NCT00879034

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.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
5

participants targeted

Target at below P25 for phase_2

Timeline
Completed

Started Mar 2009

Shorter than P25 for phase_2

Geographic Reach
1 country

1 active site

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

March 1, 2009

Completed
1 month until next milestone

Primary Completion

Last participant's last visit for primary outcome

April 1, 2009

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

April 1, 2009

Completed
7 days until next milestone

First Submitted

Initial submission to the registry

April 8, 2009

Completed
1 day until next milestone

First Posted

Study publicly available on registry

April 9, 2009

Completed
8.3 years until next milestone

Results Posted

Study results publicly available

July 31, 2017

Completed
Last Updated

June 13, 2019

Status Verified

June 1, 2019

Enrollment Period

1 month

First QC Date

April 8, 2009

Results QC Date

May 24, 2017

Last Update Submit

June 11, 2019

Conditions

ProgeriaHutchinson-Gilford Syndrome

Keywords

Hutchinson-Gilford Progeria SyndromeHGPSProgeriaFTIFarnesyltransferase InhibitorLonafarnibZoledronic AcidPravastatin

Outcome Measures

Primary Outcomes (1)

  • 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 Outcomes (5)

  • To Describe Any Acute and Chronic Toxicities Associated With Treating Progeria Patients With the Combination of Zoledronic Acid, Pravastatin and Lonafarnib

    4 weeks

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

    4 weeks

  • To Assess the Pharmacokinetics of Lonafarnib in Patients With Progeria.

    4 weeks

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

    4 weeks

  • 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.

    4 weeks

Study Arms (1)

Zoledronic Acid,Pravastatin,and Lonafarnib

EXPERIMENTAL

Lonafarnib;Zoledronic acid;Pravastatin

Drug: LonafarnibDrug: Zoledronic AcidDrug: Pravastatin

Interventions

LonafarnibDRUG

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.

Also known as: Sarasar, SCH 66336
Zoledronic Acid,Pravastatin,and Lonafarnib
Zoledronic AcidDRUG

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.

Also known as: Zometa, Reclast
Zoledronic Acid,Pravastatin,and Lonafarnib
PravastatinDRUG

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.

Also known as: Pravachol
Zoledronic Acid,Pravastatin,and Lonafarnib

Eligibility Criteria

Sexall
Healthy VolunteersNo
Age GroupsChild (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

  • 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

You may not qualify if:

  • 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.

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Children's Hospital Boston

Boston, Massachusetts, 02115, United States

Location

Related Publications (4)

  • 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.

    PMID: 24795390BACKGROUND

  • 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.

    PMID: 27400896RESULT

  • Gordon LB, Norris W, Hamren S, Goodson R, LeClair J, Massaro J, Lyass A, D'Agostino RB Sr, Tuminelli K, Kieran MW, Kleinman ME. Plasma Progerin in Patients With Hutchinson-Gilford Progeria Syndrome: Immunoassay Development and Clinical Evaluation. Circulation. 2023 Jun 6;147(23):1734-1744. doi: 10.1161/CIRCULATIONAHA.122.060002. Epub 2023 Mar 15.

    PMID: 36919608DERIVED

  • 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.

    PMID: 24249802DERIVED

Related Links

MeSH Terms

Conditions

Progeria

Interventions

lonafarnibZoledronic AcidPravastatin

Condition Hierarchy (Ancestors)

LaminopathiesGenetic Diseases, InbornCongenital, Hereditary, and Neonatal Diseases and AbnormalitiesMetabolism, Inborn ErrorsMetabolic DiseasesNutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

DiphosphonatesOrganophosphonatesOrganophosphorus CompoundsOrganic ChemicalsImidazolesAzolesHeterocyclic Compounds, 1-RingHeterocyclic CompoundsNaphthalenesPolycyclic Aromatic HydrocarbonsHydrocarbons, AromaticHydrocarbons, CyclicHydrocarbonsPolycyclic Compounds

Limitations and Caveats

This was an open label clinical trial on a very rare disease population. Patient numbers are small, though 5 participants represents a small but significant portion of the world's population of children with HGPS.

Results Point of Contact

Title
Dr. Mark Kieran
Organization
Dana-Farber Cancer Institute
mark_kieran@dfci.harvard.edu
617-632-4907

Study Officials

  • Mark W Kieran, MD, PhD

    Dana-Farber Cancer Institute; Boston Children's Hospital

    STUDY CHAIR

Publication Agreements

PI is Sponsor Employee
No
Restrictive Agreement
No

Study Design

Study Type
interventional
Phase
phase 2
Allocation
NA
Masking
NONE
Masking Details
Open Label
Purpose
TREATMENT
Intervention Model
SINGLE GROUP
Sponsor Type
OTHER
Responsible Party
PRINCIPAL INVESTIGATOR
PI Title
Critical Care

Study Record Dates

First Submitted

April 8, 2009

First Posted

April 9, 2009

Study Start

March 1, 2009

Primary Completion

April 1, 2009

Study Completion

April 1, 2009

Last Updated

June 13, 2019

Results First Posted

July 31, 2017

Record last verified: 2019-06

Locations

US(1)