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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00879034
Recruitment Status : Completed
First Posted : April 9, 2009
Results First Posted : July 31, 2017
Last Update Posted : June 13, 2019
Dana-Farber Cancer Institute
Brigham and Women's Hospital
Information provided by (Responsible Party):
Monica E. Kleinman, Boston Children's Hospital

Brief 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.

Condition or disease Intervention/treatment Phase
Progeria Hutchinson-Gilford Syndrome Drug: Lonafarnib Drug: Zoledronic Acid Drug: Pravastatin Phase 2

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 5 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Masking Description: 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
Study Start Date : March 2009
Actual Primary Completion Date : April 2009
Actual Study Completion Date : April 2009

Arm Intervention/treatment
Experimental: Zoledronic Acid,Pravastatin,and Lonafarnib
Lonafarnib;Zoledronic acid;Pravastatin
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.
Other Name: Sarasar, SCH 66336

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.
Other Name: Pravachol

Primary Outcome Measures :
  1. 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 ]
    Feasibility was assessed by determining the number of participants with adverse events occurring over the course of the 4 week study.

Secondary Outcome Measures :
  1. 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 ]
    Number of participants with acute and chronic toxicities associated with treating progeria patients with the combination of zoledronic acid, pravastatin and lonafarnib

  2. To Investigate Which Clinical and Laboratory Studies Are Needed to Monitor or Alter Therapy to Prevent Unacceptable Toxicity [ Time Frame: 4 weeks ]
    The number of participants with abnormal CBC w/diff panel, LFTs, renal functions and lipid panels.

  3. To Assess the Pharmacokinetics of Lonafarnib in Patients With Progeria. [ Time Frame: 4 weeks ]
  4. To Assay for the Inhibition of HDJ-2 Farnesylation in Peripheral Blood Leukocytes (PBL) [ Time Frame: 4 weeks ]
  5. 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 ]
    The number of participants from whom baseline clinical and Laboratory data was obtained.

Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00879034

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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
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Study Chair: Mark W Kieran, MD, PhD Dana-Farber Cancer Institute; Boston Children's Hospital
Additional Information:
Publications of Results:
Other Publications:
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Monica E. Kleinman, Critical Care, Boston Children's Hospital Identifier: NCT00879034    
Other Study ID Numbers: 09-02-0074
P06087 ( Other Identifier: Schering-Plough )
First Posted: April 9, 2009    Key Record Dates
Results First Posted: July 31, 2017
Last Update Posted: June 13, 2019
Last Verified: June 2019
Keywords provided by Monica E. Kleinman, Boston Children's Hospital:
Hutchinson-Gilford Progeria Syndrome
Farnesyltransferase Inhibitor
Zoledronic Acid
Additional relevant MeSH terms:
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Pathologic Processes
Genetic Diseases, Inborn
Metabolism, Inborn Errors
Metabolic Diseases
Zoledronic Acid
Bone Density Conservation Agents
Physiological Effects of Drugs
Anticholesteremic Agents
Hypolipidemic Agents
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors