RYZ101-301 ACTION-1 (JCP134)

Phase 1b/3 global, randomized, controlled, open-label trial comparing treatment with RYZ101 to standard of care (SoC) therapy in subjects with inoperable, advanced, somatostatin receptor expressing (SSTR+), well-differentiated gastro-enteropancreatic neuroendocrine tumors (GEP-NETs) that have progressed following prior 177Lu-labelled somatostatin analogue (177Lu-SSA) therapy

---

Population: Gastroenteropancreatic neuroendocrine tumors (GEP-NET)

Line of therapy: 3L

Intervention: RYZ101 compared with investigator-selected standard of care therapy (Everolimus 10 mg daily; Sunitinib 37.5 mg daily; High-dose octreotide LAR 60 mg Q4W; High dose frequency lanreotide 120 mg Q2W)

Key Inclusion Criteria

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.

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

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

   
   

Key Exclusion Criteria

1. Prior radioembolization

2. Any surgery, chemoembolization, and radiofrequency ablation within 12 weeks prior to first dose of study drug

3. 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 4 weeks

4. Part 2: Prior EBRT within 6 weeks prior to study enrollment or any prior EBRT to more than 25% of the bone marrow

5. Prior participation in any interventional clinical study within 30 days prior to first dose of study drug

6. 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.

7. 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)

8. Uncontrolled diabetes mellitus as defined by hemoglobin A1C (HgB A1C) ≥8%

9. 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.

10. 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.

11. PRRT other than Lu-177 SSA

12. 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.

Sponsor: RayzeBio Inc.

CRP Contact: oleg.lapsin@ladydavis.ca

CRP PI: Dr. P. Kavan

Status: Open to accrual