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

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Brief Title

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

Official Title

A Phase I, Single-Arm, Sequential Study to Evaluate the Effect of Food on the Gastrointestinal Toxicity and Pharmacokinetics of Selumetinib After Multiple Doses in Adolescent Children With Neurofibromatosis Type 1 Related Plexiform Neurofibromas

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
      toxicity 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.
    

Detailed Description

      Selumetinib is approved by the FDA for the treatment of paediatric patients 2 years of age
      and older with NF1 who have symptomatic, inoperable PN.

      The efficacy of selumetinib in the treatment of NF1 related inoperable PN in paediatric
      participants was demonstrated in the SPRINT study in which selumetinib was taken at 25 mg/m2
      bid under fasted conditions (fast for 2 hours before each dose and 1 hour after each dose).
      Safety data from this study showed that selumetinib has a generally predictable and
      manageable safety profile in this population. Gastrointestinal AEs were commonly reported but
      were predominantly mild/moderate in severity, predictable, and generally did not affect the
      ability of participants to remain on treatment. However, GI AEs in this paediatric study were
      reported at a higher frequency than that reported in an analysis of selumetinib in adult
      oncology participants. Dosing in a fed state is known to reduce GI toxicity for some oncology
      drugs; such a dosing regimen has an added benefit of improving compliance and adherence to
      dosing posology.

      Food-effect studies conducted in healthy participants (Study D1532C00069) and adult
      participants with cancer (Study D1532C00020) show that consumption of a high fat meal reduces
      absorption of selumetinib: in healthy participants Cmax was reduced by 50% and AUC by 16%;
      and in participants with cancer Cmax was reduced by 62% and AUC by 19%. A further study in
      adult healthy participants (D1532C00089) found that a low fat, low calorie meal reduces the
      rate of absorption (Cmax reduced by 65% and tmax delayed by 2.5 hours) and the extent of
      absorption (AUC reduced by 38%) after a single dose of selumetinib. The finding that a low
      fat meal had a greater impact on exposure than a high fat meal is unusual and without a clear
      explanation although in vitro dissolution data suggest that the capsule shell disintegration
      may be impacted by food.

      The study is designed to evaluate the steady state systemic exposure and safety (especially
      GI toxicity) of selumetinib 25 mg/m2 bid given with a low fat meal versus the same dose given
      in a fasted state. A third treatment period (T3) will be initiated if there is a significant
      reduction in exposure (AUC0-12, SS between T2 vs T1) when selumetinib is given with a low fat
      meal compared with a fasted state; T3 will evaluate the PK and safety of an adjusted dose of
      selumetinib when given with a low fat meal. The recommendation as to whether to initiate T3,
      and the dose to be used in T3, will be made by a DRC. This recommendation will be reviewed
      with FDA before dosing in T3 is initiated.

      Approximately 20 participants will be enrolled to achieve 16 evaluable participants
      completing T2. An evaluable participant is defined as having received study treatment and
      provided the last required PK sample in T2.

      A Data Review Committee(DRC) will review the PK and safety data from T1 and T2 and determine
      whether T3 is required. If T3 is required the DRC will select the dose to be used. The
      recommendation will be reviewed with FDA before dosing in T3 is initiated.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

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

Secondary Outcome

 Adverse events(AEs) graded by CTCAE Version 5.0

Condition

Neurofibromatosis Type 1

Intervention

Selumetinib

Study Arms / Comparison Groups

 selumetinib single arm
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

19

Start Date

November 9, 2021

Completion Date

February 21, 2023

Primary Completion Date

April 15, 2022

Eligibility Criteria

        Inclusion Criteria:

          -  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 who have had prior treatment with any MEKi (including selumetinib) may be
             considered for inclusion in this study.

          -  Participants must have a BSA ≥ 1.3 and ≤ 2.5 m2

        Exclusion Criteria:

          -  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.
      

Gender

All

Ages

12 Years - 17 Years

Accepts Healthy Volunteers

No

Contacts

Study physician Study physician, MD, , 

Location Countries

Poland

Location Countries

Poland

Administrative Informations


NCT ID

NCT05101148

Organization ID

D1346C00015


Responsible Party

Sponsor

Study Sponsor

AstraZeneca

Collaborators

 Merck Sharp & Dohme Corp.

Study Sponsor

Study physician Study physician, MD, Study Director, AstraZeneca


Verification Date

January 2022