Neurofibromatosis
Conditions
Keywords
Gleevec
Brief summary
THe primary objective is to estimate the response rate at 6 months to Gleevec® in patients with plexiform neurofibromas
Detailed description
This is an open-label Phase II Study to determine the efficacy of Gleevec® in neurofibromatosis (NF1) patients with plexiform neurofibromas with the secondary goals of determining the toxicity, and tumor markers in this genetically defined population. The rationale for this study arises from the response of human and murine NF1 cells to Gleevec® in vitro and the response of a single NF1 patient treated with Gleevec® for airway compression by a plexiform neurofibroma with a dramatic response not previously seen in NF1 therapy. The plan of therapy will include oral dosing of Gleevec® at 440 mg/m\^2/day (max 800 mg/day) for pediatric subjects and 800 mg/day for adult patients. (with 25% dose reduction for significant toxicity). Treatment will continue for 6 months with an option to continue as long as the patient remains on study provided the patient shows benefit from treatments with Gleevec® and there are no safety concerns.
Interventions
DRUGGleevec
Gleevec® will be dosed orally 440 mg/m\^2/day (max 800 mg/day) for pediatric subjects and 800 mg/day for adult patients.
Sponsors
Indiana University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Patients 3-65 years of age. 2. Diagnosis of neurofibromatosis (NF1), as outpatients. 3. Presence of clinically significant plexiform neurofibromas (biopsy proven if possible with tissue blocks available); that is tumors that are potentially life threatening or are impinging on vital structures or significantly impair the quality of life from pain or other symptoms. 4. Patients must have measurable disease by magnetic resonance imaging (MRI). Patients must have a Karnofsky or Lansky Performance score of \> 80% and a life expectancy of \> 2 months. 5. Adequate end organ function, defined as the following: total bilirubin \< 1.5 x ULN, SGOT and SGPT \< 2.5 x UNL, creatinine \< 1.5 x ULN, ANC \> 1.5 x 109/L, platelets \> 100 x 109/L. 6. Female patients of childbearing potential must have negative pregnancy test within 7 days before initiation of study drug dosing. Postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Male and female patients of reproductive potential must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug. 7. Written, voluntary informed consent.
Exclusion criteria
1. Patient has received any other investigational agents within 28 days of first day of study drug dosing, unless the disease is rapidly progressing. 2. Patient is \< 5 years free of another primary malignancy except: if the other primary malignancy is not currently clinically significant nor requiring active intervention, or if other primary malignancy is a basal cell skin cancer or a cervical carcinoma in situ. Existence of any other malignant disease is not allowed. 3. Patient with Grade III/IV cardiac problems as defined by the New York Heart Association Criteria. (i.e., congestive heart failure, myocardial infarction within 6 months of study) 4. Female patients who are pregnant or breast-feeding. 5. Patient has a severe and/or uncontrolled medical disease (i.e., uncontrolled diabetes, chronic renal disease, or active uncontrolled infection). 6. Patient has a known brain metastasis. Non-specific CNS changes on MRI/CT characteristic of NF1 are allowed, but not known CNS malignancies. 7. Patient has known chronic liver disease (i.e., chronic active hepatitis, and cirrhosis). 8. Patient has a known diagnosis of human immunodeficiency virus (HIV) infection. 9. Patient received chemotherapy within 4 weeks (6 weeks for nitrosourea or mitomycin-C) prior to study entry, unless the disease is rapidly progressing. 10. Patient previously received radiotherapy to greater than 25 % of the bone marrow 11. Patient had a major surgery within 2 weeks prior to study entry. 12. Patient with any significant history of non-compliance to medical regimens or with inability to grant reliable informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Tumor Volume at 6 Months | baseline to 6 months | Volumetric measures were performed using MRI scan analysis. Response criteria include greater than 20 percent decrease in tumor volume as responsive. Greater than 20 percent increase in tumor volume as tumor progression. Less then 20 percent increase or decrease in tumor volume is stable disease |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serum Bioactivity | 7 days and 1 month | The investigators will quantitate the biologic activity of patient serum on fibroblast proliferation, migration, and collagen synthesis pre and post-Gleevec (7 days and 1 month) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Administration of Gleevec Gleevec® will be dosed orally 440 mg/m2/day (max 800 mg/day) for pediatric subjects and 800 mg/day for adult patients.
Gleevec: Gleevec® will be dosed orally 440 mg/m2/day (max 800 mg/day) for pediatric subjects and 800 mg/day for adult patients. | 36 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Physician Decision | 5 |
| Overall Study | Withdrawal by Subject | 8 |
Baseline characteristics
| Characteristic | Administration of Gleevec |
|---|---|
| Age, Categorical <=18 years | 25 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 32 Participants |
| Region of Enrollment United States | 36 participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 12 / 36 |
| serious Total, serious adverse events | 1 / 36 |
Outcome results
Primary
Percent Change From Baseline in Tumor Volume at 6 Months
Volumetric measures were performed using MRI scan analysis. Response criteria include greater than 20 percent decrease in tumor volume as responsive. Greater than 20 percent increase in tumor volume as tumor progression. Less then 20 percent increase or decrease in tumor volume is stable disease
Time frame: baseline to 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Administration of Gleevec | Percent Change From Baseline in Tumor Volume at 6 Months | 17 percentage change of tumor volume |
Secondary
Serum Bioactivity
The investigators will quantitate the biologic activity of patient serum on fibroblast proliferation, migration, and collagen synthesis pre and post-Gleevec (7 days and 1 month)
Time frame: 7 days and 1 month
Population: unable to measure this outcome because assay became unavailable