous treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Initial Findings on the Use of [225Ac]Ac-DOTATATE Therapy as a Theranostic Application in Patients with Neuroendocrine Tumors. Demirci, E., Alan Selçuk, N., Beydağı, G., et al.[2023]

Radioiodine therapy remains the gold standard for treating differentiated thyroid cancer, achieving near-total remission in about 50% of patients with bone and lung metastases and a 15-year survival rate of approximately 90%.

Emerging therapies like somatostatin receptor-targeted radionuclide treatments show promising results, with progression-free survival of 24-36 months in phase 2 trials, and ongoing phase 3 trials are evaluating their efficacy in specific neuroendocrine tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Radionuclide therapy of endocrine-related cancer]. Kratochwil, C., Giesel, FL.[2021]

In a phase 1/2 study involving 15 Japanese patients with advanced neuroendocrine tumors, 177 Lu-DOTATATE treatment resulted in a 53% objective response rate, indicating significant tumor shrinkage.

The treatment was well-tolerated, with absorbed radiation doses to the kidneys and bone marrow remaining within safe limits, although some patients experienced Grade 3 adverse events like lymphopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and response after peptide receptor radionuclide therapy with 177 Lu-DOTATATE for neuroendocrine tumors in phase 1/2 prospective Japanese trial. Kudo, A., Tateishi, U., Yoshimura, R., et al.[2022]

In a phase II trial involving 1,109 patients with neuroendocrine cancers, treatment with the somatostatin-based radiopeptide [(90)Y-DOTA]-TOC resulted in significant responses, with 34.1% showing morphologic response and 15.5% biochemical response, correlating with longer survival rates.

While [(90)Y-DOTA]-TOC was effective, 12.8% of patients experienced severe hematologic toxicities and 9.2% faced serious renal toxicity, indicating the need for careful monitoring of kidney function during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers. Imhof, A., Brunner, P., Marincek, N., et al.[2022]

In patients with high-grade pancreatic neuroendocrine tumors (PNET), SSTR2 expression is decreased due to promoter methylation, which limits the effectiveness of targeted therapies like 177Lu-DOTATATE.

Using histone deacetylase inhibitors (HDACi) to reverse this methylation can restore SSTR2 expression, leading to significantly improved tumor uptake of 177Lu-DOTATATE and enhanced antitumor responses in preclinical models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Upregulation of Somatostatin Receptor Type 2 Improves 177Lu-DOTATATE Therapy in Receptor-Deficient Pancreatic Neuroendocrine Tumor Model. Sharma, R., Earla, B., Baidoo, KE., et al.[2023]

In a study of 56 patients with advanced neuroendocrine tumors treated with (177)Lu-DOTATOC, the median progression-free survival was 17.4 months and overall survival was 34.2 months, indicating significant efficacy in managing these tumors.

The treatment demonstrated a favorable safety profile, with no serious adverse events reported and only one case of mild myelotoxicity, suggesting it is safe even for patients with pre-existing renal issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[(177)Lu-DOTA](0)-D-Phe(1)-Tyr(3)-Octreotide ((177)Lu-DOTATOC) For Peptide Receptor Radiotherapy in Patients with Advanced Neuroendocrine Tumours: A Phase-II Study. Baum, RP., Kluge, AW., Kulkarni, H., et al.[2022]

In a study of 71 patients aged 70 and older with advanced neuroendocrine tumors treated with 177Lu-DOTATATE, the treatment showed a median progression-free survival of 36 months and overall survival of 47 months, indicating its efficacy in this age group.

The treatment was well-tolerated, with only 2.8% experiencing significant myelosuppression, and there was no decline in health-related quality of life, suggesting that 177Lu-DOTATATE is a safe option for older patients with advanced NET.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

177Lu-DOTATATE in older patients with metastatic neuroendocrine tumours: safety, efficacy and health-related quality of life. Chen, L., Navalkissoor, S., Quigley, AM., et al.[2021]

Combining peptide receptor radionuclide therapy (PRRT) with anti-PD1 immunotherapy significantly enhances treatment response in neuroendocrine tumors (NETs), with the most effective approach being to administer PRRT before anti-PD1 therapy.

In a study involving 96 mice with human NET cells, the early PRRT regimen led to the greatest reduction in tumor size and increased T-cell activation, indicating a robust inflammatory response compared to other treatment combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of Peptide Receptor Radiotherapy to Immune Checkpoint Inhibition Therapy Improves Outcomes in Neuroendocrine Tumors. Esfahani, SA., De Aguiar Ferreira, C., Summer, P., et al.[2023]

In a study of 67 patients with pancreatic and small bowel neuroendocrine tumors, treatment with (90)Y-DOTATATE resulted in a median progression-free survival of 25 months for pancreatic NETs and 28 months for small bowel NETs, indicating its effectiveness in managing these tumors.

The median overall survival was 42 months for pancreatic NETs and 38.5 months for small bowel NETs, with no significant differences in survival outcomes based on tumor type, suggesting that (90)Y-DOTATATE may be equally effective for both types of NETs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term efficacy of (90)Y-DOTATATE in patients with nonresectable pancreatic and small bowel neuroendocrine neoplasms. Rogowski, W., Wachuła, E., Lewczuk, A., et al.[2017]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37616528/

Preclinical Efficacy in Small-Cell Lung Cancer RYZ101 is a highly potent, alpha-emitting radiopharmaceutical agent, and preclinical data demonstrate the potential of RYZ101 for the treatment of patients ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.3091

Phase Ib portion of the ACTION-1 phase Ib/3 trial ... 8 patients (47.1%) had stable disease and 3 patients (17.6%) had progressive disease. Updated safety and efficacy data, including duration of ...

3. aacrjournals.org aacrjournals.org/mct/article/22/12/1434/730266/RYZ101-Ac-225-DOTATATE-Opportunity-beyond

RYZ101 (Ac-225 DOTATATE) Opportunity beyond ... In multiple SSTR2-positive xenograft models, RYZ101 significantly inhibited tumor growth with greater responses observed in tumors with higher SSTR2 expression ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0001299825000728

Advances With 225Ac-DOTATATE Targeted Alpha Therapy ... In preclinical models, two doses of approximately 30 kBq administered 10 days apart led to 100% survival, with complete tumor remission rates of 80% in the NCI- ...

5. jnm.snmjournals.org jnm.snmjournals.org/content/64/2/211

Survival Outcomes in Metastatic Gastroenteropancreatic ... Our results provide further evidence that 225Ac-DOTATATE is effective in patients with neuroendocrine tumors, a group with few therapeutic ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.4_suppl.661

Phase 1b portion of the ACTION-1 phase 1b/3 trial ... Conclusions: RYZ101 was well tolerated, and a fixed dose of 10.2 MBq was declared the recommended phase 3 dose. Initial data suggest promising ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1556086424012528

P1.13A.09 RYZ101 (225Ac-DOTATATE) + Carboplatin + ... Here we describe preliminary safety data from a single-arm, open-label, phase 1b dose-escalation and dose-expansion trial of RYZ101 in combination with standard ...

8. annalsofoncology.org annalsofoncology.org/article/S0923-7534(23)01567-3/fulltext

1198P Phase Ib portion of the ACTION-1 phase Ib/3 trial ... RYZ101 (225Ac-DOTATATE) is an alpha-emitting radiopharmaceutical in development for SSTR2+ solid tumors. Alpha-particles have a shorter path length/higher ...

9. rayzebio.com rayzebio.com/wp-content/uploads/2023/06/Strosberg-ACTION-1-ASCO-2023-poster-UPLOAD2.pdf

ACTION-1 phase Ib/3 trial of RYZ101 in somatostatin ... As the data do not suggest an influence of body mass with exposure levels or safety findings, the dose to be used in the Phase 3 study is a flat ...

10. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40162745/

Alpha radioligand therapy in neuroendocrine neoplasms While long-term safety and efficacy data are awaited, alpha RLT agents such as RYZ101 offer a unique opportunity to enhance the therapeutic promise of RLT in ...