Trial short name: ACTION-1
Official title: 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 177Lulabelled somatostatin analogue (177Lu-SSA) therapy
Principal Investigator: Dr. Sten Myrehaug
Cancer type: Neuroendocrine
Cancer location: Neuroendocrine
Disease stage: Early Cancer
Trial phase: Phase 3
Intervention:
Registration #:
NCT05477576 
Contact e-mail: cancerclinicaltrials@sunnybrook.ca
Trial description:
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.
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) <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 a fasting glucose >2 x ULN
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. Brain metastases as defined below:
Part 1: Known brain metastases
Part 2: Subjects with previously treated central nervous system (CNS) metastases who have not recovered from acute side effects of radiotherapy. Note: Subjects with previously treated CNS metastases should be receiving a stable or decreasing dose regimen 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.
