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

Study Identifier:
RGL-RET-001
CT.gov Identifier:
NCT07704658
EudraCT Identifier:
202552315815
EU Trial (CTIS) Number:
2025-523158-15-00
Study Contact Information:
(210) 593-5651 or [email protected]
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Study Summary

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

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
Solid Tumor
Phase
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
Phase IV
Sex
Female & Male
Age
18+ years
Study Drug
Drug: EXPERIMENTAL: Pralsetinib with CYP450 Probe Substrates and Hormonal Contraceptive
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Drug: Drug: CYP3A4, CYP2C8, and CYP2C9 substrates, and hormonal contraceptive
Drug: 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.
Drug: Drug: Pralsetinib
Drug: Pralsetinib 400mg orally (PO) once daily (QD) from Day 4 to Day 10, with an option to continue up to Day 33
Study Status
Indicates the current recruitment status or the expanded access status
Recruiting

Requirements information
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. 1 Patients is willing and able to participate and comply with all study requirements and to provide signed and dated written consent prior to initiation of any study procedures.
  • 2 Patient is an adult male or female patient ≥18 years of age at the time of signing the informed consent form (ICF).
  • 3 Patient’s body mass index is ≥ 18 and ≤ 32 kg/m2, with a minimum body weight of 50 kg at Screening.
  • 4 Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
  • 5 Recovery from the non-hematologic toxic effects of prior treatment to Grade ≤ 1, or baseline value according to National Cancer Institute (NCI)–Common Terminology Criteria for Adverse Events (CTCAE, version 5) classification (excluding infertility, alopecia, or Grade 1 neuropathy)
  • 6 Confirmed diagnosis of advanced or metastatic solid tumors that have relapsed or are not responsive to standard therapies and have an oncogenic RET fusion or mutation as detected by a validated test.
  • 7 Patient must have adequate organ function, defined by the following: a. Absolute neutrophil count (ANC) ≥ 1.0 × 109/L. b. Platelet count ≥75 × 109/L. c. Hemoglobin ≥ 9 g/dL. Red blood cell (RBC) transfusion may be used to reach at least 9.0 g/dL, but must have been administered at least 2 weeks prior to the first dose of study drug. d. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) values ≤ 3 × upper limit of normal (ULN). e. Total bilirubin ≤ 1.5 × ULN (≤ 3 × ULN in patients with Gilbert Syndrome). f. Creatinine clearance ≥ 40 mL/min (using Cockroft-Gault), or serum creatinine ≤ 1.5 × ULN. g. Total serum phosphorous ≤ 5.5 mg/dL. h. International normalized ratio (INR) or prothrombin time and activated partial thromboplastin time (aPTT) within the normal laboratory limits.
  • 8 Patients must be ≥4 weeks since major surgery, radiotherapy, chemotherapy, immunotherapy, or kinase/targeted or gene therapies and recovered from the toxicity of prior treatment to ≤ Grade 1, exclusive of alopecia. Patients must be ≥ 6 weeks since last treatment if they received a long-acting agent such as a nitrosourea, mitomycin, or monoclonal antibodies such as bevacizumab or programmed cell death 1 (PD1) blockade therapy. In general, patients who received long-acting agents, a treatment interval of two half-lives should be considered and discussed with the Sponsor. (Concurrent cancer therapy of any type is not permitted).
  • 9 Female patients may be enrolled if they are documented to be surgically sterile or postmenopausal (amenorrhea >1 year and follicle stimulating hormone [FSH] ≥ 30 mU/mL). However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-estrogens, or ovarian suppression.
  • 10 Male patients with female partners of childbearing potential may be enrolled if they agree to use a highly effective method of contraception during the course of the study (from Day -1 on) until 90 days after the last administration of pralsetinib.
  • 11 Male patients must refrain from donating sperm during the assessment period (from Day -1 on) until at least 90 days after the last administration of pralsetinib.
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. 1 Clinically relevant abnormal medical history, abnormal findings on physical examination, vital signs, electrocardiogram (ECG), or laboratory tests at screening that the investigator judges as likely to interfere with the objectives of the trial or the safety of the patient.
  • 2 Surgery (e.g., stomach bypass) or medical condition that might significantly affect absorption of medicines (as judged by the investigator).
  • 3 History of pneumonitis within the last 12 months.
  • 4 History of active or latent tuberculosis (TB), regardless of treatment history, or has a positive screening test for latent mycobacterium TB infection by QuantiFERON® TB Gold. Indeterminate results may be confirmed by repeat or by a purified protein derivative (PPD) skin test.
  • 5 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's safety (e.g. COVID or influenza).
  • 6 Cardiovascular issues including: a. Clinically significant, uncontrolled, cardiovascular disease, including Grade III or IV congestive heart failure according to the New York Heart Association (NYHA) classification. b. Myocardial infarction or unstable angina within the previous 6 months, clinically significant, uncontrolled arrhythmias, including bradyarrhythmias that may cause QT prolongation (eg, Type II 2nd or 3rd degree heart block). c. Uncontrolled treated/untreated hypertension, defined as a mean of 3 repeated measurements for systolic blood pressure ≥ 180 mmHg and/or diastolic blood pressure ≥110 mmHg; current or documented history of repeated clinically significant hypotension or severe episodes of orthostatic hypotension (systolic blood pressure < 90 mmHg and/or diastolic blood pressure <50 mmHg). d. History of prolonged QT syndrome or torsades de pointes, or familial history of prolonged QT syndrome. e. Corrected QT-interval (QTc) using Fridericia correction (QTcF) at screening or check-in (Day -1) ≥ 470 ms demonstrated on at least 2 ECGs that are performed >30 minutes apart.
  • 7 Central nervous system (CNS) metastases or a primary CNS tumor.
  • 8 Concurrent, recent (≤ 4 weeks ago) systemic corticosteroids
  • 9 More than 30 Gy of radiotherapy to the lung in the 6 months before check-in.
  • 10 History of multiple and/or severe allergies to drugs or foods or a history of severe anaphylactic reaction.
  • 11 Use of prohibited medications or procedures as outline below: - Strong inducers and/or inhibitors of CYP enzymes - Any live, attenuated vaccine within 4 weeks prior to check-in and during the assessment period - Any immunotherapy within 28 days or if a long half-life agent such as an antibody therapy, within 6 weeks prior to the first dose of study. - Any other prescription medications or products during the screening period until End-of-Treatment unless deemed acceptable - Any over-the-counter non-prescription medications (including vitamins, minerals, and phytotherapeutic/herbal/plant-derived preparations) from 7 days prior to Day 1 until EOT.
  • 12 Medical conditions or underlying diseases that constitute contraindications on the use of substrates or probes used in this study
  • 13 Positive urine drug screen (if not due to concomitant medication) or alcohol breath test at screening and/or check-in (Day -1). Ingestion of alcohol within 72 hours prior to first study drug administration and during the study period.
  • 14 Participation in another investigational drug trial within 30 days prior to study drug administration or exposure to more than 3 new investigational agents within 12 months prior to study drug administration.
  • 15 Positive serology for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody at screening. A negative polymerase chain reaction (PCR) test overrides a positive serological test. Positive for human immunodeficiency virus (HIV) at screening. (Screening tests may include: antibody tests, antigen/antibody tests, and/or nucleic acid tests)
  • 16 Legal incapacity, limited legal capacity, or other vulnerable patients.
  • 17 Female patient who is pregnant or breastfeeding.
  • 18 Patient plans to become pregnant or father a child (including ova or sperm donation) while enrolled in this study or within 3 months after last dose of study drug.
  • 19 Patients receiving treatment with strong or moderate CYP1A2, 2B6, 2C8, 2C9, 2C19, and/or 3A4 inhibitors within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study drug
  • 20 Patients receiving treatment with strong or moderate CYP1A2, 2B6, 2C8, 2C9, 2C19, and/or 3A4 inducers within 14 days or 5 half-lives (whichever is longer) prior to the first dose of study drug.

Clinical Study Information for Healthcare Providers

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Study Locations

Location
Investigator
Status
Condition(s) Treated at Site
Location
START La Rioja
Logroño, La Rioja, Spain, 26006
Investigator
Maria de Miguel
Status
Recruiting
Condition(s) Treated at Site
Solid Tumor
Location
START Madrid, Spain (CIOCC)
Madrid, Spain, 28050
Investigator
Irene Moreno
Status
Recruiting
Condition(s) Treated at Site
Solid Tumor