Study of RYZ101 Compared With SOC in Pts w Inoperable SSTR+ Well-differentiated GEP-NET That Has Progressed Following 177Lu-SSA Therapy (ACTION-1)

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

This study aims to determine the safety, pharmacokinetics (PK) and recommended Phase 3 dose (RP3D) of RYZ101 in Part 1, and the safety, efficacy, and PK of RYZ101 compared with investigator-selected standard of care (SoC) therapy in Part 2 in subjects with inoperable, advanced, well-differentiated, somatostatin receptor expressing (SSTR+) gastroenteropancreatic neuroendocrine tumors (GEP-NETs) that have progressed following treatment with Lutetium 177-labelled somatostatin analogue (177Lu-SSA) therapy, such as 177Lu-DOTATATE or 177Lu-DOTATOC (177Lu-DOTATATE/TOC), or 177Lu-high affinity [HA]-DOTATATE.

Study Overview

• Status: Recruiting
• Conditions: Neuroendocrine Tumors; Carcinoid Tumor; Gastroenteropancreatic Neuroendocrine Tumor; Carcinoid; GEP-NET; Gastroenteropancreatic Neuroendocrine Tumor Disease; Pancreatic NET
• Intervention / Treatment: Drug: Everolimus; Drug: RYZ101; Drug: Sunitinib; Drug: Octreotide; Drug: Lanreotide

• Study Type: Interventional
• Enrollment (Estimated): 338
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: RayzeBio Clinical Trials; Phone Number: +1 619 657 0057; Email: clinicaltrials@rayzebio.com

Study Locations

• Belgium
  • Brussels, Belgium
    • Recruiting
    • Research Facility
    • Contact: Site Contact
  • Leuven, Belgium
    • Active, not recruiting
    • Research Facility
  • Roeselare, Belgium
    • Active, not recruiting
    • Research Facility
• Brazil
  • Brasília, Brazil
    • Active, not recruiting
    • Research Facility
  • Rio de Janeiro, Brazil
    • Completed
    • Research Facility
  • São Paulo, Brazil
    • Active, not recruiting
    • Research Facility
• Canada
  • Ontario
    • London, Ontario, Canada
      • Active, not recruiting
      • Research Facility
    • Toronto, Ontario, Canada, M4N 3M5
      • Active, not recruiting
      • Research Facility
  • Quebec
    • Montreal, Quebec, Canada
      • Active, not recruiting
      • Research Facility
• France
  • Clichy, France
    • Recruiting
    • Research Facility
    • Contact: Site Contact
  • Lille, France
    • Recruiting
    • Research Facility
    • Contact: Site Contact
  • Montpellier, France
    • Active, not recruiting
    • Research Facility
  • Nantes, France
    • Active, not recruiting
    • Research Facility
  • Vandœuvre-lès-Nancy, France
    • Recruiting
    • Research Facility
    • Contact: Site Contact
  • Villejuif, France
    • Active, not recruiting
    • Research Facility
• Netherlands
  • Amsterdam, Netherlands
    • Recruiting
    • Research Facility
    • Contact: Site Contact
  • Maastricht, Netherlands
    • Active, not recruiting
    • Research Facility
  • Utrecht, Netherlands
    • Recruiting
    • Research Facility
    • Contact: Site Contact
• South Korea
  • Seoul, South Korea
    • Active, not recruiting
    • Research Facility
• Spain
  • Barcelona, Spain
    • Recruiting
    • Research Facility
    • Contact: Site Contact
  • Madrid, Spain
    • Recruiting
    • Research Facility
    • Contact: Site Contact
  • Zaragoza, Spain
    • Completed
    • Research Facility
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Active, not recruiting
      • Research Facility
  • California
    • Duarte, California, United States, 91010
      • Completed
      • Research Facility
    • Irvine, California, United States, 92663
      • Recruiting
      • Research Facility
      • Contact: Site Contact
    • Los Angeles, California, United States, 90095
      • Active, not recruiting
      • Research Facility
    • Palo Alto, California, United States, 94305
      • Active, not recruiting
      • Research Facility
    • San Francisco, California, United States, 94143
      • Active, not recruiting
      • Research Facility
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Active, not recruiting
      • Research Facility
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20010
      • Active, not recruiting
      • Research Facility
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Active, not recruiting
      • Research Facility
    • Miami, Florida, United States, 33165
      • Recruiting
      • Research Facility
      • Contact: Site Contact
    • Tampa, Florida, United States, 33607
      • Recruiting
      • Research Facility
      • Contact: Site Contact
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Active, not recruiting
      • Research Facility
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Recruiting
      • Research Facility
      • Contact: Site Contact
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • Recruiting
      • Research Facility
      • Contact: Site Contact
  • Maryland
    • Glen Burnie, Maryland, United States, 21061
      • Recruiting
      • Research Facility
      • Contact: Site Contact
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Active, not recruiting
      • Research Facility
    • Boston, Massachusetts, United States, 02118
      • Active, not recruiting
      • Research Facility
  • Michigan
    • Troy, Michigan, United States, 48098
      • Completed
      • Research Facility
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Active, not recruiting
      • Research Facility
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Recruiting
      • Research Facility
      • Contact: Site Contact
  • Nebraska
    • Omaha, Nebraska, United States, 68130
      • Recruiting
      • Research Facility
      • Contact: Site Contact
  • New York
    • New York, New York, United States, 10065
      • Recruiting
      • Research Facility
      • Contact: Site Contact
    • New York, New York, United States, 10029
      • Active, not recruiting
      • Research Facility
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Active, not recruiting
      • Research Facility
    • Columbus, Ohio, United States, 43221
      • Recruiting
      • Research Facility
      • Contact: Site Contact
  • Oregon
    • Portland, Oregon, United States, 97239
      • Active, not recruiting
      • Research Facility
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Active, not recruiting
      • Research Facility
    • Pittsburgh, Pennsylvania, United States, 15232
      • Recruiting
      • Research Facility
      • Contact: Site Contact
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Active, not recruiting
      • Research Facility
  • Texas
    • Houston, Texas, United States, 77030
      • Active, not recruiting
      • Research Facility
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Recruiting
      • Research Facility
      • Contact: Site Contact
  • Washington
    • Seattle, Washington, United States, 98109
      • Recruiting
      • Research Facility
      • Contact: Site Contact

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion:

• Histologically proven, Grade 1-2 well differentiated, inoperable, advanced GEP-NETs (Ki67 ≤20%) Eastern Cooperative Oncology Group (ECOG) status 0-2. Ki67% <20% is not required for the ad hoc subcohort of the PK/ECG substudy.
• Progressive, SSTR-PET positive (i.e., Krenning score 3 or 4) GEP-NET (GI or pancreas) following 2-4 cycles of treatment with 177Lu-labeled SSA. Must have achieved disease control for at least 6 months following Lu-177 SSA (archival tissue is not required for the ad hoc subcohort of the PK/ECG substudy). No time limit is defined between 177Lu-SSA treatment and randomization. There must be at least 1 SSTR-PET imaging-positive measurable site of disease (according to RECIST v1.1) and no RECIST v1.1 measurable metastatic lesions that are SSTR imaging-negative.
• Adequate renal function, as evidenced by estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 (calculated using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) (Levey et al. 2009)
• Adequate hematologic function, defined by the following laboratory results:
• Part 2: Hemoglobin concentration ≥5.0 mmol/L (≥8.0 g/dL); ANC ≥1000 cells/µL (≥1000 cells/mm3); platelets ≥75 x 109/L (75 x 103/mm3).
• Total bilirubin ≤3 x upper limit normal (ULN)
• Serum albumin ≥3.0 g/dL unless prothrombin time is within the normal range

Exclusion:

• Prior radioembolization
• Significant cardiovascular disease, such as New York Heart Association (NYHA) Class ≥II heart failure, left ventricular ejection fraction (LVEF) <40% or QT interval corrected for heart rate using Fridericia's formula (QTcF) >450 ms for males and >470 ms for females.
• Resistant hypertension, defined as uncontrolled blood pressure (BP) >140/90 mmHg while on optimal doses of at least 3 antihypertensive medications with 1 being a diuretic (Whelton et al. 2018)
• Uncontrolled diabetes mellitus as defined by hemoglobin A1C (HgB A1C) ≥8%
• PRRT other than Lu-177 SSA (not applicable for ad hoc subcohort of the PK/ECG substudy)
• Any condition requiring systemic treatment with high-dose glucocorticoids within 14 days prior to first dose of study treatment and/or which cannot be stopped while on study. Inhaled or topical steroids are permitted.
• Prior history of liver cirrhosis or liver transplantation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Phase 3 - RYZ101; Actinium 225 radiolabeled somatostatin analog (SSA) for injection	Drug: RYZ101; RP3D as determined in Phase 1b
Active Comparator: Phase 3 - Standard of Care; Investigator's choice of standard of care between everolimus, sunitinib, octreotide, or lanreotide.	Drug: Everolimus; Everolimus; Drug: Sunitinib; Sunitinib; Drug: Octreotide; High-dose octreotide; Drug: Lanreotide; Lanreotide
Experimental: Phase 1b - RYZ101; 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.	Drug: RYZ101; RP3D as determined in Phase 1b
Active Comparator: Phase 3 - RYZ101, PK/ECG Substudy adhoc subcohort; Actinium 225 radiolabeled somatostatin analog (SSA) for injection	Drug: RYZ101; RP3D as determined in Phase 1b

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1b: RP3D	Incidence of DLTs during the first 56 days of study treatment will be assessed.	56 days of study treatment
Phase 3: PFS as determined by BICR	PFS will be defined as the time from the date of randomization until the date of progression (as determined by BICR from tumor assessments using RECIST v1.1) or death due to any cause, whichever occurs earlier.	After the target number of 143 PFS events have occurred

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1b: Cmax		Up to Day 8
Phase 1b: Tmax		Up to Day 8
Phase 1b: AUC		Up to Day 8
Phase 1b: Volume of Distribution		Up to Day 8
Phase 1b: Clearance		Up to Day 8
Phase 1b: Terminal Half-life		Up to Day 8
Phase 1b: TIAC of RYZ101 to critical organs and tumors	Calculated mean TIAC (hours) and absorbed radiation dose coefficients (mGy/MBq) to critical organs (e.g., the kidneys and bone marrow) and tumors after the 1st and 4th RYZ101 infusions will be assessed	Up to Day 184
Phase 1b: Absorbed radiation doses of RYZ101 to critical organs and tumors	Calculated mean TIAC (hours) and absorbed radiation dose coefficients (mGy/MBq) to critical organs (e.g., the kidneys and bone marrow) and tumors after the 1st and 4th RYZ101 infusions will be assessed	Up to Day 184
Phase 3: OS	OS will be defined as the time from the date of randomization until the date of death due to any cause.	Up to 80 months or until a total of 130 deaths have occurred, whichever occurs first
Phase 3: ORR by BICR	ORR, as determined by BICR according to RECIST v1.1.	Up to 80 months
Phase 3: PFS	PFS as determined by Investigator	Up to 80 months
Phase 3: ORR by Inv	ORR, as assessed by the Investigator according to RECIST v1.1	Up to 80 months
Phase 3: BOR	Assessed by BICR and by the Investigator according to RECIST v1.1	Up to 80 months
Phase 3: Disease Control Rate	Assessed by BICR and by the Investigator according to RECIST v1.1	Up to 80 months
Phase 3: DoR	Only for subjects with a RECIST v.1.1 response, assessed by BICR and by the Investigator according to RECIST v1.1	Up to 80 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1b and 3: Incidence and severity of AEs by NCI CTCAE v5, including SAEs, laboratory changes, ECG changes, and other safety findings	Incidence and severity of AEs by NCI CTCAE v5, including SAEs, laboratory changes, ECG changes, and other safety findings	Up to 80 months
Phase 3: Cmax		Up to 80 months
Phase 3: AUC		Up to 80 months
Phase 3: Average Concentration		Up to 80 months
Phase 3: Relationship between exposure endpoints and clinical outcomes		Up to 80 months
Phase 3: Relationship between biomarkers including but not limited to CgA in the serum and (5-HIAA) in the urine, with AEs of special interest and/or efficacy endpoints (e.g., PFS, OS, BOR, DoR)	Relationship between biomarkers, including but not limited to CgA in the serum and (5-HIAA) in the urine, with AEs of special interest and/or efficacy endpoints (e.g., PFS, OS, BOR, DoR)	Up to 80 months
Phase 3: Changes in EQ-5D-5L questionnaire scores		Up to 80 months
Phase 3: Changes in EORTC QLQ-C30 questionnaire scores		Up to 80 months
Phase 3: Changes in EORTC QLQ GI NET21 questionnaire scores		Up to 80 months
Phase 3: QTc	Measured by continuous ECG recording using a 12-lead Holter monitoring device	Up to 80 months

Collaborators and Investigators

• Sponsor: RayzeBio, Inc.
• Investigators: Study Director: Ye Yuan, MD, RayzeBio Sr. Medical Director

Publications and helpful links

General Publications

• Taunk NK, Escorcia FE, Lewis JS, Bodei L. Radiopharmaceuticals for Cancer Diagnosis and Therapy: New Targets, New Therapies-Alpha-Emitters, Novel Targets. Cancer J. 2024 May-Jun 01;30(3):218-223. doi: 10.1097/PPO.0000000000000720.

Study record dates

Study Major Dates

• Study Start (Actual): March 24, 2022
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2030

Study Registration Dates

• First Submitted: July 20, 2022
• First Submitted That Met QC Criteria: July 25, 2022
• First Posted (Actual): July 28, 2022

Study Record Updates

• Last Update Posted (Actual): March 30, 2026
• Last Update Submitted That Met QC Criteria: March 27, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: sunitinib; Everolimus; octreotide; Neuroendocrine Tumors; PRRT; lanreotide; GEP-NET; SSTR+; targeted radiotherapy; Gastroenteropancreatic Neuroendocrine Tumor; RayzeBio; Actinium; Ac 225; Dotatate; alpha emitter
• Additional Relevant MeSH Terms: Endocrine System Diseases; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Adenoma; Carcinoma; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Pancreatic Neoplasms; Neuroendocrine Tumors; Adenoma, Islet Cell; Carcinoid Tumor; Gastro-enteropancreatic neuroendocrine tumor; Peptides; Amino Acids, Peptides, and Proteins; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Azoles; Polycyclic Compounds; Indoles; Macrolides; Lactones; Pyrroles; Macrocyclic Compounds; Peptides, Cyclic; Sirolimus; Sunitinib; Everolimus; Octreotide; lanreotide
• Other Study ID Numbers: RYZ101-301

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No