Randomized Controlled Trial of RYZ101 Versus Standard of Care in Advanced SSTR+ Gastroenteropancreatic Neuroendocrine Tumors Post-177Lu-SSA Therapy
- Trial ID
- 2023-509334-19-00
- Protocol
- RYZ101-301
- Sponsor
- Rayzebio Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the recommended Phase 3 dose (RP3D) of **RYZ101** and to assess its safety and tolerability in subjects with somatostatin receptor-positive (SSTR+) gastro-enteropancreatic neuroendocrine tumors (GEP-NETs) that have progressed following treatment with 177Lu-labelled somatostatin analogue (177Lu-SSA). Additionally, the study aims to evaluate whether treatment with RYZ101, compared to standard of care (SoC) therapy, improves centrally confirmed progression-free survival (PFS) in study subjects. This is clinically relevant as it may offer a new therapeutic option for patients with advanced GEP-NETs who have limited treatment alternatives after progression on 177Lu-SSA therapy.
Secondary objectives include: - Determining if RYZ101 improves overall survival (OS) and objective response rate (ORR) compared to SoC therapy. - Evaluating the efficacy of RYZ101 in terms of investigator-assessed PFS. - Further assessing efficacy through investigator-assessed ORR, best overall response (BOR), duration of response (DoR), and disease control rate as determined by both blinded independent central review (BICR) and the investigator. - Characterizing the safety and tolerability of RYZ101. - Evaluating the pharmacokinetics (PK) of RYZ101. - Assessing PK and electrocardiogram (ECG) parameters in a subset of approximately 30 subjects.
Participants
The clinical trial involves a total of **210 participants** diagnosed with **gastro-enteropancreatic neuroendocrine tumors (GEP-NETs)**. The study population includes both male and female subjects, with an age range that corresponds to the adult category. Participants were selected based on their progression following treatment with 177Lu-SSA and their candidacy for standard of care (SoC) therapies such as Everolimus, Sunitinib, high-dose octreotide LAR, or high-dose frequency lanreotide. The trial includes individuals with adequate renal and hematologic function, as well as those with controlled bilirubin and serum albumin levels. Lifestyle considerations include the requirement for women of childbearing potential and sexually active male subjects to adhere to specific contraceptive measures during and after the study treatment. The trial also involves a vulnerable population, ensuring comprehensive safety and ethical oversight.
Plans and Procedures
The clinical trial is designed as a **randomized**, controlled, open-label study to evaluate the efficacy and safety of RYZ101 compared to standard of care (SoC) therapy in subjects with inoperable, advanced, somatostatin receptor-expressing, well-differentiated **gastro-enteropancreatic neuroendocrine tumors (GEP-NETs)** that have progressed following prior 177Lu-labelled somatostatin analogue therapy. The trial is divided into two parts: Part 1 aims to determine the recommended Phase 3 dose (RP3D) of RYZ101 and assess its safety and tolerability, while Part 2 focuses on comparing the progression-free survival (PFS) of subjects treated with RYZ101 versus those receiving SoC therapy. The trial is expected to last until August 2030, with recruitment starting in August 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as adequate renal and hematologic function, and for women of childbearing potential, a negative pregnancy test. Following randomization, subjects will receive either RYZ101 or one of the SoC options, which include **everolimus**, **sunitinib**, high-dose **octreotide** LAR, or high-dose frequency **lanreotide**. The study will include regular follow-up visits to monitor safety, efficacy, and any adverse events, with the primary endpoint being the incidence of dose-limiting toxicities (DLTs) during the first 56 days of treatment in Part 1, and PFS in Part 2. The end-of-study visit will conclude the participant's involvement, which is anticipated to last up to 260 days, depending on the treatment arm and individual response.
Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial will also assess secondary endpoints such as overall survival (OS), objective response rate (ORR), and the relationship between biomarkers and clinical outcomes. The study's design ensures rigorous monitoring and data collection to evaluate the therapeutic potential of RYZ101 in this patient population.
Treatment
The clinical trial involves the administration of several experimental and non-experimental treatments. **RYZ101**, also known as **Actinium (Ac 225) Oxodotreotide**, is the primary investigational product. It is administered as an **injection** with a pharmaceutical form of **INJECTION**. The maximum daily dose is 10.2 MBq, with a total maximum dose of 40.8 MBq over a treatment period of 32 days. The route of administration is **intravenous use**. This investigational product is being evaluated for its safety, tolerability, and efficacy in subjects with somatostatin receptor-expressing gastro-enteropancreatic neuroendocrine tumors (GEP-NETs).
**Sunitinib** is used as a comparator treatment in the trial. It is provided in the form of a **hard capsule** for **oral use**. The maximum daily dose is 37.5 mg, with a total maximum dose of 68,250 mg over a treatment period of 260 days. This medication is a standard-of-care therapy for certain types of tumors and is included in the trial to compare its efficacy against the investigational product.
**Everolimus** is another comparator treatment, administered as a **tablet** for **oral use**. The maximum daily dose is 10 mg, with a total maximum dose of 18,200 mg over 260 days. Everolimus is a standard treatment option for certain cancer types and is used in this trial to evaluate its performance relative to the investigational product.
**L-Arginine Hydrochloride** is administered as a **solution for infusion** via **intravenous use**. The maximum daily dose is 25 g, with a total maximum dose of 100 g over a 32-day period. This compound is used as an auxiliary treatment in the trial.
**Lanreotide** is provided as a **solution for injection in a pre-filled syringe** for **subcutaneous use**. The maximum daily dose is 120 mg, with a total maximum dose of 15,600 mg over 260 days. Lanreotide is a comparator treatment in the study, commonly used in the management of neuroendocrine tumors.
**L-Lysine Hydrochloride** is also administered as a **solution for infusion** via **intravenous use**. The maximum daily dose is 25 g, with a total maximum dose of 100 g over 32 days. This compound serves as an auxiliary treatment in the trial.
**Octreotide** is provided as a **powder and solvent for suspension for injection** for **intramuscular use**. The maximum daily dose is 60 mg, with a total maximum dose of 3,900 mg over 260 days. Octreotide is a comparator treatment, often used in the treatment of neuroendocrine tumors.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocols. The trial aims to assess the relative efficacy and safety of the investigational product compared to standard-of-care therapies in subjects with advanced GEP-NETs.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint for Part 2 of the trial is **Progression-Free Survival (PFS)**, which will be determined by Blinded Independent Central Review (BICR). PFS is defined as the time from the date of randomization until the date of progression, as determined by BICR from tumor assessments using RECIST v1.1, or death due to any cause, whichever occurs first. Secondary endpoints include Overall Survival (OS), Objective Response Rate (ORR) as determined by BICR according to RECIST v1.1, and PFS as determined by the Investigator. Additional secondary endpoints involve Best Overall Response (BOR), disease control rate, and Duration of Response (DoR) assessed by BICR and the Investigator according to RECIST v1.1.
Other secondary endpoints include the incidence and severity of adverse events (AEs) by NCI CTCAE v5, including serious adverse events (SAEs), laboratory changes, ECG changes, and other safety findings. The relationship between biomarkers, such as Chromogranin A (CgA) in the serum and 5-Hydroxyindoleacetic Acid (5-HIAA) in the urine, with AEs of special interest and/or efficacy endpoints like PFS, OS, BOR, and DoR will also be evaluated. Changes in patient-reported outcomes will be measured using the EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ GI NET21 questionnaire scores. Pharmacokinetic parameters, including Cmax, Tmax, AUC, volume of distribution (Vd), clearance, and half-life (T1/2), will be measured, along with ECG parameters using continuous ECG recording with a 12-lead Holter monitoring device.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.
- Adequate renal function, as evidenced by eGFR ≥60 mL/min (calculated using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation) (Levey et al. 2009) multiplied by individual subject’s BSA and divided by 1.73 m2 (KDIGO 2024 Clinical Practice Guidelines for the Evaluation and Management of Chronic Kidney Disease) (refer to Appendix 7) )
- 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 >100x 109/L (100 x 103/mm3).
- Total bilirubin ≤3 x upper limit normal (ULN)
- Serum albumin ≥3.0 g/dL unless prothrombin time (PT) is within the normal range
- 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 while receiving study treatment and for 7 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. 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 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).
- Sexually active male subjects must use a condom during intercourse while receiving study treatment and for 4 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 while receiving study treatment and for 4 months following their last dose of RYZ101. Alternatively, total abstinence is also considered a highly effective contraception method. 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.
Exclusion Criteria
- 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.
- 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
- 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. Patients with baseline hypertension may be eligible after initiation of antihypertensive therapy.
- Uncontrolled diabetes mellitus as defined by hemoglobin A1C (HgB A1C) ≥8%
- 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.
- 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.
- 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.(Note: Long-acting SSAs can be transitioned to short-acting SSAs for these 4 weeks. Long-acting SSAs can be re-started as early as 4 hours after the end of a RYZ101 infusion.)
- Subject requires other treatment that in the opinion of the investigator would be more appropriate than the therapy offered in the study
- Unable or unwilling to comply with the requirements of the study protocol
- PRRT other than 177Lu-DOTATATE/TOC or 177Lu-HA-DOTATATE as described in Inclusion Criterion #7
- 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.
- Known hypersensitivity to 225Actinium, 68Gallium, 64Copper, octreotate, or any of the excipients of DOTATATE imaging agents
- Prior history of liver cirrhosis or liver transplantation.
- Part 1: Prior treatment with alkylating agents
- Prior radioembolization
- Any surgery, chemoembolization, and radiofrequency ablation within 12 weeks prior to first dose of study treatment
- 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
- 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 the first dose of study treatment ii. Prior external beam radiation therapy to more than 25% of the bone marrow
- Prior participation in any interventional clinical study within 30 days prior to first dose of study treatment
- Current somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study
- Pregnancy or breastfeeding
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 10 Aug 2023 | 17 |
 France | Not Recruiting | 10 Aug 2023 | 28 |
 The Netherlands | Recruiting | 10 Aug 2023 | — |
 Spain | Recruiting | 10 Aug 2023 | 18 |
| Netherlands | — | — | 15 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
RYZ101 | Test | INJECTION | INTRAVENOUS USE | 10.2 | 32 | PRD11076314 |
EVEROLIMUS | Comparator | — | ORAL USE | 10 | 260 | SUB02065MIG |
SUNITINIB | Comparator | — | ORAL USE | 37.5 | 260 | SUB22321 |
LANREOTIDE | Comparator | — | SUBCUTANEOUS USE | 120 | 260 | SUB08402MIG |
OCTREOTIDE | Comparator | — | INTRAMUSCULAR USE | 60 | 260 | SUB09417MIG |
L-ARGININE HYDROCHLORIDE | Other | — | INTRAVENOUS USE | 25 | 32 | SUB22706 |
L-LYSINE HYDROCHLORIDE | Other | — | INTRAVENOUS USE | 25 | 32 | SUB127503 |