| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Neurofibromatosis type 1 associated plexiform neurofibromas
Neurofibromatosis type 1 associated progressive or relapsed optic pathway glioma |
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| E.1.1.1 | Medical condition in easily understood language |
| Neurofibromatosis type 1 is an inherited condition. Plexiform neurofibromas are benign tumours of the sheath covering nerves. Optic pathway Gliomas are tumours of the nerve which controls vision |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10029270 |
| E.1.2 | Term | Neurofibromatosis, type 1 (von Recklinghausen's disease) |
| E.1.2 | System Organ Class | 100000004850 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065866 |
| E.1.2 | Term | Plexiform neurofibroma |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10030935 |
| E.1.2 | Term | Optic nerve glioma |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of the phase 1 aspect of this study is to investigate using a new intermittent schedule of taking selumetinib in NF1 patients with inoperable plexiform neurofibromas (PN), in order to establish the maximum tolerated dose (MTD). For this study, the new intermittent schedule would involve patients taking selumetinib twice daily for 5 out of every 7 days. Based on the Paediatric Brain Tumour Consortium study and the NCI study in the US, both of which evaluated selumetinib in patients with NF1 and either inoperable PN or low grade gliomas, the starting dose level will be 25mg/m2/dose taken twice daily. The purpose of this part of the study will be to define the acute and chronic toxicities, of selumetinib in addition to evaluating what happens to the drug in the body after patients have taken it. The purpose of this part of the study, will be to establish the maximum tolerated dose and to determine the dose of selumetinib which will be used in the phase 2 aspect o |
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| E.2.2 | Secondary objectives of the trial |
Secondary objectives of the phase 1 part of the study will include contributing to our knowledge of the effect of selumetinib on the growth rate of PN.
Secondary objectives of the phase 2 part of the study will include further evaluation of the acute and chronic toxicities of selumetinib in the NF1 population, and to assess the clinical status and quality of life of this population while taking selumetinib.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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.(for details refer to protocol sec 2.1)
Phase 2 (Dose expansion): Two cohorts are eligible for inclusion in the dose expansion cohort.
Cohort A (approx 10 patients) Patients with NF1 and inoperable measurable PNs (as per Phase I)
and
Cohort B (approx 10 patients) NF-1 related progressive optic pathway glioma is eligible if the patient 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): Patients must have at least one measurable PN, defined as a lesion of at least 3 cm measured in one dimension. Patients who underwent surgery for resection of a PN are eligible provided the PN was incompletely resected and is measurable. The target PN will be defined as the clinically most relevant PN, which has to be amendable to volumetric MRI anlaysis . PN will be classified as ‘typical PN’ versus ‘nodular PN’ versus ‘solitary nodular PN’ prior to enrolment. Measurable disease (OPG): Patients must have one measurable OPG lesions according to RANO criteria (vander Bent 2011) with minimal bi-perpendicular diameter that must be at least twice the imaging slice thickness to be used for efficacy assessment.
4. Prior Therapy: Patients 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. (for details please refer to protocol sec 2.1)
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%. 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.
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 measured as described in (Appendix IB). 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. |
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| E.4 | Principal 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:
a. Known inherited coronary disease
b. Symptomatic heart failure (NYHA Class II-IV prior or current cardiomyopathy, or severe valvular heart disease)
c. Prior or current cardiomyopathy
d. Severe valvular heart disease
e. History of atrial fibrillation
18. Ophthalmologic conditions:
a. Current or past history of central serous retinopathy
b. Current or past history of retinal vein occlusion
a. 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.
b. Subjects with any other significant abnormality on ophthalmic examination (performed by an ophthalmologist) should be discussed with the PI for potential eligibility
c. 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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary outcome of the phase 1 part of the study is to determine the MTD and extended toxicity profile of selumetinib in paediatric patients (≥3 and ≤ 18 years) with NF1 and inoperable PN. Toxicities observed for the first cycle will be used to define the MTD. Three patients will be entered at each dose level, and the MTD dose level will be expanded up to an additional 3 patients to a total of 6 patients if feasible. The starting dose level will be 25 mg/m2/dose (as per RP2D from NCI and PBTC studies using continuous schedule). This will be followed by up to three dose escalations, with the highest dose level being equivalent to the adult MTD (40mg/m2/dose). Each increment will be 5mg/m2/dose Therefore there are a total of 4 dose levels and an additional dose-1 level if required. . Volumetric MRI analysis will be used to monitor PN growth rate, and progression will be defined as a ≥20% increase in PN volume. This trial will also evaluate the plasma pharmacokinetics of selumetinib during cycle number 1 and 2.
The primary outcome of the phase 2 aspect of the study is to evaluate the confirmed objective response rate in participants with PN and the confirmed objective response rate in participants with NF1 related OPG. All objective responses will be determined by MRI analysis for both PN and OPG. All objective responses must be confirmed on at least 2 consecutive MRI scans with the second scan being performed at least 4 weeks after the first. PNs will be assessed using volumetric analysis on MRI scans. All OPG will be analysed using LGG RANO MRI criteria as per van den Bent MJ et al 2011, volumetric analysis of the OPG will be undertaken also.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The Maximum Tolerated Dose will be evaluated in the 1st cycle of treatment (i.e. 28 days after commencing treatment with selumetinib). Three patients will be entered at each dose level and each patient must complete 1 cycle of treatment to evaluate the MTD.
The confirmed objective response rate which is evaluated at the primary outcome of the phase II of the study will be assessed at 12 weekly intervals. I.e. each patient will only have their initial response assessment after 3 cycles of treatment (12 weeks) unless they present with clinical deterioration. All objective responses need to be confirmed on 2 consecutive MRI scans and the second scan must be at least 4 weeks after the first scan. Therefore the earliest that response can be assessed is after 16 weeks of treatment. |
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| E.5.2 | Secondary end point(s) |
The Secondary end points include:
• To determine the long-term tolerability and safety of Selumetinib with long term follow up evaluation, detailed clinical evaluation, laboratory studies ECG/ECHO, ophthalmologic exams, symptom checklist, patient diary and Adverse event reporting.
• To determine the duration of response to Selumetinib with duration of response assessing using 3D MRI volumetric analysis
• To determine the effect of selumetinib on pain using pain surveys
• To determine the effect of selumetinib on the quality of life using Quality of Life Surveys
• To determine the effect of selumetinib on physical functioning using endurance tests
• To determine the effect of selumetinib on functional outcomes depending on PN location using function studies and Patient reported outcomes.
• To determine the effect of selumetinib on PN causing morbidity using functional assessments
• To determine the effect of selumetinib on the PN growth rate using volumetric analysis of MRI studies
• To determine time to progression and Progression Free Survival in progressive PN suing 3dMRI volumetric analysis
• To determine the effect of selumetinib on visual function in patients with OPG using REiNS visual Function assessments.
• To determine pharmacokinetics of selumetinib by analysis of Day 1 steady state PK
• To determine the effect of selumetinib on stable NF1 related OPG and other gliomas using evaluation of clinically indicated MRI scans.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The long term tolerability and safety of selumetinib will only be evaluated after 3 years of follow up, i.e. 3 years after the end of 2 years of treatment, or 5 years from the beginning of treatment.
All other secondary endpoints will be evaluated after the full cohort of patients on phase II complete 2 years of treatment. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 25 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 17 |
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