A Randomised, Double-Blind Study to Assess the Efficacy of Selumetinib
(AZD6244, Hyd-Sulfate) in Combination with Dacarbazine Compared with
Placebo in Combination with Dacarbazine as First Systemic Therapy in
Patients with Metastatic Uveal Melanoma (SUMIT)

Uveal melanoma (also known as ocular or choroidal melanoma) is the most common
primary tumour of the eye.Uveal melanoma has a distinct molecular profile with
the vast majority (80%) harbouring mutations in either the guanidine nucleotide
binding protein (G protein), Q polypeptide 1 (GNAQ) or the G protein alpha 11
(GNA11) gene. Currently, there are no effective or approved therapies for
metastatic uveal melanoma. Dacarbazine is the most commonly prescribed
chemotherapy for both metastatic cutaneous and uveal melanoma. However,
pre-clinical studies with selumetinib and clinical experience to date suggest
that cell lines and tumours with activating mutations in RAS/RAF/MEK/ERK
transduction pathway may be particularly sensitive to MEK inhibition.
Selumetinib (AZD6244; ARRY 142886) is a potent, selective, uncompetitive
inhibitor of the mitogen-activated protein kinase (MEK). Therefore, selumetinib
in combination with dacarbazine may offer superior clinical benefit to patients
with advanced uveal melanoma compared with dacarbazine alone.
Protocol "Introduction" section 1.1.1 - 1.3.2 page 20 - 25

Objectives
Primary objective
1. To assess the efficacy of selumetinib in combination with dacarbazine
compared with placebo in combination with dacarbazine in terms of Progression
Free Survival (PFS) assessed by blinded independent central review (BICR)
Secondary objectives
1. To assess the efficacy of selumetinib in combination with dacarbazine
compared with placebo in combination with dacarbazine in terms of:
* Objective Response Rate (ORR) by BICR
* Duration of Response (DoR) by BICR
* Change in tumour size at Week 6 by BICR
2. To assess overall survival (OS) in patients taking selumetinib in
combination with dacarbazine compared with those taking placebo in combination
with dacarbazine
3. To assess the safety and tolerability profile of selumetinib in combination
with dacarbazine compared with placebo in combination with dacarbazine
Exploratory objectives
1. To explore the efficacy of selumetinib by assessment of OS adjusting for the
impact of treatment options available post-progression as confirmed by BICR
2. To explore symptoms and health-related quality of life (HRQL) in patients
treated with selumetinib in combination with dacarbazine and in patients
receiving placebo in combination with dacarbazine using the European
Organization for Research and Treatment of Cancer 30-item core quality of life
questionnaire version 3 (EORTC-QLQC30 v3)
3. To investigate the health economic impact of treatment and the disease on
hospital related resource use and health state utility
4. To investigate the relationship between selumetinib and/or N-desmethyl
selumetinib plasma concentrations/exposure and clinical outcomes, efficacy,
adverse events (AEs) and/or safety parameters if deemed appropriate
5. To explore mitogen-activated protein kinase (MEK) pathway mutations in GNAQ
and GNA11
6. Future exploratory research into factors that may influence development of
cancer and/or response to treatment (where response is defined broadly to
include efficacy, tolerability or safety) may be performed on the collected and
stored archival tumour samples (if available) and blood samples at baseline and
on treatment discontinuation (mandated)
7. To collect and store DNA according to each country*s local and ethical
procedures for future exploratory research into genes/genetic variation that
may influence response (ie, distribution, safety, tolerability and efficacy) to
study treatments and/or susceptibility to disease (optional)
8. To collect a tumour biopsy at the treatment discontinuation visit following
confirmation of objective disease progression by BICR to allow assessment of
the biology of resistance (optional)

This is a randomised, double-blind, placebo-controlled study assessing the
efficacy and safety of selumetinib (75 mg, twice daily on a continuous oral
administration) in combination with dacarbazine (1000 mg/m2, intravenously (iv)
on Day 1 of every 21-day cycle) compared with matching placebo in combination
with dacarbazine (1000 mg/m2, iv on Day 1 of every 21-day cycle) in patients
who have not previously had a systemic therapy for metastatic uveal melanoma.
Patients who fulfil all the eligibility criteria will be randomised in a ratio
of 3:1 to receive:
• Selumetinib 75 mg twice daily in combination with dacarbazine 1000 mg/m2 (on
Day 1 of every 21-day cycle)
Or
• Placebo twice daily in combination with dacarbazine 1000 mg/m2 (on Day 1 of
every 21 day cycle)
Patients will be stratified based on the presence or absence of liver
metastases (yes/no) at randomisation.
Following randomisation, patients will attend scheduled study visits as
outlined in the study plan (Table 3). All randomised patients will be assessed
by computed tomography (CT) or magnetic resonance imaging (MRI) at screening,
Week 6 and every 6 weeks thereafter, relative to the date of randomisation. The
same method for imaging tumours (ie, CT or MRI scan) should be used throughout
the study. Tumour evaluation will be performed according to the Response
Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1) guidelines.
It is important that patients are assessed according to the intended scanning
schedule to prevent the bias in analysis that can occur if one treatment group
is assessed more often or sooner than the other. All imaging assessments
including unscheduled visit scans will be collected on an ongoing basis and
sent to an AstraZeneca appointed central imaging vendor for BICR.
Up to the data cut-off for the primary analysis, patients must be followed
until evidence of RECIST 1.1-defined objective disease progression as confirmed
by BICR. If a patient discontinues study treatment (selumetinib/placebo and/or
dacarbazine) for reasons other than objective disease progression, RECIST 1.1
assessments should continue according to the original schedule until BICR
confirmed objective disease progression occurs. Evaluation of CT/MRI scans
according to RECIST 1.1 will be used to derive the primary variable of PFS and
secondary variables of ORR, DoR and change in tumour size at Week 6. BICR of
CT/MRI scans will continue until confirmation of objective disease progression.
Following confirmation of objective disease progression by BICR, patients will
be unblinded to identify whether they were receiving selumetinib or placebo.
All patients, regardless of initial treatment, will have three options for
post-progression therapy to consider:
1. Receive alternative treatment approach at the investigative site
2. Receive open-label selumetinib monotherapy
3. Receive open-label selumetinib in combination with dacarbazine.
Patients may receive any post-progression therapy that is, in the opinion of
the Investigator, providing clinical benefit without significant toxicity
concerns and it does not contravene local practice.
Patients who opt to receive an alternative treatment approach at the
investigative site will be seen for the 30-day follow-up visit and will then be
followed for survival every 8 weeks (with any subsequent therapies documented)
until death, withdrawal of consent or the end of the study, whichever occurs
first.
Patients who opt to receive open-label selumetinib as post-progression therapy
will need to sign a separate Informed Consent Form (ICF) and will follow one of
two assessment schedules depending on whether they received selumetinib in
combination with dacarbazine or placebo in combination with dacarbazine in the
main study. During the open-label extension phase, tumour assessments will be
performed in accordance with local practice at the investigational site and
will not be sent for BICR.
Once a patient has had objective disease progression confirmed by BICR,
discontinued all study treatment and received their 30-day follow-up visit,
they are to be followed up for survival status every 8 weeks (with all
subsequent therapies documented) until death, withdrawal of consent or the end
of the study, whichever occurs first.
After the data cut-off for the primary analysis, BICR of tumour assessments (CT
or MRI scans) will no longer be performed and confirmation of objective disease
progression will be by investigational site review of CT or MRI scans only.
However, following confirmation of objective disease progression by
investigational site review, the patients will still have three options for
post-progression therapy as described above including the option to receive
open-label selumetinib.
If a patient wishes to withdraw their consent to further participation in the
study, including survival follow-up (which could be conducted by telephone)
this should be clearly documented in the patient notes and in the clinical
study database.

At each dispensing visit, patients will receive sufficient selumetinib/placebo
capsules for 21 days treatment, plus overage. Individual bottles will be
dispensed in accordance with the medication identification numbers provided by
the IVRS/IWRS.
Patients should swallow three selumetinib/placebo 25 mg capsules twice daily,
commencing on Day 1 after the required Day 1 assessments are completed.
Capsules should be taken whole and with approximately 240 mL water.
The initial dose of selumetinib/placebo can be reduced/adjusted in accordance
with the circumstances described in Section 5.5.6.

Currently there are no effective systemic treatments for uveal melanoma. In
Study ISS62440007, selumetinib monotherapy demonstrated a promising therapeutic
effect in patients with uveal melanoma.
Although used and prescribed for patients with uveal melanoma, the activity of
non-targeted medicines approved for cutaneous melanoma have not been
characterised for patients with uveal melanoma. As discussed above, there are
pre-clinical and clinical data to support the use
of selumetinib in combination with dacarbazine in patients with uveal melanoma.
Results from the phase II Study D1532C00006 in patients receiving first line
treatment for BRAF mutation positive advanced cutaneous or unknown primary
melanoma showed the combination of selumetinib and dacarbazine had a safety
profile consistent with monotherapy profiles with AEs managed in accordance
with routine clinical practice. Study D1532C00006 also showed that the
combination significantly improved PFS and ORR compared with dacarbazine alone
(Robert et al 2013). The combination of pre-clinical and clinical experience to
date indicates an acceptable benefit:risk ratio to explore the use of
selumetinib in combination with dacarbazine in patients with uveal melanoma.