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

Progeria Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00879034
• Other study ID #: 09-02-0074
• Secondary ID: P06087
• Status: Completed
• Phase: Phase 2
• Start date: March 2009
• Est. completion date: April 2009

Study information

• Verified date: June 2019
• Source: Boston Children’s Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 5
• Est. completion date: April 2009
• Est. primary completion date: April 2009
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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.

Related Conditions & MeSH terms

• Hutchinson-Gilford Syndrome
• Progeria
• Syndrome

Intervention

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.
• 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.
• 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.

Locations

Country	Name	City	State
United States	Children's Hospital Boston	Boston	Massachusetts

Sponsors (4)

Lead Sponsor	Collaborator
Boston Children’s Hospital	Brigham and Women's Hospital, Dana-Farber Cancer Institute, Schering-Plough

Country where clinical trial is conducted

United States, 

References & Publications (2)

Gordon LB, Kleinman ME, Massaro J, D'Agostino RB Sr, Shappell H, Gerhard-Herman M, Smoot LB, Gordon CM, Cleveland RH, Nazarian A, Snyder BD, Ullrich NJ, Silvera VM, Liang MG, Quinn N, Miller DT, Huh SY, Dowton AA, Littlefield K, Greer MM, Kieran MW. Clini — View Citation

Gordon LB, Massaro J, D'Agostino RB Sr, Campbell SE, Brazier J, Brown WT, Kleinman ME, Kieran MW; Progeria Clinical Trials Collaborative. Impact of farnesylation inhibitors on survival in Hutchinson-Gilford progeria syndrome. Circulation. 2014 Jul 1;130(1):27-34. doi: 10.1161/CIRCULATIONAHA.113.008285. Epub 2014 May 2. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Feasibility was assessed by determining the number of participants with adverse events occurring over the course of the 4 week study.	4 weeks
Secondary	To Describe Any Acute and Chronic Toxicities Associated With Treating Progeria Patients With the Combination of Zoledronic Acid, Pravastatin and Lonafarnib	Number of participants with acute and chronic toxicities associated with treating progeria patients with the combination of zoledronic acid, pravastatin and lonafarnib	4 weeks
Secondary	To Investigate Which Clinical and Laboratory Studies Are Needed to Monitor or Alter Therapy to Prevent Unacceptable Toxicity	The number of participants with abnormal CBC w/diff panel, LFTs, renal functions and lipid panels.	4 weeks
Secondary	To Assess the Pharmacokinetics of Lonafarnib in Patients With Progeria.		4 weeks
Secondary	To Assay for the Inhibition of HDJ-2 Farnesylation in Peripheral Blood Leukocytes (PBL)		4 weeks
Secondary	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.	The number of participants from whom baseline clinical and Laboratory data was obtained.	4 weeks

External Links

•   Progeria Research Foundation