Single-arm Study of Selumetinib in Combination With Docetaxel, in Advanced Gastric Adenocarcinoma Patients With Low/High MEK Signature, RAS Mutation or RAS Amplification as a Second-line Chemotherapy

Inclusion criteria

• Provision of fully informed consent prior to any study specific procedures.
• Patients must be ≥20 years of age.
• Advanced gastric adenocarcinoma (including GEJ) that has progressed during or after firstline therapy.

• The 1st line regimen must have contained doublet 5-fluoropyrimidine and platinum based regimen.
• Relapse within 6 months of completion of adjuvant/neoadjuvant chemotherapy containing doublet 5-fluoropyrimidine and platinum-based regimen could be considered as 1st line therapy.
• Previous adjuvant/neoadjuvant chemotherapy is allowed, if completed more than 6 months prior to starting the 1st line therapy.
• Provision of tumor sample (from either a resection or biopsy)
• Patients with MEK signature, RAS mutation or amplification through the VIKTORY trial.

(The VIKTORY trial uses Ion Torrent PGM to screen for a panel of cancer mutations and nanostring, copy number variation panel (see addendum for the VIKTORY trial)

• Patients are willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations.
• ECOG performance status 0-1.
• Patients must have a life expectancy ≥ 3 months from proposed first dose date.
• Patients must have acceptable bone marrow, liver and renal function measured within 28 days prior to administration of study treatment as defined below:

• Haemoglobin ≥9.0 g/L (transfusion allowed)
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
• White blood cells (WBC) > 3 x 109/L
• Platelet count ≥100 x 109/L (transfusion allowed)
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (does not include patients with Glibert's disease)
• AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present in which case it must be ≤ 5x ULN
• Serum creatinine ≤1.5 x institutional ULN
• At least one measurable lesion that can be accurately assessed by imaging or physical examination at baseline and following up visits.
• Negative urine or serum pregnancy test within 28 days of study treatment, confirmed prior to treatment on day 1. for women of childbearing potential.
• Provision of consent for mandatory biopsy at progression

Exclusion criteria

• More than one prior chemotherapy regimen (except for adjuvant/neoadjuvant chemotherapy with more than 6 month wash out period) for the treatment of gastric cancer in the advanced setting.
• Any previous treatment with MEK, RAS or RAF inhibitors
• Any previous treatment with docetaxel.
• Patients with second primary cancer, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for ≤5 years.
• HER2 positive patients (defined by HER2 3+ by immunohistochemistry or HER2 SISH +)
• Patients unable to swallow orally administered medication.
• Treatment with any investigational product during the last 14 days before the enrollment (or a longer period depending on the defined characteristics of the agents used).
• Patients receiving any systemic chemotherapy, radiotherapy (except for palliative reasons), within 3 weeks from the last dose prior to study treatment (or a longer period depending on the defined characteristics of the agents used). The patient can receive a stable dose of bisphosphonates or denusomab for bone metastases, before and during the study as long as these were started at least 4 weeks prior to treatment.
• Concomitant use of known potent CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir.
• With the exception of alopecia, any ongoing toxicities (>CTCAE grade 1) caused by previous cancer therapy.
• Intestinal obstruction or CTCAE grade 3 or grade 4 upper GI bleeding within 4 weeks before the enrollment.
• Resting ECG with measurable QTcB > 480 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome.
• Patients with cardiac problem as follows: uncontrolled hypertension (BP ≥150/95 mmHg despite medical therapy) Baseline Left ventricular ejection fraction below the LLN of <55% measured by echocardiography or institution's LLN for MUGA, Atrial fibrillation with a ventricular rate >100 bpm on ECG at rest , Symptomatic heart failure (NYHA grade II-IV), Prior or current cardiomyopathy, Severe valvular heart disease, Uncontrolled angina (Canadian Cardiovascular Society grade II-IV despite medical therapy), Acute coronary syndrome within 6 months prior to starting treatment
• Ophthalmological conditions as follows:Intra-ocular pressure >21 mmHg, or uncontrolled glaucoma (irrespective of intra-ocular pressure), Current or past history of retinal pigment epithelial detachment/central serous retinopathy or or current or past history retinal vein occlusion
• Female patients who are breast-feeding or child-bearing and Male or female patients of reproductive potential who are not employing an effective method of contraception
• 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)