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Part 1 is an uncontrolled dose de-escalation study to confirm the safety and determine the RP3D of RYZ101 based on Bayesian optimal interval design. Eligible participants will be enrolled in cohorts of 6 to receive RYZ101 up to 4 infusions every 8 weeks. If the initial dose level is not tolerated, the dose will be de-escalated; up to 3 dose levels will be assessed.

Actinium 225 radiolabeled somatostatin analog (SSA) for injection

Investigator's choice of standard of care between everolimus, sunitinib, octreotide, or lanreotide.

RYZ101

Everolimus 10 mg

Sunitinib 37.5 MG

High-dose octreotide LAR 60 mg Q4W by i.m. injection

Octreotide LAR 60 MG Injection

High dose frequency lanreotide 120 mg Q2W by deep s.c. injection

Lanreotide 120Mg Sa Susp Inj Syringe

Denis Ferreira, MD

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.

Study of RYZ101 Compared With SOC in Pts w Inoperable SSTR+ Well-differentiated GEP-NET That Has Progressed Following 177Lu-SSA Therapy

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

Incidence and severity of AEs by NCI CTCAE v5, including SAEs, laboratory changes, ECG changes, and other safety findings

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)

Measured by continuous ECG recording using a 12-lead Holter monitoring device

Incidence of DLTs during the first 56 days of study treatment will be assessed.

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.

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

OS will be defined as the time from the date of randomization until the date of death due to any cause.

ORR, as determined by BICR according to RECIST v1.1.

ORR, as assessed by the Investigator according to RECIST v1.1

Assessed by BICR and by the Investigator according to RECIST v1.1

Only for subjects with a RECIST v.1.1 response, assessed by BICR and by the Investigator according to RECIST v1.1

RayzeBio, Inc.

Amino Acids

Ibrutinib

Tyrosine Kinase Inhibitors

Tyrosine

Ibrutinib Initial Dose 560 mg by mouth (PO) every day (QD)

Ibrutinib will be administered orally once daily and each cycle will be defined as 4 weeks duration. Study treatment should begin within 14 days following enrollment into the study and continue until disease progression, unacceptable toxicity, or withdrawal of consent.

Jonathan Strosberg, M.D.

This is a prospective phase II open-label trial, stratifying patients equally into two cohorts consisting of carcinoid tumors and pancreatic neuroendocrine tumors (pNETs). The purpose of this study is to test any good and bad effects of the study drug called Ibrutinib.

The study population will consist of adult patients with histologically confirmed low to intermediate grade NETs of the GI tract, lungs and unknown primary (carcinoid tumors) or pNETs. All patients must be confirmed to have advanced disease. The study will enroll up to 51 patients in two cohorts (30 carcinoid and 21 pNET patients).

Phase II Study of Ibrutinib in Advanced Carcinoid and Pancreatic Neuroendocrine Tumors

Response rate as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. For this study, measurable disease is defined as the presence of at least one measurable lesion.

Measurable lesions must be accurately measured in at least one dimension (longest diameter in the plane of measurement is to be recorded) with a minimum size of: 10 mm by CT scan (CT scan slice thickness no greater than 5 mm (when CT scans have slice thickness \>5 mm, the minimum size should be twice the slice thickness); 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured with calipers should be recorded as non-measurable); 20 mm by chest X-ray.

Complete Response (CR): complete disappearance of all target lesions, confirmed by repeat assessments at no less than 4 weeks after the criteria for response are first met. Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum longest diameter.

Progression free survival at one year. PFS, determined as the time from administration of the initial dose of ibrutinib until objective tumor progression using RECIST, or death. Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this may include the baseline sum). The sum must also demonstrate an absolute increase of at least 5 mm.

Overall Survival determined from the time of drug administration to death from any cause.

Adverse events possibly related to study treatment with Ibrutinib. Safety and tolerability will be assessed according to the NIH/NCI Common TerminologyCriteria for Adverse Events version 4 (CTCAE v4).

Duration of response, defined as time from first observation of an objective response which is subsequently confirmed, to first disease progression or death due to any cause.

Pharmacyclics LLC.

H. Lee Moffitt Cancer Center and Research Institute

SAEs are reported that occurred after first dose of study drug through 30 days after discontinuation of study drug.

Ibrutinib Initial Dose 560 mg by mouth (PO) every day (QD)

Ibrutinib: Ibrutinib will be administered orally once daily and each cycle will be defined as 4 weeks duration. Study treatment should begin within 14 days following enrollment into the study and continue until disease progression, unacceptable toxicity, or withdrawal of consent.

Ibrutinib Therapy

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Jonathan Strosberg, MD

All participants who received at least one dose of study drug.

Overall Radiographic Response Rate (ORR)

Progression Free Survival (PFS)

Overall Survival (OS)

All participants who received at least one dose of study drug and had at least one adverse event that was possibly probably or definitely related to study treatment.

Occurrence of Possibly Related Adverse Events (AEs)

No participants experienced objective response

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Study of RYZ101 Compared With SOC in Pts w Inoperable SSTR+ Well-differentiated GEP-NET That Has Progressed Following 177Lu-SSA Therapy	NCT05477576	GEP-NET Gastroenteropan... Gastroenteropan... Neuroendocrine ... Carcinoid Carcinoid Tumor Pancreatic NET	RYZ101 Everolimus 10 m... Sunitinib 37.5 ... Octreotide LAR ... Lanreotide 120M...	18 Years -	RayzeBio, Inc.
Phase II Study of Ibrutinib in Advanced Carcinoid and Pancreatic Neuroendocrine Tumors	NCT02575300	Carcinoid Tumor... Pancreatic NET	Ibrutinib	18 Years -	H. Lee Moffitt Cancer Center and Research Institute

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