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Trial of TRC105 and Sorafenib in Patients With HCC

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ClinicalTrials.gov Identifier: NCT02560779
Recruitment Status : Recruiting
First Posted : September 25, 2015
Last Update Posted : November 15, 2018
Sponsor:
Information provided by (Responsible Party):
Tracon Pharmaceuticals Inc.

Brief Summary:

The purpose of the phase 1b portion is to evaluate safety and tolerability and determine a recommended phase 2 dose for TRC105 when added to standard dose sorafenib in patients with hepatocellular carcinoma. Up to 18 patients will be treated.

The purpose of the phase 2 portion is to estimate the ORR of patients with hepatocellular carcinoma by RECIST 1.1. Up to 21 patients will be treated in phase 2.


Condition or disease Intervention/treatment Phase
Hepatocellular Carcinoma Drug: Carotuximab (TRC105) Drug: Sorafenib Phase 1 Phase 2

Detailed Description:
Sorafenib is an oral multikinase inhibitor targeting several receptor tyrosine kinases, including the VEGF receptor (VEGFR), implicated in pathologic angiogenesis, tumor growth, and cancer progression. Sorafenib is approved for the treatment of unresectable hepatocellular carcinoma (HCC). TRC105 is an antibody to endoglin, an important angiogenic target on proliferating endothelial cells that is distinct from VEGFR. TRC105 inhibits angiogenesis, tumor growth and metastases and complements the activity of bevacizumab and multi-kinase inhibitors that target the VEGFR in preclinical models. Together, the use of TRC105 with sorafenib may result in more effective angiogenesis inhibition and improved clinical efficacy over that seen with sorafenib alone.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 39 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open Label Phase 1B/2 Trial of TRC105 and Sorafenib in Patients With Hepatocellular Carcinoma (HCC)
Actual Study Start Date : November 2016
Estimated Primary Completion Date : November 2019
Estimated Study Completion Date : November 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Carotuximab (TRC105) and Sorafenib
Carotuximab (TRC105) in combination with standard dose Sorafenib.
Drug: Carotuximab (TRC105)
Bi-weekly iv TRC105 (15 mg/kg) will be given with 400mg sorafenib twice daily in the phase 1B portion of the study. Weekly iv TRC105 (10 mg/kg) will be given with 400mg sorafenib twice daily in the phase 2 portion of the study.
Other Name: Chimeric Antibody (TRC105) to CD105

Drug: Sorafenib
400 mg of sorafenib will be given twice daily.
Other Name: Nexavar




Primary Outcome Measures :
  1. Maximum Tolerated Dose of TRC105 in Combination with Sorafenib (Phase 1b). [ Time Frame: 4 months ]
    If 1 of 3 patients experiences DLT, the dose level will be expanded to 6 patients. The maximum tolerated dose (MTD) will have been exceeded if ≥ 33% of patients experience DLT at a given dose level. DLT will have occurred when a patient has 1 or more toxicity outlined in the protocol that is at least possibly related to TRC105 during the first 56 days (cycle 1 and 2).

  2. Estimate the ORR of patients with unresectable hepatocellular carcinoma given TRC105 and sorafenib (Phase 2) [ Time Frame: 4 months ]
    by RECIST 1.1


Secondary Outcome Measures :
  1. Preliminary evidence of antitumor activity when TRC105 is added to sorafenib will be assessed by Overall Response Rate (ORR) (Phase 1b). [ Time Frame: 4 months ]
    Patients will be followed for RECIST 1.1-defined disease progression and overall survival

  2. Preliminary evidence of antitumor activity when TRC105 is added to sorafenib will be assessed by progression-free survival (PFS) (Phase 1b). [ Time Frame: 4 months ]
    Patients will be followed for RECIST 1.1-defined disease progression and overall survival

  3. Preliminary evidence of antitumor activity when TRC105 is added to sorafenib will be assessed by overall survival (OS) (Phase 1b). [ Time Frame: 4 months ]
    Patients will be followed for RECIST 1.1-defined disease progression and overall survival

  4. Determine the frequency and severity of adverse events (Phase 1b & 2) [ Time Frame: 4 months ]
    As assessed by NCI CTCAE (Version 4.03)

  5. Pharmacokinetic profile of TRC105 when given with sorafenib (Phase 1b and Phase 2) [ Time Frame: 19 months ]
    Serum TRC105 concentrations will be measured using validated methods and assessed for potential correlations with response, PFS, survival, adverse events, baseline characteristics and immunogenicity using descriptive statistics and models as appropriate.

  6. Pharmacokinetic profile of Sorafenib when given with TRC105 (Phase 1b and Phase 2) [ Time Frame: 19 months ]
    Plasma sorafenib concentrations will be measured using validated methods and assessed for potential correlations with response, PFS, survival, adverse events, baseline characteristics and immunogenicity using descriptive statistics and models as appropriate.

  7. TRC105 immunogenicity as assessed by Anti-Product Antibody (APA). (Phase 1b and Phase 2) [ Time Frame: 19 months ]
    Anti-Product Antibody (APA) concentrations will be measured using validated ELISA methods. APA concentrations will be evaluated in the context of pharmacokinetic parameters and AE profiles.

  8. Changes in circulating angiogenic biomarkers following treatment with TRC105 and sorafenib. (Phase 1b and Phase 2) [ Time Frame: 19 months ]
    Angiogenic protein biomarker data for each patient who received at least one dose of TRC105 study drug will be evaluated and correlated with response data.

  9. Assess IGF-1-modified Child-Pugh score [1] and outcomes in patients with HCC treated with sorafenib and TRC105 (Phase 2) [ Time Frame: 19 months ]
    Prospective assessment

  10. Determine duration of response (Phase 2) [ Time Frame: 19 months ]
    by RECIST 1.1

  11. Estimate PFS, and determine overall survival (OS) (Phase 2) [ Time Frame: 19 months ]
    PFS will be estimated by RECIST 1.1 and patients will be followed for survival



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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. Patients must have confirmed hepatocellular carcinoma (HCC) by histopathology or imaging criteria according to AASLD guidelines.
  2. Patients must have disease that is not amenable to potentially curative resection or ablative techniques or that has recurred following ablative techniques. In addition, disease must not be amenable to transhepatic arterial chemoembolization (TACE) or must have progressed on TACE. Patients must not be candidates for liver transplantation.
  3. If liver cirrhosis is present, patient must have a Child-Pugh A or B (7 points) classification.
  4. No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission per investigators' clinical judgment.
  5. Measurable disease by RECIST 1.1 (Phase 2 only)
  6. Age of 18 years or older
  7. ECOG performance status ≤ 1
  8. Resolution of all acute adverse events resulting from prior cancer therapies to NCI CTCAE grade ≤ 1 or baseline
  9. Adequate organ function
  10. Willingness and ability to consent to participate in study
  11. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures
  12. Men who are sterile OR agree to use at least two forms of a reliable and highly effective method of birth control and to not donate sperm and for at least 180 days following last dose of TRC105 or sorafenib.
  13. Woman of non-child bearing potential due to surgical sterilization confirmed by medical history or menopause, OR woman of child bearing potential who test negative for pregnancy at time of enrollment based on serum pregnancy test and agree to use at least 2 forms of a reliable and highly effective method of birth control during the study and for at least 180 days after stopping TRC105 or sorafenib.

Exclusion Criteria:

  1. Prior anticancer systemic therapy
  2. Current treatment on another therapeutic clinical trial
  3. Prior radiation therapy within 28 days of starting the study treatment
  4. No major surgical procedure or significant traumatic injury within 6 weeks prior to study registration, and must have fully recovered from any such procedure.
  5. Proteinuria
  6. Uncontrolled chronic hypertension defined as systolic > 150 or diastolic > 90 despite optimal therapy.
  7. History of brain involvement with cancer, spinal cord compression, or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease.
  8. Angina, MI, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, arterial embolism, pulmonary embolism, PTCA or CABG within the past 6 months.
  9. Active bleeding or pathologic condition that carries a high risk of bleeding. No bleeding diathesis.
  10. Thrombolytic use within 10 days prior to first day of study therapy
  11. History of hemorrhage or hemoptysis (> ½ teaspoon bright red blood) within 3 months of starting study treatment
  12. Need for anticoagulation
  13. History of liver transplant
  14. History of bleeding esophageal varices in previous 6 months, which have not been adequately managed with banding or sclerotherapy.
  15. History of peptic ulcer disease within 3 months of treatment.
  16. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness
  17. Patients may not have received a strong CYP3A4 inducer within 12 days prior to registration
  18. Patients with known hypersensitivity to Chinese hamster ovary products or other recombinant human, chimeric, or humanized antibodies.
  19. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality
  20. Ascites or pleural effusion requiring intervention or that required intervention within the last month and has recurred
  21. Pericardial effusion (except trace effusion identified by echocardiogram)

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): NCT02560779


Contacts
Contact: Clinical Trials Information Clinicaltrials@traconpharma.com

Locations
United States, Alabama
University of Alabama Recruiting
Birmingham, Alabama, United States, 35294-3300
United States, California
City of Hope Withdrawn
Duarte, California, United States, 91010
United States, Maryland
National Cancer Institute Withdrawn
Bethesda, Maryland, United States, 20892
United States, Ohio
University Hospitals Recruiting
Cleveland, Ohio, United States, 44106
United States, Texas
MD Anderson Recruiting
Houston, Texas, United States, 77030-4009
Sponsors and Collaborators
Tracon Pharmaceuticals Inc.
Investigators
Study Director: Charles Theuer, MD, PhD Tracon Pharmaceuticals Inc.

Responsible Party: Tracon Pharmaceuticals Inc.
ClinicalTrials.gov Identifier: NCT02560779     History of Changes
Other Study ID Numbers: 105HCC101
First Posted: September 25, 2015    Key Record Dates
Last Update Posted: November 15, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Tracon Pharmaceuticals Inc.:
TRC105
CD105
Endoglin
Angiogenesis inhibitor
HCC
TKI
Tyrosine Kinase Inhibitor
Sorafenib
Nexavar

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
Antibodies, Monoclonal
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances
Physiological Effects of Drugs
Immunologic Factors