A Phase 2 interventional study of Lonafarnib and Zoledronic Acid in Progeria and Hutchinson-Gilford Syndrome, sponsored by Boston Children's Hospital. Completed at 1 site in United States. Per ClinicalTrials.gov, last updated 2019-06-13.
Sponsored by Boston Children's Hospital · Phase 2, Interventional, and Treatment
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.
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.
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Exclusion Criteria:
Lonafarnib;Zoledronic acid;Pravastatin
Drug: Lonafarnib · Drug: Zoledronic Acid · Drug: Pravastatin
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 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
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
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.
Time frame: 4 weeks
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
Time frame: 4 weeks
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.
Time frame: 4 weeks
To Assess the Pharmacokinetics of Lonafarnib in Patients With Progeria.
Time frame: 4 weeks
To Assay for the Inhibition of HDJ-2 Farnesylation in Peripheral Blood Leukocytes (PBL)
Time frame: 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.
The number of participants from whom baseline clinical and Laboratory data was obtained.
Time frame: 4 weeks
4 patients with classic HGPS from the United States were enrolled in March 2009 at Boston Children's Hospital. 1 additional patient had nonclassic mutations.
| Milestone | Zoledronic Acid, Pravastatin, and Lonafarnib |
|---|---|
| Started | 5 |
| Received treatment | 4 |
| Completed | 5 |
| Not completed | 0 |
Feasibility was assessed by determining the number of participants with adverse events occurring over the course of the 4 week study.
| Participants | Zoledronic Acid, Pravastatin, and Lonafarnib |
|---|---|
| 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 | 0 |
Number of participants with acute and chronic toxicities associated with treating progeria patients with the combination of zoledronic acid, pravastatin and lonafarnib
| Participants | Zoledronic Acid, Pravastatin, and Lonafarnib |
|---|---|
| To Describe Any Acute and Chronic Toxicities Associated With Treating Progeria Patients With the Combination of Zoledronic Acid, Pravastatin and Lonafarnib | 0 |
The number of participants with abnormal CBC w/diff panel, LFTs, renal functions and lipid panels.
| Participants | Zoledronic Acid, Pravastatin, and Lonafarnib |
|---|---|
| To Investigate Which Clinical and Laboratory Studies Are Needed to Monitor or Alter Therapy to Prevent Unacceptable Toxicity | 0 |
No measurements were reported for this outcome.
No measurements were reported for this outcome.
The number of participants from whom baseline clinical and Laboratory data was obtained.
| Participants | Zoledronic Acid, Pravastatin, and Lonafarnib |
|---|---|
| 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. | 5 |
Collected over Up to 4 weeks. Assessed at week 0 and week 4.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Zoledronic Acid, Pravastatin, and Lonafarnib | 0/5 (0%) | 0/5 (0%) | 0/5 (0%) |
| Age, Categorical(Participants) | Zoledronic Acid, Pravastatin, and Lonafarnib |
|---|---|
| <=18 years | 5 |
| Between 18 and 65 years | 0 |
| >=65 years | 0 |
| Sex: Female, Male(Participants) | Zoledronic Acid, Pravastatin, and Lonafarnib |
|---|---|
| Female | 1 |
| Male | 4 |
| Race and Ethnicity Not Collected(Participants) | Zoledronic Acid, Pravastatin, and Lonafarnib |
|---|
| Region of Enrollment(participants) | Zoledronic Acid, Pravastatin, and Lonafarnib |
|---|---|
| United States | 5 |
This study is completed, as verified in Jun 2019. You cannot join it, but the record below documents what was studied.
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Progeria
Boston Children's Hospital