An Open Label Phase II Trial of Zoledronic Acid, Pravastatin, and Lonafarnib for Patients With Hutchinson-Gilford Progeria Syndrome(HGPS) and Progeroid Laminopathies
Hutchinson-Gilford Progeria Syndrome (Progeria) is a rare autosomal disease that results in premature death at a median age of 13 years due to cardiovascular and cerebralvascular compromise. The mutation for this disease has been identified and results in a mutant form of lamin A that cannot be de-farnesylated. This study evaluates the combination of pravastain (a statin), lonafarnib (a farnesyltransferase inhibitor) and zoledronic acid (a bisphosphonate) in an open label phase II efficacy trial in children with Progeria. These agents all target farnesylation pathways at different points. Patients with genetically confirmed progeria will be eligible for this protocol. Treatment will be initiated for 24 months duration. Clinical and biologic parameters will be examined to assess response.
• Genetic Diagnosis: All patients must have confirmatory mutational analysis showing mutation in the lamin A gene.
• Clinical Diagnosis: Patients must display clinical signs of progeria as per the clinical trial team.
• Travel: Patients must be willing and able to come to Boston for appropriate studies and examinations at initiation of study and at months 6, 12, 18 and 24 on study.
• Patient must have adequate organ and marrow function as defined by the following parameters:
• Blood: APC (ANC + bands + monocytes = APC) \> 1,000/microliters, Platelets \> 75,000/microliters (transfusion independent); Hemoglobin \>9g/dl.
• Renal: creatinine Less than or equal 1.5 times normal for age or GFR \> 70 ml/min/1.73m2.
• Hepatic: bilirubin Less than or equal to 1.5 x upper limit of normal for age; SGPT (ALT) \< and SGOT (AST) \< 5 x normal range for age.
• PT/PTT: PT/PTT \< 120% upper limit of normal OR PI approval
• No overt renal, hepatic, pulmonary disease or immune dysfunction.
• 25-hydroxyvitamin D ≥ 20 ng/ml within 4 weeks of bisphosphonate infusion.
• Signed informed consent according to institutional guidelines must be obtained and patient must begin therapy within twenty eight (28) days.