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

Study Overview
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Brief Summary
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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.

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

Conditions
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Advanced Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: Oprozomib
* Drug: Sorafenib


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Patients with advanced HCC 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 Cirrhotic status of Child-Pugh Class A only Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 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: 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) Renal failure requiring hemo- or peritoneal dialysis History of cardiac disease Active clinically serious infections. Hepatitis B is allowed if no active replication is present. Hepatitis C is allowed if no antiviral treatment is required Known history of human immunodeficiency virus (HIV) infection Known history or symptomatic metastatic brain or meningeal tumors 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 History of organ allograft Known or suspected allergy to the investigational agent or any agent given in association with this trial 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 Uncontrolled diabetes Any contraindication to oral hydration (e.g., preexisting cardiac impairment or fluid restriction) Uncontrolled ascites Pleural effusion or ascites that causes respiratory compromise (NCI-CTCAE ≥ Grade 2 dyspnea). Women who are pregnant and/or breastfeeding Prior use of any systemic anticancer chemotherapy for HCC Prior use of systemic investigational agents for HCC Concomitant treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors Known hypersensitivity or intolerance to dexamethasone or 5-HT3 antagonist

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oprozomib with Sorafenib<br>Phase 1b: Oprozomib doses will be escalated in sequential groups of at least 2 subjects. Study subjects will receive oprozomib at dose levels of 90, 120, 150, 180, 210, or 240 mg + sorafenib to reach the dose levels of 600 or 800 mg total daily dose until the maximum tolerated dose (MTD) is reached. Phase 2: Study subjects who meet the entry criteria will receive oprozomib + sorafenib at the RP2D (recommended Phase 2 dose) established in the Phase 1b portion of the study. | Drug: Oprozomib<br>* 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<br>Drug: Sorafenib<br>* Study subjects will receive sorafenib tablets twice a day for Days 1-28<br>|
| Active Comparator: Sorafenib<br>Phase 2: Study subjects who meet the entry criteria will receive sorafenib 400 mg twice a day (800 mg total daily dose). | Drug: Sorafenib<br>* Study subjects will receive sorafenib tablets twice a day for Days 1-28<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) - Phase 1b | 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). | 16 months | 
| Time To Progression (TTP) - Phase 2 | 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. | 16 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events (AEs) and Serious Adverse Events (SAEs) - Phase 1b & Phase 2 | 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). | Until 30 days after the end of study (32 months) | 
| Pharmacokinetics (PK) parameters - Phase 1b | 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. | 16 months | 
| Pharmacodynamic (PDn) parameter - Phase 1b | 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. | 16 months | 
| Overall Response Rate (ORR) - Phase 2 | 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. | 16 months | 
| Progression-free Survival (PFS) - Phase 2 | Progression-free survival (PFS), defined as time from randomization to the earlier of PD or death due to any cause. | 16 months | 
| Overall Survival (OS) - Phase 2 | Overall survival (OS) is defined as time from randomization to death due to any cause. | 16 months |