A Study of Zoledronic Acid, Pravastatin, and Lonafarnib for Patients With Progeria
Condition: Progeria; Hutchinson-Gilford Syndrome
MeSH terms: Progeria; Syndrome
Intervention: Lonafarnib; Zoledronic Acid; Pravastatin
Intervention description: Lonafarnib capsules are to be orally administered twice per day approximately every 12 hours. Lonafarnib dosing will begin at 150 mg/m2 by mouth twice daily. Dose levels are 150, 115, 90 and 70 mg/m2. Patients experiencing significant drug related grade 3 or 4 toxicity and not responding to therapy interruption or supportive care measures will be dose reduced by one dose level.; Zoledronic acid will be administered intravenously at week one of this treatment trial. Week one administration will consist of one infusion over a 30 minute period, 0.0125 mg/kg body weight.; Pravastatin will begin at 5 mg by mouth once daily for children weighing less than 10 kg, and 10 mg by mouth once daily for children weighing 10 kg or greater.
Intervention MeSH terms: Zoledronic Acid; Pravastatin; Lonafarnib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Masking description: Open Label
Enrollment: 5.0
Sex: All
Healthy volunteers: No
Keywords: Hutchinson-Gilford Progeria Syndrome; HGPS; Progeria; FTI; Farnesyltransferase Inhibitor; Lonafarnib; Zoledronic Acid; Pravastatin

Summary:

      This is an open label single arm feasibility trial. A combination of two oral agents
      (pravastatin and lonafarnib) and one intravenous (IV) agent (zoledronic acid) will be
      administered at doses and schedule currently applied in pediatrics. These agents all target
      farnesylation pathways at different points. Our goal is to inhibit farnesylation of abnormal
      lamin, the disease-causing protein in Hutchinson-Gilford Progeria Syndrome and progeroid
      laminopathies (henceforth "progeria"). The drugs will include the intravenous bisphosphonate
      zoledronic acid, oral HMG co-reductase inhibitor pravastatin and the oral farnesyltransferase
      inhibitor (FTI) lonafarnib (SCH 66336). Patients with genetically confirmed progeria will be
      eligible for this protocol. Treatment will be initiated for 4 weeks duration and may be
      extended depending on tolerability. This study will assess the feasibility of this treatment
      regimen in the first 4 weeks. If tolerated for 4 weeks, patients can be treated with this
      regimen for up to 6 months.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Genetic Diagnosis: All patients must have confirmatory mutational analysis showing
             mutation in the lamin A gene.

          -  Patients must display clinical signs of progeria as per the clinical trial team.

          -  Patients must be willing and able to come to Boston for appropriate studies and
             examinations at initiation of study and at week 4 of study.

          -  Patient must have adequate organ and marrow function as defined by study parameters

        Exclusion Criteria:

          -  Other than the drugs used in this protocol, other drugs targeted to treat Progeria are
             excluded. Drugs to treat symptoms of Progeria are permitted.

          -  Patients must not be taking medications that significantly affect the metabolism of
             lonafarnib at the time they start lonafarnib.

          -  Patient must have no uncontrolled infection.

          -  Subjects who have known or suspected hypersensitivity to any of the excipients
             included in the formulation should not be treated.

          -  Patients must not be pregnancy of breast-feeding. Female patients of childbearing
             potential must have negative serum or urine pregnancy test. Male and female patients
             of reproductive potential must agree to use a medically accepted form of birth control
             while on study and up to 10 weeks after treatment. It is permissible for female
             patients to take oral contraceptives or other hormonal methods while receiving
             treatment with lonafarnib.