Patient case: 32-year-old male with dilated cardiomyopathy; genetic feature: LMNA

Clinical trial: Study of Zoledronic Acid, Pravastatin, and Lonafarnib for Patients With Progeria

Summary: 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.


Eligibility: Inclusion Criteria:
  -  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.
  Exclusion Criteria:
  -  Other than the drugs used in this protocol, 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 pregnant or 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.

Relevance to patient case: not relevant