- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03582618
CVM-1118 and Sorafenib Combination in Subjects With Advanced Hepatocellular Carcinoma
A Phase 2, Open-Label Study With Orally Administered CVM-1118 and Sorafenib in Subjects With Advanced Hepatocellular Carcinoma
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Sorafenib is a multi-kinase inhibitor that inhibits tumor growth and angiogenesis. Although sorafenib is the first-line treatment of advanced hepatocellular cancer (HCC), patients developing resistance to sorafenib have been reported.
To meet the medical need, TaiRx, Inc. develops a new small molecule drug, CVM-1118 targeting the formation of vasculogenic mimicry (VM). VM has been associated with tumor metastasis and poor clinical outcomes. VM is reported to be particularly active in tumor under hypoxia state when patients are treated with the potent vascular endothelial growth factor (VEGF) inhibitor like sorafenib. Hence, the ability of inhibiting the VM network make CVM-1118 a potential good combination drug with sorafenib for advanced diseases.
The safety profile of CVM-1118 dosing has been established in the phase 1 study. The analysis of metabolism pathways further showed that the potential of CVM-1118 and sorafenib drug-drug interactions are very low.
Based on the mechanism of actions and the safety analysis of sorafenib and CVM-1118, the design of phase 2 trial with the combination therapy might have great potential for the patients with advanced HCC.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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Tainan, Taiwan, 704
- National Cheng Kung University Hospital
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Taipei, Taiwan, 11502
- National Taiwan University Hospital
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South Carolina
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Charleston, South Carolina, United States, 29403
- Charleston Hematology Oncology Associates
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Signed, informed consent
- Age 18 or older (for all treatment locations with exception of Taiwan), or age 20 or older (Taiwan only)
- Pathologically or cytologically-confirmed, advanced-stage hepatocellular carcinoma without prior systemic treatment except for prior immunotherapy and Child-Pugh liver function class A appropriate for treatment with sorafenib
- Measurable disease according to modified Response Evaluation Criteria in Solid Tumors criteria (mRECIST)
- Eastern Cooperative Oncology Group (ECOG) performance status: 0 to 1
Adequate laboratory parameters including:
- Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤ 3.0 x upper limit of normal (ULN), or AST and ALT ≤ 5.0 x ULN if liver function abnormalities are due to underlying malignancy
- Total serum bilirubin ≤ 2.0 x ULN (except for subjects with documented Gilbert's syndrome who have a limit of ≤ 3.0 x ULN)
- Absolute neutrophil count (ANC):1500/µL
- Platelets: 90,000/µL
- Hemoglobin: 9.0 g/dL
- Serum creatinine ≤ 2.0 x ULN or creatinine clearance of ≥ 50 mL/min
- Serum albumin ≥ 3.0 g/dL
- International normalized ratio (INR) ≤ 1.4
- Prothrombin Time (PT)/ Activated Partial Thromboplastin Time (aPTT) ≤ 1.2 x ULN
- QTc interval (using Fridericia correction) of ≤ 470 msec (QTc interval may be derived from up to 3 separate EKGs performed at least 5 minutes apart)
- Willingness to participate in collection of pharmacokinetic and other exploratory blood collection as defined in the protocol
- Willingness to use adequate contraception throughout study and for a period of 3 months after last dose of CVM-1118
Exclusion Criteria:
- Major surgery (other than diagnostic surgery) or radiation therapy within 28 days of starting study treatment
- Prior systemic immunotherapy for hepatoma within 28 days of starting study treatment
- Systemic anticancer therapy (e.g., chemotherapy, hormonal, investigational, biological therapies) within 28 days (or fewer than 5 half-lives, whichever is shorter) of starting study treatment except for ongoing hormonal therapy administered for control of a second cancer (e.g., breast or prostate cancer)
- Receipt of a CYP3A4 inducer less than 28 days or 5 half-lives of the CYP3A4 inducer prior to the first day of sorafenib administration
- Other known active cancer(s) likely to require treatment in the next two (2) years or likely to impact the assessment of any study endpoints
- Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy (e.g., subjects with known HBV or HCV infections controlled on antivirals are allowed)
- Known Central Nervous system (CNS) metastases unless appropriately treated and neurologically stable for ≥ 4 weeks off steroids
- Pregnant or currently breast-feeding
- Known HIV-positive
- Patients with impaired gastrointestinal (GI) diseases that may significantly alter the absorption of oral medications
- Psychiatric illness/social situations that would interfere with compliance with study requirements
- History of clinically significant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure (New York Heart Association classification ≥ 2), unstable angina, poorly controlled arrhythmias, myocardial infarction within 6 months of study entry
- Other severe acute or chronic medical or psychiatric conditions or laboratory abnormalities that would impart, in the judgement of the PI and/or Sponsor, excess risk associated with study participation or study drug administration, which would make the subject inappropriate for entry into this study
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Sorafenib + CVM-1118
Cycle 0 (at least 3 weeks): sorafenib tolerability assessment period (sorafenib alone) 400mg BID daily (starting dose); The subject will be assessed for the need for a dose reduction in sorafenib during this period. Cycle 1+ (28-day cycles): combination period (sorafenib+CVM-1118) Tolerable dose of sorafenib and CVM-1118 150 (starting dose) or 200 mg BID will be administered continuously for a 28-day cycle until progressive disease, unacceptable toxicity, or consent withdrawal. |
Sorafenib will be administered orally at a starting dose of 400mg BID daily and the necessity of dose reduction will be assessed during sorafenib tolerability assessment period
Other Names:
CVM-1118 will be administered orally at 150 mg BID or 200 mg BID daily and combined with the tolerable dose of sorafenib for a 28-day cycle
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Objective Response Rate (ORR)
Time Frame: 24 weeks after the last subject starts CVM-1118
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Assessment by modified RECIST criteria
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24 weeks after the last subject starts CVM-1118
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Overall survival (OS)
Time Frame: 24 weeks after the last subject starts CVM-1118 and up to 1 year after the last-dose
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Overall survival (OS) is defined as time from first dose of study drug to death
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24 weeks after the last subject starts CVM-1118 and up to 1 year after the last-dose
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Progression-free survival (PFS)
Time Frame: 24 weeks after the last subject starts CVM-1118 and up to 1 year after the last-dose
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Progression-free survival (PFS) is defined as time from the first dose of study drug to the time of progression or death
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24 weeks after the last subject starts CVM-1118 and up to 1 year after the last-dose
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Time to progression (TTP)
Time Frame: 24 weeks after the last subject starts CVM-1118 and up to 1 year after the last-dose
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Time to progression (TTP) is defined as the time from the first dose of study drug to the time of progression
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24 weeks after the last subject starts CVM-1118 and up to 1 year after the last-dose
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Duration of response (DoR)
Time Frame: 24 weeks after the last subject starts CVM-1118 and up to 1 year after the last-dose
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Duration of response (DoR) is defined as time from the first documentation of response to the time of progression
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24 weeks after the last subject starts CVM-1118 and up to 1 year after the last-dose
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Disease control rate (DCR)
Time Frame: 24 weeks after the last subject starts CVM-1118 and up to 1 year after the last-dose
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Disease control rate (DCR) is defined as the sum of complete response (CR), partial response (PR), and stable disease rate (SD) as assessed by modified RECIST criteria
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24 weeks after the last subject starts CVM-1118 and up to 1 year after the last-dose
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Rate of Adverse event (AE) and Serious Adverse Event (SAE)
Time Frame: During the course of trial and within 28 days following the last dose of CVM-1118 or prior to the start of new treatment, whichever comes first
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Rate of Adverse event (AE) and Serious Adverse Event (SAE) are assessed using Common Terminology Criteria for Adverse Events v5 (CTCAE) criteria
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During the course of trial and within 28 days following the last dose of CVM-1118 or prior to the start of new treatment, whichever comes first
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Assessed the baseline and out-of-range vital signs_ body temperature, blood pressure, heart rate, and respiratory rate by CTCAE v4.03
Time Frame: During the course of trial and within 28 days following the last dose of CVM-1118 or prior to the start of new treatment, whichever comes first
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A list of all laboratory normal ranges will also be provided.
Values with CTCAE v4.03 Grade ≧ 3 will be identified with flags.
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During the course of trial and within 28 days following the last dose of CVM-1118 or prior to the start of new treatment, whichever comes first
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Assessed the baseline and out-of range laboratory parameters_hematology, chemistry, coagulation, and urinalysis by CTCAE v4.03
Time Frame: During the course of trial and within 28 days following the last dose of CVM-1118 or prior to the start of new treatment, whichever comes first
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A list of all laboratory normal ranges will also be provided.
Values with CTCAE v4.03 Grade ≧ 3 will be identified with flags.
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During the course of trial and within 28 days following the last dose of CVM-1118 or prior to the start of new treatment, whichever comes first
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Abnormalities in electrocardiography (ECG)
Time Frame: During the course of trial and within 28 days following the last dose of CVM-1118 or prior to the start of new treatment, whichever comes first
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a 12-lead (with a 10-second rhythm strip) tracing, with a capacity to calculate the standard intervals automatically, will be used.
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During the course of trial and within 28 days following the last dose of CVM-1118 or prior to the start of new treatment, whichever comes first
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Maximum Plasma Concentration [Cmax] of sorafenib, CVM-1118, and its metabolite CVM-1125 after CVM-1118 dosing
Time Frame: During Cycle 1 and Cycle 2 (each cycle is 28 days)
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Maximum Plasma Concentration [Cmax] of sorafenib, CVM-1118, and its metabolite CVM-1125 will be measured to see maximum exposure after CVM-1118 dosing
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During Cycle 1 and Cycle 2 (each cycle is 28 days)
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Area Under the Curve [AUC] of sorafenib, CVM-1118, and its metabolite CVM-1125 after CVM-1118 dosing
Time Frame: During Cycle 1 and Cycle 2 (each cycle is 28 days)
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Area Under the Curve [AUC] of sorafenib, CVM-1118, and its metabolite CVM-1125 will be measured to see drug exposure after CVM-1118 dosing
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During Cycle 1 and Cycle 2 (each cycle is 28 days)
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Pharmacodynamics analysis for the relationship of Cmax and ORR
Time Frame: During Cycle 1 and Cycle 2 (each cycle is 28 days)
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Relationship between Cmax and ORR will be evaluated
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During Cycle 1 and Cycle 2 (each cycle is 28 days)
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Pharmacodynamics analysis for the relationship of AUC and ORR
Time Frame: During Cycle 1 and Cycle 2 (each cycle is 28 days)
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Relationship between AUC and ORR will be evaluated
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During Cycle 1 and Cycle 2 (each cycle is 28 days)
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Pharmacodynamics analysis for the relationship of Cmax and Adverse Event (AE)
Time Frame: During Cycle 1 and Cycle 2 (each cycle is 28 days)
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Relationship between Cmax and AE will be evaluated
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During Cycle 1 and Cycle 2 (each cycle is 28 days)
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Pharmacodynamics analysis for the relationship of AUC and Adverse Event (AE)
Time Frame: During Cycle 1 and Cycle 2 (each cycle is 28 days)
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Relationship between AUC and AE will be evaluated
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During Cycle 1 and Cycle 2 (each cycle is 28 days)
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Collaborators and Investigators
Sponsor
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimate)
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
- CVM-004
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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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