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

Primary Purpose

Progeria, Hutchinson-Gilford Syndrome

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Lonafarnib

Zoledronic Acid

Pravastatin

About this trial

This is an interventional treatment trial for Progeria focused on measuring Hutchinson-Gilford Progeria Syndrome, HGPS, Progeria, FTI, Farnesyltransferase Inhibitor, Lonafarnib, Zoledronic Acid, Pravastatin

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.
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.

Sites / Locations

Children's Hospital Boston

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Zoledronic Acid,Pravastatin,and Lonafarnib

Arm Description

Lonafarnib;Zoledronic acid;Pravastatin

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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

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.

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 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.

Full Information

NCT ID

NCT00879034

First Posted

April 8, 2009

Last Updated

June 11, 2019

Sponsor

Boston Children's Hospital

Collaborators

Dana-Farber Cancer Institute, Brigham and Women's Hospital, Schering-Plough

1. Study Identification

Unique Protocol Identification Number

NCT00879034

Brief Title

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

2. Study Status

Record Verification Date

June 2019

Overall Recruitment Status

Completed

Study Start Date

March 2009 (undefined)

Primary Completion Date

April 2009 (Actual)

Study Completion Date

April 2009 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Boston Children's Hospital

Collaborators

Dana-Farber Cancer Institute, Brigham and Women's Hospital, Schering-Plough

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

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

Progeria, Hutchinson-Gilford Syndrome

Keywords

Hutchinson-Gilford Progeria Syndrome, HGPS, Progeria, FTI, Farnesyltransferase Inhibitor, Lonafarnib, Zoledronic Acid, Pravastatin

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

5 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Zoledronic Acid,Pravastatin,and Lonafarnib

Arm Type

Experimental

Arm Description

Lonafarnib;Zoledronic acid;Pravastatin

Intervention Type

Drug

Intervention Name(s)

Lonafarnib

Other Intervention Name(s)

Sarasar, SCH 66336

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Zoledronic Acid

Other Intervention Name(s)

Zometa, Reclast

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Pravastatin

Other Intervention Name(s)

Pravachol

Intervention Description

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.

Primary Outcome Measure Information:

Title

Description

Feasibility was assessed by determining the number of participants with adverse events occurring over the course of the 4 week study.

Time Frame

4 weeks

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

Description

Number of participants with acute and chronic toxicities associated with treating progeria patients with the combination of zoledronic acid, pravastatin and lonafarnib

Time Frame

4 weeks

Title

To Investigate Which Clinical and Laboratory Studies Are Needed to Monitor or Alter Therapy to Prevent Unacceptable Toxicity

Description

The number of participants with abnormal CBC w/diff panel, LFTs, renal functions and lipid panels.

Time Frame

4 weeks

Title

To Assess the Pharmacokinetics of Lonafarnib in Patients With Progeria.

Time Frame

4 weeks

Title

To Assay for the Inhibition of HDJ-2 Farnesylation in Peripheral Blood Leukocytes (PBL)

Time Frame

4 weeks

Title

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.

Description

The number of participants from whom baseline clinical and Laboratory data was obtained.

Time Frame

4 weeks

10. Eligibility

Sex

All

Accepts Healthy Volunteers

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Mark W Kieran, MD, PhD

Organizational Affiliation

Dana-Farber Cancer Institute; Boston Children's Hospital

Official's Role

Study Chair

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

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

background

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

result

PubMed Identifier

24249802

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.

Results Reference

derived

Links:

URL

http://www.progeriaresearch.org/

Description

Progeria Research Foundation

Learn more about this trial

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

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