A PAEDIATRIC PHASE I/II STUDY OF INTERMITTENT DOSING OF THE MEK-1 INHIBITOR SELUMETINIB IN CHILDREN WITH NEUROFIBROMATOSIS TYPE-1 AND INOPERABLE PLEXIFORM NEUROFIBROMA AND/OR PROGRESSIVE OPTIC PATHWAY GLIOMA

Phase 1

• Conditions: Neurofibromatosis type 1 associated plexiform neurofibromas Neurofibromatosis type 1 associated progressive or relapsed optic pathway glioma; MedDRA version: 20.0 Level: LLT Classification code 10029270 Term: Neurofibromatosis, type 1 (von Recklinghausen's disease) System Organ Class: 100000004850; MedDRA version: 20.0 Level: LLT Classification code 10065866 Term: Plexiform neurofibroma System Organ Class: 100000004864; MedDRA version: 20.0 Level: LLT Classification code 10030935 Term: Optic nerve glioma System Organ Class: 100000004864; Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

• Registration Number: EUCTR2017-002635-41-GB
• Lead Sponsor: Great Ormond Street Hospital

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2019-06-19
• Last Update Posted: 30 June 2019

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: Not specified
• Target Recruitment: 38

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

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 Cl

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified