ACTINIUM (AC 225) OXODOTREOTIDE for Gastroenteropancreatic neuroendocrine tumor

Inclusion criteria

• {"criterion_text":"- 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.\n- 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) )\n- 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).\n- Total bilirubin ≤3 x upper limit normal (ULN)\n- Serum albumin ≥3.0 g/dL unless prothrombin time (PT) is within the normal range\n- 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).\n- 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

• {"criterion_text":"- 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.\n- PRRT other than 177Lu-DOTATATE/TOC or 177Lu-HA-DOTATATE as described in Inclusion Criterion #7\n- 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.\n- Known hypersensitivity to 225Actinium, 68Gallium, 64Copper, octreotate, or any of the excipients of DOTATATE imaging agents\n- Prior history of liver cirrhosis or liver transplantation.\n- Part 1: Prior treatment with alkylating agents\n- Prior radioembolization\n- Any surgery, chemoembolization, and radiofrequency ablation within 12 weeks prior to first dose of study treatment\n- 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\n- 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\n- Prior participation in any interventional clinical study within 30 days prior to first dose of study treatment\n- 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\n- Current somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study\n- Pregnancy or breastfeeding\n- 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.\n- Uncontrolled diabetes mellitus as defined by hemoglobin A1C (HgB A1C) ≥8%\n- 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.\n- 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.\n- 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.)\n- Subject requires other treatment that in the opinion of the investigator would be more appropriate than the therapy offered in the study\n- Unable or unwilling to comply with the requirements of the study protocol"}

Primary endpoints

• {"endpoint_text":"- Part 1: - Incidence of DLTs during the first 56 days of study treatment","definition_or_measurement_approach":"DLTs counted during first 56 days of study treatment (Part 1)."}
• {"endpoint_text":"- Part 1: Incidence and severity of AEs by NCI CTCAE v5, including SAEs, laboratory changes, ECG changes, and other safety findings","definition_or_measurement_approach":"Adverse events graded per NCI CTCAE v5, includes SAEs, laboratory and ECG changes and other safety findings."}
• {"endpoint_text":"- Part 2: - PFS as determined by BICR PFS will be 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.","definition_or_measurement_approach":"PFS determined by Blinded Independent Central Review (BICR) using RECIST v1.1; defined as time from randomization to progression per BICR or death."}

Secondary endpoints

• {"endpoint_text":"- Part 2: - OS will be defined as the time from the date of randomization until the date of death due to any cause.","definition_or_measurement_approach":"Overall survival defined as time from randomization to death from any cause."}
• {"endpoint_text":"- ORR, as determined by BICR according to RECIST v1.1","definition_or_measurement_approach":"Objective response rate assessed by BICR per RECIST v1.1."}
• {"endpoint_text":"- PFS as determined by the Investigator","definition_or_measurement_approach":"Investigator-assessed PFS (no central review) using tumor assessments."}
• {"endpoint_text":"- ORR, as assessed by the Investigator according to RECIST v1.1","definition_or_measurement_approach":"Investigator-assessed ORR per RECIST v1.1."}
• {"endpoint_text":"- BOR, disease control rate (PR + CR + SD), and DoR (only for subjects with a RECIST v1.1 response) assessed by BICR and by the Investigator according to RECIST v1.1","definition_or_measurement_approach":"Best overall response, disease control rate (PR+CR+SD), and duration of response per RECIST v1.1 assessed by both BICR and Investigator."}
• {"endpoint_text":"- Incidence and severity of AEs by NCI CTCAE v5, including SAEs, laboratory changes, ECG changes, and other safety findings","definition_or_measurement_approach":"Safety assessments per NCI CTCAE v5 including SAEs, labs, ECGs."}
• {"endpoint_text":"- PFS2 as determined by the investigator PFS2 will be defined as the time from randomization to second objective disease progression after subsequent anti-cancer therapy, or death from any cause, whichever first.","definition_or_measurement_approach":"PFS2 defined as time from randomization to second objective progression after subsequent therapy or death; Investigator-determined."}
• {"endpoint_text":"- Relationship between biomarkers, including but not limited to CgA in the serum and (5 HIAA) in the urine, with AEs of special interest and/or efficacy endpoints (e.g., PFS, OS, BOR, DoR)","definition_or_measurement_approach":"Correlative analyses of biomarkers (e.g., serum CgA, urine 5-HIAA) with safety and efficacy outcomes."}
• {"endpoint_text":"- Changes in: • EQ-5D-5L • EORTC QLQ-C30 and • EORTC QLQ GI NET21 questionnaire scores","definition_or_measurement_approach":"Patient-reported outcomes measured by EQ-5D-5L, EORTC QLQ-C30 and EORTC QLQ GI-NET21 questionnaires."}
• {"endpoint_text":"- Population predicted exposure parameters (i.e. Cmax, AUC, average concentration)","definition_or_measurement_approach":"PK population exposure parameters including Cmax, AUC and average concentration."}
• {"endpoint_text":"- Relationship between exposure endpoints and clinical outcomes (efficacy and safety)","definition_or_measurement_approach":"PK/PD analyses correlating exposure endpoints with efficacy and safety outcomes."}
• {"endpoint_text":"- PK parameters, measured by: • Cmax, Tmax, AUC, Vd, clearance, T1/2 • Percentage of radioactivity of the injected parent drug recovered in urine • ECG parameters (including QTc), measured by continuous ECG recording using a 12 lead Holter monitoring device","definition_or_measurement_approach":"Pharmacokinetic parameters measured (Cmax, Tmax, AUC, Vd, clearance, T1/2), percentage radioactivity in urine, and continuous 12-lead Holter ECG parameters including QTc."}

Methods

• Recruitment procedure documents present (K1_Recruitment Procedure Description) describing site-level recruitment processes.
• Patient advertisement materials including 'K2_Patient Advertisement material_Email Communication' (email communication) and scout materials (Scout Study Brochure, Scout Information Letter) for engaging potential participants.
• Country-specific patient-facing documents and informed consent forms (multiple languages) for site-based recruitment.

Netherlands

Earliest CTIS Part Ii Submission Date

27-02-2024

Latest Decision Or Authorization Date

12-03-2026

Processing Time Days

744

Number Of Sites

3

Number Of Participants

15

Belgium

Earliest CTIS Part Ii Submission Date

27-02-2024

Latest Decision Or Authorization Date

12-03-2026

Processing Time Days

744

Number Of Sites

4

Number Of Participants

17

France

Earliest CTIS Part Ii Submission Date

27-02-2024

Latest Decision Or Authorization Date

17-03-2026

Processing Time Days

749

Number Of Sites

6

Number Of Participants

28

Spain

Earliest CTIS Part Ii Submission Date

27-02-2024

Latest Decision Or Authorization Date

17-03-2026

Processing Time Days

749

Number Of Sites

7

Number Of Participants

18

Primary sponsor

Full Name

Rayzebio Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Parexel International (IRL) Limited

Responsibilities

Sponsor duties codes: 1, 12, 5, 6, 7 (as listed in CTIS record)

Third parties

• {"country":"United States","full_name":"Eurofins Central Laboratory LLC","duties_or_roles":"code:4","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"RTMS; code:7","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Netherlands","full_name":"Propharma Group The Netherlands B.V.","duties_or_roles":"code:14","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Biotel Research LLC","duties_or_roles":"Blinded Independent Central Review","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Fisher Clinical Services GmbH","duties_or_roles":"code:14","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Clario","duties_or_roles":"EKG services","organisation_type":"Industry"}
• {"country":"Netherlands","full_name":"Van Overeem Nuclear B.V.","duties_or_roles":"code:14","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Invicro LLC","duties_or_roles":"Urine and Blood PK","organisation_type":"Pharmaceutical company"}
• {"country":"Belgium","full_name":"CluePoints","duties_or_roles":"code:6","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Greenphire LLC","duties_or_roles":"Patient reimbursement","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Ireland","full_name":"Parexel International (IRL) Limited","duties_or_roles":"codes:1,12,5,6,7","organisation_type":"Pharmaceutical company"}