Study of Zoledronic Acid, Pravastatin, and Lonafarnib for Patients With Progeria - Full Text View

Sponsor:	Children's Hospital Boston
Collaborators:	Progeria Research Foundation Schering-Plough
Information provided by:	Children's Hospital Boston
ClinicalTrials.gov Identifier:	NCT00916747

Purpose

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.

Condition	Intervention	Phase
Progeria	Drug: Lonafarnib, Zoledronic Acid, and Pravastatin	Phase II

Study Type:	Interventional
Study Design:	Endpoint Classification: Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	An Open Label Phase II Trial of Zoledronic Acid, Pravastatin, and Lonafarnib for Patients With Hutchinson-Gilford Progeria Syndrome(HGPS) and Progeroid Laminopathies

Resource links provided by NLM:

Genetics Home Reference related topics: Hutchinson-Gilford progeria syndrome

Drug Information available for: Pravastatin Pravastatin sodium Zoledronic acid Lonafarnib

U.S. FDA Resources

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

Primary Outcome Measures:

To evaluate the therapeutic effects of the combination of zoledronic acid, pravastatin and lonafarnib in patients with HGPS. [ Time Frame: 2 years ] [ Designated as safety issue: No ]

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: 2 years ] [ Designated as safety issue: Yes ]
To investigate which clinical and laboratory studies are needed to monitor or alter therapy to prevent unacceptable toxicity. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
To assess the pharmacokinetics of lonafarnib in patients with progeria. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
To assay for the inhibition of HDJ-2 farnesylation in Peripheral Blood Leukocytes (PBL). [ Time Frame: 2 years ] [ Designated as safety issue: No ]
To assay for changes in research-based potential markers of efficacy such as levels of prelamin A, mature lamin A, progerin, and HP1 in protein isolated from PBL. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
To assess changes in leptin levels, glucose utilization, skeletal abnormalities including bone mineral density and X-ray finding, joint contracture and function, and growth [ Time Frame: 2 years ] [ Designated as safety issue: No ]
To assess changes in auditory function, dental anomalies, dermatologic changes including hair density, nutrition with calorie analysis and energy expenditure, body composition analysis by DXA scan, and cardiovascular structure and function. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
To compare and incorporate clinical and laboratory data obtain from this study with that obtained during the single agent lonafarnib trial as well as the pilot combination trial of zoledronic acid, pravastatin and lonafarnib [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Estimated Enrollment:	45
Study Start Date:	August 2009
Estimated Study Completion Date:	February 2012
Estimated Primary Completion Date:	February 2012 (Final data collection date for primary outcome measure)

Intervention Details:

Lonafarnib: Lonafarnib dosing will begin at 150 mg/m2 by mouth twice daily. Lonafarnib will be orally administered without planned breaks, approximately every 12 hours, for a period of 24 months. For patients unable to swallow capsules, the capsules can be opened and dissolved into Ora Blend SF or Ora-Plus.

Zoledronic Acid: Zoledronic acid will be administered intravenously at week one, and months 6, 12, 18 and 24 of this treatment trial. Treatment will consist of one infusion over a 30 minute period.

Pravastatin: Pravastatin will be orally administered once daily without planned breaks, approximately every 24 hours, for a period of 24 months. The drug may be taken with meals. For patients unable to swallow pills, pills can be crushed into food. Pravastatin will be dosed according to the patient weight. Patients less than 10 kg will receive 5 mg pravastatin orally, once daily. Patients weighing 10 kg or greater will receive 10 mg pravastatin daily.

Eligibility

Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00916747

Locations

United States, Massachusetts
Children's Hospital Boston
Boston, Massachusetts, United States, 02115

Sponsors and Collaborators

Children's Hospital Boston

Progeria Research Foundation

Schering-Plough

Investigators

Principal Investigator:

Mark Kieran, MD, PhD

Children's Hospital Boston/ Dana-Farber Cancer Instittue

More Information

Additional Information:

The Progeria Research Foundation This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	Mark Kieran, MD, PhD, Children's Hospital Boston/ Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier:	NCT00916747 History of Changes
Other Study ID Numbers:	Progeria Efficacy
Study First Received:	June 5, 2009
Last Updated:	May 9, 2011
Health Authority:	United States: Food and Drug Administration

Keywords provided by Children's Hospital Boston:

Progeria

Additional relevant MeSH terms:

Progeria
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Pravastatin
Zoledronic acid
Diphosphonates
Anticholesteremic Agents
Hypolipidemic Agents

Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Lipid Regulating Agents
Therapeutic Uses
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors
Bone Density Conservation Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on February 09, 2012