- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02227914
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.
Study Overview
Status
Conditions
Intervention / Treatment
Study Type
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
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California
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Burlington, California, United States
- Lahey Hospital & Medical Center
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Colorado
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Denver, Colorado, United States
- Rocky Mountain Cancer Centers
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Florida
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Miami, Florida, United States
- University of Miami Hospital & Clinics
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Illinois
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Chicago, Illinois, United States
- The University of Chicago Medical Center
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Ohio
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Columbus, Ohio, United States
- The Ohio State University, Martha Morehouse Medical Plaza
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Wisconsin
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Madison, Wisconsin, United States
- University of Wisconsin Comprehensive Cancer Center
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Oprozomib with Sorafenib
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. |
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
Study subjects will receive sorafenib tablets twice a day for Days 1-28
|
Active Comparator: Sorafenib
Phase 2: Study subjects who meet the entry criteria will receive sorafenib 400 mg twice a day (800 mg total daily dose). |
Study subjects will receive sorafenib tablets twice a day for Days 1-28
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Maximum Tolerated Dose (MTD) - Phase 1b
Time Frame: 16 months
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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).
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16 months
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Time To Progression (TTP) - Phase 2
Time Frame: 16 months
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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.
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16 months
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Adverse Events (AEs) and Serious Adverse Events (SAEs) - Phase 1b & Phase 2
Time Frame: Until 30 days after the end of study (32 months)
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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).
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Until 30 days after the end of study (32 months)
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Pharmacokinetics (PK) parameters - Phase 1b
Time Frame: 16 months
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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.
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16 months
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Pharmacodynamic (PDn) parameter - Phase 1b
Time Frame: 16 months
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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.
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16 months
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Overall Response Rate (ORR) - Phase 2
Time Frame: 16 months
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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.
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16 months
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Progression-free Survival (PFS) - Phase 2
Time Frame: 16 months
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Progression-free survival (PFS), defined as time from randomization to the earlier of PD or death due to any cause.
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16 months
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Overall Survival (OS) - Phase 2
Time Frame: 16 months
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Overall survival (OS) is defined as time from randomization to death due to any cause.
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16 months
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Collaborators and Investigators
Sponsor
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Digestive System Diseases
- Neoplasms by Histologic Type
- Neoplasms
- Neoplasms by Site
- Adenocarcinoma
- Neoplasms, Glandular and Epithelial
- Digestive System Neoplasms
- Liver Diseases
- Liver Neoplasms
- Carcinoma
- Carcinoma, Hepatocellular
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antineoplastic Agents
- Protein Kinase Inhibitors
- Sorafenib
Other Study ID Numbers
- OPZ011
- 2014-003149-85 (EudraCT Number)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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