Boston University - Clinical & Translational Science Institute

Eligibility

Eligible Ages

Over 18 Years

Eligible Genders

All

Accepts Healthy Volunteers

No

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. 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