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

Sponsor

RayzeBio, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT05477576

Collaborator

(none)

218

Enrollment

Locations

Arms

75.3

Anticipated Duration (Months)

54.5

Patients Per Site

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Condition or Disease	Intervention/Treatment	Phase
GEP-NET Gastroenteropancreatic Neuroendocrine Tumor Gastroenteropancreatic Neuroendocrine Tumor Disease Neuroendocrine Tumors Carcinoid Carcinoid Tumor Pancreatic NET	Drug: RYZ101 Drug: Everolimus 10 mg Drug: Sunitinib 37.5 MG Drug: Octreotide LAR 60 MG Injection Drug: Lanreotide 120Mg Sa Susp Inj Syringe	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

218 participants

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 DOTATATE (177Lu-DOTATATE) or 177Lu-DOTATOC (177Lu-DOTATATE/TOC).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 DOTATATE (177Lu-DOTATATE) or 177Lu-DOTATOC (177Lu-DOTATATE/TOC).

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Mar 24, 2022

Anticipated Primary Completion Date :

Jul 1, 2025

Anticipated Study Completion Date :

Jul 1, 2028

Arms and Interventions

Arm	Intervention/Treatment
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.	Drug: RYZ101 RP3D as determined in Phase 1b
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 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

Arm

Intervention/Treatment

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.

Drug: RYZ101

RP3D as determined in Phase 1b

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 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

Outcome Measures

Primary Outcome Measures

Phase 1b: RP3D [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 [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.

Secondary Outcome Measures

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 [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 [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 [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 [Up to 80 months]
ORR, as determined by BICR according to RECIST v1.1.
Phase 3: PFS [Up to 80 months]
PFS as determined by Investigator
Phase 3: ORR by Inv [Up to 80 months]
ORR, as assessed by the Investigator according to RECIST v1.1
Phase 3: BOR [Up to 80 months]
Assessed by BICR and by the Investigator according to RECIST v1.1
Phase 3: Disease Control Rate [Up to 80 months]
Assessed by BICR and by the Investigator according to RECIST v1.1
Phase 3: DoR [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

Other Outcome Measures

Phase 1b and 3: Incidence and severity of AEs by NCI CTCAE v5, including SAEs, laboratory changes, ECG changes, and other safety findings [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 [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) [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 [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 [Up to 80 months]
Measured by continuous ECG recording using a 12-lead Holter monitoring device

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

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

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 3 months following Lu-177 SSA. Premature discontinuation of Lu-177 SSA treatment should not have been due to PD.
Part 2: Subject is a candidate for therapy with 1 of the following SoC options:
Everolimus 10 mg daily
Sunitinib 37.5 mg daily
High-dose octreotide LAR 60 mg Q4W
High dose frequency lanreotide 120 mg every 2 weeks (Q2W)
Adequate renal function, as evidenced by creatinine clearance (CrCl) ≥50 mL/min (calculated using the Cockcroft-Gault formula) (Cockcroft and Gault, 1976) (Appendix

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

Known hypersensitivity to 225Actinium, 68Gallium, 64Copper, octreotate, or any of the excipients of DOTATATE imaging agents
Part 1: Prior treatment with alkylating agents
Prior radioembolization
Any surgery, chemoembolization, and radiofrequency ablation within 12 weeks prior to first dose of study drug
Use of anticancer agents within the following intervals prior to the first dose of study drug:
PRRT: within <8 weeks
Chemotherapy: within <6 weeks
Small molecule inhibitors: within <4 weeks
Biological agents: within <7 days or <5 half-lives
Prior external-beam radiation (EBRT) therapy as defined below:
Part 1: Any prior EBRT, including SBRT
Part 2: Prior EBRT within 6 weeks prior to study enrollment or any prior EBRT to more than 25% of the bone marrow
Prior participation in any interventional clinical study within 30 days prior to first dose of study drug
Current somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study
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 a fasting glucose >2 x ULN
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.
Brain metastases as defined below:
Part 1: Known brain metastases
Part 2: Subjects with previously treated central nervous system (CNS) metastases who have not recovered from acute side effects of radiotherapy. Note: Subjects with previously treated CNS metastases should be receiving a stable or decreasing dose regimen of steroids
Subject requires other treatment that in the opinion of the investigator would be more appropriate than the therapy offered in the study
Pregnancy or lactation
Unable or unwilling to comply with the requirements of the study protocol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope	Duarte	California	United States	91010
2	Advanced Molecular Imaging and Therapy	Glen Burnie	Maryland	United States	21061
3	Nebraska Cancer Specialists	Omaha	Nebraska	United States	68124
4	MD Anderson	Houston	Texas	United States	77030