Phase I Study to Assess the Effect of Food on the PK and Gastrointestinal Tolerability of Selumetinib in Adolescent Children With Neurofibromatosis Type 1 Related Plexiform Neurofibromas

NCT05101148 | Active Not Recruiting Phase 1 FDA Drug

• 3 other identifiers: D1346C000152024-517216-29-002020-005648-52
• Study Type: interventional
• Target: 24
• Locations: 4 countries
• Sites: 9

Brief Summary

This study in adolescent participants with NF1 who have inoperable PN is designed to evaluate the effect of a low fat meal on steady state selumetinib exposure; to assess the effect on GI tolerability when selumetinib is dosed under fed and fasted conditions; and potentially, to confirm an appropriate dosing recommendation of selumetinib with a low fat meal that maintains efficacy with acceptable safety. These results may support labelling statements with regard to posology and food.

Conditions

Neurofibromatosis Type 1

Keywords

Neurofibromatosis Type 1

Outcome Measures

Primary Outcomes (6)

• Selumetinib area under the plasma concentration-time curve from zero to 12 hours post-dose (AUC0-12)

  To compare the AUC0-12, SS of the fed (same dose and dose adjustment if necessary) versus fasted state

  At pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours post-dose (Cycle 1 Day 8 of each treatment period 1, 2 and 3); Each treatment period 1 and 2 has 1 cycle (Each cycle is 28 days). If needed, treatment period 3 will be started approximately 5 cycles later.

• Gastrointestinal Adverse Events graded by CTCAE Ver 5.0 (Grade 1 to 5)

  To investigate the gastrointestinal toxicities of selumetinib capsules after multiple doses

  from screening until 30 days after last dose

• Assessing change of Gastrointestinal toxicity diary: Modified Bristol Stool Form Scale for Children (mBSFS-C)

  To investigate the gastrointestinal toxicities of selumetinib capsules after multiple doses

  At screening (at least 14 days), Cycle 1 of each treatment period 1, 2 and 3 (1 cycle is 28 days)

• Assessing change of Gastrointestinal toxicity diary: Nausea and Vomiting Symptom Rating Scale (adapted from the Children's Cancer and Leukaemia Group)

  To investigate the gastrointestinal toxicities of selumetinib capsules after multiple doses

  At screening (at least 14 days), Cycle 1 of each treatment period 1, 2 and 3 (1 cycle is 28 days)

• Number of patients who take each gastrointestinal medication

  Collecting gastrointestinal concomitant medications taken including, but not restricted to, medications used to treat diarrhoea, nausea and vomiting.

  From screening until 30 days after last dose

• Proportion of patients who take each gastrointestinal medication

  Collecting gastrointestinal concomitant medications taken including, but not restricted to, medications used to treat diarrhoea, nausea and vomiting.

  From screening until 30 days after last dose

Secondary Outcomes (5)

• Adverse events(AEs) graded by CTCAE Version 5.0

  From screening until 30 days after last dose

• Maximum Peak plasma concentration (Cmax) of selumetinib and N-desmethyl selumetinib

  At pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours post-dose (Cycle 1 Day 8 of each treatment period 1, 2 and 3); Each treatment period 1 and 2 has 1 cycle (Each cycle is 28 days). If needed, treatment period 3 will be started approximately 5 cycles later.

• Area under the concentration-time curve from time zero to time of last measurable concentration (AUClast) of selumetinib and N-desmethyl selumetinib

  At pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours post-dose (Cycle 1 Day 8 of each treatment period 1, 2 and 3); Each treatment period 1 and 2 has 1 cycle (Each cycle is 28 days). If needed, treatment period 3 will be started approximately 5 cycles later.

• Time to maximum concentration (tmax) of selumetinib and N-desmethyl selumetinib

  At pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours post-dose (Cycle 1 Day 8 of each treatment period 1, 2 and 3); Each treatment period 1 and 2 has 1 cycle (Each cycle is 28 days). If needed, treatment period 3 will be started approximately 5 cycles later.

• Time to last measurable concentration (tlast) of selumetinib and N-desmethyl selumetinib

  At pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours post-dose (Cycle 1 Day 8 of each treatment period 1, 2 and 3); Each treatment period 1 and 2 has 1 cycle (Each cycle is 28 days). If needed, treatment period 3 will be started approximately 5 cycles later.

Study Arms (1)

selumetinib single arm

EXPERIMENTAL

This is a sequential study consisting of a screening period lasting up to 28 days, a 28 day (1 cycle) treatment period (T1) in a fed state, a 7 day washout period, a further 1 cycle treatment period (T2) in a fasted state and an extension to T2 until results from the primary analysis are available. During Treatment Period 1 and 2 all participants will receive selumetinib (25 mg/m2 bid). If a third treatment period (T3) is required, participants will enter a 7 day washout period followed by a treatment period in a fed state at an adjusted dose for 3 cycles.

Drug: Selumetinib

Interventions

Selumetinib DRUG

The dosing regimen for selumetinib (25 mg/m2 bid) will be based on BSA, during T1 and T2 the dose will be 25mg/m2, consistent with the approved prescribing information in the US. If T3 is required, appropriate dose of selumetinib will be defined by Data Review Committee for T3.

selumetinib single arm

Eligibility Criteria

• Age: 12 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Male and female participants aged ≥ 12 to \< 18 years at the time of signing the informed consent.
• All study participants must be diagnosed with (i) NF1 per NIH Consensus Development Conference Statement and (ii) inoperable PN. In addition to PN, participants must have at least 1 other diagnostic criterion for NF1 as defined in protocol.
• Participants must require treatment for NF1 and inoperable PN due to actual symptoms or because of the potential to develop significant clinical complications, as judged by the Investigator, as defined in the protocol.
• Participants must have a BSA ≥ 1.3 and ≤ 2.5 m2

You may not qualify if:

• Evidence or suspicion of optic glioma, malignant glioma, MPNST, or other cancer requiring treatment with chemotherapy or radiation therapy
• Prior malignancy requiring active treatment (except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the participant had been disease free for ≥ 2 years or which would not have limited survival to \< 2 years).
• A life-threatening illness, medical condition, organ system dysfunction of laboratory finding which, in the Investigator's opinion, could compromise the participant's safety, interfere with the absorption or metabolism of selumetinib, or put the study outcomes at undue risk.
• Participants with clinically significant cardiovascular disease as listed in the protocol.
• Liver function tests: bilirubin \> 1.5 × the ULN for age (with the exception of those with Gilbert syndrome) or AST/ALT \> 2 × upper limit of normal.
• Renal Function: Creatinine clearance or radioisotope glomerular filtration rate \< 30 mL/min/1.73 m2 or a serum creatinine \> 1.2 mg/dL (for participants aged between 12 and 15 years) or \> 1.5 mg/dL for participants aged \> 15 years).
• Participants with abnormal ophthalmological findings/conditions as listed in the protocol.
• Have any unresolved chronic toxicity, associated with previous therapy for NF1-PN: Gastrointestinal toxicity of CTCAE Grade 1 or higher; Have any other unresolved chronic toxicity with CTCAE Grade ≥ 2, except hair changes (such as alopecia or hair lightening).
• Participants who have previously been treated with a MEKi (including selumetinib) and either discontinued treatment or required a dose reduction due to toxicity
• Have had recent major surgery within a minimum of 4 weeks prior to starting study intervention, with the exception of surgical placement for vascular access. Have planned major surgery during the treatment period.
• Any multivitamin containing vitamin E must be stopped at least 7 days prior to initiation of selumetinib.

Sponsors & Collaborators

• AstraZeneca: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (9)

Research Site

Rochester, Minnesota, 55905, United States

Location

Research Site

Akron, Ohio, 44308, United States

Location

Research Site

Bydgoszcz, 85-094, Poland

Location

Research Site

Gdansk, 80-952, Poland

Location

Research Site

Warsaw, 02-091, Poland

Location

Research Site

Moscow, 119620, Russia

Location

Research Site

Moscow, 125412, Russia

Location

Research Site

Barcelona, 08950, Spain

Location

Research Site

Madrid, 28009, Spain

Location

Related Publications (1)

• Viskochil D, Wysocki M, Learoyd M, Sun P, So K, Evans A, Lai F, Hernandez HS. Effect of food on selumetinib pharmacokinetics and gastrointestinal tolerability in adolescents with neurofibromatosis type 1-related plexiform neurofibromas. Neurooncol Adv. 2024 Mar 16;6(1):vdae036. doi: 10.1093/noajnl/vdae036. eCollection 2024 Jan-Dec.

  PMID: 38721358 DERIVED

Related Links

• CSR Synopsis

MeSH Terms

Conditions

Neurofibromatosis 1

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

Study Officials

• Study physician Study physician, MD

  AstraZeneca

  STUDY DIRECTOR

Study Design

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

Study Record Dates

• First Submitted: June 16, 2021
• First Posted: November 1, 2021
• Study Start: July 21, 2021
• Primary Completion: April 6, 2022
• Study Completion (Estimated): April 28, 2028
• Last Updated: February 23, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: CSR
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Locations

US (2); ES (2); RU (2); PL (3)