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

Neuroendocrine Tumors Clinical Trial

— ACTION-1  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05477576
• Other study ID #: RYZ101-301
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: March 24, 2022
• Est. completion date: July 2028

Study information

• Verified date: April 2024
• Source: RayzeBio, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 288
• Est. completion date: July 2028
• Est. primary completion date: July 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Carcinoid
• Carcinoid Tumor
• Gastroenteropancreatic Neuroendocrine Tumor
• Intestinal Neoplasms
• Neoplasms
• Neuroendocrine Tumors
• Pancreatic Neoplasms
• Pancreatic NET
• Stomach Neoplasms

Intervention

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

Locations

Country	Name	City	State
Belgium	Cliniques universitaires Saint-Luc	Brussel
Belgium	Institut Jules Bordet	Brussels
Belgium	UZ Leuven	Leuven
Belgium	AZ Delta	Roeselare
Brazil	Sociedade Beneficente De Senhoras Hospital - Sírio-Libanês Brasilia	Brasília
Brazil	Instituto D'or de Pesquisa e Ensino	Rio De Janeiro
Brazil	Instituto Nacional de Cancer	Rio De Janeiro
Brazil	Fundacao Antonio Prudente - A.C. Camargo Cancer Center	São Paulo
Brazil	Hospital Israelita Albert Einstein	São Paulo
Brazil	Sociedade Beneficente de Senhoras Hospital Sirio-Libanes	São Paulo
Canada	London Health Sciences Centre	London	Ontario
Canada	Jewish General Hospital	Montréal	Quebec
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
Canada	University Health Network - Princess Margaret Cancer Centre	Toronto
France	CHU Beaujon, APHP.Nord - Université Paris Cité	Clichy
France	CHRU de Lile	Lille
France	CHU De Nantes	Nantes
France	CHRU de Nancy Hôpital de Brabois	Vandoeuvre-Lès-Nancy
France	Institut Gustave Roussy	Villejuif
Netherlands	UMC Utrecht	Utrecht
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Hospital HM Universitario Sanchinarro	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Ramon Y Cajal	Madrid
Spain	MD Anderson Cancer Center	Madrid
Spain	Hospital Universitario Miguel Servet	Zaragoza
United States	Winship Cancer Institute, Emory University Hospital Midtown	Atlanta	Georgia
United States	Boston Medical Center	Boston	Massachusetts
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	City of Hope	Duarte	California
United States	Advanced Molecular Imaging and Therapy	Glen Burnie	Maryland
United States	MD Anderson	Houston	Texas
United States	University of Iowa Hospitals & Clinics	Iowa City	Iowa
United States	Mayo Clinic Florida	Jacksonville	Florida
United States	University of Kentucky Markey Cancer Center	Lexington	Kentucky
United States	UCLA Nuclear Medicine	Los Angeles	California
United States	Biogenix Molecular	Miami	Florida
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Yale Cancer Center	New Haven	Connecticut
United States	Icahn School of Medicine at Mount Sinai	New York	New York
United States	Memorial Sloan Kettering	New York	New York
United States	Hoag Memorial Hospital Presbyterian	Newport Beach	California
United States	Nebraska Cancer Specialists	Omaha	Nebraska
United States	Stanford University	Palo Alto	California
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Mayo Clinic Arizona	Phoenix	Arizona
United States	UPMC Hillman Cancer Center	Pittsburgh	Pennsylvania
United States	Oregon Health & Science University	Portland	Oregon
United States	Mayo Clinic Rochester	Rochester	Minnesota
United States	Washington University - St. Louis	Saint Louis	Missouri
United States	Huntsman Cancer Hospital University of Utah	Salt Lake City	Utah
United States	University of California, San Francisco	San Francisco	California
United States	Fred Hutchinson Cancer Center	Seattle	Washington
United States	Moffitt Cancer Center	Tampa	Florida
United States	Profound Research LLC/MHP Radiation Oncology Institute	Troy	Michigan
United States	MedStar Washington Hospital Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
RayzeBio, Inc.

Countries where clinical trial is conducted

United States,  Belgium,  Brazil,  Canada,  France,  Netherlands,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	Phase 3: Cmax		Up to 80 months
Other	Phase 3: AUC		Up to 80 months
Other	Phase 3: Average Concentration		Up to 80 months
Other	Phase 3: Relationship between exposure endpoints and clinical outcomes		Up to 80 months
Other	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
Other	Phase 3: Changes in EQ-5D-5L questionnaire scores		Up to 80 months
Other	Phase 3: Changes in EORTC QLQ-C30 questionnaire scores		Up to 80 months
Other	Phase 3: Changes in EORTC QLQ GI NET21 questionnaire scores		Up to 80 months
Other	Phase 3: QTc	Measured by continuous ECG recording using a 12-lead Holter monitoring device	Up to 80 months
Primary	Phase 1b: RP3D	Incidence of DLTs during the first 56 days of study treatment will be assessed.	56 days of study treatment
Primary	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	Phase 1b: Cmax		Up to Day 8
Secondary	Phase 1b: Tmax		Up to Day 8
Secondary	Phase 1b: AUC		Up to Day 8
Secondary	Phase 1b: Volume of Distribution		Up to Day 8
Secondary	Phase 1b: Clearance		Up to Day 8
Secondary	Phase 1b: Terminal Half-life		Up to Day 8
Secondary	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
Secondary	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
Secondary	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
Secondary	Phase 3: ORR by BICR	ORR, as determined by BICR according to RECIST v1.1.	Up to 80 months
Secondary	Phase 3: PFS	PFS as determined by Investigator	Up to 80 months
Secondary	Phase 3: ORR by Inv	ORR, as assessed by the Investigator according to RECIST v1.1	Up to 80 months
Secondary	Phase 3: BOR	Assessed by BICR and by the Investigator according to RECIST v1.1	Up to 80 months
Secondary	Phase 3: Disease Control Rate	Assessed by BICR and by the Investigator according to RECIST v1.1	Up to 80 months
Secondary	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