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

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