A Phase II Study of the mTOR Inhibitor Sirolimus in Neurofibromatosis Type 1 Related Plexiform Neurofibromas (Protocol 102)
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT00634270|
Recruitment Status : Completed
First Posted : March 13, 2008
Results First Posted : February 14, 2017
Last Update Posted : November 17, 2017
- Study Details
- Tabular View
- Study Results
- How to Read a Study Record
This phase II study will evaluate the activity of sirolimus in children and adults with NF1 and inoperable plexiform neurofibromas that have the potential to cause significant morbidity. The following disease strata will be studied:
Stratum 1: Progressive plexiform neurofibroma(s) that have the potential to cause significant morbidity. The endpoint will be time to tumor progression based on volumetric tumor measurements.
Stratum 2: Plexiform neurofibromas without documented radiographic progression at trial entry. The endpoint will be radiographic response. As of May 2009, Stratum 2 was closed to enrollment. Stratum 1 is active.
|Condition or disease||Intervention/treatment||Phase|
|Neurofibromatosis Type 1||Drug: Sirolimus||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||58 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase II Study of the mTOR Inhibitor Sirolimus in Neurofibromatosis Type 1 Related Plexiform Neurofibromas|
|Study Start Date :||April 2008|
|Actual Primary Completion Date :||November 2014|
|Actual Study Completion Date :||December 2015|
This phase II study will evaluate children and adults with neurofibromatosis type-1 (NF1) and plexiform neurofibromas treated with sirolimus. It is divided in two strata. The first stratum will evaluate time to progression (TTP) in children and adults with NF1 and progressive plexiform neurofibromas with the potential to cause significant morbidity treated with sirolimus. The second stratum will evaluate objective radiographic response to sirolimus in children and adults with NF1 and inoperable plexiform neurofibromas with the potential to cause significant morbidity that do not have documented progression of the PN at time of trial entry.
- Time to Disease Progression Based on Volumetric MRI [ Time Frame: 24 Months Stratum 1 ]Median time to progression in Stratum 1 as defined as an increase of at least 20% of the volume of the primary lesion. Note: Since Stratum 2 looked at response rate only, median time to progression was not reviewed for this outcome.
- 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 ]Stratum 2 outcome - Response
- Toxicity [ Time Frame: 24 weeks Stratum 1 / 48 weeks Stratum 2 ]Number of participants experiencing adverse events
- 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 ]An iterative 2-stage Bayesian method was used for the PK parameter analyses
- 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 ]An iterative 2-stage Bayesian method was used for the PK parameter analyses
- 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 ]An iterative 2-stage Bayesian Method was used for the PK parameter analyses
- 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 ]An iterative 2-stage Bayesian Method was used for the PK parameter analyses
- 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 ]An iterative 2-stage Bayesian Method was used for the PK parameter analyses
- 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 ]An iterative 2-stage Bayesian method was used for the PK parameter analyses
- 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 ]Self-reported, age-appropriate PedsQL Scale. Assessments included: Inventory for physical function, emotional function, social function and school function - number system 0-4 was used with 4 being the worse maximum threshold); inventory for chronic illness used a 5-point likert scale - 5 being the worst maximum threshold; Skindex-Teen used a scale of 0 to 100 - the higher the number the more frequent the experience; Pain intensity was measured using a line with a happy and sad face - marks toward the sad face indicated more intense pain; and, the McGill Pain Questionnaire - higher values indicating worse pain of a scale from 0-3. All assessments were combined for an overall PedsQL score by rating each item 0-4, then reverse transforming each to a 0 - 100 scale. The total scores were calculated by averaging the item scores, with higher scores being better.
- 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 ]The study provided central review of all MRIs using a three-dimensional volumetric protocol. As the STOPN protocol began, research had already demonstrated the superiority of this approach to 1-D or 2-D analyses, so these were not used in the STOPN study.
- 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 ]Response by Volumetric MRI.
- 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 ]There were no data collected for this outcome measure.
- 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 ]Trough concentration of sirolimus is reported in nanograms per mL.
- 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 ]Number of patients who experienced hyperlipidemia is being reported.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
|Ages Eligible for Study:||3 Years to 75 Years (Child, Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
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 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, OR A measurable increase of the plexiform neurofibroma (> or equal to 20% increase in the volume, or a > or equal to 13% increase in the product of the two longest perpendicular diameters, or a > or equal to 6% increase in the longest diameter) over the last two consecutive scans (MRI or CT), or over the time period of approximately one year prior to evaluation for this study.
Specific eligibility criteria stratum 2 Disease status:
- Radiographic disease progression as defined in Section 4.2.1 is not required for trial entry.
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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00634270
|United States, Alabama|
|The University of Alabama at Birmingham|
|Birmingham, Alabama, United States, 35294|
|United States, District of Columbia|
|Children's National Medical Center|
|Washington, D.C., District of Columbia, United States, 20010|
|United States, Illinois|
|University of Chicago|
|Chicago, Illinois, United States, 60637|
|United States, Maryland|
|National Cancer Institute (NCI)|
|Bethesda, Maryland, United States, 20892|
|United States, Massachusetts|
|Children's Hospital Boston|
|Boston, Massachusetts, United States, 02115|
|United States, Missouri|
|Saint Louis, Missouri, United States, 63110|
|United States, Ohio|
|Cincinnati Children's Hospital Medical Center|
|Cincinnati, Ohio, United States, 45229-4006|
|United States, Pennsylvania|
|Children's Hospital of Philadelphia|
|Philadelphia, Pennsylvania, United States, 19096|
|United States, Utah|
|University of Utah|
|Salt Lake City, Utah, United States, 84132|
|Principal Investigator:||Bruce Korf, MD||The University of Alabama at Birmingham|
|Principal Investigator:||Brian Weiss, MD||Children's Hospital Medical Center, Cincinnati|
|Study Director:||Roger Packer, MD||Children's National Medical Center - Chairman of the NF Consortium|
|Responsible Party:||Bruce Korf, MD, Principal Investigator, University of Alabama at Birmingham|
|Other Study ID Numbers:||
DOD: W81XWH-05-615. ( Other Identifier: Department of Defense )
UAB: 251558. ( Other Identifier: UAB Link Number )
|First Posted:||March 13, 2008 Key Record Dates|
|Results First Posted:||February 14, 2017|
|Last Update Posted:||November 17, 2017|
|Last Verified:||October 2017|
Plexiform, Neurofibromatosis Type 1, Sirolimus, Phase II
Nerve Sheath Neoplasms
Neoplasms, Nerve Tissue
Neoplasms by Histologic Type
Neoplastic Syndromes, Hereditary
Nervous System Diseases
Heredodegenerative Disorders, Nervous System
Genetic Diseases, Inborn
Peripheral Nervous System Diseases
Peripheral Nervous System Neoplasms
Nervous System Neoplasms
Physiological Effects of Drugs