Clinical Trial: A Study of Zoledronic Acid, Pravastatin, and Lonafarnib for Patients With Progeria
Study Status: Completed
Recruit Status: Completed
Study Type: Interventional
Official Title: A Phase II Pilot Study of Zoledronic Acid, Pravastatin, and Lonafarnib (SCH66336) for Patients With Hutchinson-Gilford Progeria Syndrome (HGPS) and Progeroid Laminopathies
Brief Summary:
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.
Detailed 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.
Sponsor: Boston Children’s Hospital
Current Primary Outcome: The primary objective of this study is to evaluate the feasibility of administering intravenous zoledronic acid, oral pravastatin and oral lonafarnib, to patients with Progeria for a minimum of 4 weeks [ Time Frame: 4 weeks ]
Original Primary Outcome: Same as current
Current Secondary Outcome:
- To describe any acute and chronic toxicities associated with treating progeria patients with the combination of zoledronic acid, pravastatin and lonafarnib [ Time Frame: 4 weeks ]
- To investigate which clinical and laboratory studies are needed to monitor or alter therapy to prevent unacceptable toxicity [ Time Frame: 4 weeks ]
- To assess the pharmacokinetics of lonafarnib in patients with progeria. [ Time Frame: 4 weeks ]
- To assay for the inhibition of HDJ-2 farnesylation in Peripheral Blood Leukocytes (PBL) [ Time Frame: 4 weeks ]
- To obtain baseline clinical and laboratory data so that longer-term measures of efficacy will be achievable if treatment continues beyond the 4-week feasibility study period. [ Time Frame: 4 weeks ]
Original Secondary Outcome: Same as current
Information By: Boston Children’s Hospital
Dates:
Date Received: April 8, 2009
Date Started: March 2009
Date Completion:
Last Updated: April 20, 2010
Last Verified: April 2010
