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

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ClinicalTrials.gov Identifier: NCT03582618
Recruitment Status : Recruiting
First Posted : July 11, 2018
Last Update Posted : December 25, 2018
Sponsor:
Information provided by (Responsible Party):
TaiRx, Inc.

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Hepatocellular Carcinoma Advanced Cancer Drug: Sorafenib Drug: CVM-1118 Phase 2

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 : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2, Open-Label Study With Orally Administered CVM-1118 and Sorafenib in Subjects With Advanced Hepatocellular Carcinoma
Actual Study Start Date : July 12, 2018
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : June 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.

Drug: Sorafenib
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 Name: Nexavar

Drug: CVM-1118
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 Name: TRX-818




Primary Outcome Measures :
  1. Objective Response Rate (ORR) [ Time Frame: 24 weeks after the last subject starts CVM-1118 ]
    Assessment by modified RECIST criteria


Secondary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: 24 weeks after the last subject starts CVM-1118 and up to 1 year after the last-dose ]
    Overall survival (OS) is defined as time from first dose of study drug to death

  2. Progression-free survival (PFS) [ Time Frame: 24 weeks after the last subject starts CVM-1118 and up to 1 year after the last-dose ]
    Progression-free survival (PFS) is defined as time from the first dose of study drug to the time of progression or death

  3. Time to progression (TTP) [ Time Frame: 24 weeks after the last subject starts CVM-1118 and up to 1 year after the last-dose ]
    Time to progression (TTP) is defined as the time from the first dose of study drug to the time of progression

  4. Duration of response (DoR) [ Time Frame: 24 weeks after the last subject starts CVM-1118 and up to 1 year after the last-dose ]
    Duration of response (DoR) is defined as time from the first documentation of response to the time of progression

  5. Disease control rate (DCR) [ Time Frame: 24 weeks after the last subject starts CVM-1118 and up to 1 year after the last-dose ]
    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

  6. 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 ]
    Rate of Adverse event (AE) and Serious Adverse Event (SAE) are assessed using Common Terminology Criteria for Adverse Events v5 (CTCAE) criteria

  7. 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 ]
    A list of all laboratory normal ranges will also be provided. Values with CTCAE v4.03 Grade ≧ 3 will be identified with flags.

  8. 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 ]
    A list of all laboratory normal ranges will also be provided. Values with CTCAE v4.03 Grade ≧ 3 will be identified with flags.

  9. 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 ]
    a 12-lead (with a 10-second rhythm strip) tracing, with a capacity to calculate the standard intervals automatically, will be used.

  10. 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) ]
    Maximum Plasma Concentration [Cmax] of sorafenib, CVM-1118, and its metabolite CVM-1125 will be measured to see maximum exposure after CVM-1118 dosing

  11. 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) ]
    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

  12. Pharmacodynamics analysis for the relationship of Cmax and ORR [ Time Frame: During Cycle 1 and Cycle 2 (each cycle is 28 days) ]
    Relationship between Cmax and ORR will be evaluated

  13. Pharmacodynamics analysis for the relationship of AUC and ORR [ Time Frame: During Cycle 1 and Cycle 2 (each cycle is 28 days) ]
    Relationship between AUC and ORR will be evaluated

  14. Pharmacodynamics analysis for the relationship of Cmax and Adverse Event (AE) [ Time Frame: During Cycle 1 and Cycle 2 (each cycle is 28 days) ]
    Relationship between Cmax and AE will be evaluated

  15. Pharmacodynamics analysis for the relationship of AUC and Adverse Event (AE) [ Time Frame: During Cycle 1 and Cycle 2 (each cycle is 28 days) ]
    Relationship between AUC and AE will be evaluated



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03582618


Contacts
Contact: Kirsten Dorr, IMBA 858-642-0386 ext 209 kdorr@sciquus.com
Contact: Terri Melink, NP, MSN 858-642-0386 ext 206 tmelink@sciquus.com

Locations
United States, California
Innovative Clinical Research Institute Recruiting
Whittier, California, United States, 90603
United States, South Carolina
Charleston Hematology Oncology Associates Recruiting
Charleston, South Carolina, United States, 29403
Taiwan
National Cheng Kung University Hospital Recruiting
Tainan, Taiwan, 704
National Taiwan University Hospital Not yet recruiting
Taipei, Taiwan, 11502
Sponsors and Collaborators
TaiRx, Inc.

Responsible Party: TaiRx, Inc.
ClinicalTrials.gov Identifier: NCT03582618     History of Changes
Other Study ID Numbers: CVM-004
First Posted: July 11, 2018    Key Record Dates
Last Update Posted: December 25, 2018
Last Verified: December 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by TaiRx, Inc.:
Oncology
Hepatocellular Carcinoma (HCC)
Sorafenib
Hepatoma

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Sorafenib
Niacinamide
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances
Physiological Effects of Drugs