Trial of TRC105 and Sorafenib in Patients With HCC

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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An Open Label Phase 1B/2 Trial of TRC105 and Sorafenib in Patients With Hepatocellular Carcinoma (HCC)

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: Carotuximab (TRC105)
* Drug: Sorafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have confirmed hepatocellular carcinoma (HCC) by histopathology or imaging criteria according to AASLD guidelines. 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. If liver cirrhosis is present, patient must have a Child-Pugh A or B (7 points) classification. 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. Measurable disease by RECIST 1.1 (Phase 2 only) Age of 18 years or older ECOG performance status ≤ 1 Resolution of all acute adverse events resulting from prior cancer therapies to NCI CTCAE grade ≤ 1 or baseline Adequate organ function Willingness and ability to consent to participate in study Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures 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. 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: Prior anticancer systemic therapy Current treatment on another therapeutic clinical trial Prior radiation therapy within 28 days of starting the study treatment No major surgical procedure or significant traumatic injury within 6 weeks prior to study registration, and must have fully recovered from any such procedure. Proteinuria Uncontrolled chronic hypertension defined as systolic > 150 or diastolic > 90 despite optimal therapy. History of brain involvement with cancer, spinal cord compression, or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease. Angina, MI, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, arterial embolism, pulmonary embolism, PTCA or CABG within the past 6 months. Active bleeding or pathologic condition that carries a high risk of bleeding. No bleeding diathesis. Thrombolytic use within 10 days prior to first day of study therapy History of hemorrhage or hemoptysis (> ½ teaspoon bright red blood) within 3 months of starting study treatment Need for anticoagulation History of liver transplant History of bleeding esophageal varices in previous 6 months, which have not been adequately managed with banding or sclerotherapy. History of peptic ulcer disease within 3 months of treatment. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness Patients may not have received a strong CYP3A4 inducer within 12 days prior to registration Patients with known hypersensitivity to Chinese hamster ovary products or other recombinant human, chimeric, or humanized antibodies. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality Ascites or pleural effusion requiring intervention or that required intervention within the last month and has recurred Pericardial effusion (except trace effusion identified by echocardiogram)

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: Carotuximab (TRC105) and Sorafenib<br>Carotuximab (TRC105) in combination with standard dose Sorafenib. | Drug: Carotuximab (TRC105)<br>* 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.<br>* Other names: Chimeric Antibody (TRC105) to CD105;Drug: Sorafenib<br>* 400 mg of sorafenib will be given twice daily.<br>* Other names: Nexavar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Who Experience Dose Limiting Toxicities by Dose Level | If 1 of 3 patients experienced a DLT, the dose level was expanded to 6 patients. The maximum tolerated dose (MTD) would have been exceeded if ≥ 33% of patients experience DLT at a given dose level. DLT occurred when a patient had 1 or more toxicities outlined in the protocol that was considered at least possibly related to TRC105 during the first 4 months of participation in the trial. The number of DLTs by dose cohort have been presented. | 4 months | 
| Overall Response Rate (ORR) | Number of patients with a response (PR or CR) are included by dose level. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Patients must have had a screening scan and at least 1 on study scan to be eligible for RECIST 1.1 evaluation. | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic Profile of TRC105 When Given With Sorafenib | Steady state mean trough serum concentrations by dose level of TRC105 after 5 weeks of dosing were measured using validated methods after 5 weeks of dosing. | 5 weeks | 
| TRC105 Immunogenicity as Assessed by Anti-Product Antibody (APA) | Number of patients who tested positive for antibodies to TRC105 by dose level. Anti-Product Antibody (APA) concentrations were measured using validated ELISA methods. | 19 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Endoglin, TRC105, CD105, Angiogenesis inhibitor, HCC, TKI, Tyrosine Kinase Inhibitor, Sorafenib, Nexavar