Study of Bavituximab and Sorafenib In Patients With Advanced Liver Cancer

Study Overview
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Brief Summary
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This is a non-randomized, open-label, single-institution phase I/II therapeutic trial of bavituximab and sorafenib in patients with advanced hepatocellular carcinoma (HCC). This study will be activated at the UT Southwestern Medical Center, comprised of The Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Hospitals-St. Paul and Parkland Memorial Hospital System. Advanced HCC is defined as disease that is not amenable to surgical resection or orthotopic liver transplantation or is metastatic in nature.

Detailed Description
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The investigators are looking for men or women aged 18 years or older with hepatocellular carcinoma not suitable for surgical resection or hepatic transplantation. Prior locoregional therapy including but not limited to transarterial chemoembolization (TACE), radiofrequency ablation (RFA) or ethanol injection is allowed as long as the treatment was 4 weeks previous. Patients must be Child-Pugh A with no previous treatment with sorafenib or other vascular endothelial growth factor (VEGF) inhibitors.

Official Title
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A Phase I/II Study of Bavituximab and Sorafenib In Patients With Advanced Hepatocellular Carcinoma

Conditions
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Hepatocellular Carcinoma, Liver Cancer

Intervention / Treatment
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* Drug: bavituximab (0.3 mg/kg) and sorafenib
* Drug: bavituximab (1.0 mg/kg ) and sorafenib
* Drug: bavituximab (3.0 mg/kg) and sorafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have a diagnosis of hepatocellular carcinoma by at least one criterion listed below: Histologically confirmed. MRI or CT consistent with liver cirrhosis and at least one solid liver lesion >2 cm with early enhancement and delayed enhancement washout regardless of AFP. AFP >400 ng/ml and evidence of at least one solid liver lesion >2 cm regardless of specific imaging characteristics on CT or MRI. Locally advanced or metastatic disease. Patients with locally advanced disease must have disease deemed to be unresectable or not eligible for hepatic transplantation. Determination will occur in the weekly GI DMT meeting by surgical oncologists and transplant surgeons. Measurable disease, as defined as lesions that can accurately be measured in at least one dimension (longest diameter to be measured) according to Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) at least 2 cm with conventional techniques or at least 1 cm with spiral computed tomography. Child-Pugh Score A. Age ≥ 18 years. Eastern Cooperative Oncology Group (ECOG) Performance Score of 0-2. Absolute neutrophil count ≥ 1,500 cells/mm3. Platelet count ≥ 75,000 cells/mm3. Total bilirubin ≤ 3.0 mg/dl. Hemoglobin ≥ 8.5 g/dl. AST and ALT ≤ 5.0 times upper limit of normal. D-dimer ≤ 3 times upper limit of normal. INR ≤ 1.8 (therapeutic anticoagulation allowed as long as medically indicated. Exclusion Criteria: History of bleeding diathesis or coagulopathy. Symptomatic or clinically active brain metastases. Major surgery within previous 4 weeks. History of thromboembolic events (including both pulmonary embolisms and deep vein thrombosis); central venous catheter-related thrombosis > 6 months prior is allowed. Prior adjuvant therapy with sorafenib or other Raf/MEK/RAS or VEGFR inhibitors. Prior adjuvant therapy is allowed provided it was completed > 6 months ago and there is documented recurrence of hepatocellular carcinoma.

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bavituximab:0.3 mg/kg weekly Sorafenib: 400mg PO twice daily<br>Cohort 1: Participants were administered Bavituximab:0.3 mg/kg weekly Sorafenib: 400mg PO twice daily | Drug: bavituximab (0.3 mg/kg) and sorafenib<br>* Bavituximab:0.3 mg/kg weekly Sorafenib: 400mg PO twice daily<br>|
| Experimental: Bavituximab: 1.0 mg/kg weekly Sorafenib: 400mg PO twice daily<br>Cohort 2: Participants were administered Bavituximab:1.0 mg/kg weekly Sorafenib: 400mg PO twice daily | Drug: bavituximab (1.0 mg/kg ) and sorafenib<br>* Bavituximab: 1.0 mg/kg weekly Sorafenib: 400mg PO twice daily<br>|
| Experimental: Bavituximab: 3.0 mg/kg weekly Sorafenib: 400mg PO twice daily<br>Cohort 3: Participants were administered Bavituximab:3.0 mg/kg weekly Sorafenib: 400mg PO twice daily | Drug: bavituximab (3.0 mg/kg) and sorafenib<br>* Bavituximab: 3.0 mg/kg weekly Sorafenib: 400mg PO twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Radiographic Time to Progression (TTP) Calculated From Treatment Initiation to First Evidence of Disease Progression or Last Follow-up. | Median radiographic time to progression (TTP) was calculated from treatment initiation to first evidence of disease progression or last follow-up by using the Kaplan-Meier method. The 95% confidence intervals (CIs) for time-to-progression data was calculated using Greenwood's formula. | Treatment initiation to first evidence of disease progression or last follow-up, an average of 24 months | 
| Number of Patients With Dose Limiting Toxicity | Dose limiting toxicity by serious adverse events by CTCAE version 4.0 | 8 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety, as Measured by the Number of Patients With Adverse Event Related to the Treatment That Experienced Grade 3 or Greater. | Safety was measured by the number of patients with at least one adverse event as assess by NCI Common Terminology criteria for adverse events (CTCAE) | Up to 3 months of patient enrollment (phase 1) | 
| Median Months of Overall Survival Calculated From Treatment Initiation to Death or Last Follow-up. | Median months of overall survival was calculated from treatment initiation to death or last follow-up by using the Kaplan-Meier method. The 95% confidence intervals (CIs) for median months of overall survival was calculated using Greenwood's formula. | Treatment initiation to death or last follow-up, an average 24 months | 
| Median Months of Disease Specific Survival Calculated From Treatment Initiation to Death From Advanced HCC (Hepatocellular Carcinoma) or Last Follow-up. | Median months of disease specific survival was calculated from treatment initiation to first evidence of death from advanced liver cancer or last follow-up by using the Kaplan-Meier method. The 95% confidence intervals (CIs) for time-to-disease specific survival data was calculated using Greenwood's formula. | Treatment initiation to first evidence of death from advanced liver cancer or last follow-up, an average of 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cirrhosis, GI Cancer, Hepatitis, Oncology