A Study of Zoledronic Acid, Pravastatin, and Lonafarnib for Patients With Progeria
A Study of Zoledronic Acid, Pravastatin, and Lonafarnib for Patients With Progeria
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.
Progerias are rare "premature aging" diseases in which children die of severe atherosclerosis
 leading to strokes and heart attacks. It is a multisystem disease with objective clinical
 markers for disease progression. These include abnormalities in growth and body composition,
 bone mineral density, join function, endocrine function, alopecia, and vascular disease.
 There is currently no therapy proven effective for any of the progressive and deleterious
 aspects of this disorder.

 Progeria is caused by a gene defect in the gene LMNA, coding for the nuclear protein lamin A.
 Lamin A is normally expressed by most differentiated cells, and requires posttranslational
 farnesylation to incorporate into the nuclear membrane. This trial proposes to use three
 agents (zoledronic acid, pravastatin, and lonafarnib) to inhibit farnesylation of abnormal
 lamin, the disease causing protein in Progeria. The primary objective of this study is to
 evaluate the feasibility of administering intravenous zoledronic acid, oral pravastatin and
 oral lonafarnib, to patients wtih Progeria for a minimum of 4 weeks.
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.