Clinical Trials /

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

NCT03582618

Description:

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.

Related Conditions:
  • Hepatocellular Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: CVM-004
  • NCT ID: NCT03582618

Conditions

  • Hepatocellular Carcinoma
  • Advanced Cancer

Interventions

DrugSynonymsArms
SorafenibNexavarSorafenib + CVM-1118
CVM-1118TRX-818Sorafenib + CVM-1118

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Sorafenib + CVM-1118ExperimentalCycle 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
  • CVM-1118

Eligibility Criteria

        Inclusion Criteria:

          1. Signed, informed consent

          2. Age 18 or older (for all treatment locations with exception of Taiwan), or age 20 or
             older (Taiwan only)

          3. Pathologically or cytologically-confirmed, advanced-stage hepatocellular carcinoma
             without prior systemic treatment and Child-Pugh liver function class A appropriate for
             treatment with sorafenib

          4. Measurable disease according to modified Response Evaluation Criteria in Solid Tumors
             criteria (mRECIST)

          5. Eastern Cooperative Oncology Group (ECOG) performance status: 0 to 1

          6. Adequate laboratory parameters including:

               1. 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

               2. Total serum bilirubin ≤ 2.0 x ULN (except for subjects with documented Gilbert's
                  syndrome who have a limit of ≤ 3.0 x ULN)

               3. Absolute neutrophil count (ANC):1500/µL

               4. Platelets: 90,000/µL

               5. Hemoglobin: 9.0 g/dL

               6. Serum creatinine ≤ 2.0 x ULN or creatinine clearance of ≥ 50 mL/min

               7. Serum albumin ≥ 3.0 g/dL

               8. International normalized ratio (INR) ≤ 1.4

               9. Prothrombin Time (PT)/ Activated Partial Thromboplastin Time (aPTT) ≤ 1.2 x ULN

          7. 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)

          8. Willingness to participate in collection of pharmacokinetic and other exploratory
             blood collection as defined in the protocol

          9. Willingness to use adequate contraception throughout study and for a period of 3
             months after last dose of CVM-1118

        Exclusion Criteria:

          1. Major surgery (other than diagnostic surgery) or radiation therapy within 28 days of
             starting study treatment

          2. 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)

          3. 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

          4. 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

          5. 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)

          6. Known Central Nervous system (CNS) metastases unless appropriately treated and
             neurologically stable for ≥ 4 weeks off steroids

          7. Pregnant or currently breast-feeding

          8. Known HIV-positive

          9. Patients with impaired gastrointestinal (GI) diseases that may significantly alter the
             absorption of oral medications

         10. Psychiatric illness/social situations that would interfere with compliance with study
             requirements

         11. 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

         12. 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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

Secondary Outcome Measures

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

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:TaiRx, Inc.

Trial Keywords

  • Oncology
  • Hepatocellular Carcinoma (HCC)
  • Sorafenib
  • Hepatoma

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