P3, N=288, Recruiting, RayzeBio, Inc.

SOM suppressed the EMT progression in PC cells through its regulation of the TGF-β/Smad signaling pathway.

P3, N=288, Recruiting, RayzeBio, Inc. | Phase classification: P1b --> P3

Medical treatment with dopamine agonists (DA), mainly cabergoline, is considered the primary therapy for these patients...Patients with aggressive and DA-resistant adenomas or with rare PRL-secreting carcinomas can be treated off-label with temozolomide (TMZ), a DNA alkylating agent...Other therapeutic options include aromatase inhibitors, the somatostatin receptor ligand pasireotide, peptide receptor radionuclide therapy (PRRT), immune-checkpoint inhibitors, tyrosine-kinase inhibitors, or everolimus, the mammalian target of rapamycin inhibitor. These experimental treatments were effective in some patients carrying refractory prolactinomas showing usually partial tumor control. However, the number of treated patients with any of these new therapeutic options is very limited and treatment results are inconsistent, thus additional experience with more patients is required.

P1b, N=288, Recruiting, RayzeBio, Inc. | N=218 --> 288

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.

Long-acting SSAs are an effective and safe initial therapy of patients with well differentiated NET, allowing tumor growth as well as symptoms control for long-time in selected patients.

Conformal or stereotactic radiotherapy may be discussed on a case-by-case basis, especially in case of drug inefficacy or poor tolerance. Acromegaly should be managed by a multidisciplinary team, preferably within an expert center such as a reference or skill center for rare pituitary diseases.

When first-generation somatostatin analogues (SSAs) fail to control hypoglycemia syndrome, second-generation SSAs and everolimus have to be considered for exploiting their hyperglycemic effect...PRRT seems to be an effective treatment when surgery and SSAs fail. The application of these therapeutic modalities has been shown to be efficacious in controlling the manifestations of the secretory syndrome and prolonging overall survival of patients suffering from these malignancies.

Most of the earlier studies used different definitions of POPF and other complications; included patients with varied pancreatic pathologies such as cancer, chronic pancreatitis, and benign lesions; surgical techniques such as pancreaticoduodenectomy, distal pancreatectomy, and other procedures; use of somatostatin and its analogs such as octreotide, lanreotide, pasireotide, and vapreotide; varied surgeon and institutional volume; and so on. Data indicate favorable role of newer somatostatin analogs, and further studies are urgently needed. The question about the efficacy of prophylactic octreotide to reduce POPF after pancreaticoduodenectomy remains open to debate.

In contrast, densely granulated somatotroph and corticotroph tumors express high levels of somatostatin receptors and are more responsive to somatostatin analogs. Since ACTH-producing PitNETs express SSTR5 without SSTR2, the second-generation somatostatin analog, pasireotide, is effective against ACTH-producing PitNETs.

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.

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).

Synthetic therapeutic agonists showing selectivity for SSTR2 (Octreotide) or for SSTR2 and SSTR5 (Pasireotide) have been approved for the treatment of patients with acromegaly and Cushing's syndrome, as their pituitary tumors highly express SSTR2 or SSTR2/SSTR5, respectively...Furthermore, ITF2984 displays antitumor activity that is dependent on SSTR3 expression levels in the MENX (homozygous mutant) NFPA rat model, which closely recapitulates human disease. Therefore, ITF2984 may represent a novel therapeutic option for patients affected by NFPA.

The most widely used are somatostatin analogues with three clinically approved drugs: lanreotide and octreotide (first-generation) and pasireotide (second-generation). Both everolimus and interferon used in combination with octreotide have shown significant reduction in urinary 5-hydroxyindoleacetic acid compared to octreotide alone. Telotristat ethyl has been increasingly utilised for patients with symptoms despite taking somatostatin analogues...There are therefore numerous different therapies. This paper describes the pathophysiology and therapy of carcinoid syndrome.

Low-dose (1 mg) dexamethasone suppression test reduced AM cortisol to 1.7 µg/dL and ACTH of 8 pg/mL...Some medications for CD impede pregnancy through their mechanism (eg, mifepristone)...Although her CD symptoms returned when pasireotide was discontinued, she delivered a healthy infant; limited pasireotide data in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. Our case underscores the potential for successful conception for women with CD when cortisol levels are normalized with treatment that avoids suppressing menstruation.

High-dose diazoxide, everolimus, dexamethasone, glucagon, pasireotide, or enteral feeding did not produce a response. No adverse effects have been observed. In summary, the anti-insulin receptor monoclonal antibody RZ358 effectively controlled hypoglycemia refractory to multiple other therapies, allowing restoration of normoglycemia and enabling additional successful cancer therapy.

Our results provide new insights into potential PRKCD contribution in Pasireotide mechanism of action and suggest that PRKCD might be a possible marker of therapeutic response in ACTH-secreting pituitary tumors.

P2, N=217, Suspended, Gustave Roussy, Cancer Campus, Grand Paris | Recruiting --> Suspended | Trial primary completion date: Feb 2023 --> Jul 2023

Patient is waiting for a second surgery via craniotomy and, given the SG finding on histology, pasireotide therapy will be offered...Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*

Depending on the route of administration in the parent study, pts received pasireotide long-acting release (LAR; n=303) or subcutaneous (sc; n=38) as monotherapy (n=36), or sc in combination with cabergoline (n=2). Hyperglycemia is an expected AE during pasireotide treatment, often occurring in the first 3 months of therapy. These data in pts with acromegaly, CD or other endocrine disorders support pasireotide as a well-tolerated long-term treatment and affirm that pts continue to receive long-term benefit, with a low discontinuation rate over 8 years.*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins.

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.

P1b, N=218, Recruiting, RayzeBio, Inc. | Active, not recruiting --> Recruiting

Due to the beneficial effects reported by some studies, somatostatin analogs may offer a novel last-option treatment for severely ill-patients. Nonetheless, only a controlled study, preferably a randomized clinical trial, could clarify the efficacy of somatostatin analogs.

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.

P1b, N=218, Active, not recruiting, RayzeBio, Inc. | Recruiting --> Active, not recruiting

Pasireotide may lead to complete and sustained remission of hypercortisolism, until surgical therapy is feasible. The expression of SSTR2 from typical carcinoids may be critical in allowing the use of very low drug doses for achieving disease control, while minimizing the risk of adverse events.

We also summarize recent clinical data related to the development of resistance on conventional and non-conventional modes of administration of the first-generation SSAs and the second-generation SSA pasireotide. We explore mechanisms used to counteract the resistance to SSAs using higher doses or more frequent mode of administration of SSAs and/or combination treatments. There is considerable heterogeneity in the development of resistance to SSAs that is tumor-specific necessitating the delineation of the underlying pathophysiological processes to further expand their therapeutic applications.

Relacorilant sensitized PitNET organoid responsiveness to Pasireotide. Therefore, our study identified the potential therapeutic use of relacorilant in combination with somatostatin analogs and demonstrated the advantages of relacorilant over Mifepristone, supporting its further development for use in the treatment of CD patients.

Clinical efficacy/effectiveness, safety, and HRQoL outcomes in adults with acromegaly were similar and costs lower with EDIs versus standard regimens. Physicians may consider acromegaly treatment at EDIs, especially for patients with good disease control.

P1b, N=31, Recruiting, RayzeBio, Inc. | Not yet recruiting --> Recruiting

Remarkably, CORT-silencing drastically enhanced proliferation rate and blunted the antitumor activity of SST-analogues (octreotide/pasireotide) in AI-PCa cells. Altogether, we provide evidence that SST/CORT system and SST-analogues could represent a potential therapeutic option for PCa, especially for CRPC, and that endogenous CORT could act as an autocrine/paracrine regulator of PCa progression.

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.

P1b, N=31, Not yet recruiting, RayzeBio, Inc.

Our data showed that c-Peg-V and Pasi-Lar are chosen for the treatment of invasive tumors. The partial response to first gen-SSA seems to be the main determinant for the choice of Pasi-Lar and positively predicts the treatment outcome.

This study aimed to assess whether clinical, biochemical, imaging and pathological characteristics can predict surgical remission and response to first-generation somatostatin receptor ligands (SRLs) and pasireotide-LAR in acromegaly...Fasting GH concentration <36.6 µg/L and DG tumor turned out to be independent predictors of good response to first-generation SRLs (OR=0.96, p=0.06 and OR=10.68, p=0.002, respectively). Younger age at diagnosis, male sex, lower GH, IGF-1 and PRL concentrations, smaller tumor size at diagnosis as well as positive α-SU staining, lower Ki-67 index and DG tumors predicted better treatment outcome in acromegaly patients.