To Determine the Effect of CYP Induction Following Administration of Nirogacestat in Healthy Adult Male Participants

NCT07259330 | Completed Phase 1

• 2 other identifiers: NIR-DT-1062025-521402-18-00
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

This study will evaluate the effects of nirogacestat 100 mg twice daily (BID) on the pharmacokinetics (PK) of a cytochrome P450 (CYP) cocktail.

Conditions

Healthy

Outcome Measures

Primary Outcomes (2)

• Plasma area under the concentration-time curve from dosing extrapolated to infinity (AUCinf) and maximum observed plasma concentration (Cmax) for the CYP cocktail probes alone, and coadministered with nirogacestat.

  Area under the concentration-time curve from dosing extrapolated to infinity. AUCinf = (AUClast + Clast/Kel) where Clast is the plasma concentration at the last quantifiable timepoint estimated from the log-linear regression analysis and Kel is the terminal elimination phase rate constant estimated by linear regression based on observations justified to describe the terminal phase on the log-linear concentration-time profile.

  CYP cocktail - Day -3 and Day 15 at predose (-60 minutes) and at 0.5, 1, 2, 3, 4, 6, 8, (10% nominal), 12, 24, 48, and 72 hours and nirogacestat Days 1 through 17 predose trough samples should be obtained within 1 hour of the nominal time from dosing.

• Maximum Observed Plasma Concentration (Cmax) of the CYP cocktail probes alone, and coadministered with nirogacestat.

  Maximum observed plasma concentration. Observed directly from the data.

  CYP cocktail - Day -3 and Day 15 at predose (-60 minutes) and at 0.5, 1, 2, 3, 4, 6, 8, (10% nominal), 12, 24, 48, and 72 hours and nirogacestat Days 1 through 17 predose trough samples should be obtained within 1 hour of the nominal time from dosing.

Secondary Outcomes (14)

• Plasma AUClast for the CYP cocktail probes alone and coadministered with nirogacestat.

  CYP cocktail - Day -3 and Day 15 at predose (-60 minutes) and at 0.5, 1, 2, 3, 4, 6, 8, (10% nominal), 12, 24, 48, and 72 hours and nirogacestat Days 1 through 17 predose trough samples should be obtained within 1 hour of the nominal time from dosing.

• Plasma time of maximum observed concentration (Tmax) for the CYP cocktail probes alone and coadministered with nirogacestat.

  CYP cocktail - Day -3 and Day 15 at predose (-60 minutes) and at 0.5, 1, 2, 3, 4, 6, 8, (10% nominal), 12, 24, 48, and 72 hours and nirogacestat Days 1 through 17 predose trough samples should be obtained within 1 hour of the nominal time from dosing.

• Plasma apparent terminal elimination half-life (t1/2) for the CYP cocktail probes alone and coadministered with nirogacestat.

  CYP cocktail - Day -3 and Day 15 at predose (-60 minutes) and at 0.5, 1, 2, 3, 4, 6, 8, (10% nominal), 12, 24, 48, and 72 hours and nirogacestat Days 1 through 17 predose trough samples should be obtained within 1 hour of the nominal time from dosing.

• Plasma apparent oral clearance (CL/F) for the CYP cocktail probes alone and coadministered with nirogacestat.

  CYP cocktail - Day -3 and Day 15 at predose (-60 minutes) and at 0.5, 1, 2, 3, 4, 6, 8, (10% nominal), 12, 24, 48, and 72 hours and nirogacestat Days 1 through 17 predose trough samples should be obtained within 1 hour of the nominal time from dosing.

• Plasma apparent oral volume of distribution (Vd/F) for the CYP cocktail probes alone and coadministered with nirogacestat.

  CYP cocktail - Day -3 and Day 15 at predose (-60 minutes) and at 0.5, 1, 2, 3, 4, 6, 8, (10% nominal), 12, 24, 48, and 72 hours and nirogacestat Days 1 through 17 predose trough samples should be obtained within 1 hour of the nominal time from dosing.

Study Arms (2)

Nirogacestat

ACTIVE COMPARATOR

Nirogacestat 100 mg BID will be administered orally from Day 1 through Day 17

Drug: Nirogacestat

Nirogacestat and CYP cocktail

EXPERIMENTAL

Nirogacestat 100 mg BID will be administered orally from Day 1 through Day 17 and an oral dose of CYP cocktail (CYP2B6 \[bupropion 20 mg\], CYP2C8 \[repaglinide 0.05 mg\], CYP2C9 \[flurbiprofen 10 mg\], CYP2C19 \[omeprazole 10 mg\], and CYP3A4 \[midazolam 1 mg\]) will be administered on Day -3, and again on Day 15.

Drug: Nirogacestat and Cocktail of CYP Specific Probe Substrates

Interventions

Nirogacestat DRUG

100 mg tablet Day 1 through Day 17

Nirogacestat

Nirogacestat and Cocktail of CYP Specific Probe Substrates DRUG

Drug: Nirogacestat 100 mg tablet Day 1 through Day 17 and Drug: Cocktail of CYP Specific Probe Substrates administered Day 15.

Nirogacestat and CYP cocktail

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Participant understands the study procedures, is willing to comply with all study requirements and restrictions and agrees to participate in the study by providing written informed consent prior to any study-related procedures being performed.
• Participant is a male between 18 and 55 years of age (inclusive) at the time of informed consent.
• Participant has a body mass index (BMI) ≥18 kg/m2 and ≤32 kg/m2 (inclusive) at Screening and Day -4, and a total body weight \>50 kg.
• Participant is considered to be medically healthy, as determined by a responsible and experienced investigator, based on a clinical evaluation (including medical history, physical examination, clinical laboratory tests, vital sign measurements, and a 12-lead electrocardiogram \[ECG\] and the results of clinical chemistry coagulation and urinalysis carried out at Screening and Day -4.
• Participant has alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels less than 1.5×the upper limit of normal at Screening and at Day -4.
• Participant has a renal function (creatinine clearance ≥90 mL/min), as evidenced by normal estimated glomerular filtration rate measured by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation at Screening and at Day -4.
• Participants that agree to the following during the Treatment Period, and for at least 7 days after the last dose of study treatment:
• Refrain from donating or preserving sperm; PLUS either
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent.
• OR c. Must agree to use a male condom when having sexual intercourse with women of childbearing potential (WOCBP). An additional form of contraception must also be used by the female partner if she is of childbearing potential.
• Has sufficiently good venous access in at least 1 arm to confidently enable serial blood sampling.

You may not qualify if:

• \. Participant has a history or presence of oncologic, cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, ocular, endocrine, immunologic, dermatologic, musculoskeletal, neurologic, psychiatric, or other disease or condition or the laboratory test abnormality that, in the investigator's judgment, poses a significant risk to the safety of the participant or the achievement of study objectives.
• \. Participant has a history or presence of any condition possibly affecting drug absorption (e.g., gastrectomy).
• \. Participant has a medical history or abnormal findings at Screening or Day -4 that the investigator judges may put at risk achieving the objectives of the study or protecting the safety of the participant.
• \. Participant has an acute illness with symptoms or treatment that has started or persisted within 14 days prior to study treatment administration, unless mild in severity, and enrollment is approved by both investigator and sponsor's medical monitor.
• \. Participant has tested positive for hepatitis B virus, hepatitis C virus, or HIV, or has a clinically significant infection.
• \. Participant has blood pressure (BP) that is ≥140 mmHg systolic or ≥90 mmHg diastolic following at least 5 minutes of supine rest at Screening or Day -4. Additionally, BP that is \<90 mmHg systolic or \<45 mmHg diastolic following at least 5 minutes of a supine rest at Screening or Day -4.
• \. Participant has heart rate (HR) that is \<40 bpm or \>100 bpm after resting in a supine position for 5 minutes at Screening or Day -4.
• \. Participant has averaged QT interval corrected using Fridericia's formula results from valid triplicate ECGs \>450 msec at Screening or Day -4.
• \. Participant has family history of long QT syndrome, or of unexplained sudden death or drowning in a first-degree relative under age 50.
• \. Participant has an ECG waveform abnormality that interferes with QT/QTc interval measurement or interpretation. A participant with mild sinus arrhythmia or sparse isolated premature ventricular contractions is eligible at the investigator's discretion.
• \. Participant has a positive serum alcohol test or other drug screen test at Screening and/or Day -4.
• \. Participant has received any vaccine within 14 days prior to the first dose of study treatment administration on Day -3.
• \. Participant has received any CYP3A4 inhibitors or inducers within 21 days or 5 half-lives (whichever is longer) prior to Day -3.
• \. Participant has had concurrent use of, or has used any long-acting gastric acid reducing agents, including histamine-2 receptor antagonists and proton pump inhibitors, including over-the-counter agents, in the last 21 days prior to Day -3.
• \. Participant has received any prescription or nonprescription drugs (including vitamins and dietary or herbal supplements) within 3 weeks or 5 half-lives, if known (whichever is longer), prior to study treatment administration on Day -3, unless in the opinion of the investigator and sponsor that the medication will not interfere with the study.

Sponsors & Collaborators

• SpringWorks Therapeutics, Inc., a healthcare company of Merck KGaA, Darmstadt, Germany: lead

Study Sites (1)

ICON Martini Groningen CRU

Groningen, 9728 NZ, Netherlands

Location

MeSH Terms

Interventions

nirogacestat

Study Officials

• Jeroen van de Wetering, MD

  ICON plc

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 19, 2025
• First Posted: December 2, 2025
• Study Start: October 27, 2025
• Primary Completion: March 27, 2026
• Study Completion: March 27, 2026
• Last Updated: May 1, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)