Pralsetinib (Gavreto) drug drug interaction study in patients with RET+ advanced or metastatic solid tumors.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Rigel Pharmaceuticals Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2025-11-25

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Rigel Pharmaceuticals Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic

To evaluate the effect of pralsetinib on the exposure of probe substrates of CYP3A, CYP2C8, and CYP2C9, and hormones estradiol/norethisterone acetate

Secondary objectives 1

1. To evaluate the effect of pralsetinib on the other PK properties of probe substrates of CYP3A4, CYP2C8, and CYP2C9 and hormones estradiol/norethisterone acetate

Conditions and MedDRA coding

Patients with advanced or metastatic solid tumors

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

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 20

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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The following PK parameters will be estimated for the probe substrates and their relevant metabolites: • Area under the plasma concentration-time curve from zero to 24 hours (AUC0-inf) • Area under the plasma concentration-time curve from time zero to time of last measurable concentration (AUClast) • Maximum (peak) plasma concentration (Cmax)

Secondary endpoints 1

1. The following PK parameters will be estimated for the probe substrates and their relevant metabolites: • Time to maximum plasma concentration (tmax) • Terminal half-life (t1/2) • Percent of area under the plasma concentration-time curve obtained at extrapolation (%AUCex) • Mean residence time (MRT) • Terminal elimination rate constant (λz) • Apparent total body clearance (CL/F) • Apparent volume of distribution (Vz/F)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Rigel Pharmaceuticals Inc.

Sponsor organisation

Rigel Pharmaceuticals Inc.

Address

1180 Veterans Boulevard

City

South San Francisco

Postcode

94080-1985

Country

United States

Scientific contact point

Organisation

Rigel Pharmaceuticals Inc.

Contact name

Lisa Rojkjaer

Public contact point

Organisation

Rigel Pharmaceuticals Inc.

Contact name

Jill DeFratis

Third parties 1

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications