Pralsetinib DDI Study in Patients With Advanced or Metastatic Solid Tumors

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:

• Absolute neutrophil count (ANC) ≥ 1.0 × 10⁹/L.
• Platelet count ≥ 75 × 10⁹/L.
• Hemoglobin ≥ 9 g/dL.
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN), or ≤ 5 × ULN in patients with known liver metastases.
• Total bilirubin ≤ 1.5 × ULN (≤ 3 × ULN in patients with Gilbert syndrome).
• Creatinine clearance ≥ 40 mL/min using the Cockcroft-Gault equation.
• Serum phosphorus ≤ 5.5 mg/dL.
• 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:

• New York Heart Association (NYHA) Class III or IV congestive heart failure.
• 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).
• 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.
• History of prolonged QT syndrome or torsades de pointes, or familial history of long QT syndrome.
• 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.