Evaluate the Effects of Famotidine or Rabeprazole on the PK of Nirogacestat

NCT07171619 | Completed Phase 1 FDA Drug

• 1 other identifier: NIR-DT-107
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

This study will evaluate the effects of the H2 blocker famotidine or the PPI rabeprazole on the PK of nirogacestat in healthy male participants

Conditions

Healthy

Outcome Measures

Primary Outcomes (4)

• Area under the concentration-time curve from time zero to infinity of nirogacestat.

  Serum AUCinf of nirogacestat.

  Serial blood samples will be collected to determine concentrations of nirogacestat (in serum) on Day 1, Day 6, and Day 17 predose (-30 minutes) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours postdose

• Maximum serum concentration (Cmax) of nirogacestat.

  Serum Cmax of nirogacestat.

  Serial blood samples will be collected to determine concentrations of nirogacestat (in serum) on Day 1, Day 6, and Day 17 predose (-30 minutes) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours postdose

• Effect of a single 2-hour staggered dose of famotidine on the PK AUCinf of nirogacestat

  Serum AUCinf of nirogacestat.

  Serial blood samples will be collected to determine concentrations of nirogacestat (in serum) on Day 1, Day 6, and Day 17 predose (-30 minutes) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours postdose

• Effect of a single 2-hour staggered dose of famotidine on the PK Cmax of nirogacestat

  Serum Cmax of nirogacestat.

  Serial blood samples will be collected to determine concentrations of nirogacestat (in serum) on Day 1, Day 6, and Day 17 predose (-30 minutes) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours postdose

Secondary Outcomes (10)

• Determine the effect of rabeprazole or famotidine on nirogacestat PK (AUClast) Area under the concentration-time curve from zero to the time last quantifiable concentration

  Serial blood samples will be collected to determine concentrations of nirogacestat (in serum) on Day 1, Day 6, and Day 17 predose (-30 minutes) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours postdose

• Determine the effect of rabeprazole or famotidine on nirogacestat PK (Tmax) time of maximum concentration

  Serial blood samples will be collected to determine concentrations of nirogacestat (in serum) on Day 1, Day 6, and Day 17 predose (-30 minutes) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours postdose

• Determine the effect of rabeprazole or famotidine on nirogacestat PK (T1/2) Terminal elimination half-life

  Serial blood samples will be collected to determine concentrations of nirogacestat (in serum) on Day 1, Day 6, and Day 17 predose (-30 minutes) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours postdose

• Determine the effect of rabeprazole or famotidine on nirogacestat PK (CL/F) apparent clearance after oral dose

  Serial blood samples will be collected to determine concentrations of nirogacestat (in serum) on Day 1, Day 6, and Day 17 predose (-30 minutes) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours postdose

• Determine the effect of rabeprazole or famotidine on nirogacestat PK (Vd/F) Apparent oral volume of distribution

  Serial blood samples will be collected to determine concentrations of nirogacestat (in serum) on Day 1, Day 6, and Day 17 predose (-30 minutes) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours postdose

Study Arms (3)

Period 1 - Nirogacestat Dose (Reference)

ACTIVE COMPARATOR

Nirogacestat will be administered, after at least a 10-hour fast, in the morning on Day 1, Day 6, and Day 17

Drug: Nirogacestat

Period 2 - Nirogacestat and Famotidine (Test)

ACTIVE COMPARATOR

Famotidine will be administered as an oral tablet 2 hours after the administration of nirogacestat on Day 6.

Drug: Nirogacestat and Famotidine

Period 3 Nirogacestat and Rabeprazole (Test)

ACTIVE COMPARATOR

Rabeprazole will be administered as an oral tablet in the evenings on Day 10 through Day 16.

Drug: Nirogacestat and Rabeprazole

Interventions

Nirogacestat DRUG

oral dose of 150 mg nirogacestat

Also known as: PF-03084014- GS (gamma secretase) inhibitor

Period 1 - Nirogacestat Dose (Reference)

Nirogacestat and Famotidine DRUG

oral dose of 150 mg nirogacestat \& oral dose of 40 mg famotidine

Also known as: Histamine H2-Receptor Antagonist (H2 Blocker)

Period 2 - Nirogacestat and Famotidine (Test)

Nirogacestat and Rabeprazole DRUG

oral dose of 150 mg nirogacestat and oral dose of 20 mg rabeprazole

Also known as: Proton Pump Inhibitor (PPI)

Period 3 Nirogacestat and Rabeprazole (Test)

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 as described in Appendix 1 of the protocol, prior to any study-related procedures being performed.
• Participant is a male (assigned at birth) between 18 and 55 years of age (inclusive) at the time of informed consent.
• Participant has a body mass index (BMI) ≥18.0 kg/m2 and ≤32.0 kg/m2 (inclusive) at Screening 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 ECG performed, and the results of clinical chemistry, hematology, coagulation, and urinalysis carried out at Screening and Day -1.
• Participant has alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin levels \<1.5 × the upper limit of normal (ULN) at Screening and at Day -1.
• Participant has normal renal function (creatinine clearance ≥90 mL/min) as evidenced by normal estimated glomerular filtration rate (eGFR) measured by the CKD-EPI equation.
• Participant agrees to the following during the treatment periods 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.
• Must agree to use a male condom when having sexual intercourse with women of childbearing potential (WOCBP). An additional form of contraception should also be used by the female partner if she is of childbearing potential.
• Has sufficiently good venous access in at least one 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 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 -1 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 symptom 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 active Helicobacter pylori (H. pylori) infection.
• Participant has tested positive for hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (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 rest in the supine position at Screening and Day -1. Additionally, BP that is \<90 mmHg systolic or 45 mmHg diastolic following at least 5 minutes of rest at Screening and Day -1.
• Participant has heart rate (HR) that is \<40 bpm or \>100 bpm after resting in a supine position for 5 minutes at Screening and Day -1.
• Participant has averaged QT interval corrected using Fridericia formula (QTcF) results from valid triplicate ECGs \>450 msec at Screening and Day -1.
• 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 (PVC) is eligible at the investigator's discretion.
• Participant has a positive alcohol breath test, positive cotinine test, or other positive drug screen test at Screening or Day -1.
• Participant has a positive nasopharyngeal rapid antigen test for SARS-CoV-2 on Day -1 or has had any known close contact with a person who tested positive for SARS-CoV-2 or with a COVID-19 patient within 2 weeks prior to admission.
• Participant has received any vaccine within 14 days prior to the first dose of study treatment administration on Day 1.
• Participant has received any CYP3A4 inhibitors or inducers within 21 days or 5 half-lives (whichever is longer) prior to Day 1.

Sponsors & Collaborators

• SpringWorks Therapeutics, Inc.: lead

Study Sites (1)

Medpace

Cincinnati, Ohio, 45227, United States

Location

MeSH Terms

Interventions

nirogacestat; Amyloid Precursor Protein Secretases; Famotidine; Histamine H2 Antagonists; Rabeprazole; Proton Pump Inhibitors

Intervention Hierarchy (Ancestors)

Endopeptidases; Peptide Hydrolases; Hydrolases; Enzymes; Enzymes and Coenzymes; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Histamine Antagonists; Histamine Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Physiological Effects of Drugs; 2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Pyridines; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Enzyme Inhibitors

Study Officials

• Mary Beth Brune, MD

  Medpace, Inc.

  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

Model Details: Three period Crossover

Study Record Dates

• First Submitted: August 7, 2025
• First Posted: September 12, 2025
• Study Start: August 21, 2025
• Primary Completion: November 10, 2025
• Study Completion: November 10, 2025
• Last Updated: April 1, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)