Intermittent Dosing Of Selumetinib In Childhood NF1 Associated Tumours

NCT03326388 | Completed Phase 1

• 1 other identifier: 15Hi53
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 2

Brief Summary

Phase I and II study of the MEK inhibitor Selumetinib given twice daily on 5 out of 7 days in children with NF1 and inoperable plexiform neurofibromas or progressive/relapsed optic pathway gliomas. This study will test the early and late toxicities of selumetinib when it is given in this intermittent schedule (in 5 out of 7 days) and will also test the effectiveness of the drug in reducing the size of plexiform neurofibromas and optic pathway gliomas in children with NF1. It will also test the effectiveness of the drug in improving the participants function in day to day life.

Conditions

Neurofibromatosis Type 1; Plexiform Neurofibroma; Optic Nerve Glioma

Outcome Measures

Primary Outcomes (3)

• Phase 1: To evaluate the Maximum Tolerated Dose

  Phase 1: Definition of the maximum tolerated dose using number of participants with treatment related adverse events as assessed by CTCAEv4.0

  6 months

• Phase 2: Objective response rate in NF1 inoperable plexiform neurofibroma and optic pathway glioma

  Phase 2:To evaluate the objective response rate of children (≥3 and ≤ 18 years old) with NF1 and inoperable plexiform neurofibroma using 3D volumetric analysis.

  2 years

• Best Objective response rate in NF1 related optic pathway gliomas

  To evaluate the best objective response rate (including MR, PR and CR) of children (≥3 and ≤ 18 years old) with NF1 related optic pathway glioma using 2D assessment of tumour size.

  2 years

Secondary Outcomes (24)

• Cardiac Function - fractional shortening

  5 years

• Cardiac Function - QTc

  5 years

• Retinal detachment.

  5 years

• Treatment related Adverse Events

  5 years

• Pharmacokinetics of selumetinib. Phase 1 only

  6 months

Study Arms (1)

Selumetinib Intermittent Dosing

EXPERIMENTAL

Phase 1 of the study to evaluate Intermittent Dosing (Selumetinib given twice daily on 5 out of 7 days) in children with NF1 and inoperable plexiform neurofibromas. The Maximum tolerated dose will define the Recommended phase 2 dose of selumetinib.

Drug: Selumetinib

Interventions

Selumetinib DRUG

Selumetinib Intermittent Dosing

Also known as: AZD6244,, ARRY-142886, AR00142886, AR-142886-X

Selumetinib Intermittent Dosing

Eligibility Criteria

• Age: 3 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.
• 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.
• 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
• 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.
• 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.

You may not qualify if:

• 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.
• 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.
• Recent major surgery within a minimum of 4 weeks prior to starting study treatment, with the exception of surgical placement for vascular access.
• 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.
• An investigational agent within the past 28 days.
• Any unresolved chronic toxicity with toxicity ≥ CTCAE Grade 2 from previous anti-cancer therapy, except for alopecia.
• Ongoing radiation therapy, chemotherapy, hormonal therapy directed at the tumour, immunotherapy, or biological therapy.
• 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)
• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study.
• Inability to swallow capsules, since capsules cannot be crushed or broken.
• 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.
• Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption.
• Prior treatment with selumetinib or another specific MEK1/2 inhibitor.
• 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.

Sponsors & Collaborators

• Great Ormond Street Hospital for Children NHS Foundation Trust: lead
• AstraZeneca: collaborator

Study Sites (2)

Great Ormond Street Hospital for Children NHS Foundation Trust

London, wc1n 1eh, United Kingdom

Location

Great Ormond Street Hospital NHS Foundatin Trust

London, WC1N 3JH, United Kingdom

Location

Related Publications (2)

• Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, Whitcomb P, Martin S, Aschbacher-Smith LE, Rizvi TA, Wu J, Ershler R, Wolters P, Therrien J, Glod J, Belasco JB, Schorry E, Brofferio A, Starosta AJ, Gillespie A, Doyle AL, Ratner N, Widemann BC. Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas. N Engl J Med. 2016 Dec 29;375(26):2550-2560. doi: 10.1056/NEJMoa1605943.

  PMID: 28029918 BACKGROUND

• Banerjee A, Jakacki RI, Onar-Thomas A, Wu S, Nicolaides T, Young Poussaint T, Fangusaro J, Phillips J, Perry A, Turner D, Prados M, Packer RJ, Qaddoumi I, Gururangan S, Pollack IF, Goldman S, Doyle LA, Stewart CF, Boyett JM, Kun LE, Fouladi M. A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study. Neuro Oncol. 2017 Aug 1;19(8):1135-1144. doi: 10.1093/neuonc/now282.

  PMID: 28339824 BACKGROUND

MeSH Terms

Conditions

Neurofibromatosis 1; Neurofibroma, Plexiform; Optic Nerve Glioma

Interventions

AZD 6244

Condition Hierarchy (Ancestors)

Neurofibromatoses; Neurofibroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Peripheral Nervous System Neoplasms; Nervous System Neoplasms; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Glandular and Epithelial; Optic Nerve Neoplasms; Cranial Nerve Neoplasms; Neoplasms by Site; Cranial Nerve Diseases; Optic Nerve Diseases; Eye Diseases

Study Officials

• Darren Hargrave, MB Bch

  Great Ormond Street Hospital NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Single Arm Study of Intermittent Schedule of Drug Dosing

Study Record Dates

• First Submitted: September 8, 2017
• First Posted: October 31, 2017
• Study Start: September 26, 2019
• Primary Completion: February 14, 2024
• Study Completion: February 14, 2024
• Last Updated: April 4, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

GB (2)