A Multicentre, Open Label, Phase I Trial in Japan of the MEK Inhibitor Pimasertib Given Orally to Subjects With Solid Tumors as Monotherapy

Inclusion Criteria:

Cohort A: A histologically or cytologically confirmed diagnosis of advanced solid tumors which is either refractory after standard therapy for the disease or for which no effective standard therapy is available. Archived tumor tissue available or biopsy of tumor tissue needs to be performed.

Cohort B: A histologically or cytologically confirmed diagnosis of advanced hepatocellular carcinoma (HCC) which is either refractory after standard therapy for the disease or for which no effective standard therapy is available. Archived tumor tissue available or biopsy of tumor tissue needs to be performed. Subjects with Child Pugh A.

• Male or female Japanese, age ≥ 18 years.
• Subject has read and understands the informed consent form and is willing and able to give informed consent. The subject fully understands requirements of the trial and is willing to comply with all trial visits and assessments.
• Women of childbearing potential must have a negative blood pregnancy test at the screening visit.
• Female subjects of childbearing potential and male subjects with female partners of childbearing potential must be willing to avoid pregnancy by using an adequate method of contraception for 2 weeks prior to, during and four weeks after the last dose investigational medicinal product (IMP).
• Life expectancy of at least 3 months

Exclusion Criteria:

Hematological abnormality Cohort A: Hematological test abnormalities of Hemoglobin < 9.0 g/dL, Neutrophil count < 1.0*10^9/L and Platelet count < 100*10^9/L.

Cohort B: Hematological test abnormalities of Hemoglobin < 9.0 g/dL, Neutrophil count < 1.0*10^9/L, Platelet count < 75*10^9/L, subjects with hepatic encephalopathy

• Renal impairment as evidenced by serum creatinine > 1.5*upper limit of normal (ULN), and calculated creatinine clearance < 60 mL/min by Cockcroft-Gault formula.
• Liver function abnormality of Total Bilirubin > 1.5*ULN, or aspartate transaminase 9AST) or alkaline phosphatase (ALT)> 2.5*ULN. For subjects with HCC or liver involvement AST/ALT > 5*ULN.
• History of central nervous system (CNS) metastases, unless subject has been previously treated for CNS metastases
• History of difficulty swallowing, malabsorption or other chronic gastro-intestinal disease or conditions
• Eastern Cooperative Oncology Group Performance status (ECOG PS) greater than 1.
• Has received chemotherapy, immunotherapy, hormonal therapy, biologic therapy, or any other anticancer therapy (including any investigational agent) or surgical intervention within 28 days or 5 half lives for non-cytotoxics of registration.
• Baseline corrected QT interval on screening ECG (QTc) ≥ 480 ms or left ventricular ejection fraction (LVEF) < 40% on screening echocardiogram
• Cohort B: Subjects with hepatic encephalopathy, remarkable ascites and subjects with history of esophageal varices rupture within 6 months (subjects with symptom improvement after treatment are eligible)
• Other serious illness or medical conditions.
• Retinal degenerative disease.
• Previous treatment with MEK inhibitors.
• Legal incapacity or limited legal capacity.