| Description |
For inclusion in the study subjects should fulfil the following criteria based on local regulations:
1. Patients with Neurofibromatosis type I, in whom genetic study was performed for the germline NF1 mutations, and have significant symptoms/comorbidities as well as those with the potential to develop symptoms/comorbidities due to inoperable measurable plexiform neurofibroma (Surgeon’s statement of inoperability should be documented).
2. Patients must have at least one measurable plexiform neurofibroma, defined as a lesion of at least 3 cm measured in one dimension.
3. Patients with an absolute neutrophil count ≥1000/μL, hemoglobin ≥ 9 g/dL, and platelet ≥ 100,000/μL.
4. Patients must have bilirubin within 1.5 x the upper limit of normal for age, with the exception of Gilbert syndrome, and Alanie aminotranferaase and aspartate aminotranferase within ≤ 1.5 x upper limit of normal.
5. Renal Function: age-adjusted normal serum creatinine.
6. Cardiac function: Normal ejection fraction; echocardiogram ≥ 55% (if a range is given then the upper value of the range will be used).
7. Performance status: Patients ≥ 16 years of age must have a Karnofsky performance level of ≥70%, and children < 16 years old must have a Lansky performance of ≥70%
8. Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial must only be done after obtaining written informed consent from all patients or their legal guardians (if the patient is <19 years old). When appropriate, pediatric patients will be included in all discussions. |
| Exclusion Criteria |
1. Any prior exposure to MEK, RASs, or RAF inhibitors, or any treatment regimen that involves the comparator / combination medications.
2. Known severe hypersensitivity to selumetinib, comparator or combination medications or any excipient of these medicinal products or history of allergic reactions attributed to compounds of similar chemical or biologic composition to selumetinib or comparator
3. Have received or are receiving an investigational medicinal product (IMP) or other systemic anticancer treatment within 4 weeks.
4. Have had recent major surgery within a minimum 4 weeks prior to starting study treatment, with the exception of surgical placement for vascular access.
5. The last radiation therapy within 4 weeks prior to starting study treatment, or limited field of radiation for palliation within 7 days of the first dose of study treatment.
6. Evidence of a malignant glioma, malignant peripheral nerve sheath tumor, or other cancer requiring treatment with chemotherapy or radiation therapy.
7. Any unresolved toxicity ≥ CTCAE (Common Terminology Criteria for Adverse Events) Grade 2 from previous anti-cancer therapy, except for alopecia
8. Cardiac conditions as follows:
a. Uncontrolled hypertension (BP ≥ 150/95 mmHg despite medical therapy)
b. Acute coronary syndrome within 6 months prior to starting treatment
c. Uncontrolled Angina - Canadian Cardiovascular Society grade II-IV despite medical therapy
d. Symptomatic heart failure NYHA Class II-IV, prior or current cardiomyopathy, or severe valvular heart disease
e. Prior or current cardiomyopathy including but not limited to the following:
i. Known hypertrophic cardiomyopathy
ii. Known arrhythmogenic right ventricular cardiomyopathy
f. Previous moderate or severe impairment of left ventricular systolic function (Left ventricular ejection fraction <45% on echocardiography or equivalent on multiple gated acquisition scan) even if full recovery has occurred.
g. Severe valvular heart disease
h. Baseline Left ventricular ejection fraction below the lower limit of normal or <55% measured by echocardiography or institution’s lower limit of normal for multiple gated acquisition scan
i. Atrial fibrillation with a ventricular rate >100 bpm on electrocardiogram at rest
j. QTcF >450ms or other factors that increase the risk of QT prolongation
9. Laboratory values as listed below (SI units):
a. Absolute Neutrophil Count <1.5x1000,000,000/L (1500 per mm3)
b. Platelets <100x1000,000,000/L (100,000 per mm3)
c. Hemoglobin ≤9.0 g/dL
d. Serum creatinine ≤1.5 X upper limit of normal (ULN)
e. Serum bilirubin >1.5 x ULN (Note that this will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of evidence of hemolysis or hepatic pathology), who may be allowed included in specific studies, at the discretion of the doctor / physician responsible for the treatment.)
f. Alanine aminotransferase or Aspartate aminotransferase > 2.5 x Upper limit of normal for patients with no liver metastasis.
g. Alanine aminotransferase or Aspartate aminotransferase > 5 x Upper limit of normal for patients with liver metastasis.
h. Alanine aminotransferase or Aspartate aminotransferase > 3.5 x Upper limit of normal and < 5 x Upper limit of normal for patients with liver metastasis and Alakaline phosphatase > 6 x Upper limit of normal
10. Ophthalmological conditions as follows:
a. Current or past history of retinal pigment epithelial detachment (RPED)/central serous retinopathy (CSR) or retinal vein occlusion
b. Intraocular pressure (IOP) > 21 mmHg or uncontrolled glaucoma (irrespective of IOP). Patients with known glaucoma and increased IOP who do not have meaningful vision (light perception only or no light perception) and are not experiencing pain related to the glaucoma, may be eligible after discussion with the study chair.
c. Ophthalmological findings secondary to long-standing optic pathway glioma (such as visual loss, optic nerve pallor or strabismus) or longstanding orbito-temporal PN (such as visual loss, strabismus) will NOT be considered a significant abnormality for the purposes of the study
11. Have evidence of any other significant clinical disorder or laboratory finding that, as judged by the investigator, makes it undesirable for the patient to participate in the study.
12. Inability to swallow capsules, since capsules cannot be crushed or broken.
13. Inability to undergo Magnetic resonance imaging and/or contraindication forMagnetic resonance imaging examinations.
14. Prosthesis or orthopedic or dental braces that would interfere with volumetric analysis of target plexiform neurofibroma on Magnetic resonance imaging .
15. Have any evidence of a severe or uncontrolled systemic disease (e.g. unstable or uncompensated respiratory, cardiac, hepatic, or renal disease, active infection (including hepatitis B, hepatitis C, Human immunodeficiency virus), active bleeding diatheses or renal transplant.
16. Have refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory bowel disease), or significant bowel resection that would adversely affect the absorption / bioavailability of the orally administered study medication.
17. Male or female patients of reproductive potential and, as judged by the investigator, are not employing an effective method of birth control.
18. Female patients who are breast-feeding.
19. Supplementation with vitamin E greater than 100% of the daily recommended dose.
20. While not an exclusion criterion, unless clinically indicated, patients should avoid taking other additional non-study medications that may interfere with the study medications; in particular, patients should avoid medications that are known to either induce or inhibit the activity of hepatic microsomal isoenzymes CYP1A2, CYP2C19 and CYP3A4
21. Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study. |