Neuroendocrine Tumors Clinical Trial
— ACTION-1Official title:
Phase 1b/3 Global, Randomized, Controlled, Open-label Trial Comparing Treatment With RYZ101 to Standard of Care Therapy in Subjects With Inoperable, Advanced, SSTR+, Well-differentiated GEP-NETs That Have Progressed Following Prior 177Lu-SSA Therapy
Verified date | April 2024 |
Source | RayzeBio, Inc. |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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.
Status | Active, not recruiting |
Enrollment | 288 |
Est. completion date | July 2028 |
Est. primary completion date | July 2025 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years and older |
Eligibility | 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. Radiographic progression must be demonstrated within 18 months of randomization. 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: 1. Everolimus 10 mg daily 2. Sunitinib 37.5 mg daily 3. High-dose octreotide LAR 60 mg Q4W 4. High dose frequency lanreotide 120 mg every 2 weeks (Q2W) 7. Adequate renal function, as evidenced by creatinine clearance (CrCl) =60 mL/min (calculated using the Cockcroft-Gault formula) (Cockcroft and Gault, 1976) 8. Adequate hematologic function, defined by the following laboratory results: 1. 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) 2. 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: 1. PRRT: within <6 months 2. Chemotherapy: within <6 weeks 3. Small molecule inhibitors: within <4 weeks 4. Biological agents: within 4 weeks 6. Prior external-beam radiation (EBRT) therapy as defined below: 1. Part 1: Any prior EBRT, including SBRT 2. 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 hemoglobin A1C (HgB A1C) =8% 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. 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. 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. 19. Prior history of liver cirrhosis |
Country | Name | City | State |
---|---|---|---|
Belgium | Cliniques universitaires Saint-Luc | Brussel | |
Belgium | Institut Jules Bordet | Brussels | |
Belgium | UZ Leuven | Leuven | |
Belgium | AZ Delta | Roeselare | |
Brazil | Sociedade Beneficente De Senhoras Hospital - Sírio-Libanês Brasilia | Brasília | |
Brazil | Instituto D'or de Pesquisa e Ensino | Rio De Janeiro | |
Brazil | Instituto Nacional de Cancer | Rio De Janeiro | |
Brazil | Fundacao Antonio Prudente - A.C. Camargo Cancer Center | São Paulo | |
Brazil | Hospital Israelita Albert Einstein | São Paulo | |
Brazil | Sociedade Beneficente de Senhoras Hospital Sirio-Libanes | São Paulo | |
Canada | London Health Sciences Centre | London | Ontario |
Canada | Jewish General Hospital | Montréal | Quebec |
Canada | Sunnybrook Health Sciences Centre | Toronto | Ontario |
Canada | University Health Network - Princess Margaret Cancer Centre | Toronto | |
France | CHU Beaujon, APHP.Nord - Université Paris Cité | Clichy | |
France | CHRU de Lile | Lille | |
France | CHU De Nantes | Nantes | |
France | CHRU de Nancy Hôpital de Brabois | Vandoeuvre-Lès-Nancy | |
France | Institut Gustave Roussy | Villejuif | |
Netherlands | UMC Utrecht | Utrecht | |
Spain | Hospital Universitari Vall d'Hebron | Barcelona | |
Spain | Hospital HM Universitario Sanchinarro | Madrid | |
Spain | Hospital Universitario 12 de Octubre | Madrid | |
Spain | Hospital Universitario La Paz | Madrid | |
Spain | Hospital Universitario Ramon Y Cajal | Madrid | |
Spain | MD Anderson Cancer Center | Madrid | |
Spain | Hospital Universitario Miguel Servet | Zaragoza | |
United States | Winship Cancer Institute, Emory University Hospital Midtown | Atlanta | Georgia |
United States | Boston Medical Center | Boston | Massachusetts |
United States | Dana-Farber Cancer Institute | Boston | Massachusetts |
United States | University Hospitals Cleveland Medical Center | Cleveland | Ohio |
United States | City of Hope | Duarte | California |
United States | Advanced Molecular Imaging and Therapy | Glen Burnie | Maryland |
United States | MD Anderson | Houston | Texas |
United States | University of Iowa Hospitals & Clinics | Iowa City | Iowa |
United States | Mayo Clinic Florida | Jacksonville | Florida |
United States | University of Kentucky Markey Cancer Center | Lexington | Kentucky |
United States | UCLA Nuclear Medicine | Los Angeles | California |
United States | Biogenix Molecular | Miami | Florida |
United States | Vanderbilt University Medical Center | Nashville | Tennessee |
United States | Yale Cancer Center | New Haven | Connecticut |
United States | Icahn School of Medicine at Mount Sinai | New York | New York |
United States | Memorial Sloan Kettering | New York | New York |
United States | Hoag Memorial Hospital Presbyterian | Newport Beach | California |
United States | Nebraska Cancer Specialists | Omaha | Nebraska |
United States | Stanford University | Palo Alto | California |
United States | University of Pennsylvania | Philadelphia | Pennsylvania |
United States | Mayo Clinic Arizona | Phoenix | Arizona |
United States | UPMC Hillman Cancer Center | Pittsburgh | Pennsylvania |
United States | Oregon Health & Science University | Portland | Oregon |
United States | Mayo Clinic Rochester | Rochester | Minnesota |
United States | Washington University - St. Louis | Saint Louis | Missouri |
United States | Huntsman Cancer Hospital University of Utah | Salt Lake City | Utah |
United States | University of California, San Francisco | San Francisco | California |
United States | Fred Hutchinson Cancer Center | Seattle | Washington |
United States | Moffitt Cancer Center | Tampa | Florida |
United States | Profound Research LLC/MHP Radiation Oncology Institute | Troy | Michigan |
United States | MedStar Washington Hospital Center | Washington | District of Columbia |
Lead Sponsor | Collaborator |
---|---|
RayzeBio, Inc. |
United States, Belgium, Brazil, Canada, France, Netherlands, Spain,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | Phase 1b and 3: Incidence and severity of AEs by NCI CTCAE v5, including SAEs, laboratory changes, ECG changes, and other safety findings | Incidence and severity of AEs by NCI CTCAE v5, including SAEs, laboratory changes, ECG changes, and other safety findings | Up to 80 months | |
Other | Phase 3: Cmax | Up to 80 months | ||
Other | Phase 3: AUC | Up to 80 months | ||
Other | Phase 3: Average Concentration | Up to 80 months | ||
Other | Phase 3: Relationship between exposure endpoints and clinical outcomes | Up to 80 months | ||
Other | Phase 3: 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) | 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) | Up to 80 months | |
Other | Phase 3: Changes in EQ-5D-5L questionnaire scores | Up to 80 months | ||
Other | Phase 3: Changes in EORTC QLQ-C30 questionnaire scores | Up to 80 months | ||
Other | Phase 3: Changes in EORTC QLQ GI NET21 questionnaire scores | Up to 80 months | ||
Other | Phase 3: QTc | Measured by continuous ECG recording using a 12-lead Holter monitoring device | Up to 80 months | |
Primary | Phase 1b: RP3D | Incidence of DLTs during the first 56 days of study treatment will be assessed. | 56 days of study treatment | |
Primary | Phase 3: 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 earlier. | After the target number of 143 PFS events have occurred | |
Secondary | Phase 1b: Cmax | Up to Day 8 | ||
Secondary | Phase 1b: Tmax | Up to Day 8 | ||
Secondary | Phase 1b: AUC | Up to Day 8 | ||
Secondary | Phase 1b: Volume of Distribution | Up to Day 8 | ||
Secondary | Phase 1b: Clearance | Up to Day 8 | ||
Secondary | Phase 1b: Terminal Half-life | Up to Day 8 | ||
Secondary | Phase 1b: TIAC of RYZ101 to critical organs and tumors | Calculated mean TIAC (hours) and absorbed radiation dose coefficients (mGy/MBq) to critical organs (e.g., the kidneys and bone marrow) and tumors after the 1st and 4th RYZ101 infusions will be assessed | Up to Day 184 | |
Secondary | Phase 1b: Absorbed radiation doses of RYZ101 to critical organs and tumors | Calculated mean TIAC (hours) and absorbed radiation dose coefficients (mGy/MBq) to critical organs (e.g., the kidneys and bone marrow) and tumors after the 1st and 4th RYZ101 infusions will be assessed | Up to Day 184 | |
Secondary | Phase 3: OS | OS will be defined as the time from the date of randomization until the date of death due to any cause. | Up to 80 months or until a total of 130 deaths have occurred, whichever occurs first | |
Secondary | Phase 3: ORR by BICR | ORR, as determined by BICR according to RECIST v1.1. | Up to 80 months | |
Secondary | Phase 3: PFS | PFS as determined by Investigator | Up to 80 months | |
Secondary | Phase 3: ORR by Inv | ORR, as assessed by the Investigator according to RECIST v1.1 | Up to 80 months | |
Secondary | Phase 3: BOR | Assessed by BICR and by the Investigator according to RECIST v1.1 | Up to 80 months | |
Secondary | Phase 3: Disease Control Rate | Assessed by BICR and by the Investigator according to RECIST v1.1 | Up to 80 months | |
Secondary | Phase 3: DoR | Only for subjects with a RECIST v.1.1 response, assessed by BICR and by the Investigator according to RECIST v1.1 | Up to 80 months |
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