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

Primary Purpose

Progeria

Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Lonafarnib, Zoledronic Acid, and Pravastatin
Sponsored by
Boston Children's Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Progeria focused on measuring Progeria

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Children's Hospital Boston

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment arm

Arm Description

All patients will receive zoledronic acid, pravastatin and lonafarnib

Outcomes

Primary Outcome Measures

To evaluate the therapeutic effects of the combination of zoledronic acid, pravastatin and lonafarnib in patients with HGPS.

Secondary Outcome Measures

To describe any acute and chronic toxicities associated with treating progeria patients with the combination of zoledronic acid, pravastatin and lonafarnib.
To investigate which clinical and laboratory studies are needed to monitor or alter therapy to prevent unacceptable toxicity.
To assess the pharmacokinetics of lonafarnib in patients with progeria.
To assay for the inhibition of HDJ-2 farnesylation in Peripheral Blood Leukocytes (PBL).
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.
To assess changes in leptin levels, glucose utilization, skeletal abnormalities including bone mineral density and X-ray finding, joint contracture and function, and growth
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.
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

Full Information

First Posted
June 5, 2009
Last Updated
February 23, 2023
Sponsor
Boston Children's Hospital
Collaborators
Schering-Plough, Merck Sharp & Dohme LLC, Eiger BioPharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT00916747
Brief Title
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

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
August 2009 (undefined)
Primary Completion Date
February 2022 (Actual)
Study Completion Date
December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Boston Children's Hospital
Collaborators
Schering-Plough, Merck Sharp & Dohme LLC, Eiger BioPharmaceuticals

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Progeria
Keywords
Progeria

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Masking Description
Open Label
Allocation
N/A
Enrollment
85 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment arm
Arm Type
Experimental
Arm Description
All patients will receive zoledronic acid, pravastatin and lonafarnib
Intervention Type
Drug
Intervention Name(s)
Lonafarnib, Zoledronic Acid, and Pravastatin
Intervention Description
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.
Primary Outcome Measure Information:
Title
To evaluate the therapeutic effects of the combination of zoledronic acid, pravastatin and lonafarnib in patients with HGPS.
Time Frame
2 years
Secondary Outcome Measure Information:
Title
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
Title
To investigate which clinical and laboratory studies are needed to monitor or alter therapy to prevent unacceptable toxicity.
Time Frame
2 years
Title
To assess the pharmacokinetics of lonafarnib in patients with progeria.
Time Frame
2 years
Title
To assay for the inhibition of HDJ-2 farnesylation in Peripheral Blood Leukocytes (PBL).
Time Frame
2 years
Title
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
Title
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
Title
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
Title
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

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mark Kieran, MD, PhD
Organizational Affiliation
Children's Hospital Boston/ Dana-Farber Cancer Instittue
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Hospital Boston
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
27400896
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.
Results Reference
derived
PubMed Identifier
24795390
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.
Results Reference
derived
Links:
URL
http://www.progeriaresearch.org/
Description
The Progeria Research Foundation

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

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