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

• Sponsor: Boston Children's Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT00879034
• Collaborator: Dana-Farber Cancer Institute (Other), Brigham and Women's Hospital (Other), Schering-Plough (Industry)
• Enrollment: 5
• Location: 1
• Arm: 1
• Duration (Months): 1
• Patients Per Site Per Month: 4.9

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Progeria; Hutchinson-Gilford Syndrome	Drug: Lonafarnib; Drug: Zoledronic Acid; Drug: Pravastatin	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 5 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Masking Description: Open Label
• Primary Purpose: Treatment
• 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 Start Date: Mar 1, 2009
• Actual Primary Completion Date: Apr 1, 2009
• Actual Study Completion Date: Apr 1, 2009

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Zoledronic Acid,Pravastatin,and Lonafarnib Lonafarnib;Zoledronic acid;Pravastatin

Drug: Lonafarnib; 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.; Other Names: Sarasar, SCH 66336 ; Drug: Zoledronic Acid; 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.; Other Names: Zometa, Reclast ; Drug: Pravastatin; 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.; Other Names: Pravachol

Outcome Measures

Primary Outcome Measures

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 [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

1. To Describe Any Acute and Chronic Toxicities Associated With Treating Progeria Patients With the Combination of Zoledronic Acid, Pravastatin and Lonafarnib [4 weeks]

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

2. To Investigate Which Clinical and Laboratory Studies Are Needed to Monitor or Alter Therapy to Prevent Unacceptable Toxicity [4 weeks]

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

3. To Assess the Pharmacokinetics of Lonafarnib in Patients With Progeria. [4 weeks]

4. To Assay for the Inhibition of HDJ-2 Farnesylation in Peripheral Blood Leukocytes (PBL) [4 weeks]

5. 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]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital Boston	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Boston Children's Hospital
• Dana-Farber Cancer Institute
• Brigham and Women's Hospital
• Schering-Plough

Investigators

• Study Chair: Mark W Kieran, MD, PhD, Dana-Farber Cancer Institute; Boston Children's Hospital

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Progeria Research Foundation

Publications

• 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.

• Responsible Party: Monica E. Kleinman, Critical Care, Boston Children's Hospital
• ClinicalTrials.gov Identifier: NCT00879034
• Other Study ID Numbers: 09-02-0074; P06087
• First Posted: Apr 9, 2009
• Last Update Posted: Jun 13, 2019
• Last Verified: Jun 1, 2019

• Keywords provided by Monica E. Kleinman, Critical Care, Boston Children's Hospital: Hutchinson-Gilford Progeria Syndrome; HGPS; Progeria; FTI; Farnesyltransferase Inhibitor; Lonafarnib; Zoledronic Acid; Pravastatin
• Additional relevant MeSH terms: Progeria; Syndrome; Zoledronic Acid; Pravastatin; Lonafarnib

Study Results

Participant Flow

Recruitment Details	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.
Pre-assignment Detail	All patients screened to participate in study were consented onto the study as planned.

Arm/Group Title	Zoledronic Acid, Pravastatin, and Lonafarnib
Arm/Group 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. 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. 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.
Period Title: Overall Study
STARTED	5
Received Treatment	4
COMPLETED	5
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Zoledronic Acid, Pravastatin, and Lonafarnib
Arm/Group 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. 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. 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.
Overall Participants	5
Age (Count of Participants)
<=18 years	5 100%
Between 18 and 65 years	0 0%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	1 20%
Male	4 80%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (participants) [Number]
United States	5 100%

Outcome Measures

1. Primary Outcome

Title	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
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

Outcome Measure Data

Analysis Population Description

Results are reported for the 5 patients who completed the 4 weeks of therapy.

Arm/Group Title	Zoledronic Acid, Pravastatin, and Lonafarnib
Arm/Group 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. 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. 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.
Measure Participants	5
Count of Participants [Participants]	0 0%

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Zoledronic Acid, Pravastatin, and Lonafarnib
Arm/Group 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. 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. 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.
Measure Participants	5
Count of Participants [Participants]	0 0%

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Zoledronic Acid, Pravastatin, and Lonafarnib
Arm/Group 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. 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. 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.
Measure Participants	5
Count of Participants [Participants]	0 0%

4. Secondary Outcome

Title	To Assess the Pharmacokinetics of Lonafarnib in Patients With Progeria.
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

This data was not collected for this feasibility study. Pharmacokinetics assessment of lonafarnib in these 5 patients was analyzed at the end of a different protocol, NCT00916747.

Arm/Group Title	Zoledronic Acid, Pravastatin, and Lonafarnib
Arm/Group 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. 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. 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.
Measure Participants	0

5. Secondary Outcome

Title	To Assay for the Inhibition of HDJ-2 Farnesylation in Peripheral Blood Leukocytes (PBL)
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

This data was not collected for this feasibility study. HDJ-2 assessment in these 5 patients was analyzed at the end of a different protocol, NCT00916747.

Arm/Group Title	Zoledronic Acid, Pravastatin, and Lonafarnib
Arm/Group 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. 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. 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.
Measure Participants	0

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Zoledronic Acid, Pravastatin, and Lonafarnib
Arm/Group 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. 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. 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.
Measure Participants	5
Count of Participants [Participants]	5 100%

Adverse Events

Time Frame	Up to 4 weeks. Assessed at week 0 and week 4.
Arm/Group Title	Zoledronic Acid, Pravastatin, and Lonafarnib
Arm/Group 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. 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. 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.
All Cause Mortality
	Zoledronic Acid, Pravastatin, and Lonafarnib
	Affected / at Risk (%)	# Events
Total	0/5 (0%)
Serious Adverse Events
	Zoledronic Acid, Pravastatin, and Lonafarnib
	Affected / at Risk (%)	# Events
Total	0/5 (0%)
Other (Not Including Serious) Adverse Events
	Zoledronic Acid, Pravastatin, and Lonafarnib
	Affected / at Risk (%)	# Events
Total	0/5 (0%)

Limitations/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.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.