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 177Lu-labelled somatostatin analogue (177Lu-SSA) therapy (ACTION-1)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Rayzebio Inc.

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

17 Oct 2024 → ongoing

Decision date (initial)

2024-03-27

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

RayzeBio, Inc.

External identifiers

EU CT number

2023-509334-19-00

EudraCT number

2022-000507-12

ClinicalTrials.gov

NCT05477576

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Dose response, Others, Pharmacokinetic, Safety, Efficacy

Part 1:
- To determine the RP3D of RYZ101
- To assess the safety and tolerability of RYZ101 in subjects with SSTR+ GEP-NET that has progressed following treatment with 177Lu-SSA
Part 2:
- To determine if treatment with RYZ101, compared to SoC therapy, improves centrally confirmed PFS in study subjects.

Secondary objectives 8

1. To determine if treatment with RYZ101, compared to SoC therapy, improves OS in study subjects.
2. To determine if treatment with RYZ101, compared to SoC therapy, improves ORR in study subjects
3. To evaluate the efficacy of RYZ101 compared to SoC therapy in terms of Investigator-assessed PFS
4. To further evaluate the efficacy of RYZ101 compared to SoC therapy by Investigator-assessed ORR, as well as BOR, DoR, and disease control rate as determined by BICR and by the Investigator
5. To characterize the safety and tolerability of RYZ101 in study subjects
6. To evaluate the PK of RYZ101
7. To evaluate PK and ECG parameters in a subset of approximately 30 subjects
8. To study the evolution and determinants of subjects’ HRQoL

Conditions and MedDRA coding

gastro-enteropancreatic neuroendocrine tumors (GEP-NETs)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

IPD plan description

The plan description for what IPD to share, when and with whom, and for what type of analyses, will be determined as the trial progresses and IPD is gathered.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. 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.
2. 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) )
3. 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).
4. Total bilirubin ≤3 x upper limit normal (ULN)
5. Serum albumin ≥3.0 g/dL unless prothrombin time (PT) is within the normal range
6. 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).
7. 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 21

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. 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
3. 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.
4. Uncontrolled diabetes mellitus as defined by hemoglobin A1C (HgB A1C) ≥8%
5. 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.
6. 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.
7. 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.)
8. Subject requires other treatment that in the opinion of the investigator would be more appropriate than the therapy offered in the study
9. Unable or unwilling to comply with the requirements of the study protocol
10. PRRT other than 177Lu-DOTATATE/TOC or 177Lu-HA-DOTATATE as described in Inclusion Criterion #7
11. 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.
12. Known hypersensitivity to 225Actinium, 68Gallium, 64Copper, octreotate, or any of the excipients of DOTATATE imaging agents
13. Prior history of liver cirrhosis or liver transplantation.
14. Part 1: Prior treatment with alkylating agents
15. Prior radioembolization
16. Any surgery, chemoembolization, and radiofrequency ablation within 12 weeks prior to first dose of study treatment
17. 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
18. 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
19. Prior participation in any interventional clinical study within 30 days prior to first dose of study treatment
20. Current somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study
21. Pregnancy or breastfeeding

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Part 1: - Incidence of DLTs during the first 56 days of study treatment
2. Part 1: Incidence and severity of AEs by NCI CTCAE v5, including SAEs, laboratory changes, ECG changes, and other safety findings
3. 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.

Secondary endpoints 12

1. Part 2: - OS will be defined as the time from the date of randomization until the date of death due to any cause.
2. ORR, as determined by BICR according to RECIST v1.1
3. PFS as determined by the Investigator
4. ORR, as assessed by the Investigator according to RECIST v1.1
5. 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
6. Incidence and severity of AEs by NCI CTCAE v5, including SAEs, laboratory changes, ECG changes, and other safety findings
7. 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.
8. 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)
9. Changes in: • EQ-5D-5L • EORTC QLQ-C30 and • EORTC QLQ GI NET21 questionnaire scores
10. Population predicted exposure parameters (i.e. Cmax, AUC, average concentration)
11. Relationship between exposure endpoints and clinical outcomes (efficacy and safety)
12. 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

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 4

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Rayzebio Inc.

Sponsor organisation

Rayzebio Inc.

Address

3013 Science Park Road

City

San Diego

Postcode

92121-1101

Country

United States

Scientific contact point

Organisation

Rayzebio Inc.

Contact name

RayzeBio Senior Medical Director

Public contact point

Organisation

Rayzebio Inc.

Contact name

RayzeBio Senior Medical Director

Third parties 11

Locations

4 EU/EEA countries · 20 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 3 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 62 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

9 submissions — initial application plus substantial / non-substantial modifications