Phase I/II Trial of Everolimus in Combination With Lonafarnib in Progeria

This is a phase I/II dose-escalation trial of everolimus in combination with lonafarnib in Hutchinson-Gilford Progeria Syndrome (HGPS) and progeroid laminopathies (henceforth "progeria"). The study will be conducted at a single clinical site utilizing the Clinical and Translational Study Unit (CTSU) at Boston Children's Hospital. Lonafarnib will be administered at doses previously established in the pediatric population and in this population of progeria subjects. This study will first determine the dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD) of everolimus when administered in combination with lonafarnib. It will then determine the efficacy of everolimus when administered at its MTD in combination with lonafarnib for disease in progeria.

Study Overview

• Status: Enrolling by invitation
• Conditions: Progeria
• Intervention / Treatment: Drug: Everolimus and lonafarnib

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 25 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Genetically-confirmed progeria.
• display clinical signs of progeria as per the clinical trial team.
• currently receiving lonafarnib under protocol 09-06-0298
• have not experienced a grade 3 or 4 toxicity within two months preceding enrollment
• willing and able to come to Boston for appropriate studies and examinations.
• no recent fractures or major surgery (within four weeks)
• Absolute poly count (Absolute neutrophil count + bands + monocytes) >1,000/uL
• platelets >75,000/uL (transfusion independent)
• hemoglobin >9 g/dL
• creatinine ≤ 1.5 times upper limit of normal (ULN) for age or Glomerular filtration rate (GFR) >70 mL/min/1.73m2
• bilirubin ≤ 1.5x upper limit of normal for age
• SGPT (ALT) < and SGOT (AST) ≤ 2.5x normal range for age
• serum albumin greater than or equal to 2 g/dL
• PT/PTT: INR <1.3 (or <3 on anticoagulants)

• Fasting LDL cholesterol within 1.5x ULN per institutional guidelines (ie, <195 mg/dL for 2 - 18 years of age, <240 mg/dL for subjects >18 years old)* and Fasting serum cholesterol <300 mg/dL (<7.75 mmol/L)* and Fasting triglycerides <2.5 ULN (<325 mg/dL for ages 2 - 18, <400 for ages >18)*

  *may be re-evaluated for eligibility after initiation of lipid-lowering therapy

• Signed informed consent according to institutional guidelines must be obtained and subject must begin therapy within twenty-eight (28) days.

Exclusion Criteria:

• Subjects must not be taking medications that significantly affect the metabolism of lonafarnib
• Subjects receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent. Subjects with endocrine deficiencies are allowed to receive physiologic or stress doses of steroids if necessary. Topical or inhaled steroids are allowed.
• Subjects who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug; have not recovered from the side effects of any major surgery (defined as requiring general anesthesia but excluding a procedure for insertion of central venous access); or who may require major surgery during the course of the study.
• 13.2.5 Subjects with an active bleeding diathesis or on oral anti-vitamin K medication (except low dose coumadin).

• Subjects who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:

  • known severely impaired lung function
  • active (acute or chronic) or uncontrolled severe infections.
  • liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis.
  • History of hepatitis B or hepatitis C
• Other concurrent severe and/or uncontrolled medical disease that could compromise participation in the study (i.e., uncontrolled diabetes, uncontrolled hypertension, severe infection, severe malnutrition, chronic liver or renal disease, active upper GI tract ulceration).
• A known history of Human Immunodeficiency Virus (HIV) seropositivity or known immunodeficiency.
• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection). A nasogastric tube (NG tube) or gastric tube (G tube) is allowed.
• Subjects who have known or suspected hypersensitivity to any of the excipients included in the formulation should not be treated.
• Subjects must not be pregnant or breast-feeding. Female subjects of childbearing potential must have negative serum or urine pregnancy test. Sexually active male and female subjects 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 subjects to take oral contraceptives or other hormonal methods while receiving treatment with everolimus.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Everolimus and Lonafarnib; Single arm. Phase I: Lonafarnib with escalating doses of everolimus to determine MTD Phase II: Lonafarnib plus everolimus at MTD (efficacy assessment)	Drug: Everolimus and lonafarnib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum-tolerated dose (MTD) of everolimus when administered orally in combination with lonafarnib in subjects with progeria	For Phase I portion of protocol	12 Months
Number and type of dose-limiting toxicities when everolimus and lonafarnib are administered in combination to children with progeria	For Phase I portion of protocol	12 Months
Annual increase in weight gain	For Phase II portion of protocol	24 Months
Change in pulse wave velocity (PWV)	For Phase II portion of protocol	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Markers of progeria-specific activity	For Phase II portion of protocol	24 Months
Trough levels of everolimus in combination with lonafarnib in progeria	For Phase I portion of protocol	12 months

Collaborators and Investigators

• Sponsor: Boston Children's Hospital
• Investigators: Principal Investigator: Monica Kleinman, M.D., Boston Children's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2015
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 1, 2027

Study Registration Dates

• First Submitted: October 13, 2015
• First Submitted That Met QC Criteria: October 15, 2015
• First Posted (Estimated): October 19, 2015

Study Record Updates

• Last Update Posted (Actual): April 2, 2026
• Last Update Submitted That Met QC Criteria: March 27, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Laminopathies; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Progeria; Organic Chemicals; Macrolides; Lactones; Sirolimus; Everolimus; lonafarnib
• Other Study ID Numbers: P00017505