Methodology of the SORENTO clinical trial: Assessing the efficacy and safety of high exposure octreotide subcutaneous depot in patients with GEP-NETs.
Authors: Singh Simron , Capdevila Jaume , Chan Jennifer A. , de Herder Wouter , Ferone Diego , Halperin Daniel M. , Mailman Josh , Dorkhan Mozhgan , Hellström Lisa , Svedberg Agneta , Tiberg Fredrik 
Published: June 2022

TPS4178 Background: Somatostatin receptor ligands (SRLs) are first-line standard of care therapies for gastroenteropancreatic neuroendocrine tumors (GEP-NETs), showing efficacy in tumor/symptom control with an established safety profile. Yet, disease progression may occur despite standard-dose SRL treatment, requiring more aggressive and toxic therapies. Retrospective/non-randomized data suggest higher-dose SRLs may benefit patients with GEP-NETs who do not respond to standard-dose treatment and provide improved disease control. Octreotide depot (CAM2029) is a novel high-exposure, subcutaneous (SC) formulation. Clinical trials showed ̃500% higher CAM2029 bioavailability versus octreotide long-acting release (LAR) (Tiberg et al. 2015), and maintenance/reduction of NET symptoms (Pavel et al. 2019). Prospective, randomized data are needed to confirm the efficacy/safety of novel SRLs with higher bioavailability such as CAM2029, vs standard-dose SRLs including octreotide LAR and lanreotide Autogel (ATG). Methods: SORENTO is a randomized, multi-center, open-label, active-controlled Phase 3 trial, aiming to enroll 302 adults with GEP-NETs. Key eligibility criteria: advanced, well-differentiated NET of GEP/presumed GEP origin; ≥1 measurable SR positive (by nuclear imaging) lesion according to RECIST 1.1; no or < 6 months consecutive treatment with long-acting SRLs. Notably, patients with Grade 3 GEP-NETs (excluded by CLARINET/PROMID trials) are eligible. Patients will be randomized 1:1 to CAM2029 20 mg Q2W, or active comparator (octreotide LAR 30 mg intramuscular or lanreotide ATG 120 mg SC, Q4W). CAM2029 self/carer administration is allowed after ≥3 successful supervised administrations. Randomization stratified by: histological grade, tumor origin, intended comparator. Primary outcome: progression free survival (PFS; time from randomization to date of first documented disease progression [RECIST 1.1] or death), assessed by a Blinded Independent Review Committee. The study is powered to detect a hazard ratio of 0.65. Key secondary outcomes: overall survival; response rate; rescue medication use; patient satisfaction; adverse events. After primary PFS analysis, patient overall survival will be followed for up to 2 years. If CAM2029 displays superiority in the primary analysis, the comparator group may switch to CAM2029 20 mg Q2W. Patients in any treatment group experiencing progressive disease in the randomized part of the study may proceed to an open-label extension with intensified CAM2029 treatment, to investigate effects of higher frequency dosing. First patient randomized in Nov-2021, with readout (following 194 events) expected by 2024 end. This novel head-to-head superiority trial is anticipated to demonstrate the potential benefits of CAM2029 as a first line-therapy in patients with well-differentiated GEP-NETs. Clinical trial information: NCT05050942.