Advanced Hepatocellular Carcinoma
Conditions
Brief summary
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.
Interventions
DRUGOprozomib
Study subjects will receive oprozomib tablets once a day on Days 1, 2, 8, 9, 15, 16, 22 and 23 of a 28 day cycle
DRUGSorafenib
Study subjects will receive sorafenib tablets twice a day for Days 1-28
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) - Phase 1b | 16 months | To determine the maximum tolerated dose (MTD) and identify the recommended Phase 2 dose (RP2D) of oprozomib in combination with sorafenib in subjects with advanced hepatocellular carcinoma (HCC). |
| Time To Progression (TTP) - Phase 2 | 16 months | To evaluate the efficacy of oprozomib in combination with sorafenib versus sorafenib alone in subjects with advanced HCC, as measured by time to progression (TTP), defined as time from randomization to disease progression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacodynamic (PDn) parameter - Phase 1b | 16 months | The extent of inactivation of proteasome activity in red blood cells (RBCs) after oprozomib dosing will be monitored as a PDn parameter. Pharmacodynamic inhibition will be listed by dose cohort, exposure, and response status. |
| Overall Response Rate (ORR) - Phase 2 | 16 months | To estimate the overall response rate (ORR), defined as the proportion of subjects with a best overall response of complete response (CR) and partial response (PR) for subjects receiving oprozomib in combination with sorafenib and for subjects receiving sorafenib alone. |
| Adverse Events (AEs) and Serious Adverse Events (SAEs) - Phase 1b & Phase 2 | Until 30 days after the end of study (32 months) | Number of patients that experience Adverse Events (AEs). Adverse Events (AEs) and Serious Adverse Events (SAEs) graded according to the NCI-CTCAE (Version 4.03). |
| Overall Survival (OS) - Phase 2 | 16 months | Overall survival (OS) is defined as time from randomization to death due to any cause. |
| Progression-free Survival (PFS) - Phase 2 | 16 months | Progression-free survival (PFS), defined as time from randomization to the earlier of PD or death due to any cause. |
| Pharmacokinetics (PK) parameters - Phase 1b | 16 months | Evaluate population pharmacokinetic (PK) parameters, including maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), area under the curve at the last measurable time point (AUC0-t), and area under the curve extrapolated to infinity (AUC0-inf) using noncompartmental methods. |
Countries
United States
Outcome results
None listed