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A Study of Zoledronic Acid, Pravastatin, and Lonafarnib for Patients With Progeria

This study has been completed.
Dana-Farber Cancer Institute
Brigham and Women's Hospital
Information provided by:
Boston Children’s Hospital Identifier:
First received: April 8, 2009
Last updated: April 20, 2010
Last verified: April 2010

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.

Condition Intervention Phase
Drug: Lonafarnib
Drug: Zoledronic Acid
Drug: Pravastatin
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:

Further study details as provided by Boston Children’s Hospital:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 5
Study Start Date: March 2009
Study Completion Date: April 2009
Primary Completion Date: April 2009 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Lonafarnib
    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.
    Drug: Zoledronic Acid
    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.
    Other Name: Zometa, Reclast
    Drug: Pravastatin
    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.
Detailed Description:
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.

Ages Eligible for Study:   Child, Adult, Senior
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.
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Please refer to this study by its identifier: NCT00879034

United States, Massachusetts
Children's Hospital Boston
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
Boston Children’s Hospital
Dana-Farber Cancer Institute
Brigham and Women's Hospital
  More Information

Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: Mark Kieran, M.D, Ph.D, Children's Hosptial Boston/ Dana-Farber Cancer Institute Identifier: NCT00879034     History of Changes
Other Study ID Numbers: 09-02-0074
Study First Received: April 8, 2009
Last Updated: April 20, 2010

Additional relevant MeSH terms:
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Zoledronic acid
Anticholesteremic Agents
Hypolipidemic Agents
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors
Bone Density Conservation Agents
Physiological Effects of Drugs processed this record on April 24, 2017