Pralsetinib DDI Study in Patients With Advanced or Metastatic Solid Tumors

A Multi-center, Open-label, Drug-drug Interaction Study to Evaluate the Effect of Pralsetinib (Gavreto) on the Pharmacokinetics of CYP3A4, CYP2C8, and CYP2C9 Substrates, and Hormones Estradiol/Norethisterone Acetate in Patients With Advanced or Metastatic Solid Tumors

An open-label drug-drug interaction study to evaluate the effects of pralsetinib (Gavreto) on the pharmacokinetics of a CYP450 probe substrate cocktail and, in female participants, a hormonal probe substrate, in participants with rearranged during transfection (RET) fusion- or mutation-positive solid tumors

Study Overview

• Status: Recruiting
• Conditions: Thyroid Cancer; Advanced Malignancies; Solid Tumor Malignancies; NSCLC (Non-small Cell Lung Cancer)
• Intervention / Treatment: Drug: Pralsetinib; Drug: CYP3A4, CYP2C8, and CYP2C9 substrates, and hormonal contraceptive

• Study Type: Interventional
• Enrollment (Estimated): 12
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Kay Patel; Phone Number: (650) 624-1100; Email: kpatel@rigel.com
• Study Contact Backup: Name: Jill DeFratis; Phone Number: (650) 624-1100; Email: jdefratis@rigel.com

Study Locations

• Spain
  • Madrid, Spain, 28050
    • Recruiting
    • Hospital Universitario HM Sanchinarro
    • Contact: Irene Moreno, MD; Email: irene.moreno@startmadrid.com
  • La Rioja
    • Logroño, La Rioja, Spain, 26006
      • Recruiting
      • Hospital Universitario San Pedro
      • Contact: Maria De Miguel, MD, PhD, MBA; Email: maria.demiguel@startrioja.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Must be willing and able to participate and comply with all study requirements and to provide signed and dated written informed consent
• Adult male or female ≥ 18 years of age at the time of signing the informed consent form.
• Must have a body mass index (BMI) ≥ 18 and ≤ 32 kg/m² and a minimum body weight of 50 kg at screening.
• Must have an Eastern Cooperative Oncology Group performance status ≤ 2.
• Must have recovered from the non-hematologic toxic effects of prior treatment to Grade ≤ 1, or baseline value (excluding infertility, alopecia, or Grade 1 neuropathy)
• Must have a confirmed diagnosis of advanced or metastatic solid tumor that has relapsed after, or is not responsive to, standard therapies and harbors an oncogenic RET fusion or mutation as determined by a validated test.

• Must have adequate organ function, defined by the following:

  1. Absolute neutrophil count (ANC) ≥ 1.0 × 10⁹/L.
  2. Platelet count ≥ 75 × 10⁹/L.
  3. Hemoglobin ≥ 9 g/dL.
  4. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN), or ≤ 5 × ULN in patients with known liver metastases.
  5. Total bilirubin ≤ 1.5 × ULN (≤ 3 × ULN in patients with Gilbert syndrome).
  6. Creatinine clearance ≥ 40 mL/min using the Cockcroft-Gault equation.
  7. Serum phosphorus ≤ 5.5 mg/dL.
  8. International normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (aPTT) within normal laboratory limits.
• Must be at least 4 weeks from major surgery, radiotherapy, chemotherapy, immunotherapy, kinase/targeted therapy, or gene therapy prior to the first dose of study treatment and recovered from treatment-related toxicities to ≤ Grade 1 (excluding alopecia). Must be ≥ 6 weeks since last treatment if they received a long-acting agent such as a nitrosourea, mitomycin, or monoclonal antibodies. In general, a treatment interval of two half-lives should be considered and discussed with the Sponsor. (Concurrent cancer therapy of any type is not permitted).
• Female patients may participate if they are not of childbearing potential (e.g., surgically sterile or postmenopausal).
• Male patients with female partners of childbearing potential must agree to use highly effective contraception during study treatment and for 90 days after the last dose of study treatment.
• Male patients must refrain from sperm donation during study treatment and for 90 days after the last dose of study treatment.

Exclusion Criteria:

• Clinically relevant abnormal medical history, abnormal findings on physical examination, vital signs, electrocardiogram (ECG), or laboratory tests at screening that, in the investigator's judgment, are likely to interfere with the objectives of the trial or the safety of the patient.
• Surgery (e.g., gastric bypass) or medical condition that may significantly affect absorption of study medications, as judged by the investigator.
• History of pneumonitis within the last 12 months.
• History of active or latent tuberculosis (TB), regardless of treatment history, or a positive screening test for latent Mycobacterium tuberculosis infection by QuantiFERON® TB Gold. Indeterminate results may be confirmed by repeat testing or by a purified protein derivative (PPD) skin test.
• Serious infection requiring intravenous or systemic antibiotics within 7 days prior to initiation of study treatment, or any active infection that, in the opinion of the investigator, could impact patient safety (e.g., COVID-19 or influenza).

• Clinically significant, uncontrolled cardiovascular disease, including:

  1. New York Heart Association (NYHA) Class III or IV congestive heart failure.
  2. Myocardial infarction or unstable angina within the previous 6 months, clinically significant uncontrolled arrhythmias, including bradyarrhythmias that may cause QT prolongation (e.g., second- or third-degree heart block).
  3. Uncontrolled hypertension (i.e., mean systolic blood pressure ≥180 mmHg and/or diastolic blood pressure ≥110 mmHg on 3 repeated measurements) or clinically significant hypotension (i.e., systolic blood pressure <90 mmHg and/or diastolic blood pressure <50 mmHg) or severe episodes of orthostatic hypotension.
  4. History of prolonged QT syndrome or torsades de pointes, or familial history of long QT syndrome.
  5. QTcF ≥470 ms on at least 2 ECGs performed >30 minutes apart.
• Central nervous system (CNS) metastases or primary CNS tumor.
• Use of systemic corticosteroids within 4 weeks prior to first dose of study treatment.
• More than 30 Gy of radiotherapy to the lung within 6 months prior to check-in.
• History of multiple and/or severe allergies to drugs or foods, or history of severe anaphylactic reaction.
• Use of prohibited medications or procedures
• Medical conditions, treatments, or underlying diseases that constitute contraindications to the use of study substrates or probe drugs
• Ingestion of alcohol within 72 hours prior to first study drug administration and during the study period.
• Participation in another investigational drug trial within 30 days prior to study drug administration (or within 5 half-lives of the investigational drug, whichever is longer) or exposure to more than 3 investigational agents within 12 months prior to study drug administration.
• Positive serology for hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibody at screening (a negative PCR test overrides a positive serology).
• Positive human immunodeficiency virus (HIV) test at screening.
• Positive urine drug screen (unless attributable to concomitant medication) or positive alcohol breath test at screening and/or Day -1.
• Patients who are legally incapacitated, have limited legal capacity, or are otherwise considered vulnerable.
• Female patients who are pregnant or breastfeeding.
• Patients who plan to become pregnant or father a child (including ova or sperm donation) during the study or within 3 months after the last dose of study drug.
• Known allergy or history of hypersensitivity to study drug(s) or their excipients.
• Concomitant use of strong or moderate CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and/or CYP3A4 inhibitors within 7 days or 5 half-lives (whichever is longer) prior to first dose of study treatment.
• Concomitant use of strong or moderate CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and/or CYP3A4 inducers within 14 days or 5 half-lives (whichever is longer) prior to first dose of study treatment.
• History of or active clinically significant cardiovascular, respiratory, gastrointestinal, renal, hepatic, neurological, psychiatric, musculoskeletal, genitourinary, dermatologic, hematologic, or other disorder that, in the investigator's judgment, could interfere with study participation or the absorption, metabolism, or excretion of study treatment.
• History of prior second malignancy unless disease-free for ≥ 12 months or considered surgically cured. Patients with nonmelanoma skin cancers or with carcinomas in situ at any time following curative intent surgery and low grade, early-stage prostate cancer (Gleason score 6 or below, stage 1 or 2) with no requirement for therapy at any time prior to the study, or previously resected are also eligible.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Pralsetinib with CYP450 Probe Substrates and Hormonal Contraceptive

Drug: Pralsetinib; Pralsetinib 400mg orally (PO) once daily (QD) from Day 4 to Day 10, with an option to continue up to Day 33; Drug: CYP3A4, CYP2C8, and CYP2C9 substrates, and hormonal contraceptive; Midazolam, repaglinide, and losartan (CYP probe substrates) and, for female participants, estradiol/norethisterone acetate (hormonal probe substrate), administered orally (PO) once on Day 1 and once on Day 9.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Plasma Concentration-Time Curve from zero to infinity (AUC0-inf)	To evaluate the effect of pralsetinib on the overall exposure of CYP3A4, CYP2C8, and CYP2C9, probe substrates, and hormonal contraceptive by measuring AUC0-inf for each probe substrate and its relevant metabolites.	Up to 48 hours post-dose or as appropriate for each probe substrate
Area under the plasma concentration-time curve from time zero to time of last measurable concentration (AUClast)	To evaluate the effect of pralsetinib on the overall exposure of CYP3A4, CYP2C8, and CYP2C9 probe substrates, and hormonal contraceptive by measuring AUClast for each probe substrate and its relevant metabolites.	Up to 48 hours after each probe drug administration
Maximum Peak Plasma Concentration (Cmax)	To evaluate how pralsetinib affects the peak levels of probe substrates, and hormonal contraceptive, in the blood after they are taken alone and again after treatment with pralsetinib	Up to 48 hours after each probe drug administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Maximum Plasma Concentration (tmax)	Venous whole blood samples will be collected for activity-based pharmacokinetics characterization to assess how pralsetinib affects the time required to reach peak plasma concentration for each probe drug.	Up to 48 hours after each probe drug administration
Terminal Half-Life (t½)	Venous whole blood samples will be collected for activity-based pharmacokinetics characterization To evaluate the effect of pralsetinib on the terminal half-life of each probe drug	Up to 48 hours after each probe drug administration
Percent of Area Under the plasma concentration-time curve obtained at extrapolation (%AUCex)	Venous whole blood samples will be collected for activity-based pharmacokinetics characterization to determine the proportion of the AUC that is extrapolated, providing insight into pralsetinib's effect on drug elimination	Up to 48 hours after each probe drug administration
Mean residence time (MRT)	Venous whole blood samples will be collected for activity-based pharmacokinetics characterization to assess how pralsetinib affects the average time each probe drug remains in the body	Up to 48 hours after each probe drug administration
Terminal Elimination Rate Constant (λz)	Venous whole blood samples will be collected for activity-based pharmacokinetics characterization to assess how pralsetinib affects the terminal elimination rate constant of each probe drug	Up to 48 hours after each probe drug administration
Apparent Total Body Clearance (CL/F)	Venous whole blood samples will be collected for activity-based pharmacokinetics characterization to evaluate the effect of pralsetinib on the apparent total body clearance of each probe drug	Up to 48 hours after each probe drug administration
Apparent Volume of Distribution (Vz/F)	Venous whole blood samples will be collected for activity-based pharmacokinetics characterization to assess how pralsetinib influences the apparent volume of distribution of each probe drug	Up to 48 hours after each probe drug administration
Safety and Tolerability	Incidence, frequency, relatedness, and severity of treatment-emergent adverse events (TEAEs) associated with co-administration of pralsetinib and probe substrates	From the start of treatment through approximately 30 days after the last dose of study treatment

Collaborators and Investigators

• Sponsor: Rigel Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): July 30, 2027
• Study Completion (Estimated): August 30, 2027

Study Registration Dates

• First Submitted: July 9, 2026
• First Submitted That Met QC Criteria: July 9, 2026
• First Posted (Actual): July 15, 2026

Study Record Updates

• Last Update Posted (Actual): July 15, 2026
• Last Update Submitted That Met QC Criteria: July 9, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Oncology; Medical Oncology; RET Fusion Positive; Drug-Drug Interactions; RET Gene Mutation; Pharmacokinetic (PK)
• Additional Relevant MeSH Terms: Endocrine System Diseases; Neoplasms by Site; Respiratory Tract Diseases; Lung Diseases; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Thyroid Diseases; Neoplasms; Carcinoma, Non-Small-Cell Lung; Thyroid Neoplasms; Amino Acids, Peptides, and Proteins; Proteins; Enzymes; Enzymes and Coenzymes; Oxidoreductases; Cytochromes; Mixed Function Oxygenases; Oxygenases; Hemeproteins; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 Enzyme System; Cytochrome P450 Family 2; Oxidoreductases Acting on CH-NH Group Donors; Cytochrome P450 Family 3; Oxidoreductases, N-Demethylating; pralsetinib; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A
• Other Study ID Numbers: RGL-RET-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes