ACTION-1

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.

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. 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: 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)
7. Adequate renal function, as evidenced by creatinine clearance (CrCl) ≥50 mL/min (calculated using the Cockcroft-Gault formula) (Cockcroft and Gault, 1976)
8. 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).
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: PRRT: within <6 months Chemotherapy: within <6 weeks Small molecule inhibitors: within <4 weeks Biological agents: within <7 days or <5 half-lives
6. 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
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)