This study evaluates safety and tolerability of a single ascending dose of a tesevatinib liquid formulation administered to pediatric subjects with ARPKD.


Drug: Tesevatinib

Inclusion Criteria:

  • Clinical diagnosis of ARPKD the presence of bilaterally enlarged echogenic kidneys demonstrating poor corticomedullary differentiation and at least 1 of the following:
    • Biliary ductal ectasia on magnetic resonance cholangiography or biliary duct ectasia or dilation on ultrasound
    • Absence of renal cysts and/or characteristic imaging findings in both parents
    • Signs of congenital periportal hepatic fibrosis as indicated by the presence of hepatosplenomegaly and/or esophageal varices and/or coarse liver echogenicity on ultrasound
    • Hepatic periportal fibrosis on liver biopsy
    • Pathologic (biopsy or autopsy) or genetic diagnosis of ARPKD in a deceased sibling or a clinical diagnosis of ARPKD in a living affected sibling
  • The subject’s parents or legal authorized representatives have signed a written informed consent per local regulations prior to screening. Assent, when appropriate, has been obtained from the subject according to institutional guidelines.
  • The subject has a Lansky Play-Performance score of ≥ 50. Note: Subjects who are unable to walk because of paralysis, but who are in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
  • The subject has the following laboratory values:
    • Platelets > 120,000/mm3
    • Hemoglobin > 9 g/dL
    • Total bilirubin ≤ 1.5 mg/dL
    • Aspartate aminotransferase (AST) < 2.5 × upper limit of normal (ULN) for age
    • Alanine aminotransferase (ALT) < 2.5 × ULN for age
    • eGFR ≥ 50 mL/min/1.73 m2 as measured by Chronic Kidney Disease in Children (CKiD) equation
    • Serum potassium levels and serum magnesium levels above the lower limit of normal for age
    • Albumin within normal limits for age
    • Prothrombin time (PT) and partial thromboplastin time (PTT) ≤ 1.5 × ULN
  • The subject has a normal ejection fraction by echocardiogram.
  • The subject has a mean corrected QTcF of ≤ 450 msec.
  • The subject has a blood pressure < 95th percentile for age, height, and gender. Subject may be on medication for treatment of hypertension.
  • The subject has normal auditory function for age.
  • If sexually active, the subject agrees to use 2 accepted methods of contraception during the course of the study and for 3 months after their last dose of study drug.

Exclusion Criteria:

  • The subject has had a previous partial or total nephrectomy.
  • The subject has any known genetic syndrome involving the kidney or liver other than ARPKD.
  • The subject has had clinically significant gastrointestinal bleeding during the 6 months prior to enrollment.
  • The subject has received any investigational therapy within 30 days prior to the first dose of study drug.
  • The subject has a history of pancreatitis, has known risk factors for pancreatitis, or baseline elevations in serum amylase or lipase.
  • The subject meets any of the following cardiac criteria:
    • History of torsade de pointes, ventricular tachycardia or fibrillation, pathologic sinus bradycardia (< 50 bpm), heart block (excluding first-degree block, being PR interval prolongation only), congenital long QT syndrome or new ST segment elevation or depression or new Q wave on ECG. Subjects with a history of atrial arrhythmias should be discussed with the Medical Monitor
    • Family history of congenital long QT syndrome or unexplained sudden cardiac death
    • History of congenital prolonged QT syndrome, New York Heart Association class III or IV congestive heart failure
    • History of cardiac arrhythmias, stroke, or myocardial infarction
    • Has a cardiac pacemaker
  • The subject has an abnormal baseline audiogram.
  • The subject is taking or has taken any medication known to inhibit the cytochrome P450 (CYP) 3A4 isozyme or any drugs that are strong or moderate CYP3A4 inducers within 14 days prior to Day 1 of study drug.
  • The subject is taking or has taken any drugs associated with torsades de pointes or known to prolong the QTc interval, including anti-arrhythmic medications within 2 weeks prior to Day 1 of study drug.
  • The subject is receiving systemic anticoagulation.
  • The subject has an uncontrolled intercurrent illness that would limit compliance with study requirements.
  • The subject has an uncontrolled infection.
  • The subject is known to be positive for the human immunodeficiency virus or hepatitis B or C.
  • The subject is known to be immunocompromised.
  • The subject has any medical or surgical conditions that would interfere with gastrointestinal absorption of this oral agent.
  • The subject has received prior solid organ transplantation.
  • The subject, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study.
  • The subject has an allergy or hypersensitivity to components of either the tesevatinib or the formulation.
  • The subject is aphakic.
  • The subject is pregnant or breast feeding.

Contact Information:

Mohini Dutt
Children’s Hospital of Philadelphia

Theresa Kump
Children’s Hospital of Wisconsin