Clinical Trials

Inclusion Criteria: 

• Willing and able to provide written informed consent prior to any study-related procedures.
• Willing and able to comply with the study procedures as specified in the protocol, including at least 70% compliance with the Carcinoid Syndrome Symptom Diary for the 2-week period prior to the S2 Visit and prior to the Day 1 Visit.
• Male or female ≥ 18 years of age, at the time of Screening.
• 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 SRLs (for at least ≥16 weeks before Screening), they must exhibit an average of >1 flushing episode/day over a period of 14 days and have a screening plasma 5-HIAA or serotonin result ≥ 2×ULN.
  • For participants who will wash out from SRL treatment, they must 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.
  • The number of participants enrolling that meet the eligibility criteria of flushing AND > 3 BMs/day will be ≥ 78 participants. The number of participants enrolling that meet the symptomatic criteria of flushing alone (> 1 flushing episode/day and ≤ 3 BMs/day) will be capped at 63 participants.
• Evaluable documentation of locally advanced or metastatic histopathologically confirmed well-differentiated NET(s). Tumors must be Grade 1 or Grade 2 (Ki-67 index ≤ 20%, or a mitotic count of ≤20 mitoses per 10 high-power fields if the Ki-67 index is not available) per the World Health Organization neuroendocrine neoplasm classification (Rindi G 2020). Participants with Grade 3 tumors are not eligible.
• No significant disease progression as assessed by the Investigator within the last 6 months before randomization into the RCP.

Note: A CT or MRI scan will be performed during the Screening Period and should be compared with previous pretrial imaging to assess disease stability for established participants on SRL maintenance therapy, while clinical symptoms and/or biomarker assessments should be used to assess disease stability for newly diagnosed participants naïve to SRLs.

• Historical documentation of positive somatostatin receptor tumor status by PET or somatostatin receptor scintigraphy.

Note: If participant does not have historical documentation, this can be done during the Screening Period.

• Participants who are currently treated with octreotide/lanreotide and who agree to wash out of treatment must have at least 1 historical instance of an elevated 5-HIAA or serotonin level, using either a urine or blood sample.
• Female participants who engage in heterosexual intercourse must:
  • Be of nonchildbearing potential, defined as either surgically sterile (ie, hysterectomy, bilateral salpingectomy, tubal ligation for at least 3 months, or bilateral oophorectomy), OR
  • Be postmenopausal with at least 1 year of amenorrhea. In participants with less than 1 year of amenorrhea, confirmation is required with 2 FSH measurements. A documented, historical test result measured prior to Screening may be used as 1 of the 2 measurements. The FSH value should be ≥30 IU/L to confirm menopausal status, OR
  • Agree to use a highly effective method of contraception from the beginning of the Screening Period until at least 2 weeks after the last dose of study drug. Contraceptive use by men and women also should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Periodic abstinence (ie, calendar, ovulation, symptothermal, and postovulation methods) and withdrawal are not acceptable methods of contraception.
• Male participants must agree to use a condom when sexually active with a female partner of childbearing potential from Screening until at least 2 weeks after the last dose of study drug (or be surgically sterile [ie, vasectomy with a confirmed absence of sperm in ejaculate] or agree to remain abstinent on a long-term and persistent basis). Male participants should also agree to not donate sperm for the duration of the study and until at least 2 weeks after the last dose of study drug.

Exclusion Criteria: 

• Diarrhea attributed to any condition(s) other than carcinoid syndrome (including but not limited to fat malabsorption, bile acid malabsorption, short bowel syndrome, pancreatic exocrine insufficiency, infections, VIPoma, and Zollinger-Ellison syndrome). Exceptions to this include participants with prior cholecystectomy or small bowel resections, provided diarrhea is controlled prior to washout or the participant is not currently treated with any SRL therapy.
• 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, PRRT, and/or tumor debulking <12 weeks before Screening.
• Karnofsky performance status <60%.
• Major surgery within 8 weeks before Screening.
• History of another primary malignancy <3 years prior to the date of randomization in the RCP unless at least 1 of the following criteria are met:
  • Adequately treated basal or squamous cell carcinoma of the skin
  • Cancer of the breast or cervix in situ
  • 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 HbA1c ≥8.5% (ie, ≥69.5 mmol/mol) or estimated HbA1c based on fructosamine if HbA1c is not evaluable (eg, due to hemoglobinopathy).
• History of unstable angina or acute myocardial infarction within the 12 weeks preceding the Screening Period or other clinically significant cardiac disease (including clinically significant carcinoid heart disease) at the time of Screening as judged by the Investigator.
• Current use of medications that are strong inducers of multiple enzymes and transporters (ie, CYP3A4, UGT1A1, and P-gp), including but not limited to apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, and St. John’s wort) within 2 weeks prior to Screening (because they may reduce systemic exposure to paltusotine).
• Current use of medications that are UGT inhibitors (eg, atazanavir) within 2 weeks prior to Screening due to potential for increased systemic exposure to paltusotine.
• Unable to administer SA octreotide (octreotide acetate injection), or prior nonresponse documented with somatostatin agonists.
• Known allergy or hypersensitivity to any of the test materials or related compounds.
• Any clinically significant and active infection such as those requiring systemic treatment within 14 days before randomization.
• QTcF >480 msec (or QTcF>500 msec in the presence of a complete bundle branch block) or PR interval >240 msec during Screening based on a central reading of an average of 3 ECGs, each separated in time by approximately 1 minute after the participant has rested quietly in the supine position for at least 10 minutes without significant stimulation (eg, noise, television).
• 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×ULN, and/or TB >1.5×ULN. (Participants with previously diagnosed Gilbert’s syndrome not accompanied by other hepatobiliary disorders and associated with TB <3.5 mg/dL [<51.3 µmol/L] will be permitted.)
• Current alcohol or drug abuse, or use within the last year, is not permitted.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 2/05/2025. Questions regarding updates should be directed to the study team contact.