Clinical Trials

Inclusion Criteria:

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

1. Age of at least 18 years at the time of signing the informed consent.
2. Histologically proven, Grade 1-2 well differentiated, inoperable, advanced GEP-NETs. (Note:  For Part 1, eligibility will be determined based on local assessment; however, for Part 2, apart from local assessment, adequate tumor tissue must be available for retrospective central
confirmation of tumor grade.)
3. Ki67 (mitotic) index ≤20%. (Note: For Part 1, eligibility will be determined based on locally assessed Ki67 index; however, for Part 2, apart from local assessment, adequate tumor tissue must be available for retrospective central confirmation.)
4. Eastern Cooperative Oncology Group (ECOG) status 0-2.
5. Life expectancy of at least 12 weeks.
6. Subjects with functional tumors who are receiving octreotide LAR or lanreotide for symptom control must be on a stable dose for at least 12 weeks prior to enrollment (Part 1) or randomization (Part 2).
a. Subjects with nonfunctional tumors or functional tumors that do not require octreotide LAR or lanreotide for symptom control must discontinue octreotide LAR or lanreotide at
least 4 weeks prior to enrollment (Part 1) or randomization (Part 2).
7. Progressive GEP-NET (GI or pancreas) based on RECIST v1.1 following a minimum of 2 cycles and a maximum of 4 cycles of treatment with 177Lu-DOTATATE (7.4 GBq ±10% each cycle or a total cumulative dose of up to 29.6 GBq ±10%), 177Lu-DOTATOC (7.5 GBq ±10% each cycle or a total cumulative dose of up to 30 GBq ±10%), or 177Lu-HA-DOTATATE (7.4 GBq ±10% each cycle or a total cumulative dose of up to 29.6 GBq ±10%). Radiographic progression must be demonstrated within 18 months from enrollment (Part 1) or randomization (Part 2). Premature discontinuation of 177Lu-DOTATATE, 177Lu-DOTATOC, or 177Lu-HADOTATATE (i.e., 177Lu-SSA) treatment should not have been due to PD. Dose reductions for toxicity based on local labeling are allowed. No maximum time limit is defined between 177Lu-SSA treatment and enrollment (Part 1)/randomization (Part 2). Other anticancer treatments that do not meet exclusion criteria are allowed in this interval. Subjects must have progressed on or after the last non-177Lu-SSA anticancer treatment. a. CT/MRI scan should be completed within 90 days (inclusive) prior to enrollment (Part 1) or randomization (Part 2) and show disease progression compared to a previous scan obtained at least 6 months following the last 177Lu-DOTATATE/TOC or 177Lu-HADOTATATE treatment (see Exclusion Criterion #1) and within 18 months from screening (Figure 1-3). No non-SSA anticancer treatment is permitted between the most recent scan used for eligibility confirmation and the first dose of study treatment. A baseline CT/MRI scan must always be obtained within 6 weeks (42 days) prior to the first dose of study treatment for on-study response assessment (the most recent scan for confirmation of progression may be used as the baseline scan if obtained prior to enrollment/randomization and within 42 days prior to the first dose of study treatment).
b. For subjects on octreotide LAR or lanreotide, progression should be documented while
the subject was on a fixed dose of octreotide LAR or lanreotide.
c. There must be at least 1 SSTR-PET imaging-positive (using a regulatory agency-approved imaging method, e.g., 68Gallium [68Ga] or 64Copper [64Cu]-based), measurable site of disease (according to RECIST v1.1) and no RECIST v1.1 measurable metastatic lesions that are SSTR imaging-negative. Assessment of SSTR expression must be within 90 days (inclusive) prior to enrollment (Part 1) or randomization (Part 2) without any intervening non-SSA anticancer treatments for GEP-NET.
d. Tumor uptake observed in each RECIST v1.1 measurable lesion using a regulatory agency-approved SSTR-PET imaging method must be greater than the liver uptake observed on regulatory agency-approved SSTR-PET imaging (i.e., Krenning score 3 or 4) (Hope et al.
2019), to be centrally confirmed in Part 2.
8. Part 2: Subject is a candidate for therapy with 1 of the following SoC options:
a. Everolimus 10 mg daily by mouth
b. Sunitinib 37.5 mg daily by mouth
c. High-dose octreotide LAR 60 mg Q4W by intramuscular (i.m.) injection
d. High dose frequency lanreotide 120 mg every 2 weeks (Q2W) by deep subcutaneous (s.c.) injection.
9. Adequate renal function, as evidenced by creatinine clearance (CrCl) ≥50 mL/min (calculated using the Cockcroft-Gault formula) (Cockcroft and Gault, 1976) (Appendix 7)
10. Adequate hematologic function, defined by the following laboratory results:
a. 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)
b. Part 2: Hemoglobin concentration ≥5.0 mmol/L (≥8.0 g/dL); ANC ≥1000 cells/µL (≥1000 cells/mm3); platelets >100 x 109
/L (100 x 103/mm3).
Note: Colony-stimulating factors, platelet-production stimulators and/or transfusions within 4 weeks prior to screening are not permitted to meet these criteria.
11. Total bilirubin ≤3 x upper limit normal (ULN)
12. Serum albumin ≥3.0 g/dL unless prothrombin time is within the normal range
13. For women of childbearing potential (WOCBP):
a. Negative serum pregnancy test within 48 hours prior to the first dose of study treatment
b. Agreement to use barrier contraception and a second form of highly effective contraception (Clinical Trials Facilitation Group [CTFG] 2014) while receiving study treatment and for 6 months following their last dose of study treatment. Alternatively, total abstinence is also considered a highly effective contraception method when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable
methods of contraception.
c. A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥12 continuous months of amenorrhea [no menstrual
bleeding of any kind, including menstrual period, irregular bleeding, spotting, etc.] with no identified cause other than menopause), and has not undergone surgical sterilization
(total hysterectomy, or bilateral tubal ligation or bilateral oophorectomy at least 6 weeks before taking study treatment).
14. Sexually active male subjects must use a condom during intercourse while receiving study treatment and for 3 months after the last dose of the study treatment and should not father a child during this period. 
a. Male study participants whose sexual partners are WOCBP must also agree to use a second form of highly effective contraception (CTFG 2014) while receiving study treatment and for 3 months following their last dose of RYZ101. Alternatively, total abstinence is also considered a highly effective contraception method when this is in line with the preferred and usual lifestyle of the subject.
b. A condom is required to be used also by vasectomized men as well as during intercourse with a male partner to prevent delivery of the drug via seminal fluid.
15. 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.

Exclusion Criteria:

Subjects who meet any of the following criteria will be excluded from the study:

1. Subjects with a GEP-NET deemed nonresponsive to PRRT, defined as no disease control (PR,
CR, or SD) achieved for at least 6 months following the last dose of prior 177Lu-DOTATATE/TOC or 177Lu-HA-DOTATATE treatment.
2. Known hypersensitivity to 225Actinium, 68Gallium, 64Copper, octreotate, or any of the excipients of DOTATATE imaging agents
3. Part 1: Prior treatment with alkylating agents
4. Prior radioembolization
5. Any surgery, chemoembolization, and radiofrequency ablation within 12 weeks prior to first dose of study treatment
6. Use of anticancer agents within the following intervals prior to the first dose of study treatment:
a. PRRT: within <6 months ( 177Lu-DOTATATE/TOC or 177Lu-HA-DOTATATE only, as described in Inclusion Criterion #7)
b. Chemotherapy: within <6 weeks
c. Small molecule inhibitors: within <4 weeks
d. Biological agents: within 4 weeks.
7. Prior radiation therapy as defined below:
a. Part 1: Any prior external beam radiation therapy, including stereotactic body radiation therapy (SBRT)
b. Part 2: Any of the following:
i. Radiation therapy within 6 weeks prior to study enrollment
ii. Prior external beam radiation therapy to more than 25% of the bone marrow
8. Prior participation in any interventional clinical study within 30 days prior to first dose of study
treatment
9. Current somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study
10. Significant cardiovascular disease, such as New York Heart Association (NYHA) Class ≥II heart failure
a. Subjects with a known left ventricular ejection fraction (LVEF) <40% will be excluded.
b. Subjects with known coronary artery disease, congestive heart failure not meeting the above criteria, or LVEF <50% must be on a stable medical regimen that is optimized in
the opinion of the treating physician.
c. QT interval corrected for heart rate using Fridericia’s formula (QTcF) >470 ms for females and >450 ms for males, demonstrated by the average value of 3 consecutive ECGs
11. Resistant hypertension, defined as persistent 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). Patients with baseline hypertension may be eligible after initiation of anti-hypertensive therapy.
12. Uncontrolled diabetes mellitus as defined by hemoglobin A1C (HgB A1C) ≥8%
13. 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.
14. 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.
15. For subjects with functional tumors that require treatment with SSAs for symptom control:
a. Any subject receiving treatment with short-acting octreotide, which cannot be interrupted for 24 hours before the administration of RYZ101.
b. Any subject receiving treatment with octreotide LAR or lanreotide, which cannot be interrupted for at least 4 weeks before the administration of RYZ101.
SSAs can be transitioned to short-acting SSAs for these 4 weeks. Long-acting SSAs can be re-started as soon as 4 hours after a RYZ101 infusion.)
16. Subject requires other treatment that in the opinion of the investigator would be more appropriate than the therapy offered in the study 
17. Pregnancy or lactation
18. Unable or unwilling to comply with the requirements of the study protocol
19. PRRT other than 177Lu-DOTATATE/TOC or 177Lu-HA-DOTATATE as described in Inclusion Criterion #7
20. Any condition requiring systemic treatment with high-dose glucocorticoids (≥20 mg prednisone per day or equivalent) within 14 days prior to first dose of study treatment and/or which cannot be stopped while on study (unless solely for the purpose of adrenal replacement). Inhaled or topical steroids and single dose of steroids as pre-medication for CT scans with contrast are permitted.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 11/17/23. Questions regarding updates should be directed to the study team contact.