Sirolimus to Treat Plexiform Neurofibromas in Patients With Neurofibromatosis Type I

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
University of Alabama at Birmingham
ClinicalTrials.gov Identifier:
NCT00652990
First received: April 3, 2008
Last updated: March 14, 2014
Last verified: June 2013
  Purpose

Background:

  • Patients with the genetic disorder neurofibromatosis Type 1 (NF1) are at increased risk of developing tumors (usually non-cancerous) of the central and peripheral nervous system. These include plexiform neurofibromas, which are tumors of the nerve sheathes that cause debilitating complications.
  • Sirolimus is a drug that blocks the activity of a protein called mTOR, which is involved in cell growth. Increased mTOR activity is seen in neurofibromas. Blocking mTOR with sirolimus may slow or stop tumor growth in patients with NF1.

Objectives:

  • To determine if sirolimus can shrink or slow the growth of plexiform neurofibromas.
  • To identify the side effects of sirolimus in patients with NF1.
  • To learn how the body handles sirolimus in patients with NF1.
  • To evaluate the effect of sirolimus on pain and quality of life in patients with NF1.
  • To look at the relationship of certain genes and proteins to treatment effects of sirolimus in patients with NF1.

Eligibility:

-Patients 3 years of age and older with NF1 who have inoperable plexiform neurofibromas that can cause significant disability. Two groups of patients are included: those whose neurofibromas have shown recent growth and those whose neurofibromas have not shown recent growth.

Design:

  • Patients take sirolimus twice a day every day in 28-day treatment cycles. The drug is taken by mouth in liquid solution. Patients with recent tumor growth continue treatment until the tumor grows or until the drug's side effects are no longer tolerated well. Patients whose tumor has not shown recent growth receive up to six treatment cycles. They may continue treatment beyond that only if their tumor has shrunk.
  • Patients are monitored during treatment with regular physical examinations, laboratory tests and MRI scans and quality-of-life and pain questionnaires.
  • Some patients undergo pharmacokinetic studies to examine how the body handles sirolimus. For this study, nine blood samples are drawn at intervals on day 1 of cycle 1. The first sample is drawn before taking the first dose of the drug in the morning and the last is drawn 10 to 12 hours later, before the evening dose is taken.

Condition Intervention Phase
Neurofibromatosis Type 1
Plexiform Neurofibromas
Paraspinal Plexiform Neurofibromas
Drug: Sirolimus
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of the mTOR Inhibitor Sirolimus in Neurofibromatosis Type 1 Related Plexiform Neurofibromas

Resource links provided by NLM:


Further study details as provided by University of Alabama at Birmingham:

Primary Outcome Measures:
  • Time to tumor progression as assessed by volumetric MRI analysis at baseline, after courses 3, 6, 9, and 15, after every 6 courses, and then at the end of treatment (stratum 1) [ Time Frame: 48 months ] [ Designated as safety issue: No ]
  • Objective radiographic response as assessed by volumetric MRI analysis at baseline, after courses 3, 6, 9, and 15, after every 6 courses, and then at the end of the treatment (stratum 2 [closed to accrual as of 5/27/09]) [ Time Frame: 48 months ] [ Designated as safety issue: No ]
  • Toxicity [ Time Frame: 48 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Objective radiographic response as assessed by volumetric MRI analysis at baseline, after courses 3, 6, 9, and 15, after every 6 courses, and then at the end of treatment (stratum 1) [ Time Frame: 48 months ] [ Designated as safety issue: No ]
  • Time to tumor progression as assessed by volumetric MRI analysis at baseline, after courses 3, 6, 9, and 15, after every 6 courses, and at the end of treatment 9stratum 2 [closed to accrual as of 5/27/09]) [ Time Frame: 48 months ] [ Designated as safety issue: No ]
  • Comparison of volumetric 3-D MRI measurements with conventional 2-D and 1-D MRI measurements in determining tumor response [ Time Frame: 48 months ] [ Designated as safety issue: No ]
  • Clinical response, defined as improvement in function and performance status or decrease in plexiform neurofibroma-related pain [ Time Frame: 48 months ] [ Designated as safety issue: No ]

Enrollment: 18
Study Start Date: March 2008
Estimated Study Completion Date: August 2014
Estimated Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Stratum 1
Patients receive oral sirolimus twice daily on days 1-28. Treatment repeats every 28 days for up to 60 courses in the absence of disease progression or unacceptable toxicity.
Drug: Sirolimus
Given orally
Experimental: Straum 2
Patients receive oral sirolimus as in stratum 1. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with documented radiographic partial or complete response after completion of 6 courses may receive up to 6 additional courses of sirolimus after documentation of the best radiographic response.
Drug: Sirolimus
Given orally

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   3 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

INCLUSION CRITERA FOR ALL PATIENTS (STRATUM 1 AND 2):

All patients must have the clinical diagnosis of NF1 using the NIH Consensus Conference criteria. In addition to a plexiform neurofibroma, one or more of the following diagnostic criteria for NF1 must be present:

  • Six or more cafe-au-lait spots greater than or equal to 0.5 cm in prepubertal subjects or greater than or equal to 1.5 cm in postpubertal subjects).
  • Freckling in the axilla or groin
  • Optic glioma
  • Two or more Lisch nodules
  • A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex).
  • A first-degree relative with NF1

Patients must have plexiform neurofibroma(s) that have the potential to cause significant morbidity, such as (but not limited to) head and neck lesions that could compromise the airway or great vessels, brachial or lumbar plexus lesions that could cause nerve compression and loss of function, lesions that could result in major deformity (e.g., orbital lesions) or significant cosmetic problems, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. Patients with paraspinal plexiform neurofibromas will be eligible for this trial. Histologic confirmation of tumor is not necessary in the presence of consistent clinical and radiographic findings, but should be considered if malignant degeneration of a plexiform neurofibroma is clinically suspected.

Age: Patients must be greater than or equal to 3 years of age at the time of study entry.

Durable Power of Attorney: Adults evaluated for this study will be offered a durable power of attorney. Adults who are unable to provide informed consent will have to have a durable power of attorney in order to participate in this trial.

Disease status: Measurable disease: Patients must have measurable plexiform neurofibroma(s) amenable to volumetric MRI analysis. For the purpose of this study, a measurable lesion will be defined as a lesion of at least 3 cm measured in one dimension.

Performance Level: Karnofsky greater than or equal to 50 percent for patients greater than 10 years of age and Lansky greater than or equal to 50 for patients less than or equal to 10 years of age. Note: Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

Prior Therapy: Patients who underwent surgery for a progressive plexiform neurofibroma will be eligible to enter the study after the surgery, provided the plexiform neurofibroma was incompletely resected and is measurable.

Patients are only eligible if complete resection of a plexiform neurofibroma with acceptable morbidity is not feasible, or if a patient with surgical option refuses surgery.

Patients may have been previously treated for a plexiform neurofibroma but must have fully recovered from the acute toxic effects of all prior chemotherapy or radiotherapy prior to entering this study.

  • Myelosuppressive chemotherapy: Must not have received within 4 weeks of entry onto this study.
  • Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor that supports platelet, red or white cell number or function.
  • Biologic (anti-neoplastic agent): At least 14 days since the completion of therapy with a biologic agent. For agents that have known adverse events occurring beyond 14 days after administration, this period must be extended beyond the time during which adverse events are known to occur. These patients must be discussed with the Study Chair on a case-by-case basis.
  • Investigational Drugs: Patients must not have received an investigational drug within 4 weeks.
  • Steroids: Patients with endocrine deficiencies are allowed to receive physiologic or stress doses of steroids if necessary.
  • CYP3A4 inhibitors: Patients may not be currently receiving strong inhibitors of CYP3A4, and may not have received these medications within 1 week of entry. These include:

    • Macrolide Antibiotics: clarithromycin, telithromycin, erythromycin, troleandomycin.
    • Gastrointestinal prokinetic agents: cisapride, metoclopramide.
    • Antifungals: itraconazole, ketoconazole, fluconazole, voriconazole, clotrimazole
    • Calcium channel blockers: verapamil, diltiazem, nicardipine
    • Other drugs: rifampin, bromocriptine, cimetidine (tagamet), danazol, cyclosporine oral solution, lansoprazole (prevacid)
    • Grapefruit juice.
  • CYP3A4 inducers: Patients must also avoid strong inducers of CYP3A4, and may not have received these medications within 1 week of entry. These include:

    • Anticonvulsants: carbamazepine, phenobarbital, phenytoin
    • Antibiotics: rifabutin, rifapentine
    • Herbal preparations: St. John's wort (Hypericum perforatum, hypericine).
  • Enzyme inducing anticonvulsants: Patients may not be taking enzyme -inducing anticonvulsants, and may not have received these medications within 1 week of entry, as these patients may experience different drug disposition. These medications include:

    • Carbamazepine (Tegretol)
    • Felbamate (Felbtol)
    • Phenobarbitol
    • Phenytoin (Dilantin)
    • Primidone (Mysoline)
    • Oxcarbazepine (Trileptal)
  • XRT: Greater than or equal to 6 months from involved field radiation to index plexiform neurofibroma(s); greater than or equal to 6 weeks must have elapsed if patient has received radiation to areas outside index plexiform neurofibroma(s).
  • Surgery: At least 2 weeks since undergoing any major surgery.

Organ Function Requirements

  • Adequate Bone Marrow Function Defined as:

    • Peripheral absolute neutrophil count (ANC) greater than or equal to 1500/miroL
    • Platelet count greater than or equal to 100,000/micorL (transfusion independent)
    • Hemoglobin greater than or equal to 10.0 gm/dL (may receive RBC transfusions)
  • Adequate Renal Function Defined as:

A serum creatinine based on age as follows:

  • Less than or equal to 5 years old, Maximum Serum Creatinine (mg/dL) 0.8
  • 5 years old to less than or equal to 10 years old, Maximum Serum Creatinine (mg/dL) 1.0
  • 10 years old to less than or equal to 15 years old, Maximum Serum Creatinine (mg/dL) 1.2
  • Greater than 15 years old Maximum Serum Creatinine (mg/dL) 1.5

OR a creatinine clearance or radioisotope GFR greater than or equal to 70ml/min/1.73 m(2)

  • Adequate Liver Function Defined As:

    • Bilirubin (sum of conjugated plus unconjugated) less than or equal to1.5 times upper limit of normal (ULN) for age, and
    • SGPT (ALT) less than or equal to 5 times upper limit of normal (ULN) for age, and
    • Serum albumin greater than or equal to 2 g/dL.
  • Fasting LDL Cholesterol:

    • Patients must have a fasting LDL cholesterol of less than or equal to 160 mg/dL
    • Patients taking a cholesterol lowering agent must be on a single medication and on a stable dose for at least 4 weeks

SPECIFIC ELIGIBILITY CRITERIA STRATUM 1:

Disease status:

  • Patients must have a progressive plexiform neurofibroma(s). Progression at the time of study entry is defined as:

    • Presence of new plexiform neurofibromas on MRI or CT (documented by comparison with prior MRI or CT), OR
    • A measurable increase of the plexiform neurofibroma (greater than or equal to 20 percent increase in the volume, or a greater than or equal to 13 percent increase in the product of the two longest perpendicular diameters, or a greater than or equal to 6 percent increase in the longest diameter) documented by comparison of two scans (MRI or CT) in the time period of approximately one year or less prior to evaluation for this study.

SPECIFIC ELIGIBILITY CRITERIA STRATUM 2

Disease status:

  • No radiographic disease progression as defined for criteria stratum 1 (above) by comparison of two scans (MRI or CT) in the time period of approximately one year +/- one month.

EXCLUSION CRITERIA:

EXCLUSION CRITERIA (BOTH STRATA)

  • Chronic treatment with systemic steroids or another immunosuppressive agent. Patients with endocrine deficiencies are allowed to receive physiologic or stress doses of steroids if necessary.
  • Evidence of an active optic glioma, malignant glioma, malignant peripheral nerve sheath tumor, or other cancer requiring treatment with chemotherapy or radiation therapy. Patients not requiring treatment are eligible for this protocol.
  • Dental braces or prosthesis that interfere with volumetric analysis of the neurofibroma(s).
  • Other concurrent severe and/or uncontrolled medical disease which could compromise participation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension, severe infection, severe malnutrition, chronic liver or renal disease, active upper GI tract ulceration).
  • A known history of HIV seropositivity or known immunodeficiency. HIV testing will not be required as part of this trial, unless HIV is clinically suspected.
  • Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of sirolimus (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection). A nasogastric tube (NG tube) is allowed.
  • Women who are pregnant or breast feeding.
  • Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method during the period they are receiving the study drug and for 3 months thereafter. Abstinence is an acceptable method of birth control. Women of childbearing potential will be given a pregnancy test within 7 days prior to administration of sirolimus and must have a negative urine or serum pregnancy test.
  • Patients who have received prior treatment with an mTOR inhibitor.
  • History of noncompliance to medical regimens.
  • Patients unwilling to or unable to comply with the protocol, or who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study.
  • Patients who have an uncontrolled infection.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00652990

Locations
United States, Alabama
University of Alabama
Birmingham, Alabama, United States
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
University of Alabama at Birmingham
Investigators
Principal Investigator: Brigitte C Widemann, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT00652990     History of Changes
Other Study ID Numbers: 080096, 08-C-0096
Study First Received: April 3, 2008
Last Updated: March 14, 2014
Health Authority: United States: Federal Government
United States: Food and Drug Administration

Keywords provided by University of Alabama at Birmingham:
Plexiform Neurofibroma Growth
Quality of Life
Pain
Parmacokinetics
Pharmacodynamics
Neurofibromatosis Type 1
NF1
Plexiform Neurofibroma

Additional relevant MeSH terms:
Neurofibroma
Neurofibromatoses
Neurofibromatosis 1
Osteitis Fibrosa Cystica
Neurofibroma, Plexiform
Nerve Sheath Neoplasms
Neoplasms, Nerve Tissue
Neoplasms by Histologic Type
Neoplasms
Peripheral Nervous System Neoplasms
Nervous System Neoplasms
Nervous System Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases
Neoplastic Syndromes, Hereditary
Neurocutaneous Syndromes
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Bone Diseases, Endocrine
Bone Diseases
Musculoskeletal Diseases
Sirolimus
Everolimus
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antifungal Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on April 23, 2014