Study to Evaluate the Safety, Pharmacokinetics, and Dose Response of Paltusotine Treatment in Subjects with Carcinoid Syndrome

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Crinetics Pharmaceuticals Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

11 May 2023 → 24 Feb 2026

Decision date (initial)

2024-08-06

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2024-511922-30-00

EudraCT number

2022-000762-18

ClinicalTrials.gov

NCT05361668

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Dose response, Efficacy, Pharmacodynamic, Pharmacokinetic, Safety, Pharmacogenomic

Safety: To evaluate the safety and tolerability of paltusotine at 40, 80, and 120 mg QD doses
Pharmacokinetics: To assess the PK of 40, 80, and 120 mg paltusotine

Conditions and MedDRA coding

Carcinoid Syndrome

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Willing and able to provide written informed consent prior to any study-related procedures.
2. Willing and able to comply with the study procedures as specified in the protocol, including at least 70% compliance with electronic Symptom Diary for the 2-week period prior to the S2 Visit and prior to the Day 1 visit.
3. Male or female subjects ≥18 years of age, at the time of Screening.
4. Documented Carcinoid syndrome requiring medical therapy. Eligible subjects fall into one of the following categories: • Not currently treated with SRL agonists for at least 12 weeks prior to Screening, and actively symptomatic. This can include treatment-naïve subjects. • Subjects currently treated with lanreotide, octreotide LAR, or short-acting octreotide (subcutaneous or oral) who are currently symptomatically controlled and willing to wash out of their medication. The subject must demonstrate symptomatic worsening after washout. These subjects must have at least one historical instance of an elevated plasma biomarkers or serotonin level.
5. Evaluable documentation of locally advanced or metastatic histopathologically confirmed well-differentiated NET. 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 and Inzani, 2020). Grade 3 tumors are not eligible.
6. No significant disease progression* as assessed by the Investigator within the last 6 months before initiation of study drug dosing. *Pretrial imaging with MRI or CT, the most recent of which should be no more than approximately 3 months prior to Screening, should be available and compared to a previous imaging study to assess disease stability for established subjects on SRL maintenance therapy, while clinical symptoms and/or biomarker assessments should be used to assess disease stability for newly diagnosed subjects naïve to SRLs.
7. Historical documentation of positive SSTR tumor status by PET or somatostatin receptor scintigraphy.* *If subject does not have historical documentation, this can be done during Screening.
8. Plasma biomarkers over the upper limit of normal during Screening for subjects not currently treated with any SRL therapy who are not washing out of SRLs.
9. Females 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, OR must agree to use a highly effective method of contraception from the beginning of Screening to the last study visit. • Acceptable highly effective methods of contraception include: - Combined estrogen-progestin oral hormonal contraception associated with consistent inhibition of ovulation - Desogestrel-based progestin-only contraception associated with consistent inhibition of ovulation; this includes oral, injectable, and implantable methods - Intravaginal and transdermal hormone delivery methods - Intrauterine device (with or without hormone elution) - Bilateral tubal occlusion or ligation (must be documented) - Vasectomized partner (must be documented) or - Sexual abstinence (only when it is the usual and preferred lifestyle of the subject) In addition to these methods of contraception, the male partner should use a condom from the beginning of Screening to the last study visit.
10. If the subject is male, the subject should agree to use a condom when sexually active with a female partner of childbearing potential from Screening until at least 30 days after the last dose of study drug or be surgically sterile [ie, vasectomy with documentation]; or remain abstinent [when this is in line with the preferred and usual lifestyle]. Male subjects should also agree to not donate sperm for the duration of the study and until at least 30 days after the last dose of study drug.

Exclusion criteria 19

1. 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, Zollinger-Ellison syndrome). Exception to this are subjects with prior cholecystectomy or small bowel resections, provided diarrhea is controlled prior to washout or if not currently treated with any SRL therapy.
2. Uncontrolled/severe diarrhea associated with significant volume contraction, dehydration, or hypotension.
3. Requires second line treatments (eg, telotristat) for control of Carcinoid syndrome symptoms in the opinion of the Investigator.
4. Treatment with specific NET tumor 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.
5. Karnofsky performance status <60%.
6. Major surgery within 8 weeks before Screening.
7. History of another primary malignancy <3years prior to the date of first dose of study treatment unless at least one 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.
8. Life expectancy <12 months from Screening.
9. Diabetes mellitus treated with insulin for less than 6 weeks prior to the study entry.
10. Poorly controlled diabetes mellitus defined as having a hemoglobin A1c (HbA1c) ≥8.5% (ie, ≥69.5 mmol/mol) or estimated HbA1c based on fructosamine if HbA1c is not evaluable (eg, due to hemoglobinopathy).
11. History of unstable angina or acute myocardial infarction within the 12 weeks preceding the Screening Visit or other clinically significant cardiac disease (including clinically significant carcinoid heart disease) at the time of Screening as judged by the Investigator.
12. Known history of, or current alcohol or drug abuse, within the last year.
13. Concomitant mental condition rendering him/her unable to understand the nature, scope, and possible consequences of the study, and/or evidence of poor compliance with medical instructions.
14. Current use of medications that are strong inducers of cytochrome P450 3A4 (CYP3A4) (including but not limited to carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wort) within 2 weeks prior to Screening because they may reduce systemic exposure to paltusotine. Current use of medications that are sensitive substrates of CYP3A4 with a narrow therapeutic index (including but not limited to tolvaptan, lomitapide, pimozide, dronedarone, dasatinib, sirolimus) as paltusotine may increase exposure of these medications.
15. Unable to administer short-acting octreotide (octreotide acetate injection), or prior nonresponse documented with somatostatin agonists.
16. Known allergy or hypersensitivity to any of the test materials or related compounds.
17. Active COVID-19 confirmed or suspected based on SARS-CoV-2 testing and clinical symptoms.
18. QT interval corrected using Fridericia’s formula (QTcF) >480 msec (or QTcF >500 msec in the presence of 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 subject has rested quietly in the supine position for at least 10 minutes without significant stimulation (noise, television, etc.).
19. Clinically significant concomitant disease that is not a result of 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 total bilirubin >1.5× ULN. (Subjects with previously diagnosed Gilbert’s syndrome not accompanied by other hepatobiliary disorders and associated with total bilirubin <3.5 mg/dL [<51.3 µmol/L] will be permitted.)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Safety: Incidence of TEAEs, including serious TEAEs and TEAEs leading to discontinuation; change from Baseline to the EOR in safety parameters: clinical laboratory tests, physical exam findings, vital signs, 12-lead ECG, and 24-hour continuous cardiac monitoring (only for subjects on 120 mg dose)
2. Pharmacokinetics: Steady state trough levels at each dose at EOR

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Crinetics Pharmaceuticals Inc.

Sponsor organisation

Crinetics Pharmaceuticals Inc.

Address

6055 Lusk Boulevard

City

San Diego

Postcode

92121-2700

Country

United States

Scientific contact point

Organisation

Crinetics Pharmaceuticals Inc.

Contact name

Crinetics Clinical Trials

Public contact point

Organisation

Crinetics Pharmaceuticals Inc.

Contact name

Crinetics Clinical Trials

Third parties 7

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications