Back to resultsPhase 1b/2 Study of Oprozomib in Combination With Sorafenib in Subjects With Advanced Hepatocellular Carcinoma
Primary Purpose
Advanced Hepatocellular Carcinoma
Status
Withdrawn
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Oprozomib
Sorafenib
Sponsored by
About this trial
This is an interventional treatment trial for Advanced Hepatocellular Carcinoma
Eligibility Criteria
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
Sites / Locations
- Lahey Hospital & Medical Center
- Rocky Mountain Cancer Centers
- University of Miami Hospital & Clinics
- The University of Chicago Medical Center
- The Ohio State University, Martha Morehouse Medical Plaza
- University of Wisconsin Comprehensive Cancer Center
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Oprozomib with Sorafenib
Sorafenib
Arm Description
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.
Phase 2: Study subjects who meet the entry criteria will receive sorafenib 400 mg twice a day (800 mg total daily dose).
Outcomes
Primary Outcome Measures
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).
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.
Secondary Outcome Measures
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).
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.
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.
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.
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.
Overall Survival (OS) - Phase 2
Overall survival (OS) is defined as time from randomization to death due to any cause.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02227914
Brief Title
Phase 1b/2 Study of Oprozomib in Combination With Sorafenib in Subjects With Advanced Hepatocellular Carcinoma
Official Title
Phase 1b/2 Study of Oprozomib in Combination With Sorafenib in Subjects With Advanced Hepatocellular Carcinoma
Study Type
Interventional
2. Study Status
Record Verification Date
April 2017
Overall Recruitment Status
Withdrawn
Why Stopped
Study stopped due to administrative reasons
Study Start Date
December 2014 (undefined)
Primary Completion Date
March 2015 (Actual)
Study Completion Date
March 2015 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Amgen
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Advanced Hepatocellular Carcinoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
0 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Oprozomib with Sorafenib
Arm Type
Experimental
Arm Description
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.
Arm Title
Sorafenib
Arm Type
Active Comparator
Arm Description
Phase 2:
Study subjects who meet the entry criteria will receive sorafenib 400 mg twice a day (800 mg total daily dose).
Intervention Type
Drug
Intervention Name(s)
Oprozomib
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Sorafenib
Intervention Description
Study subjects will receive sorafenib tablets twice a day for Days 1-28
Primary Outcome Measure Information:
Title
Maximum Tolerated Dose (MTD) - Phase 1b
Description
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 Frame
16 months
Title
Time To Progression (TTP) - Phase 2
Description
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.
Time Frame
16 months
Secondary Outcome Measure Information:
Title
Adverse Events (AEs) and Serious Adverse Events (SAEs) - Phase 1b & Phase 2
Description
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).
Time Frame
Until 30 days after the end of study (32 months)
Title
Pharmacokinetics (PK) parameters - Phase 1b
Description
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.
Time Frame
16 months
Title
Pharmacodynamic (PDn) parameter - Phase 1b
Description
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.
Time Frame
16 months
Title
Overall Response Rate (ORR) - Phase 2
Description
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.
Time Frame
16 months
Title
Progression-free Survival (PFS) - Phase 2
Description
Progression-free survival (PFS), defined as time from randomization to the earlier of PD or death due to any cause.
Time Frame
16 months
Title
Overall Survival (OS) - Phase 2
Description
Overall survival (OS) is defined as time from randomization to death due to any cause.
Time Frame
16 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
MD
Organizational Affiliation
Amgen
Official's Role
Study Director
Facility Information:
Facility Name
Lahey Hospital & Medical Center
City
Burlington
State/Province
California
Country
United States
Facility Name
Rocky Mountain Cancer Centers
City
Denver
State/Province
Colorado
Country
United States
Facility Name
University of Miami Hospital & Clinics
City
Miami
State/Province
Florida
Country
United States
Facility Name
The University of Chicago Medical Center
City
Chicago
State/Province
Illinois
Country
United States
Facility Name
The Ohio State University, Martha Morehouse Medical Plaza
City
Columbus
State/Province
Ohio
Country
United States
Facility Name
University of Wisconsin Comprehensive Cancer Center
City
Madison
State/Province
Wisconsin
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Phase 1b/2 Study of Oprozomib in Combination With Sorafenib in Subjects With Advanced Hepatocellular Carcinoma
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