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

Phase 1

• Conditions: Carcinoid Syndrome; MedDRA version: 20.0Level: PTClassification code 10007270Term: Carcinoid syndromeSystem Organ Class: 10014698 - Endocrine disorders; Therapeutic area: Diseases [C] - Digestive System Diseases [C06]

• Registration Number: EUCTR2022-000762-18-PL
• Lead Sponsor: Crinetics Pharmaceuticals, Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2022-11-18
• Last Update Posted: 8 July 2024

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

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 (average of =4 BM/day or >2
flushing episodes per day in at least 2 days over a period of 2 weeks).
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 (average <4 BM/day and average =2
flushing episodes/day over a 2 week period) 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 5-HIAA 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.
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.
7. Historical documentation of positive SSTR tumor status by PET or
somatostatin receptor scintigraphy
8. Plasma 5-HIAA =2× ULN 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 s

Exclusion Criteria

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
ave

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified