A Phase I/II Study of Bavituximab and Sorafenib In Patients With Advanced Hepatocellular Carcinoma
This is a non-randomized, open-label, single-institution phase I/II therapeutic trial of bavituximab and sorafenib in patients with advanced 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 Zale Lipshy 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.
The phase I component of the study will consist of a traditional 3+3 dose escalation rule with the dose of sorafenib remaining constant and the dose of bavituximab escalating up to 3.0 mg/kg weekly to determine the maximum tolerate dose (MTD) that will be used during the phase II component. Sorafenib has been demonstrated in multiple phase I and II studies in advanced HCC to have minimal toxicity and to be safe, therefore doses will be constant. (13,14) Cohorts of three patients will be assigned to one dose level of bavituximab starting at 0.3 mg/kg weekly. Only the first cycle of therapy (dosing of bavituximab constitutes one cycle) will be used to determine dose limiting toxicity (DLT). The number of observed toxicities is counted and the traditional escalation rule applied:
* No toxicity: the next three patients will be assigned to next higher dose level (3.0 mg/kg of bavituximab is the highest dose assigned).
* At least two toxicities: the MTD is exceeded and the phase I component of the trial will be stopped with the next lowest dose to be defined as the MTD that will be used in the phase II component.
* One toxicity: the current dose will be administered to the next cohort as well.
o One toxicity within the last six patients: The next cohort of three patients will be assigned to the next highest dose level
o At least two toxic events within the last six patients: the MTD is exceeded and the phase I component of the trial will be stopped with the next lowest dose to be defined as the MTD that will be used in the phase II component.
The dose levels of bavituximab (0.3, 1.0 and 3.0 mg/kg weekly) were selected based on available data from preclinical and clinical studies that is predicted to achieve and sustain biologically active blood antibody levels or tumor binding in cancer patients.
* A bavituximab dose of 3 mg/kg gives a blood concentration in excess of that needed for maximal efficacy based on preclinical models while having little effect on coagulation and safety laboratory parameters and causing no significant depletion of the cofactor protein, β2GP1.
* In preclinical models, dosing above the biologically effective blood concentration of 2 μg/mL did not increase anti-tumor efficacy.
* Treatment with ≤ 3 mg/kg bavituximab appears to be well tolerated.
* β2-glycoprotein I levels are significantly depleted above 3 mg/kg bavituximab.
1. Patients must have a diagnosis of hepatocellular carcinoma by at least one criterion listed below:
a. Histologically confirmed.
2. Locally advanced or metastatic disease.
3.Patients with locally advanced disease must have disease deemed to be unresectable or not eligible for hepatic transplantation by the surgical oncologist or transplant physician”.
4. 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.
5. Child-Pugh Score A or B7.
6. Age ≥ 18 years.
7. Eastern Cooperative Oncology Group (ECOG) Performance Score of 0-2.
8. Absolute neutrophil count ≥ 1,200 cells/mm3.
9. Platelet count ≥ 70,000 cells/mm3.
10. Total bilirubin ≤ 3.0 mg/dl.
11. Hemoglobin ≥ 8.5 g/dl.
12. INR ≤ 1.8 (therapeutic anticoagulation allowed as long as medically indicated.)
13. Creatinine ≤ 1.5 times upper limit of normal.
14 Women of childbearing potential must have a negative pregnancy test.
15. No clinically significant episode of gastrointestinal bleeding within the previous 30 days.
16. Men and women of childbearing potential must be willing to consent to using effective contraception while on treatment and for at least 3 months thereafter.
17. At least 4 weeks since prior locoregional therapy including surgical resection, radiotherapy, hepatic arterial embolization or chemoembolization, radiofrequency abalation, percutaneous injection or cryablation (treatment of target lesion only, non-target lesions can be treated with locoregional therapy). Provided the target lesion increased in size by 25% or more or the target lesion was not treated with locoregional therapy.
18. Greater than 4 weeks since interferon therapy.
19. Greater than 4 weeks since prior and no concurrent use of rifampin or St John’s wort.
20. Life expectancy > 12 weeks.
21. Ability to understand informed consent and signing of written informed consent prior to initiation of protocol therapy.
22. Non-English speaking patients will be enrolled.