RYZ101 for Neuroendocrine Tumors (ACTION-1 Trial)
Palo Alto (17 mi)Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
Sponsor: RayzeBio, Inc.
No Placebo Group
Pivotal Trial (Near Approval)
Prior Safety Data
Trial Summary
What is the purpose of this trial?This trial tests RYZ101, a new drug, in patients with advanced GEP-NETs that haven't responded to previous treatments. The drug aims to target specific receptors on the tumor cells to stop their growth.
Is the treatment RYZ101 a promising treatment for neuroendocrine tumors?Yes, RYZ101, also known as 225Ac-DOTATATE, is a promising treatment for neuroendocrine tumors. Similar treatments like DOTATATE have shown positive results in clinical trials, improving survival rates and controlling tumor growth. These therapies target specific receptors on tumor cells, making them effective in treating certain types of neuroendocrine tumors.12359
What safety data is available for RYZ101 (225Ac-DOTATATE) in treating neuroendocrine tumors?The study titled 'Initial Findings on the Use of [225Ac]Ac-DOTATATE Therapy as a Theranostic Application in Patients with Neuroendocrine Tumors' provides safety data for RYZ101 (225Ac-DOTATATE). It aimed to evaluate the stability, safety, and efficacy of this alpha-targeted therapy in patients with grade 1/2 metastatic neuroendocrine tumors (NETs).467810
What data supports the idea that RYZ101 for Neuroendocrine Tumors (also known as: RYZ101, 225Ac-DOTATATE) is an effective treatment?The available research shows that RYZ101, also known as 225Ac-DOTATATE, is being studied for its effectiveness in treating neuroendocrine tumors. While specific data on RYZ101's effectiveness is not detailed, the study aimed to evaluate its stability, safety, and efficacy. In comparison, other treatments like 177Lu-DOTATATE and 90Y-DOTATATE have shown positive results in reducing tumor size and improving outcomes in patients with neuroendocrine tumors. For example, 177Lu-DOTATATE combined with immune therapy showed significant tumor size reduction and a strong immune response, indicating that similar treatments can be effective.457810
Do I need to stop my current medications for the trial?The trial protocol does not specify if you need to stop your current medications. However, you cannot be on high-dose glucocorticoids within 14 days before the study and during the study, except for inhaled or topical steroids.
Eligibility Criteria
This trial is for adults with advanced, inoperable GEP-NETs that express somatostatin receptors and have progressed after treatment with 177Lu-SSA therapy. Participants must have a life expectancy of at least 12 weeks, stable symptoms controlled by SSAs, adequate kidney and blood function, and agree to use effective contraception.Inclusion Criteria
My kidneys are working well.
My tumor is a low to intermediate grade and cannot be removed by surgery.
I can take care of myself and am up and about more than 50% of my waking hours.
Exclusion Criteria
I haven't taken high-dose steroids for my condition in the last 14 days.
I do not have serious heart disease, uncontrollable high blood pressure, or diabetes.
I have received PRRT treatment, but not with Lu-177 SSA.
I have a history of liver cirrhosis.
I am allergic to specific imaging agents or their components.
Treatment Details
The study tests RYZ101's safety and dosage compared to standard care therapies like Everolimus or Sunitinib in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). It has two parts: determining the safe dose of RYZ101 and comparing its effectiveness against other treatments.
3Treatment groups
Experimental Treatment
Active Control
Group I: Phase 1b - RYZ101Experimental Treatment1 Intervention
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.
Group II: Phase 3 - Standard of CareActive Control4 Interventions
Investigator's choice of standard of care between everolimus, sunitinib, octreotide, or lanreotide.
Group III: Phase 3 - RYZ101Active Control1 Intervention
Actinium 225 radiolabeled somatostatin analog (SSA) for injection
Find a clinic near you
Research locations nearbySelect from list below to view details:
Research FacilityDuarte, CA
Research FacilityPhoenix, AZ
Research FacilityIrvine, CA
Research FacilityLos Angeles, CA
More Trial Locations
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Who is running the clinical trial?
RayzeBio, Inc.Lead Sponsor
References
Efficacy of radionuclide treatment DOTATATE Y-90 in patients with progressive metastatic gastroenteropancreatic neuroendocrine carcinomas (GEP-NETs): a phase II study. [2022]To evaluate the clinical and radiological effectiveness of [DOTA(0), D-Phe(1), Tyr(3)]-octreotate (DOTATATE) Y-90 in patients with extensive progressive gastroenteropancreatic neuroendocrine carcinomas (GEP-NETs).
Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers. [2022]To investigate response, survival, and safety profile of the somatostatin-based radiopeptide (90)yttrium-labeled tetraazacyclododecane-tetraacetic acid modified Tyr-octreotide ([(90)Y-DOTA]-TOC) in neuroendocrine cancers.
[Radionuclide therapy of endocrine-related cancer]. [2021]This article gives an overview of the established radionuclide therapies for endocrine-related cancer that already have market authorization or are currently under evaluation in clinical trials. Radioiodine therapy is still the gold standard for differentiated iodine-avid thyroid cancer. In patients with bone and lung metastases (near) total remission is seen in approximately 50% and the 15-year survival rate for these patients is approximately 90%. In contrast to the USA, meta-iodobenzylguanidine (MIBG) therapy has market approval in Europe. According to the current literature, in the setting of advanced stage neuroblastoma and malignant pheochromocytoma or paraganglioma, radiological remission can be achieved in >30% and symptom control in almost 80% of the treated patients. Somatostatin receptor targeted radionuclide therapies (e.g. with DOTATATE or DOTATOC) demonstrated promising results in phase 2 trials, reporting progression-free survival in the range of 24-36 months. A first phase 3 pivotal trial for intestinal carcinoids is currently recruiting and another trial for pancreatic neuroendocrine tumors is planned. Radiopharmaceuticals based on glucagon-like peptide 1 (GLP1) or minigastrins are in the early evaluation stage for application in the treatment of insulinomas and medullary thyroid cancer. In general, radiopharmaceutical therapy belongs to the group of so-called theranostics which means that therapy is tailored for individual patients based on molecular imaging diagnostics to stratify target positive or target negative tumor phenotypes.
[(177)Lu-DOTA](0)-D-Phe(1)-Tyr(3)-Octreotide ((177)Lu-DOTATOC) For Peptide Receptor Radiotherapy in Patients with Advanced Neuroendocrine Tumours: A Phase-II Study. [2022]To characterise efficacy and safety of (177)Lu-DOTATOC as agent for peptide receptor radiotherapy (PRRT) of advanced neuroendocrine tumours (NET).
Long-term efficacy of (90)Y-DOTATATE in patients with nonresectable pancreatic and small bowel neuroendocrine neoplasms. [2017]To determine the efficacy of (90)Y [DOTA(0), D-Phe(1), Tyr(3)]-octreotate (DOTATATE) in 67 patients with pancreatic and small bowel neuroendocrine tumors (NETs).
177Lu-DOTATATE in older patients with metastatic neuroendocrine tumours: safety, efficacy and health-related quality of life. [2021]Label="PURPOSE">The safety and efficacy of 177Lu-DOTATATE in older patients with advanced neuroendocrine tumours (NET) are not well understood.
Safety and response after peptide receptor radionuclide therapy with 177 Lu-DOTATATE for neuroendocrine tumors in phase 1/2 prospective Japanese trial. [2022]Label="BACKGROUND" NlmCategory="BACKGROUND">The present prospective phase 1/2 study aimed to elucidate the efficacy and safety of 177 Lu-DOTATATE (four cycles of 7.4 GBq) in Japanese patients with unresectable, progressive neuroendocrine tumors (NETs).
Addition of Peptide Receptor Radiotherapy to Immune Checkpoint Inhibition Therapy Improves Outcomes in Neuroendocrine Tumors. [2023]Neuroendocrine tumors (NETs) are often diagnosed in advanced stages. Despite the advances in treatment approaches, including somatostatin analogs and peptide receptor radionuclide therapy (PRRT), these patients have no curative treatment option. Moreover, immunotherapy often yields modest results in NETs. We investigated whether combining PRRT using [177Lu]DOTATATE and immune checkpoint inhibition therapy improves treatment response in NETs. Methods: A gastroenteropancreatic NET model was generated by subcutaneous implantation of human QGP-1 cells in immune-reconstituted NOD.Cg-Prkdcscid Il2rgtm1Wjl /SzJ mice engrafted with human peripheral blood mononuclear cells (n = 96). Mice were randomly assigned to receive pembrolizumab (anti-PD1), [177Lu]DOTATATE (PRRT), simultaneous anti-PD1 and PRRT (S-PRRT), anti-PD1 on day 0 followed by PRRT on day 3 (delayed PRRT [D-PRRT]), PRRT on day 0 followed by anti-PD1 (early PRRT [E-PRRT]), or vehicle as control (n = 12/group). Human granzyme-B-specific [68Ga]NOTA-hGZP PET/MRI was performed before and 6 d after treatment initiation, as an indicator of T-cell activation. Response to treatment was based on tumor growth over 21 d and on histologic analyses of extracted tissues on flow cytometry for T cells, hematoxylin and eosin staining, and immunohistochemical staining. Results: [68Ga]NOTA-hGZP PET/MRI showed significantly increased uptake in tumors treated with E-PRRT, S-PRRT, and anti-PD1 on day 6 compared with baseline (SUVmax: 3.36 ± 0.42 vs. 0.73 ± 0.23; 2.36 ± 0.45 vs. 0.76 ± 0.30; 2.20 ± 0.20 vs. 0.72 ± 0.28, respectively; P < 0.001), whereas no significant change was seen in PET parameters in the D-PRRT, PRRT, or vehicle groups (P > 0.05). Ex vivo analyses confirmed the PET results showing the highest granzyme-B levels and T cells (specifically CD8-positive effector T cells) in the E-PRRT group, followed by the S-PRRT and anti-PD1 groups. Tumor growth follow-up showed the most significant tumor size reduction in the E-PRRT group (baseline to day 21, 205.00 ± 30.70 mm3 vs. 78.00 ± 11.75 mm3; P = 0.0074). Tumors showed less growth reduction in the PRRT, D-PRRT, and S-PRRT groups than in the E-PRRT group (P < 0.0001). The vehicle- and anti-PD-1-treated tumors showed continued growth. Conclusion: Combination of PRRT and anti-PD1 shows the most robust inflammatory response to NETs and a better overall outcome than immune checkpoint inhibition or PRRT alone. The most effective regimen is PRRT preceding anti-PD1 administration by several days.
Upregulation of Somatostatin Receptor Type 2 Improves 177Lu-DOTATATE Therapy in Receptor-Deficient Pancreatic Neuroendocrine Tumor Model. [2023]Pancreatic neuroendocrine tumors (PNET) express high levels of somatostatin receptor type 2 (SSTR2), a unique target for both tumor imaging and therapy. This surface expression is lost in metastatic high-grade PNETs, making patients ineligible for SSTR2-targeted 177 Lutetium (Lu)-DOTATATE peptide receptor radionuclide therapy (PRRT), and represents an unmet clinical need. Here, we aimed to restore SSTR2 expression through the reversal of inhibitory epigenetic gene silencing to improve tumor responsiveness to PRRT. We first assessed human SSTR2 promoter methylation and expression levels in 96 patient samples. We then used three NET cell lines (QGP-1, BON-1, GOT-1) with variable SSTR2 expression profiles for functional in vitro studies using histone deacetylase inhibitors (HDACi). Finally, the QGP-1 xenograft mouse model, with low basal SSTR2 expression, was used to assess the therapeutic efficacy of combined HDACi and 177Lu-DOTATATE therapies. We confirm that SSTR expression is decreased and correlates with SSTR2 promoter methylation in patients with high-grade NETs. When exposed to HDACis, SSTR2 surface expression is increased in three NET cell lines in vitro. In an in vivo PNET xenograft model with low basal SSTR2 expression, our studies demonstrate significantly higher tumor uptake of SSTR2-targeted 177Lu-DOTATATE in animals pretreated with HDACis compared with controls. For the first time, we show that this higher tumor uptake results in significant antitumor response when compared with standard PRRT alone. These preclinical results provide a rationale for utilizing HDACi pretreatment to improve targeted radionuclide therapy in patients with SSTR2-negative, metastatic PNETs.
Initial Findings on the Use of [225Ac]Ac-DOTATATE Therapy as a Theranostic Application in Patients with Neuroendocrine Tumors. [2023]Label="Objectives" NlmCategory="UNASSIGNED">This study aimed to evaluate the stability, safety, and efficacy of alpha-targeted therapy with [225Ac]Ac-DOTATATE in patients with grade 1/2 metastatic neuroendocrine tumors (NETs).