Clinical trial NCT00879034: A Study of Zoledronic Acid, Pravastatin, and Lonafarnib for Patients With Progeria
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Progeria
Hutchinson-Gilford Syndrome
Keywords: Hutchinson-Gilford Progeria Syndrome
HGPS
Progeria
FTI
Farnesyltransferase Inhibitor
Lonafarnib
Zoledronic Acid
Pravastatin
Lead sponsor: Boston Children's Hospital
Sponsor class: OTHER
Collaborators: name: Dana-Farber Cancer Institute
name: Brigham and Women's Hospital
name: Schering-Plough
First posted: 2009-04-09
Enrollment: 5
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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
timeFrame: 4 weeks
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: 4 weeks
measure: To Investigate Which Clinical and Laboratory Studies Are Needed to Monitor or Alter Therapy to Prevent Unacceptable Toxicity
timeFrame: 4 weeks
measure: To Assess the Pharmacokinetics of Lonafarnib in Patients With Progeria.
timeFrame: 4 weeks
measure: To Assay for the Inhibition of HDJ-2 Farnesylation in Peripheral Blood Leukocytes (PBL)
timeFrame: 4 weeks
measure: 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.
timeFrame: 4 weeks
Other outcomes:
Locations:
city: Boston
country: United States
facility: Children's Hospital Boston
state: Massachusetts
Study officials:
affiliation: Dana-Farber Cancer Institute; Boston Children's Hospital
name: Mark W Kieran, MD, PhD
role: STUDY_CHAIR
References:
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.
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: Fisher MJ, Avery RA, Allen JC, Ardern-Holmes SL, Bilaniuk LT, Ferner RE, Gutmann DH, Listernick R, Martin S, Ullrich NJ, Liu GT; REiNS International Collaboration. Functional outcome measures for NF1-associated optic pathway glioma clinical trials. Neurology. 2013 Nov 19;81(21 Suppl 1):S15-24. doi: 10.1212/01.wnl.0000435745.95155.b8.