Carcinoid Syndrome Efficacy Study Featuring an Oral Daily Paltusotine Regimen

This is a global, randomized, parallel-group, placebo-controlled study to evaluate the efficacy and safety of paltusotine in adults with carcinoid syndrome. The study includes a screening period of up to 11 weeks, a double-blinded randomized control period of 16 weeks, an open label extension period of 104 weeks, and a follow-up period of 4 weeks.

Inclusion criteria

• Male or female ≥18 years of age, at the time of Screening.
• Willing and able to comply with the study procedures as specified in the protocol, including at least 70% compliance with the study diary for the 2-week period.
• Documented carcinoid syndrome requiring medical therapy. Participants must exhibit symptoms of flushing with or without frequent BMs as follows:

• For participants who are naïve/not currently treated with somatostatin receptors ligands (SRL), they must exhibit an average of >1 flushing episode/day over a period of 14 days
• For participants who will wash out from SRL treatment, they must be symptomatically controlled and exhibit an increase in daily average flushing episodes and an average of >1 flushing episode/day over a period of 14 days during the Washout Period.
• Evaluable documentation of locally advanced or metastatic histopathologically confirmed well-differentiated neuroendocrine tumor(s) [NETs].
• No significant disease progression as assessed by the Investigator within the last 6 months before randomization.

Exclusion criteria

• Diarrhea attributed to any condition(s) other than carcinoid syndrome.
• Uncontrolled/severe diarrhea associated with significant volume contraction, dehydration, or hypotension.
• Requires second line treatments (eg, telotristat) for control of carcinoid syndrome symptoms in the opinion of the Investigator.
• Treatment with specific NET therapy <4 weeks before Screening (such as everolimus or sunitinib) or hepatic embolization, radiotherapy, peptide receptor radionuclide therapy (PRRT), and/or tumor debulking <12 weeks before Screening.
• Major surgery within 8 weeks before Screening.
• History of another primary malignancy <3 years prior to the date of randomization, except for adequately treated basal or squamous cell carcinoma of the skin, cancer of the breast has been completely locally excised and carcinoma in situ of the cervix has also been resected, previously treated malignancy, if all treatment for that malignancy was completed at least 3 years prior to first dose of study treatment, and no current evidence of disease, concurrent malignancy determined to be clinically stable and not requiring treatment.
• Diabetes mellitus treated with insulin for less than 6 weeks prior to the study entry.
• Poorly controlled diabetes mellitus defined as having a hemoglobin A1c (HbA1c) ≥8.5%
• Unable to administer short-acting (SA) octreotide (octreotide acetate injection), or prior nonresponse documented with somatostatin agonists.
• Clinically significant concomitant disease or indicator of disease that is not a result of the primary disease under study, including but not limited to cardiovascular disease, estimated glomerular filtration rate 2×upper limit of normal [ULN], and/or total bilirubin (TB) >1.5×ULN. (Participants with previously diagnosed Gilbert's syndrome not accompanied by other hepatobiliary disorders and associated with TB
• Alcohol or drug abuse is not permitted at any time during the study
• Diagnosed with symptomatic cholelithiasis