Phase 1b/2 Study of Oprozomib in Combination With Sorafenib in Subjects With Advanced Hepatocellular Carcinoma

The purpose of Phase 1b of the study is to determine the maximum tolerated dose, pharmacokinetics (PK) and pharmacodynamics (PDn) and assess the safety, tolerability and activity of oprozomib in combination with sorafenib in subjects with advanced hepatocellular carcinoma (HCC).

The purpose of Phase 2 of the study is to evaluate the efficacy of oprozomib in combination with sorafenib versus sorafenib alone and to compare the key outcome measures for subjects with advanced HCC.


Eligibility Criteria:
Key Inclusion Criteria:

1. Patients with advanced HCC
2. For the Phase 2 portion of the study, at least 1 measurable tumor lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, which has not been previously treated with local therapy
3. Cirrhotic status of Child-Pugh Class A only
4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
5. The following laboratory parameters:

   * Albumin ≥ 2.8 g/dL
   * Platelet count ≥ 60,000/mm3
   * Absolute neutrophil count (ANC) ≥ 1500/mm3
   * Hemoglobin ≥ 8.5 g/dL
   * Total bilirubin ≤ 3 mg/dL
   * Alanine aminotransaminase (ALT) and aspartate aminotransferase (AST) ≤ 3 times upper limit of normal (ULN)
   * Amylase and lipase ≤ 1.5 times ULN
   * Calculated or measured creatinine clearance (CrCl) ≥ 30 mL/min
   * Prothrombin time (PT)-international normalized ratio (INR) ≤ 2.3 or PT ≤ 6 seconds above control

Key Exclusion Criteria:

1. Previous or concurrent cancer that is distinct in primary site or histology from HCC, EXCEPT cervical and breast carcinoma in situ, adequately treated basal cell or squamous cell carcinoma of the skin, or superficial bladder tumors (Ta, Tis \& T1)
2. Renal failure requiring hemo- or peritoneal dialysis
3. History of cardiac disease
4. Active clinically serious infections. Hepatitis B is allowed if no active replication is present. Hepatitis C is allowed if no antiviral treatment is required
5. Known history of human immunodeficiency virus (HIV) infection
6. Known history or symptomatic metastatic brain or meningeal tumors
7. Clinically significant gastrointestinal (GI) bleeding, serious nonhealing wound and ulcer within 3 months prior to study entry, or bone fracture within 30 days prior to study entry
8. History of organ allograft
9. Known or suspected allergy to the investigational agent or any agent given in association with this trial
10. Inability to swallow medication, inability or unwillingness to comply with the drug administration requirements, or GI condition that could interfere with the oral absorption or tolerance of treatment
11. Uncontrolled diabetes
12. Any contraindication to oral hydration (e.g., preexisting cardiac impairment or fluid restriction)
13. Uncontrolled ascites
14. Pleural effusion or ascites that causes respiratory compromise (NCI-CTCAE ≥ Grade 2 dyspnea).
15. Women who are pregnant and/or breastfeeding
16. Prior use of any systemic anticancer chemotherapy for HCC
17. Prior use of systemic investigational agents for HCC
18. Concomitant treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors
19. Known hypersensitivity or intolerance to dexamethasone or 5-HT3 antagonist