Selumetinib

Objective response rate is defined as the proportion of participants who have a confirmed CR (defined as disappearance of the target PN, confirmed by a consecutive scan within 3 to 6 months after the first response) or confirmed PR (defined as a target PN volume decrease ≥ 20%, compared to baseline, confirmed by a consecutive scan within 3 to 6 months after the first response) by end of Cycle 16 as determined by ICR per REiNS criteria. Increase in the volume of the target PN by 20% or more compared to baseline or the time of best response after documenting a PR is considered as PD.

Progression free survival (PFS) using blinded independent central review (BICR) according to the Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1). Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Progression free survival is defined as the time from randomisation until the date of objective disease progression (RECIST 1.1) or death (by any cause in the absence of progression)

Partial response is defined as the sum volume of VS decrease ≥20% compared to baseline, confirmed by a consecutive scan after 1 to 3 treatment cycles after the first response. Complete response is defined as disappearance of VS, confirmed by a consecutive scan after 1 to 3 treatment cycles after the first response;

Percentage of participants with WRS improvement exceeding the 95% critical difference from baseline in the ear associated with the target vestibular schwannoma.

Percentage of participants with a PTA decrease of at least 10 dB from baseline in the ear associated with the target vestibular schwannoma.

Median time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression). Progression is defined using Response Evaluation Criteria in Solid Tumours (RECIST v1.1): \>= 20% increase in the sum of diameters of Target Lesions (TL) and an absolute increase in sum of diameters of \>=5mm (compared to the previous minimum sum) or progression of Non TLs or a new lesion.

Determination of the maximum administered dose and the recommended phase II dose

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

To investigate the gastrointestinal toxicities of selumetinib capsules after multiple doses

To investigate the gastrointestinal toxicities of selumetinib capsules after multiple doses

To investigate the gastrointestinal toxicities of selumetinib capsules after multiple doses

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

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

* Occurrence/frequency. * Relationship to IP as assessed by investigator. * Common Terminology Criteria for Adverse Events (CTCAE) grade. * Seriousness. * Death. * Adverse events leading to discontinuation of IP. * Adverse events of special interest.

AUC0-t after single dose and multiple doses administration

Cmax after single dose and multiple doses administration

t1/2 after single dose and multiple doses administration

Number of subjects with adverse events as a measure of safety and tolerability including changes in vital signs, electrocardiograms, safety laboratory parameters, echocardiogram and ophthalmologic assessment.

Samples taken during each of the 6 treatments

Change from baseline in QTcF at 30 minutes (msec)

This will be taken at visit 2 for Healthy volunteers and at visit 2 and 3 for patients with end stage renal disease

This will be taken at visit 2 for Healthy volunteers and at visit 2 and 3 for patients with end stage renal disease

This will be taken at visit 2 for Healthy volunteers and at visit 2 and 3 for patients with end stage renal disease

Samples taken during each of the 3 treatments

Curve taken during each of the 2 treatments

Rate and extent of absorption of selumetinib following oral doses of selumetinib by assessment of maximum plasma selumetinib concentration (Cmax). Metabolite to parent drug ratios will be calculated for the primary PK parameters AUC and Cmax, and AUC (0-t) if applicable.

Rate and extent of absorption of selumetinib following oral doses of selumetinib by assessment of area under the plasma concentration time curve from zero to infinity (AUC). Metabolite to parent drug ratios will be calculated for the primary PK parameters AUC and Cmax, and AUC (0-t) if applicable.

Rate and extent of absorption of selumetinib following oral doses of selumetinib by assessment of area under the plasma concentration time curve from zero to the last measurable time point, AUC0-t, if AUC is not adequately measurable. Metabolite to parent drug ratios will be calculated for the primary PK parameters AUC and Cmax, and AUC (0-t) if applicable.

Any toxicity not attributable to the disease or disease-related processess under investigation, considered related to the combination of chemotherapy plus selumetinib, which occurs within the timeframe and is dose limiting