Phase II Trial of Lonafarnib (a Farnesyltransferase Inhibitor) for Progeria

NCT00425607 | Completed Phase 2 Results DMC

• 2 other identifiers: 07-01-007P05009
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 1

Brief Summary

This is an open label dose adjusted phase II trial of the oral farnesyltransferase inhibitor (FTI) lonafarnib (SCH66336) for patients with HGPS and progeroid laminopathies.

Conditions

Progeria; Hutchinson-Gilford Syndrome

Keywords

Hutchinson-Gilford Progeria Syndrome; HGPS; Progeria; FTI; Farnesyltransferase Inhibitor; Lonafarnib

Outcome Measures

Primary Outcomes (1)

• Proportion of Participants With Successful Rate of Weight Gain

  Activity was assessed by determining the change in rate of weight gain over two years from baseline (determined pre-therapy for each patient). Primary outcome success was predefined as a 50% increase over pre-therapy in estimated annual rate of weight gain, or change from pre-therapy weight loss to statistically significant on-study weight gain.

  Assessed at weeks 16, 32, 52, 68, 84 and 104

Study Arms (1)

Lonafarnib

EXPERIMENTAL

All subjects initiated oral Lonafarnib twice daily at a dose of 115mg/m2 and escalated to 150 mg/m2. Two subjects de-escalated to 115mg/m2 following toxicity.

Drug: Lonafarnib

Interventions

Lonafarnib DRUG

Lonafarnib will be taken orally, twice per day, by all patients enrolled on this study. The drug is supplied to patients in capsule form, and for patients who are unable to swallow pills, the drug may be dissolved into solution. Every patient will start lonafarnib therapy at a dose of 115mg/kg. The study allows for patients to receive a dose escalation (up to 150mg/kg) if the drug is being well-tolerated. Every patient enrolled on this study will undergo two years of lonafarnib therapy.

Also known as: SCH66336

Lonafarnib

Eligibility Criteria

• Age: 1 Year+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• All patients must have confirmatory mutational analysis showing G608G mutation in the lamin A gene.
• Patients with progeroid laminopathies, showing clinical signs of Progeria but with other confirmed mutations in LMNA will be eligible for therapy. This population will be analyzed separately from those with the classical mutations.
• Patients must be willing and able to come to Boston for appropriate studies and examinations approximately once every 4 months.
• Patients must have a minimum of one year of weight data available, with five data points or more, each separated by one month or more over a one year period and approval by the study team.
• APC (ANC + bands + monocytes = APC) \> 1,000/ml, Platelets \> 75,000/ml (transfusion independent); Hemoglobin \>9g/dl.
• creatinine less than or equal to 1.5 times normal for age or GFR \> 70 ml/min/1.73m2.
• 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 \< 120% upper limit of normal OR PI approval.
• No overt renal, hepatic, pulmonary disease or immune dysfunction.
• Patients taking growth hormone when entering the study must have pretreatment weight measures while on growth hormone which are specified above. In addition, patients must remain on growth hormone treatment for the duration of the present clinical trial. Patients entering the trial not on growth hormone must remain off of growth hormone for the duration of their participation.
• Signed informed consent according to institutional guidelines must be obtained and patient must begin therapy within twenty eight (28) days.

You may not qualify if:

• Patient must not be receiving any other experimental drug therapy.
• Patients must not be taking medications that significantly affect the metabolism of lonafarnib.
• 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.

Sponsors & Collaborators

• Monica E. Kleinman: lead
• Schering-Plough: collaborator

Study Sites (1)

Children's Hospital Boston

Boston, Massachusetts, 02115, United States

Location

Related Publications (8)

• Gordon LB, Kleinman ME, Miller DT, Neuberg DS, Giobbie-Hurder A, Gerhard-Herman M, Smoot LB, Gordon CM, Cleveland R, Snyder BD, Fligor B, Bishop WR, Statkevich P, Regen A, Sonis A, Riley S, Ploski C, Correia A, Quinn N, Ullrich NJ, Nazarian A, Liang MG, Huh SY, Schwartzman A, Kieran MW. Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci U S A. 2012 Oct 9;109(41):16666-71. doi: 10.1073/pnas.1202529109. Epub 2012 Sep 24.

  PMID: 23012407 RESULT

• 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: 24795390 RESULT

• Cleveland RH, Gordon LB, Kleinman ME, Miller DT, Gordon CM, Snyder BD, Nazarian A, Giobbie-Hurder A, Neuberg D, Kieran MW. A prospective study of radiographic manifestations in Hutchinson-Gilford progeria syndrome. Pediatr Radiol. 2012 Sep;42(9):1089-98. doi: 10.1007/s00247-012-2423-1. Epub 2012 Jul 1.

  PMID: 22752073 RESULT

• Ullrich NJ, Silvera VM, Campbell SE, Gordon LB. Craniofacial abnormalities in Hutchinson-Gilford progeria syndrome. AJNR Am J Neuroradiol. 2012 Sep;33(8):1512-8. doi: 10.3174/ajnr.A3088. Epub 2012 Mar 29.

  PMID: 22460337 RESULT

• Silvera VM, Gordon LB, Orbach DB, Campbell SE, Machan JT, Ullrich NJ. Imaging characteristics of cerebrovascular arteriopathy and stroke in Hutchinson-Gilford progeria syndrome. AJNR Am J Neuroradiol. 2013 May;34(5):1091-7. doi: 10.3174/ajnr.A3341. Epub 2012 Nov 22.

  PMID: 23179651 RESULT

• Ullrich NJ, Kieran MW, Miller DT, Gordon LB, Cho YJ, Silvera VM, Giobbie-Hurder A, Neuberg D, Kleinman ME. Neurologic features of Hutchinson-Gilford progeria syndrome after lonafarnib treatment. Neurology. 2013 Jul 30;81(5):427-30. doi: 10.1212/WNL.0b013e31829d85c0. Epub 2013 Jun 28.

  PMID: 23897869 RESULT

• Suzuki M, Jeng LJB, Chefo S, Wang Y, Price D, Li X, Wang J, Li RJ, Ma L, Yang Y, Zhang X, Zheng N, Zhang K, Joseph DB, Shroff H, Doan J, Pacanowski M, Smpokou P, Donohue K, Joffe HV. FDA approval summary for lonafarnib (Zokinvy) for the treatment of Hutchinson-Gilford progeria syndrome and processing-deficient progeroid laminopathies. Genet Med. 2023 Feb;25(2):100335. doi: 10.1016/j.gim.2022.11.003. Epub 2022 Dec 12.

  PMID: 36507973 DERIVED

• Gerhard-Herman M, Smoot LB, Wake N, Kieran MW, Kleinman ME, Miller DT, Schwartzman A, Giobbie-Hurder A, Neuberg D, Gordon LB. Mechanisms of premature vascular aging in children with Hutchinson-Gilford progeria syndrome. Hypertension. 2012 Jan;59(1):92-7. doi: 10.1161/HYPERTENSIONAHA.111.180919. Epub 2011 Nov 14.

  PMID: 22083160 DERIVED

MeSH Terms

Conditions

Progeria

Interventions

lonafarnib

Condition Hierarchy (Ancestors)

Laminopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolism, Inborn Errors; Metabolic Diseases; Nutritional and Metabolic Diseases

Limitations and Caveats

This was an open label clinical trial on a very rare disease population. Patient numbers are small, though 26 participants represents a 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, Children's Hospital Boston

  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: SPONSOR INVESTIGATOR
• PI Title: Critical Care

Study Record Dates

• First Submitted: January 22, 2007
• First Posted: January 23, 2007
• Study Start: May 1, 2007
• Primary Completion: October 1, 2009
• Study Completion: October 1, 2009
• Last Updated: June 25, 2019
• Results First Posted: May 24, 2017

Record last verified: 2019-06

Locations

US (1)