Intermittent Dosing Of Selumetinib In Childhood NF1 Associated Tumours

Inclusion Criteria: 1. Age Phase I: ≥3 years and ≤18 years of age at the time of study enrolment, if able to swallow whole capsules. Age Phase II: ≥3 years and ≤ 18 years. BSA ≥ 0.55 m2, if able to swallow whole capsules. 2. Diagnosis: Phase I (Dose escalation): Patients with NF1 and inoperable PNs defined as PNs that cannot be surgically completely removed without risk for substantial morbidity due to: encasement of or close proximity to vital structures, invasiveness, or high vascularity of the PN. The PN has to cause morbidity or 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 are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. Histological confirmation of tumour is not necessary in the presence of consistent clinical and radiographic findings, but should be considered if malignant degeneration of a PN is clinically suspected. Phase 2 (Dose expansion): Two cohorts are eligible for inclusion in the dose expansion cohort. Cohort A (10 subjects) Subjects with NF1 and inoperable PNs (as per Phase I) and Cohort B (10 subjects) Subjects with NF-1 related progressive optic pathway glioma are eligible if the subject has evidence of either clinical (e.g. worsening visual function as per REiNS) or MRI based significant radiological progression and has had at least two lines of standard therapy. In addition, all study subjects (phase I and II) must have either positive genetic testing for NF1 from a certified laboratory or have at least one other diagnostic criterion for NF1 listed below: * Six or more café-au-lait macules (≥0.5cm in prepubertal subjects or ≥1.5 cm in post pubertal subjects) * Freckling in 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 3. Measurable disease (PN): Subjects must have at least one measurable PN, defined as a lesion of at least 3 cm measured in one dimension. Subjects who underwent surgery for resection of a PN are eligible provided the PN was incompletely resected and is measurable. Measurable disease (OPG): Subjects must have one measurable OPG lesions according to RANO 1.1 i.e. Tumour ≥10 x10mm in maximal perpendicular dimensions on an axial image on MRI with ≤5 mm reconstruction interval. 4. Prior Therapy: Subjects with NF1 will only be eligible if complete tumour resection is not considered to be feasible without substantial risk or morbidity, or if a patient with a surgical option refuses surgery. * Since there is no standard effective chemotherapy for patients with NF1 and PN, subjects may be treated on this trial without having received prior medical therapy directed at their PN. For Phase 2 Cohort B in subjects with NF-1 related OPGs at least two prior standard therapies need to have been received. * Subjects who have received previous investigational agents or biologic therapy except a prior MEK inhibitor are eligible for enrollment. At least 4 weeks must have elapsed since receiving medical therapy directed at the PN. Patients who received prior medical therapy for their PN must have recovered from the acute toxic effects of all prior therapy to ≤ grade 1 CTCAEv4 before entering this study. * Growth factors that support platelet or white cell number or function must not have been administered within the past 7 days. * At least 6 weeks must have elapsed prior to enrollment since the patient received any prior radiation therapy. 5. 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% (Error! Reference source not found.). Patients who are wheelchair bound because of paralysis secondary to a plexiform neurofibroma should be considered ambulatory when they are up in their wheelchair. Similarly, patients with limited mobility secondary to need for mechanical support (such as an airway PN requiring tracheostomy or CPAP) will also be considered ambulatory for the purpose of the study. 6. Haematological Function: Patients must have an absolute neutrophil count ≥1500/µl, haemoglobin ≥9g/dl, and platelet ≥100,000/µl. 7. Hepatic Function: Patients must have bilirubin within 1.5 x the upper limit of normal for age, with the exception of those with Gilbert syndrome, and AST/ALT within ≤ 2.5 x upper limit of normal. 8. Renal Function: Patients must have a creatinine clearance or radioisotope GFR ≥60ml/min/1.73 m2 or a normal serum creatinine based on age described in the table below. Age (years) Maximum Serum Creatinine (mg/dL) age ≤5: 0.8 5\<age≤10: 1.0 10\<age≤15: 1.2 age\>15: 1.5 9. Cardiac Function: Normal ejection fraction (ECHO) ≥ 55%, or institutional normal value (if a range is given then the upper value of the range will be used); QTcF ≤450 msec. 10. Adequate Blood Pressure defined as: A blood pressure (BP) ≤ the 95th percentile for age, height, and gender. Adequate blood pressure can be achieved using medications for treatment of hypertension. 11. Informed Consent: 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 \<16 years old). When appropriate, paediatric patients will be included in all discussions and appropriate assent taken. 12. Willingness to avoid excessive sun exposure and use adequate sunscreen protection if sun exposure is anticipated. 13. Willingness to avoid the ingestion of grapefruit and Seville oranges (as well as other products containing these fruits, e.g. grapefruit juice or marmalade) during the study. Exclusion Criteria: 1. Pregnant or breast-feeding females are excluded due to potential risks of foetal and teratogenic adverse events of an investigational agent. Pregnancy tests must be obtained prior to enrolment on this study for girls of reproductive potential. The need to commence pregnancy testing will be at the discretion of the treating physician to facilitate taking in to account factors such as precocious puberty, endocrine status and medications which can affect pubertal status. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method. Abstinence is an acceptable method of birth control. 2. Known severe hypersensitivity to selumetinib or any excipient of selumetinib or history of allergic reactions attributed to compounds of similar chemical or biologic composition to selumetinib. 3. Recent major surgery within a minimum of 4 weeks prior to starting study treatment, with the exception of surgical placement for vascular access. 4. Phase I: Patients who anticipate the need for surgical intervention within the first three cycles (3 months), as surgical intervention during the period of DLT evaluation may affect analysis of adherence and/or make the subject in-evaluable. Phase II: Patients who anticipate the need for surgical intervention of the target PN within the first eight cycles (8 months), as surgical intervention during the period may affect analysis of response and may make the subject in-evaluable. 5. An investigational agent within the past 28 days. 6. Any unresolved chronic toxicity with toxicity ≥ CTCAE Grade 2 from previous anti-cancer therapy, except for alopecia. 7. Ongoing radiation therapy, chemotherapy, hormonal therapy directed at the tumour, immunotherapy, or biological therapy. 8. Any evidence of severe or uncontrolled systemic disease, active infection, active bleeding diatheses or renal transplant, including any patient known to have hepatitis B, hepatitis C or human immunodeficiency virus (HIV) 9. Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study. 10. Inability to swallow capsules, since capsules cannot be crushed or broken. 11. Inability to undergo MRI and/or contraindication for MRI examinations following the MRI protocol. Prosthesis or orthopaedic or dental braces that would interfere with volumetric analysis of target PN on MRI. 12. Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption. 13. Prior treatment with selumetinib or another specific MEK1/2 inhibitor. 14. Evidence of an optic glioma (progressive OPG allowed in Phase 2), malignant glioma, malignant peripheral nerve sheath tumour, or other cancer requiring treatment with chemotherapy or radiation therapy. 15. Patients should not take any supplementation with Vitamin E. 16. Patients not achieving adequate blood pressure in spite of antihypertensive therapy for control of blood pressure. 17. Cardiac Function: 1. Known inherited coronary disease 2. Symptomatic heart failure (NYHA Class II-IV prior or current cardiomyopathy, or severe valvular heart disease) 3. Prior or current cardiomyopathy 4. Severe valvular heart disease 5. History of atrial fibrillation 18. Ophthalmologic conditions: 1. Current or past history of central serous retinopathy 2. Current or past history of retinal vein occlusion <!-- --> 1. Patients with controlled 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 PI. 2. Subjects with any other significant abnormality on ophthalmic examination (performed by an ophthalmologist) should be discussed with the PI for potential eligibility 3. Ophthalmological findings secondary to optic pathway glioma (such as visual loss, optic nerve pallor or strabismus) or long-standing orbito-temporal PN (such as visual loss, strabismus) will NOT be considered a significant abnormality for the purposes of the study 19. Clinical judgement by the investigator that the patient should not participate in the study. 20. While not an exclusion criterion, unless considered clinically indicated, patients should avoid taking other additional non-study medications that may interfere with the study medication. In particular, patients should avoid medications that are known to either induce or inhibit the activity of hepatic microsomal isoenzymes CYP1A2, CYP2C19 and CYP3A4, as this may interfere with the metabolism of selumetinib.