Efficacy and Safety Evaluation of Paltusotine in Adults with Carcinoid Syndrome Secondary to Well-Differentiated Neuroendocrine Tumors: A Randomized, Placebo-Controlled Trial

Trial ID: 2024-519875-24-00
Protocol: CRN00808-12
Sponsor: Crinetics Pharmaceuticals Inc.

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Diseases & Conditions

Carcinoid syndrome

Objectives

The primary objective of this study is to evaluate the **efficacy** of paltusotine compared to placebo in reducing flushing episodes in adults with **carcinoid syndrome** due to well-differentiated neuroendocrine tumors. This is clinically relevant as flushing episodes are a common and distressing symptom of carcinoid syndrome, impacting patients' quality of life. By assessing the reduction in flushing episodes, the study aims to determine the potential therapeutic benefit of paltusotine in managing this condition.

Secondary objectives include assessing the efficacy of paltusotine versus placebo in reducing bowel movements per day. This is important as frequent bowel movements are another debilitating symptom of carcinoid syndrome, and their reduction could significantly improve patient comfort and daily functioning.

Participants

The clinical trial involves a total of **83 participants** diagnosed with **carcinoid syndrome**, a condition characterized by symptoms such as flushing. The study population includes both male and female subjects aged **18 years and older**. Participants were selected based on their documented need for medical therapy for carcinoid syndrome, with specific symptoms such as frequent flushing episodes. The trial includes individuals with locally advanced or metastatic well-differentiated neuroendocrine tumors (NETs), classified as Grade 1 or Grade 2 according to the World Health Organization's neuroendocrine neoplasm classification. Participants must have stable disease without significant progression in the last six months, as assessed by the investigator. The trial population also includes individuals who are currently treated with octreotide or lanreotide and are willing to undergo a washout period. Both male and female participants are required to adhere to specific contraceptive measures during the study. The trial does not exclude vulnerable populations, indicating a broad inclusion of participants who meet the outlined criteria.

Plans and Procedures

The clinical trial is designed to evaluate the **efficacy** and safety of **paltusotine** in adults with **carcinoid syndrome** due to well-differentiated neuroendocrine tumors. This is a Phase 3, randomized, parallel-group, placebo-controlled study. The trial will involve a double-blind methodology to ensure unbiased results. Participants will be randomly assigned to receive either paltusotine 40 mg tablets or a placebo, administered orally. The primary objective is to assess the reduction in flushing episodes, with a primary endpoint measuring the treatment group difference in change from baseline to Week 12 in flushing episodes per day, averaged over the 14 days prior to Week 12. The secondary endpoint will evaluate changes in bowel movements per day over the same period.

The trial is expected to commence recruitment on August 1, 2025, and conclude by August 31, 2029. The study duration for each participant is anticipated to be approximately 120 days, with a maximum treatment period of 120 days. Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as documented carcinoid syndrome and stable disease status. Follow-up visits will occur at regular intervals to monitor safety and efficacy outcomes, with the final visit marking the end of the study for each participant.

Participants will be required to comply with study procedures, including maintaining at least 70% compliance with the Carcinoid Syndrome Symptom Diary. Conditions that may lead to early termination from the study include significant disease progression or non-compliance with study protocols. The trial will ensure that all participants provide written informed consent prior to any study-related procedures. The study will adhere to ethical standards and regulatory requirements to ensure the safety and well-being of all participants throughout the trial duration.

Treatment

The clinical trial involves the administration of **Paltusotine**, a somatostatin type 2 receptor agonist, in the form of 40 mg tablets. The pharmaceutical form of the medication is a tablet, and it is administered orally. The maximum daily dose of Paltusotine is 80 mg, with a total maximum dose of 67,200 mg over a treatment period of up to 120 days. The active substance, Paltusotine, is of chemical origin and is provided by Crinetics Pharmaceuticals, Inc. The trial aims to evaluate the efficacy of Paltusotine in reducing flushing episodes in adults with carcinoid syndrome due to well-differentiated neuroendocrine tumors.

The study also includes a **placebo** group, which consists of tablets identical in appearance to the Paltusotine tablets but without the active substance. The placebo is administered orally in the same manner as the experimental medication, ensuring blinding of the participants and investigators. The use of a placebo allows for a controlled comparison to assess the true efficacy of Paltusotine in the study population. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

Efficacy

The efficacy of Paltusotine in the treatment of **Carcinoid Syndrome** due to well-differentiated neuroendocrine tumors will be assessed in a randomized, parallel group, placebo-controlled clinical trial. The primary endpoint for evaluating efficacy is the treatment group difference in the change from baseline to Week 12 in the number of flushing episodes per day, averaged over the 14 days prior to Week 12. This will provide a quantitative measure of symptom reduction attributable to the treatment.

Additionally, a key secondary endpoint will assess the treatment group difference in the change from baseline to Week 12 in the number of bowel movements (BMs) per day, also averaged over the 14 days prior to Week 12. These endpoints will be measured using patient-reported outcomes, ensuring that the data reflects the participants' direct experiences with symptom changes.

The trial will involve the administration of Paltusotine 40 mg tablets, with a maximum treatment period of 120 days. The efficacy assessments will be conducted at specified timepoints, including baseline and Week 12, to capture the changes in symptoms over the course of the treatment. The data collected will be analyzed to determine the efficacy of Paltusotine compared to placebo in reducing the symptoms of Carcinoid Syndrome.

Inclusion and Exclusion Criteria

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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, 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.
Evaluable documentation of locally advanced or metastatic histopathologically confirmed well-differentiated NET(s). Tumors must be Grade 1 or Grade 2 with Ki-67 index ≤10% per the World Health Organization neuroendocrine neoplasm classification. Participants with Ki-67 index >10% 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 historical instance of an elevated 5-HIAA or serotonin level, using either a urine or blood sample. Note: For participants who do not have a historical instance of an elevated 5-HIAA or serotonin level, the result from the samples taken during screening can be considered historical as it is prior to randomization.
Female participants who engage in heterosexual intercourse must:  Be of nonchildbearing potential, defined as either surgically sterile (ie, hysterectomy, bilateral salpingectomy, 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 (coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Female condom and male condom should not be used together.
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.

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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, PRRT, and/or tumor debulking <12 weeks before Screening. In addition, the following conditions must be followed:  Completion or discontinuation of this prior treatment should have occurred according to SOC practice.  Per the Investigator’s assessment, SSAs are appropriate for management of the participant’s carcinoid syndrome symptoms, and there is no anticipated need for the participant to initiate another line of antitumor treatment within the next 4 months (ie, for the duration of the RCP).  Withholding or discontinuing antitumor SOC therapy (excluding approved SSAs) solely to enable study participation is not permitted.
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.
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.
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 <30 mL/min/1.73 m2, cirrhosis, baseline AST and/or ALT >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 within the last year, is not permitted.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Recruiting	01 Aug 2025	5
Denmark	Not Yet Recruiting	01 Aug 2025	—
France	Recruiting	01 Aug 2025	16
Germany	Recruiting	01 Aug 2025	20
Ireland	Not Yet Recruiting	01 Aug 2025	3
Italy	Recruiting	01 Aug 2025	16
Poland	Recruiting	01 Aug 2025	10
Romania	Recruiting	01 Aug 2025	11
Spain	Recruiting	01 Aug 2025	16
Sweden	Not Yet Recruiting	01 Aug 2025	—