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

• ClinicalTrials.gov Identifier: NCT05477576
• Recruitment Status: Active, not recruiting
• First Posted: July 28, 2022
• Last Update Posted: April 29, 2024
• Sponsor: RayzeBio, Inc.
• Information provided by (Responsible Party): RayzeBio, Inc.

Tracking Information

• First Submitted Date: July 20, 2022
• First Posted Date: July 28, 2022
• Last Update Posted Date: April 29, 2024
• Actual Study Start Date: March 24, 2022
• Estimated Primary Completion Date: July 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 25, 2022)

• Phase 1b: RP3D [ Time Frame: 56 days of study treatment ]
  Incidence of DLTs during the first 56 days of study treatment will be assessed.
• Phase 3: PFS as determined by BICR [ Time Frame: After the target number of 143 PFS events have occurred ]
  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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: July 25, 2022)

• Phase 1b: Cmax [ Time Frame: Up to Day 8 ]
• Phase 1b: Tmax [ Time Frame: Up to Day 8 ]
• Phase 1b: AUC [ Time Frame: Up to Day 8 ]
• Phase 1b: Volume of Distribution [ Time Frame: Up to Day 8 ]
• Phase 1b: Clearance [ Time Frame: Up to Day 8 ]
• Phase 1b: Terminal Half-life [ Time Frame: Up to Day 8 ]
• Phase 1b: TIAC of RYZ101 to critical organs and tumors [ Time Frame: Up to Day 184 ]
  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
• Phase 1b: Absorbed radiation doses of RYZ101 to critical organs and tumors [ Time Frame: Up to Day 184 ]
  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
• Phase 3: OS [ Time Frame: Up to 80 months or until a total of 130 deaths have occurred, whichever occurs first ]
  OS will be defined as the time from the date of randomization until the date of death due to any cause.
• Phase 3: ORR by BICR [ Time Frame: Up to 80 months ]
  ORR, as determined by BICR according to RECIST v1.1.
• Phase 3: PFS [ Time Frame: Up to 80 months ]
  PFS as determined by Investigator
• Phase 3: ORR by Inv [ Time Frame: Up to 80 months ]
  ORR, as assessed by the Investigator according to RECIST v1.1
• Phase 3: BOR [ Time Frame: Up to 80 months ]
  Assessed by BICR and by the Investigator according to RECIST v1.1
• Phase 3: Disease Control Rate [ Time Frame: Up to 80 months ]
  Assessed by BICR and by the Investigator according to RECIST v1.1
• Phase 3: DoR [ Time Frame: Up to 80 months ]
  Only for subjects with a RECIST v.1.1 response, assessed by BICR and by the Investigator according to RECIST v1.1

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: July 25, 2022)

• Phase 1b and 3: Incidence and severity of AEs by NCI CTCAE v5, including SAEs, laboratory changes, ECG changes, and other safety findings [ Time Frame: Up to 80 months ]
  Incidence and severity of AEs by NCI CTCAE v5, including SAEs, laboratory changes, ECG changes, and other safety findings
• Phase 3: Cmax [ Time Frame: Up to 80 months ]
• Phase 3: AUC [ Time Frame: Up to 80 months ]
• Phase 3: Average Concentration [ Time Frame: Up to 80 months ]
• Phase 3: Relationship between exposure endpoints and clinical outcomes [ Time Frame: 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) [ Time Frame: Up to 80 months ]
  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)
• Phase 3: Changes in EQ-5D-5L questionnaire scores [ Time Frame: Up to 80 months ]
• Phase 3: Changes in EORTC QLQ-C30 questionnaire scores [ Time Frame: Up to 80 months ]
• Phase 3: Changes in EORTC QLQ GI NET21 questionnaire scores [ Time Frame: Up to 80 months ]
• Phase 3: QTc [ Time Frame: Up to 80 months ]
  Measured by continuous ECG recording using a 12-lead Holter monitoring device

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Study of RYZ101 Compared With SOC in Pts w Inoperable SSTR+ Well-differentiated GEP-NET That Has Progressed Following 177Lu-SSA Therapy
• Official Title: 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
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

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.

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• GEP-NET
• Gastroenteropancreatic Neuroendocrine Tumor
• Gastroenteropancreatic Neuroendocrine Tumor Disease
• Neuroendocrine Tumors
• Carcinoid
• Carcinoid Tumor
• Pancreatic NET

Intervention

• Drug: RYZ101
  RP3D as determined in Phase 1b
• Drug: Everolimus 10 mg
  Everolimus 10 mg daily by mouth
• Drug: Sunitinib 37.5 MG
  Sunitinib 37.5 mg daily by mouth
• Drug: Octreotide LAR 60 MG Injection
  High-dose octreotide LAR 60 mg Q4W by i.m. injection
• Drug: Lanreotide 120Mg Sa Susp Inj Syringe
  High dose frequency lanreotide 120 mg Q2W by deep s.c. injection

Study Arms

• 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. Eligible participants will be enrolled in cohorts of 6 to receive RYZ101 up to 4 infusions every 8 weeks. If the initial dose level is not tolerated, the dose will be de-escalated; up to 3 dose levels will be assessed.
  Intervention: Drug: RYZ101
• Active Comparator: Phase 3 - RYZ101
  Actinium 225 radiolabeled somatostatin analog (SSA) for injection
  Intervention: Drug: RYZ101
• Active Comparator: Phase 3 - Standard of Care
  Investigator's choice of standard of care between everolimus, sunitinib, octreotide, or lanreotide.
  Interventions:

  • Drug: Everolimus 10 mg
  • Drug: Sunitinib 37.5 MG
  • Drug: Octreotide LAR 60 MG Injection
  • Drug: Lanreotide 120Mg Sa Susp Inj Syringe

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: August 30, 2023): 288
• Original Estimated Enrollment (submitted: July 25, 2022): 218
• Estimated Study Completion Date: July 2028
• Estimated Primary Completion Date: July 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Subjects must meet all the following criteria for enrollment in the study:

1. Histologically proven, Grade 1-2 well differentiated, inoperable, advanced GEP-NETs (Ki67 ≤20%)
2. Eastern Cooperative Oncology Group (ECOG) status 0-2
3. Life expectancy of at least 12 weeks

4. Subjects with functional tumors who are receiving SSAs on a stable dose for symptom control .

   Subjects that do not require octreotide LAR or lanreotide for symptom control must discontinue SSAs at least 4 weeks prior to randomization.

5. Progressive, SSTR-PET positive (i.e., Krenning score 3 or 4) GEP-NET (GI or pancreas) based on RECIST v1.1 following 2-4 cycles of treatment with 177Lu-labeled SSA. Must have achieved disease control for at least 6 months following Lu-177 SSA. Radiographic progression must be demonstrated within 18 months of randomization. No time limit is defined between 177Lu-SSA treatment and randomization. Premature discontinuation of Lu-177 SSA treatment should not have been due to PD.

6. Part 2: Subject is a candidate for therapy with 1 of the following SoC options:

   1. Everolimus 10 mg daily
   2. Sunitinib 37.5 mg daily
   3. High-dose octreotide LAR 60 mg Q4W
   4. High dose frequency lanreotide 120 mg every 2 weeks (Q2W)
7. Adequate renal function, as evidenced by creatinine clearance (CrCl) ≥60 mL/min (calculated using the Cockcroft-Gault formula) (Cockcroft and Gault, 1976)

8. Adequate hematologic function, defined by the following laboratory results:

   1. Part 1: Hemoglobin concentration ≥5.6 mmol/L (≥9.0 g/dL); absolute neutrophil count (ANC) ≥1500 cells/µL (≥1500 cells/mm3); platelets ≥100 x 109/L (100 x 103/mm3)
   2. 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).
9. Total bilirubin ≤3 x upper limit normal (ULN)
10. Serum albumin ≥3.0 g/dL unless prothrombin time is within the normal range
11. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 48 hours prior to the first dose of study drug and agree to use barrier contraception and a second form of highly effective contraception (Clinical Trials Facilitation Group [CTFG] 2014) or total abstinence while receiving study drug and for 6 months following their last dose of RYZ101.
12. Sexually active male subjects must use a condom during intercourse while receiving study drug and for 3 months after the last dose of the study drug and should not father a child during this period. If sexual partners are WOCBP must also agree to use a second form of highly effective contraception (CTFG 2014) or total abstinence while receiving study drug and for 3 months following their last dose of RYZ101.
13. Able to read and/or understand the details of the study and provide written informed consent prior to any study-specific assessments and procedures commence

Subjects who meet any of the following criteria will be excluded from the study:

1. Known hypersensitivity to 225Actinium, 68Gallium, 64Copper, octreotate, or any of the excipients of DOTATATE imaging agents
2. Part 1: Prior treatment with alkylating agents
3. Prior radioembolization
4. Any surgery, chemoembolization, and radiofrequency ablation within 12 weeks prior to first dose of study drug

5. Use of anticancer agents within the following intervals prior to the first dose of study drug:

   1. PRRT: within <6 months
   2. Chemotherapy: within <6 weeks
   3. Small molecule inhibitors: within <4 weeks
   4. Biological agents: within 4 weeks

6. Prior external-beam radiation (EBRT) therapy as defined below:

   1. Part 1: Any prior EBRT, including SBRT
   2. Part 2: Prior EBRT within 6 weeks prior to study enrollment or any prior EBRT to more than 25% of the bone marrow
7. Prior participation in any interventional clinical study within 30 days prior to first dose of study drug
8. Current somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study
9. 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.
10. 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)
11. Uncontrolled diabetes mellitus as defined by hemoglobin A1C (HgB A1C) ≥8%
12. Have a history of primary malignancy within the past 3 years other than (1) GEP-NET, (2) adequately treated carcinoma in situ or non-melanoma carcinoma of the skin, (3) any other curatively treated malignancy that is not expected to require treatment for recurrence during participation in the study, or (4) an untreated cancer on active surveillance that may not affect the subject's survival status for ≥3 years based on clinician assessment/statement and with Medical Monitor approval.
13. Known brain, meningeal or spinal cord metastases. In Part 2, subjects with previously treated brain metastases will be allowed if the following conditions are met: (a) there is no evidence of central nervous system (CNS) progression for at least 6 months as assessed by local MRI for brain metastasis during screening; (b) the subject has recovered from acute side effects of radiotherapy; and (c) the subject is receiving a stable or decreasing dose of steroids.
14. Subject requires other treatment that in the opinion of the investigator would be more appropriate than the therapy offered in the study
15. Pregnancy or lactation
16. Unable or unwilling to comply with the requirements of the study protocol
17. PRRT other than Lu-177 SSA
18. 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.
19. Prior history of liver cirrhosis

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Brazil, Canada, France, Netherlands, Spain, United States

Administrative Information

• NCT Number: NCT05477576
• Other Study ID Numbers: RYZ101-301
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

• Current Responsible Party: RayzeBio, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: RayzeBio, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Denis Ferreira, MD; RayzeBio Sr. Medical Director

• PRS Account: RayzeBio, Inc.
• Verification Date: April 2024