Selumetinib (AZD6244, ARRY-142886) J-BTC Phase 1 study

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).