CVM-1118 and Sorafenib Combination in Subjects With Advanced Hepatocellular Carcinoma

Study Overview
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Brief Summary
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CVM-1118 is a new small molecule chemical entity being developed as a potential anti-cancer therapeutic by TaiRx, Inc. CVM-1118 is a potent anti-cancer agent in numerous human cancer cell lines. The safety of administrating CVM-1118 on human is evaluated from the phase 1 study. The objectives of the phase 2 study is to further investigate the efficacy of CVM-1118 with sorafenib for subjects with advanced hepatoma.

Detailed Description
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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.

Official Title
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A Phase 2, Open-Label Study With Orally Administered CVM-1118 and Sorafenib in Subjects With Advanced Hepatocellular Carcinoma

Conditions
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Hepatocellular Carcinoma, Advanced Cancer

Intervention / Treatment
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* Drug: Sorafenib
* Drug: CVM-1118


Participation Criteria
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Eligibility Criteria
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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

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sorafenib + CVM-1118<br>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. | Drug: Sorafenib<br>* 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<br>* Other names: Nexavar;Drug: CVM-1118<br>* 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<br>* Other names: TRX-818;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Assessment by modified RECIST criteria | 24 weeks after the last subject starts CVM-1118 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Overall survival (OS) is defined as time from first dose of study drug to death | 24 weeks after the last subject starts CVM-1118 and up to 1 year after the last-dose | 
| Progression-free survival (PFS) | Progression-free survival (PFS) is defined as time from the first dose of study drug to the time of progression or death | 24 weeks after the last subject starts CVM-1118 and up to 1 year after the last-dose | 
| Time to progression (TTP) | Time to progression (TTP) is defined as the time from the first dose of study drug to the time of progression | 24 weeks after the last subject starts CVM-1118 and up to 1 year after the last-dose | 
| Duration of response (DoR) | Duration of response (DoR) is defined as time from the first documentation of response to the time of progression | 24 weeks after the last subject starts CVM-1118 and up to 1 year after the last-dose | 
| Disease control rate (DCR) | 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 | 24 weeks after the last subject starts CVM-1118 and up to 1 year after the last-dose | 
| Rate of Adverse event (AE) and Serious Adverse Event (SAE) | Rate of Adverse event (AE) and Serious Adverse Event (SAE) are assessed using Common Terminology Criteria for Adverse Events v5 (CTCAE) criteria | 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 | 
| Assessed the baseline and out-of-range vital signs_ body temperature, blood pressure, heart rate, and respiratory rate by CTCAE v4.03 | A list of all laboratory normal ranges will also be provided. Values with CTCAE v4.03 Grade ≧ 3 will be identified with flags. | 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 | 
| Assessed the baseline and out-of range laboratory parameters_hematology, chemistry, coagulation, and urinalysis by CTCAE v4.03 | A list of all laboratory normal ranges will also be provided. Values with CTCAE v4.03 Grade ≧ 3 will be identified with flags. | 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 | 
| Abnormalities in electrocardiography (ECG) | a 12-lead (with a 10-second rhythm strip) tracing, with a capacity to calculate the standard intervals automatically, will be used. | 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 | 
| Maximum Plasma Concentration [Cmax] of sorafenib, CVM-1118, and its metabolite CVM-1125 after CVM-1118 dosing | Maximum Plasma Concentration [Cmax] of sorafenib, CVM-1118, and its metabolite CVM-1125 will be measured to see maximum exposure after CVM-1118 dosing | During Cycle 1 and Cycle 2 (each cycle is 28 days) | 
| Area Under the Curve [AUC] of sorafenib, CVM-1118, and its metabolite CVM-1125 after CVM-1118 dosing | 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 | During Cycle 1 and Cycle 2 (each cycle is 28 days) | 
| Pharmacodynamics analysis for the relationship of Cmax and ORR | Relationship between Cmax and ORR will be evaluated | During Cycle 1 and Cycle 2 (each cycle is 28 days) | 
| Pharmacodynamics analysis for the relationship of AUC and ORR | Relationship between AUC and ORR will be evaluated | During Cycle 1 and Cycle 2 (each cycle is 28 days) | 
| Pharmacodynamics analysis for the relationship of Cmax and Adverse Event (AE) | Relationship between Cmax and AE will be evaluated | During Cycle 1 and Cycle 2 (each cycle is 28 days) | 
| Pharmacodynamics analysis for the relationship of AUC and Adverse Event (AE) | Relationship between AUC and AE will be evaluated | During Cycle 1 and Cycle 2 (each cycle is 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Oncology, Hepatocellular Carcinoma (HCC), Sorafenib, Hepatoma