A Multicentre, Open Label, Phase 1 Trial in Japan of the Mitogen Activated Protein Extracellular Signal Regulated Kinase (MEK) Inhibitor Pimasertib Given Orally to Subjects With Solid Tumors as Monotherapy
Condition: Advanced Solid Tumors; Hepatocellular Carcinoma
MeSH terms: Carcinoma, Hepatocellular
Intervention: Pimasertib; Pimasertib; Pimasertib; Pimasertib; Pimasertib
Intervention description: Subjects with solid tumor will be administered with Pimasertib 30 mg twice a day (BID) in 21-day cycles until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject.; Subjects with solid tumor will be administered with Pimasertib 45 mg BID in 21-day cycles until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject.; Subjects with solid tumor will be administered with Pimasertib 60 mg BID in 21-day cycles until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject.; Subjects with HCC will be administered with Pimasertib 30 mg BID in 21-day cycles until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject.; Subjects with HCC will be administered with Pimasertib 45 mg BID in 21-day cycles until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject.
Intervention MeSH terms: Niacinamide
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 26.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Advanced solid tumors; Hepatocellular carcinoma; cancer, liver

Summary:

      This is a two-part trial. "Solid tumor" in this protocol means solid tumor excluding
      hepatocellular carcinoma (HCC).

      Part 1: Dose Escalation Phase in subjects with solid tumor (Cohort A) and HCC (Cohort B). The
      dose will be increased from 45 mg twice a day (BID) with 3+3 cohort method up to the
      recommended phase 2 dose (RP2D) of pimasertib established as single agent in the global
      studies for each arm independently.

      Part 2: The Maximum Tolerated Dose (MTD) defined in Part 1 will be confirmed in more subjects
      in Cohort A (N=18) and Cohort B (N=6) separately.

      Following the recommendation by the Safety Monitoring Committee, Cohort B was discontinued
      due to hepatocellular carcinoma (HCC) and there will be no further enrollment of subjects to
      this cohort. This decision is based upon review of safety and efficacy information.
    

Eligibility criteria:

        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 greater than or equal to (>=) 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.