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Main
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Note: This record shows only 22 elements of the WHO Trial Registration Data Set. To view changes that have been made to the source record, or for additional information about this trial, click on the URL below to go to the source record in the primary register. |
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Register:
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ClinicalTrials.gov |
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Last refreshed on:
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16 December 2017 |
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Main ID: |
NCT00634270 |
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Date of registration:
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20/02/2008 |
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Prospective Registration:
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Yes |
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Primary sponsor: |
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Public title:
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A Phase II Study of the mTOR Inhibitor Sirolimus in Neurofibromatosis Type 1 Related Plexiform Neurofibromas
Protocol 102 |
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Scientific title:
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A Phase II Study of the mTOR Inhibitor Sirolimus in Neurofibromatosis Type 1 Related Plexiform Neurofibromas |
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Date of first enrolment:
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April 2008 |
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Target sample size:
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58 |
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Recruitment status: |
Completed |
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URL:
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https://clinicaltrials.gov/show/NCT00634270 |
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Study type:
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Interventional |
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Study design:
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Intervention model: Single Group Assignment. Primary purpose: Treatment. Masking: None (Open Label).
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Phase:
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Phase 2
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Countries of recruitment
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United States
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Contacts
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Name:
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Bruce Korf, MD |
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Address:
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Telephone:
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Email:
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Affiliation:
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The University of Alabama at Birmingham |
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Name:
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Brian Weiss, MD |
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Address:
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Telephone:
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Email:
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Affiliation:
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Children's Hospital Medical Center, Cincinnati |
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Name:
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Roger Packer, MD |
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Address:
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Telephone:
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Email:
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Affiliation:
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Children's National Medical Center - Chairman of the NF Consortium |
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Key inclusion & exclusion criteria
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Inclusion Criteria: all patients (stratum 1 and 2):
- All patients must have the clinical diagnosis of NF1 using the NIH Consensus
Conference criteria.
- Six or more café-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% for patients > 10 years of
age and Lansky greater than or equal to 50 for patients less than or equal to 10 years
of age (Appendix IV). 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.
- a. Myelosuppressive chemotherapy: Must not have received within 4 weeks of entry onto
this study.
- b. 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.
- c. 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.
- d. Investigational Drugs: Patients must not have received an investigational drug
within 4 weeks.
- e. Steroids: Patients with endocrine deficiencies are allowed to receive physiologic
or stress doses of steroids if necessary.
- f. 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; and, Other drugs:
rifampin, bromocriptine, cimetidine, danazol, cyclosporine oral solution.
- Grapefruit juice.
- g. 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).
- h. 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), and, Herbal preparations:
St. John's wort (Hypericum perforatum, hypericine).
- i. 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).
- j. 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/µL; Platelet count
greater than or equal to 100,000/µL (transfusion independent); and 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, OR a creatinine
clearance or radioisotope GFR greater than or equal to 70ml/min/1.73 m2
- Adequate Liver Function Defined As: Bilirubin (sum of conjugated + unconjugated) < or
equal to 1.5 x upper limit of normal (ULN) for age, and SGPT (ALT)< or equal to 5 x
upper limit of normal (ULN) for age, and Serum albumin > or equal to 2 g/dL.
- Fasting LDL Cholesterol: Patients must have a fasting LDL cholesterol of < 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 eligibili
Age minimum:
3 Years
Age maximum:
75 Years
Gender:
All
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Health Condition(s) or Problem(s) studied
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Neurofibromatosis Type 1
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Intervention(s)
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Drug: Sirolimus
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Primary Outcome(s)
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To Characterize the Pharmacokinetic Profile of Sirolimus Administered to This Patient Population (Clearance Liters/Hour (L/h))
[Time Frame: Pre-dose; Day 1 at 0.5 hours, 1.0 hours, 2.0 hours, 3.0 hours, 4.0 hours, 6.0 hours, 8.0 hours, and 10.0 to 12.0 hours]
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To Characterize the Pharmacokinetic Profile of Sirolimus When Administered to This Patient Population Using Liters/Hour Per Population Median Weight of 70kg (L/h70kg)
[Time Frame: Pre-dose; Day 1 at 0.5 hours, 1.0 hours, 2.0 hours, 3.0 hours, 4.0 hours, 6.0 hours, 8.0 hours, and 10.0 to 12.0 hours]
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To Characterize the Pharmacokinetic Profile of Sirolimus When Administered to This Patient Population - (Clearance (L/h Per 1.85 m^2)
[Time Frame: Pre-dose; Day 1 at 0.5 hours, 1.0 hours, 2.0 hours, 3.0 hours, 4.0 hours, 6.0 hours, 8.0 hours, and 10.0 to 12.0 hours]
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To Characterize the Pharmacokinetic Profile of Sirolimus in When Administered to This Patient Population - Therapeutic Dose (mg/kg Per Dose)
[Time Frame: Pre-dose; Day 1 at 0.5 hours, 1.0 hours, 2.0 hours, 3.0 hours, 4.0 hours, 6.0 hours, 8.0 hours, and 10.0 to 12.0 hours]
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Results in Objective Radiographic Responses Based on Volumetric MRI Measurements in Children and Adults With NF1 and Inoperable PN in the Absence of Documented Radiographic Progression at Trial Entry
[Time Frame: 48 weeks Stratum 2]
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Time to Disease Progression Based on Volumetric MRI
[Time Frame: 24 Months Stratum 1]
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To Characterize the Pharmacokinetic Profile of Sirolimus When Administered to This Patient Population- Therapeutic Dose (mg/m^2 Per Dose)
[Time Frame: Pre-dose; Day 1 at 0.5 hours, 1.0 hours, 2.0 hours, 3.0 hours, 4.0 hours, 6.0 hours, 8.0 hours, and 10.0 to 12.0 hours]
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To Characterize the Pharmacokinetic Profile of Sirolimus When Administered to This Patient Population - Therapeutic Dose (mg/kg)^0.75
[Time Frame: Pre-dose; Day 1 at 0.5 hours, 1.0 hours, 2.0 hours, 3.0 hours, 4.0 hours, 6.0 hours, 8.0 hours, and 10.0 to 12.0 hours]
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Toxicity
[Time Frame: 24 weeks Stratum 1 / 48 weeks Stratum 2]
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Secondary Outcome(s)
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To Evaluate the Quality of Life During Treatment With Sirolimus by Assessing Preliminary Correlations of Response With Quality-of-life Outcomes
[Time Frame: 24 weeks Stratum 1 / 48 weeks Stratum 2]
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To Evaluate the Role of Apolipoprotein E Genotypes as Predictors for Development of Hyperlipidemia During Therapy With Sirolimus.
[Time Frame: 24 weeks Stratum 1 / 48 weeks Stratum 2]
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To Evaluate the Effect of Sirolimus on Clinical Response by Reduction in Pain, or Improvement in Function or Performance Scale.
[Time Frame: 24 weeks Stratum 1 / 48 weeks Stratum 2]
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To Asses Preliminary Correlations of Radiographic Response With Changes in Pharmacodynamics Parameters Including p70s6 Kinase Activity in Peripheral Blood Mononuclear Cells.
[Time Frame: 24 weeks Stratum 1 / 48 weeks Stratum 2]
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To Assess the Value of Three-dimensional MRI (3-D MRI) in the Evaluation of Plexiform Neurofibromas and Paraspinal Neurofibromas, and to Compare 3-D MRI to Conventional Two-dimensional MRI (2-D MRI) and One Dimensional MRI (1-D MRI) Data Analysis
[Time Frame: 24 weeks Stratum 1 / 48 weeks Stratum 2]
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To Evaluate Pharmacogenetic Polymorphisms of Cytochrome P450 3A4 & 3A5 Alleles and P-glycoprotein/MDR for Their Influence on the Metabolism of Sirolimus in This Patient Population.
[Time Frame: 24 weeks Stratum 1 Only]
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Secondary ID(s)
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DOD: W81XWH-05-615.
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F071019012
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UAB: 251558.
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Source(s) of Monetary Support
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Please refer to primary and secondary sponsors
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