OUTLINE: This is a multi-center trial.~The phase 1 dose escalation trial will evaluate MLN0128 in a standard 3+3 successive cohort design to identify the highest planned dose level. Phase II trial subjects will be 1:1 randomized to receive either MLN0128 (investigational arm) or sorafenib (control arm).~PHASE I DOSE ESCALATION INVESTIGATIONAL TREATMENT:~Cohort 1 (dose level +1) will consist of 3-6 evaluable patients who will receive MLN0128 15mg on day 1 of the 28-day cycle.~Cohort 2 (dose level +2) will consist of 3-6 evaluable patients who will receive MLN0128 20mg on day 1 of the 28-day cycle.~Cohort 3 (dose level +3) will consist of 3-6 evaluable patients who will receive MLN0128 30mg on day 1 of the 28-day cycle.~Subjects will be evaluated for dose limiting toxicity (DLT) in the first 28 days of treatment (1 cycle). However, decisions to move to next dose escalation cohort will not be made until all subjects complete 2 cycles of therapy at a given dose. There will be no further dose escalation beyond dose level +3.~PHASE II INVESTIGATIONAL TREATMENT:~Randomization will take place following completion of the screening evaluations and eligibility assessments. Stratification factors will be employed during randomization to minimize between-arm assignment imbalance.~1 Child-Pugh score 5-6~2 Child-Pugh score 7~Within the strata, subjects will be randomly assigned with equal probability to either the investigational arm (Arm A: MLN0128) or the control arm (Arm B: sorafenib).~Arm A: MLN0128 will be administered orally at the recommended phase II dose (RP2D) once weekly.~Arm B: Sorafenib will be administered at 400mg PO BID daily, with dose adjustment per standard of care.~A new treatment cycle (1 cycle = 28 days) will only be initiated when all of the following conditions are met:~Absolute neutrophil count (ANC) ≥ 1.5 x 10*9/L~Platelets ≥ 50 x 10*9/L~Non-hematologic treatment related toxicities have improved to grade 1 or resolved per Common Terminology Criteria for Adverse Events v4.0 (CTCAE)~Treatment may continue until progression, unacceptable toxicity, or withdrawal from study.~Estimated Life Expectancy: ≥ 3 months~Subjects must have adequate organ function, as specified below, within 7 days before study registration:~Bone marrow reserve consistent with:~Absolute neutrophil count (ANC) ≥ 1.5 x 10*9/L~Platelet count ≥ 50 x 10*9/L~Hemoglobin ≥ 9 g/dL~Hepatic:~Total bilirubin ≤ 2 x upper limit of normal (ULN)~Transaminases (aspartate aminotransferase (AST), serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT), serum glutamic pyruvic transaminase (SGPT) ≤ 5 x ULN~Renal:~Creatinine clearance ≥50 mL/min based either on Cockcroft-Gault estimate or based on urine collection (12 or 24 hour)~Metabolic:~Fasting serum glucose (≤ 130 mg/dL) and fasting triglycerides ≤ 300 mg/dL.~Glycosylated hemoglobin (HbA1c) <7.0%
This is an open label, multi-center, randomized phase I/II study of MLN0128 versus standard sorafenib. Eligible subjects in the phase I trial will receive MLN0128 in escalating doses. Eligible subjects in the phase II trial will be 1:1 randomized to either the MLN0128 arm or the sorafenib arm.