Selumetinib (AZD6244, ARRY-142886) J-BTC Phase 1 Study
Condition: Inoperable Locally Advanced or Metastatic Biliary Tract Cancer
MeSH terms: Biliary Tract Neoplasms
Intervention: Cisplatin; Gemcitabine; Selumetinib
Intervention description: day1 and day8 at each cycle; day1 and day8 at each cycle; 25mg/day, 50mg/day and 75mg/day
Intervention MeSH terms: Gemcitabine
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 6.0
Sex: All
Minimum age: 20 Years
Maximum age: 130 Years
Healthy volunteers: No

Summary:

      The objective of this study is to investigate the safety and tolerability of oral dose of
      selumetinib in combination with chemotherapies (cisplatin and gemcitabine) in Japanese
      patients with advanced biliary tract cancer (BTC). In addition, the pharmacokinetic (PK)
      profile of selumetinib and chemotherapies will be investigated. Also, the Maximum tolerated
      dose (MTD) of selumetinib in combination with chemotherapies for Japanese BTC patients will
      be identified, if possible.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Provision of written informed consent

          2. Patients must be ≥ 20 years

          3. Histological or cytological confirmation of locally advanced or metastatic BTC (intra-
             or extra-hepatic, gallbladder or ampullary carcinoma)

          4. Patients who are eligible for treatment with standard dose of cisplatin/gemcitabine
             combination regimen

          5. World Health Organisation (WHO) performance status (PS) 0-1

          6. Evidence of post-menopausal status or negative urine/serum pregnancy test for
             nonmenopausal female patients Women will be considered postmenopausal if they are
             amenorrheic for 1 year or more without an alternative medical cause. The following
             age-specific requirements apply: i) Women under 50 years old would be consider
             postmenopausal if they have been amenorrheic for 1 year or more following cessation of
             exogenous hormonal treatments and with Luteinizing hormone (LH) and Follicle
             stimulating hormone (FSH) levels in the post-menopausal range.

        ii) Women over 50 years old would be consider postmenopausal if they have been amenorrheic
        for 1 year or more following cessation of all exogenous hormonal treatments,
        radiation-induced oophorectomy with last menses > 1 year ago, chemotherapy-induced
        menopause with >1 year interval since last menses. Or surgical sterilisation (bilateral
        oophorectomy or hysterectomy). 7. Male patients should be willing to use barrier
        contraception for a specified period 8. A lesion that can be accurately assessed at
        baseline by CT or magnetic resonance imaging (MRI) and is suitable for repeated assessment
        in accordance with RECIST 9. Patients must have a life expectancy ≥16 weeks 10. Patients
        who can remain in Hospital from Cycle 0 Day 1 up to at least the completion of Cycle 1 Day
        9 11. Patient is willing to provide fresh or archival tumour sample and biomarker blood
        sample.

        -

        Exclusion Criteria:

          1. Treatment with any of the following:

               -  Nitrosourea or mitomycin C within 6 weeks of the first dose of study treatment

               -  Any investigational agents or study drugs from a previous clinical study within 4
                  weeks of the first dose of study treatment

               -  Chemotherapy, immunotherapy or anticancer agents within 3 weeks of the first dose
                  of study treatment

               -  selumetinib(therefore, patients who have already participated in this study and
                  been taken selumetinib) or any other MEK(Mitogen-activated protein kinase kinase
                  or Mitogen-activated protein kinase (MAPK) / Extracellular signal-regulated
                  kinase (ERK) kinase) 1/2 inhibitor in past

               -  Cisplatin or gemcitabine in past

               -  Major surgery (excluding placement of vascular access) within 4 weeks of the
                  first dose of study treatment

               -  Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a
                  limited field of radiation for palliation within 2 weeks of the first dose of
                  study treatment

          2. With the exception of alopecia, any unresolved toxicities from prior therapy ≥Common
             Terminology Criteria for Adverse Events (CTCAE) Grade 2

          3. Spinal cord compression or brain metastases unless asymptomatic, treated and stable
             and not requiring steroids for at least 4 weeks prior to start of study treatment

          4. As judged by the investigator, any evidence of severe or uncontrolled systemic
             diseases, such as,

               -  active bleeding diatheses

               -  active infection including hepatitis B, hepatitis C and human immunodeficiency
                  virus (HIV)

               -  severe renal impairment, uncontrolled diabetes or renal transplant

               -  acute uncontrolled infection

               -  current unstable or uncompensated respiratory or cardiac disease

               -  peripheral vascular disease including diabetic vasculopathy Screening for chronic
                  conditions is not required

          5. Any of the following cardiac criteria:

               -  Any factors that increase the risk of QTc prolongation or risk of arrhythmic
                  events (eg, heart failure, hypokalaemia, congenital long QT syndrome, family
                  history of long QT syndrome or unexplained sudden death under 40 years of age or
                  mean resting corrected QT interval (QTc) > 470 msec)

               -  Uncontrolled hypertension (BP≥150/95 mmHg despite medical therapy)

               -  Acute coronary syndrome within 6 months prior to starting treatment

               -  Angina Canadian Cardiovascular Society Grade II-IV (despite medical therapy)

               -  Symptomatic heart failure (NYHA [New York Heart Association ] II-IV)

               -  Prior or current cardiomyopathy

               -  Baseline left ventricular ejection fraction (LVEF) <55% measured by
                  echocardiography or Multiple Gated Acquisition Scan (MUGA)

               -  Atrial fibrillation with a ventricular rate >100 bpm at rest

               -  Severe valvular heart disease

          6. Inadequate bone marrow reserve or organ function as demonstrated by any of the
             following laboratory values:

               -  Absolute neutrophil count < 1.5 x 109/L

               -  Platelet count < 100 x 109/L

               -  Haemoglobin < 90 g/L

               -  Alanine aminotransferase (ALT) > 2.5 times the upper limit of normal (ULN)

               -  Aspartate aminotransferase (AST) > 2.5 times ULN

               -  Total bilirubin > 1.5 times ULN

               -  Creatinine clearance < 50 mL/min (measured or calculated by Cockcroft and Gault
                  equation)

          7. Any of the following ophthalmological criteria:

               -  Current or past history of central serous retinopathy or retinal vein occlusion

               -  Intraocular pressure >21 mmHg

               -  Uncontrolled glaucoma (irrespective of intraocular pressure)

          8. Inadequate biliary drainage

          9. Symptomatic patients with interstitial pneumonitis or lung fibrosis confirmed by plain
             chest X-ray or chest CT

         10. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to
             swallow the formulated product or previous significant bowel resection that would
             preclude adequate absorption of selumetinib

         11. History of hypersensitivity to selumetinib or drugs with a similar chemical structure
             or class to selumetinib

         12. History of hypersensitivity to platinum and gemcitabine containing drugs

         13. Use of strong CYP(Cytochrome P450)1A2, CYP(Cytochrome P450)2C19 or CYP3A4 inducers
             and/or inhibitors (for example, but not limited to, fluvoxamine, fluconazole,
             ticlopidine, ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole,
             nelfinavir, ritonavir, saquinavir,telithromycin, voriconazole, grapefruit and seville
             orange or the juices of these fruits, rifampicin, rifabutin, phenytoin, carbamazepine,
             phenobarbital and St. John's Wort)

         14. Any contraindication to the combination chemotherapy as per local prescribing
             information

         15. Judgment by the investigators that the patient should not participate in the study if
             the patient is unlikely to comply with study procedures, restrictions and requirements

         16. Involvement in the planning and conduct of the study (applies to both AstraZeneca
             staff or staff at the study site).