Clinical trial NCT00916747: Study of Zoledronic Acid, Pravastatin, and Lonafarnib for Patients With Progeria
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Progeria
Keywords: Progeria
Lead sponsor: Boston Children's Hospital
Sponsor class: OTHER
Collaborators: name: Schering-Plough
name: Merck Sharp & Dohme LLC
name: Eiger BioPharmaceuticals
First posted: 2009-06-09
Enrollment: 85
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility 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.

Primary outcomes:
measure: To evaluate the therapeutic effects of the combination of zoledronic acid, pravastatin and lonafarnib in patients with HGPS.
timeFrame: 2 years
Secondary outcomes:
measure: To describe any acute and chronic toxicities associated with treating progeria patients with the combination of zoledronic acid, pravastatin and lonafarnib.
timeFrame: 2 years
measure: To investigate which clinical and laboratory studies are needed to monitor or alter therapy to prevent unacceptable toxicity.
timeFrame: 2 years
measure: To assess the pharmacokinetics of lonafarnib in patients with progeria.
timeFrame: 2 years
measure: To assay for the inhibition of HDJ-2 farnesylation in Peripheral Blood Leukocytes (PBL).
timeFrame: 2 years
measure: 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.
timeFrame: 2 years
measure: To assess changes in leptin levels, glucose utilization, skeletal abnormalities including bone mineral density and X-ray finding, joint contracture and function, and growth
timeFrame: 2 years
measure: 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.
timeFrame: 2 years
measure: 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
timeFrame: 2 years
Other outcomes:
Locations:
city: Boston
country: United States
facility: Children's Hospital Boston
state: Massachusetts
Study officials:
affiliation: Children's Hospital Boston/ Dana-Farber Cancer Instittue
name: Mark Kieran, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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. Clinical Trial of the Protein Farnesylation Inhibitors Lonafarnib, Pravastatin, and Zoledronic Acid in Children With Hutchinson-Gilford Progeria Syndrome. Circulation. 2016 Jul 12;134(2):114-25. doi: 10.1161/CIRCULATIONAHA.116.022188.
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.