RYZ101 for Neuroendocrine Tumors

(ACTION-1 Trial)

Recruiting at108 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: RayzeBio, Inc.

Must not be taking: High-dose glucocorticoids

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

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial tests RYZ101, a new drug, in patients with advanced GEP-NETs that haven't responded to previous treatments. The drug aims to target specific receptors on the tumor cells to stop their growth.

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.

What data supports the effectiveness of the treatment RYZ101, 225Ac-DOTATATE, for neuroendocrine tumors?

Research shows that similar treatments like 177Lu-DOTATATE and 90Y-DOTATATE have been effective in reducing tumor size in patients with neuroendocrine tumors. Additionally, combining peptide receptor radionuclide therapy (PRRT) with immune therapy has shown improved outcomes, suggesting that RYZ101, which is a type of PRRT, may also be effective. ^{1 2 3 4 5}

What safety data is available for RYZ101 (225Ac-DOTATATE) in humans?

The study on [225Ac]Ac-DOTATATE therapy for neuroendocrine tumors aimed to evaluate its safety, indicating that safety data has been collected for this treatment in humans. ^{1 2 3 5 6}

How is the drug RYZ101 different from other treatments for neuroendocrine tumors?

RYZ101, also known as 225Ac-DOTATATE, is unique because it uses a radioactive element, Actinium-225, to target and destroy cancer cells in neuroendocrine tumors. This approach is different from other treatments that use different radioactive elements like Yttrium-90 or Lutetium-177, potentially offering a new option for patients whose tumors express somatostatin receptors. ^{4 7 8 9 10}

Research Team

Denis Ferreira, MD

Principal Investigator

RayzeBio Sr. Medical Director

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• RYZ101 (Virus Therapy)

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.

Participant Groups

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+

Findings from Research

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]

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 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 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]

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]

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 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]

References

1. Turkey pubmed.ncbi.nlm.nih.gov

Initial Findings on the Use of [225Ac]Ac-DOTATATE Therapy as a Theranostic Application in Patients with Neuroendocrine Tumors. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Addition of Peptide Receptor Radiotherapy to Immune Checkpoint Inhibition Therapy Improves Outcomes in Neuroendocrine Tumors. [2023]

3. Australia 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. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Long-term efficacy of (90)Y-DOTATATE in patients with nonresectable pancreatic and small bowel neuroendocrine neoplasms. [2017]

5. Japan 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. [2022]

6. Germany pubmed.ncbi.nlm.nih.gov

177Lu-DOTATATE in older patients with metastatic neuroendocrine tumours: safety, efficacy and health-related quality of life. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Upregulation of Somatostatin Receptor Type 2 Improves 177Lu-DOTATATE Therapy in Receptor-Deficient Pancreatic Neuroendocrine Tumor Model. [2023]

8. United States 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. [2022]

9. Germany pubmed.ncbi.nlm.nih.gov

[Radionuclide therapy of endocrine-related cancer]. [2021]

10. England 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. [2022]