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    DRUG:

    Actinium-225 DOTATATE (RYZ101)

    i
    Other names: RYZ101, Actinium 225 radiolabeled somatostatin analog, 225Ac-DOTATATE, RYZ 101, RYZ-101
    Company:
    BMS
    Drug class:
    Alpha radiation emitter, SSTR2 inhibitor
    Related drugs:
    2ms
    TRACY-1: Trial of 225Ac-DOTATATE (RYZ101) Alone and with Pembrolizumab in Subjects with ER+, HER2-negative Unresectable or Metastatic Breast Cancer Expressing SSTRs (clinicaltrials.gov)
    P1/2, N=172, Recruiting, RayzeBio, Inc.
    New P1/2 trial • Combination therapy • Metastases
    |
    Keytruda (pembrolizumab) • Actinium-225 DOTATATE (RYZ101)
    3ms
    ACTION-1: Study of RYZ101 Compared With SOC in Pts w Inoperable SSTR+ Well-differentiated GEP-NET That Has Progressed Following 177Lu-SSA Therapy (clinicaltrials.gov)
    P3, N=288, Recruiting, RayzeBio, Inc. | Active, not recruiting --> Recruiting
    Enrollment open • Metastases
    |
    SSTR (Somatostatin Receptor)
    |
    sunitinib • everolimus • Actinium-225 DOTATATE (RYZ101)
    6ms
    Study of RYZ101 in Combination With SoC in Subjects With SSTR+ ES-SCLC (clinicaltrials.gov)
    P1, N=31, Recruiting, RayzeBio, Inc. | Trial primary completion date: Apr 2024 --> Mar 2025
    Trial primary completion date • Combination therapy
    |
    PD-L1 (Programmed death ligand 1) • SSTR (Somatostatin Receptor)
    |
    Tecentriq (atezolizumab) • carboplatin • etoposide IV • Actinium-225 DOTATATE (RYZ101)
    6ms
    AcTRESS: A Phase I Study to Assess the Tolerability of 225Ac-DOTATATE in Patients With Refractory and Relapsing Multiple Myeloma Expressing Somatostatin Receptors (clinicaltrials.gov)
    P1, N=30, Not yet recruiting, Jules Bordet Institute
    New P1 trial
    |
    Actinium-225 DOTATATE (RYZ101)
    7ms
    ACTION-1: Study of RYZ101 Compared With SOC in Pts w Inoperable SSTR+ Well-differentiated GEP-NET That Has Progressed Following 177Lu-SSA Therapy (clinicaltrials.gov)
    P3, N=288, Active, not recruiting, RayzeBio, Inc. | Recruiting --> Active, not recruiting
    Enrollment closed • Metastases
    |
    SSTR (Somatostatin Receptor)
    |
    sunitinib • everolimus • Actinium-225 DOTATATE (RYZ101) • Somatuline Depot (lanreotide prolonged-release subcutaneous) • octreotide acetate
    8ms
    Study of RYZ101 in Combination With SoC in Subjects With SSTR+ ES-SCLC (clinicaltrials.gov)
    P1, N=31, Recruiting, RayzeBio, Inc. | Phase classification: P1b --> P1
    Phase classification • Combination therapy
    |
    PD-L1 (Programmed death ligand 1) • SSTR (Somatostatin Receptor)
    |
    SSTR positive
    |
    Tecentriq (atezolizumab) • carboplatin • etoposide IV • Actinium-225 DOTATATE (RYZ101)
    11ms
    ACTION-1: Study of RYZ101 Compared With SOC in Pts w Inoperable SSTR+ Well-differentiated GEP-NET That Has Progressed Following 177Lu-SSA Therapy (clinicaltrials.gov)
    P3, N=288, Recruiting, RayzeBio, Inc.
    Trial completion date • Trial primary completion date • Metastases
    |
    SSTR (Somatostatin Receptor)
    |
    sunitinib • everolimus • Actinium-225 DOTATATE (RYZ101) • Somatuline Depot (lanreotide prolonged-release subcutaneous) • octreotide acetate
    1year
    ACTION-1: Study of RYZ101 Compared With SOC in Pts w Inoperable SSTR+ Well-differentiated GEP-NET That Has Progressed Following 177Lu-SSA Therapy (clinicaltrials.gov)
    P3, N=288, Recruiting, RayzeBio, Inc. | Phase classification: P1b --> P3
    Phase classification • Metastases
    |
    SSTR (Somatostatin Receptor)
    |
    sunitinib • everolimus • Actinium-225 DOTATATE (RYZ101) • Somatuline Depot (lanreotide prolonged-release subcutaneous) • octreotide acetate
    1year
    ACTION-1: Study of RYZ101 Compared With SOC in Pts w Inoperable SSTR+ Well-differentiated GEP-NET That Has Progressed Following 177Lu-SSA Therapy (clinicaltrials.gov)
    P1b, N=288, Recruiting, RayzeBio, Inc. | N=218 --> 288
    Enrollment change • Metastases
    |
    SSTR (Somatostatin Receptor)
    |
    sunitinib • everolimus • Actinium-225 DOTATATE (RYZ101) • Somatuline Depot (lanreotide prolonged-release subcutaneous) • octreotide acetate
    1year
    RYZ101 (Ac-225 DOTATATE) Opportunity Beyond Gastroenteropancreatic Neuroendocrine Tumors: Preclinical Efficacy in Small Cell Lung Cancer. (PubMed, Mol Cancer Ther)
    The anti-tumor effect was further enhanced when RYZ101 was combined with carboplatin and etoposide at clinically relevant doses. In summary, RYZ101 is a highly potent, alpha-emitting radiopharmaceutical agent, and preclinical data demonstrate the potential of RYZ101 for the treatment of patients with SSTR-positive cancers.
    Preclinical • Journal
    |
    SSTR (Somatostatin Receptor) • SSTR2 (Somatostatin Receptor 2)
    |
    SSTR positive • SSTR2 expression • SSTR Expression • SSTR2 positive
    |
    carboplatin • etoposide IV • Actinium-225 DOTATATE (RYZ101)
    over1year
    Phase Ib portion of the ACTION-1 phase Ib/3 trial of RYZ101 in gastroenteropancreatic neuroendocrine tumors (GEP-NET) progressing after 177Lu somatostatin analogue (SSA) therapy: Safety and efficacy findings (ESMO 2023)
    Initial data suggest promising efficacy. Part 2 (phase 3) is enrolling and will compare RYZ101 at 10.2MBq q8w for 4 cycles with standard of care in pts with advanced SSTR2+ GEP-NETs progressing following prior 177Lu-labeled SSAs.
    Clinical • P1 data
    |
    SSTR (Somatostatin Receptor) • SSTR2 (Somatostatin Receptor 2)
    |
    Actinium-225 DOTATATE (RYZ101)
    over1year
    RYZ101 (Ac-225 DOTATATE) Opportunity Beyond GEP-NETs: Preclinical Efficacy in Small Cell Lung Cancer (IASLC-WCLC 2023)
    In summary, RYZ101 is a first-in-class, highly potent, -emitting radiopharmaceutical therapy being developed for the treatment of SSTR+ solid tumors. Preclinical data demonstrate the potential of RYZ101 for the treatment of patients with SSTR+ SCLC. A Phase 1b trial of RYZ101 in combination with atezolizumab, carboplatin, and etoposide is underway in patients with SSTR+ ES-SCLC (NCT05595460).
    Preclinical • PD(L)-1 Biomarker
    |
    SSTR (Somatostatin Receptor) • SSTR2 (Somatostatin Receptor 2)
    |
    SSTR Expression
    |
    Tecentriq (atezolizumab) • carboplatin • etoposide IV • Actinium-225 DOTATATE (RYZ101)
    over1year
    ACTION-1 phase Ib/3 trial of RYZ101 in somatostatin receptor subtype 2–expressing (SSTR2+) gastroenteropancreatic neuroendocrine tumors (GEP-NET) progressing after 177Lu somatostatin analogue (SSA) therapy: Initial safety analysis. (ASCO 2023)
    RYZ101 was well tolerated at 120 kBq/kg, which was declared the RP3D. Part 2 (Phase 3) will commence after Part 1 and will compare RYZ101 at the RP3D with standard of care in pts with advanced SSTR2+ GEP-NETs with disease progression following prior 177Lu-labeled SSAs. Clinical trial information: NCT05477576.
    Clinical
    |
    SSTR (Somatostatin Receptor) • SSTR2 (Somatostatin Receptor 2)
    |
    SSTR2 expression
    |
    Actinium-225 DOTATATE (RYZ101)
    over1year
    ACTION-1: Study of RYZ101 Compared With SOC in Pts w Inoperable SSTR+ Well-differentiated GEP-NET That Has Progressed Following 177Lu-SSA Therapy (clinicaltrials.gov)
    P1b, N=218, Recruiting, RayzeBio, Inc. | Active, not recruiting --> Recruiting
    Enrollment open • Metastases
    |
    SSTR (Somatostatin Receptor)
    |
    sunitinib • everolimus • Actinium-225 DOTATATE (RYZ101) • Somatuline Depot (lanreotide prolonged-release subcutaneous) • octreotide acetate
    over1year
    Anti-tumor activity of RYZ101 (Ac-225 DOTATATE) in somatostatin receptor-expressing preclinical models of small-cell lung cancer (AACR 2023)
    In summary, RYZ101 is a first-in-class, highly potent, α-emitting radiopharmaceutical therapy being developed for the treatment of SSTR+ solid tumors. Preclinical data demonstrate the potential of RYZ101 for the treatment of patients with SSTR+ SCLC.
    Preclinical
    |
    SSTR (Somatostatin Receptor) • SSTR2 (Somatostatin Receptor 2)
    |
    SSTR Expression
    |
    carboplatin • etoposide IV • Actinium-225 DOTATATE (RYZ101)
    over1year
    ACTION-1: Study of RYZ101 Compared With SOC in Pts With Inoperable SSTR+ Well-differentiated GEP-NET That Has Progressed Following 177Lu-SSA Therapy (clinicaltrials.gov)
    P1b, N=218, Active, not recruiting, RayzeBio, Inc. | Recruiting --> Active, not recruiting
    Enrollment closed • Metastases
    |
    SSTR (Somatostatin Receptor)
    |
    sunitinib • everolimus • Actinium-225 DOTATATE (RYZ101) • Somatuline Depot (lanreotide prolonged-release subcutaneous) • octreotide acetate
    almost2years
    Study of RYZ101 in Combination With SoC in Subjects With SSTR+ ES-SCLC (clinicaltrials.gov)
    P1b, N=31, Recruiting, RayzeBio, Inc. | Not yet recruiting --> Recruiting
    Enrollment open • Combination therapy
    |
    PD-L1 (Programmed death ligand 1) • SSTR (Somatostatin Receptor)
    |
    SSTR positive
    |
    Tecentriq (atezolizumab) • carboplatin • etoposide IV • Actinium-225 DOTATATE (RYZ101)
    2years
    ACTION-1: A Randomized Phase Ib/3 trial of RYZ101 Compared with SoC in SSTR2+ Well-Differentiated GEP-NET with Progression Following Lu-177 SSA (NANETS 2022)
    In Part 2, ~210 patients will be randomized (1:1) to receive RYZ101 RP3D every 8 weeks for up to 4 cycles or investigator’s choice SoC (everolimus, sunitinib, or high-dose long-acting SSA); crossover to RYZ101 is permitted. Part 2 will commence after Part 1 at ~60 sites in North America, South America, Europe, and Asia. CONCLUSIONS No conclusions; TiP abstract.
    Clinical
    |
    SSTR (Somatostatin Receptor) • SSTR2 (Somatostatin Receptor 2)
    |
    SSTR Expression
    |
    sunitinib • everolimus • Actinium-225 DOTATATE (RYZ101)
    2years
    Study of RYZ101 in Combination With SoC in Subjects With SSTR+ ES-SCLC (clinicaltrials.gov)
    P1b, N=31, Not yet recruiting, RayzeBio, Inc.
    New P1 trial • Combination therapy
    |
    PD-L1 (Programmed death ligand 1) • SSTR (Somatostatin Receptor)
    |
    SSTR positive
    |
    Tecentriq (atezolizumab) • carboplatin • etoposide IV • Actinium-225 DOTATATE (RYZ101)
    over2years
    ACTION-1: Study of RYZ101 Compared With SOC in Pts With Inoperable SSTR+ Well-differentiated GEP-NET That Has Progressed Following 177Lu-SSA Therapy (clinicaltrials.gov)
    P1b, N=218, Recruiting, RayzeBio, Inc.
    New P1 trial
    |
    SSTR (Somatostatin Receptor)
    |
    sunitinib • everolimus • Actinium-225 DOTATATE (RYZ101) • Somatuline Depot (lanreotide prolonged-release subcutaneous) • octreotide acetate