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

Study Overview
=================
Brief Summary
-----------------
This study is a single-arm, phase II study of selumetinib in combination with docetaxel in patients with advanced gastric adenocarcinoma harboring MEK signature, RAS mutation or amplification as a second line chemotherapy. Selumetinib will be administered orally 75mg twice a day continuously. Docetaxel will be administered as an IV infusion over 1 hour at 60 mg/m2 every 3 week of a 21 days schedule.

Official Title
-----------------
Phase II, 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

Conditions
-----------------
Gastric Adenocarcinoma

Intervention / Treatment
-----------------
* Drug: docetaxel plus selumetinib


Participation Criteria
=================
Eligibility Criteria
-----------------
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)

Ages Eligible for Study
-----------------
Minimum Age: 20 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: docetaxel+selumetinib<br>Selumetinib 75 mg will be administered orally twice a day with continuous dosing schedule Docetaxel 60 mg/m2 will be administered via intravenous access every 3 weeks. | Drug: docetaxel plus selumetinib<br>* Selumetinib will be administered orally 75mg twice a day continuously. Docetaxel will be administered as an IV infusion over 1 hour at 60 mg/m2 every 3 week of a 21 days schedule.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| response rate |  | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| duration of response |  | 24 weeks | 
| disease control rate |  | 8weeks | 
| overall survival |  | up to 100weeks | 
| progression-free survival |  | up to 100weeks | 
| safety assessed by safety( AEs/SAEs) | The following parameters will be recorded for each ECG: date and time of ECG, heart rate (beats/min), QT (ms), QTcB (ms), sinus rhythm (yes/no), and overall evaluation (normal/abnormal) | up to 100weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
gastric adenocarcinoma patients with low/high MEK signature,