TRC105 for Liver Cancer That Has Not Responded to Sorafenib

Background:

- Worldwide, hepatocellular carcinoma (HCC) is the fifth most common malignancy with a
median survival of 6-9 months. The Study of Heart and Renal Protection (SHARP) study
established Sorafenib as a standard consideration in this disease and set the bar for
future studies of systemic therapy. There is no standard therapy for patients whose
disease has progressed despite Sorafenib therapy.

- TRC105 is a chimeric, anti-angiogenic monoclonal antibody that binds CD105, a
transmembrane receptor overexpressed by proliferating endothelial cells. TRC105 binds
to CD105-expressing endothelial cells and mediates growth inhibition, apoptosis and
antibody-dependent cell-mediated cytotoxicity (ADCC).

Objectives:

Primary:

-To evaluate time to tumor progression (TTP) for TRC105 in HCC.

Secondary:

- To evaluate safety of TRC105 in HCC.

- To evaluate the immunogenicity of TRC105 as measured by human antichimeric antibody
(HACA) and human antimouse antibody formation.

- To evaluate anti-tumor response as determined by standard and European Association for
the Study of the Liver (EASL) -modified Response Evaluation Criteria in Solid Tumors
(RECIST) response criteria.

- To perform correlative studies assessing potential biomarkers of response to TRC105.

Eligibility:

- Histologically or cytologically confirmed diagnosis of HCC.

- Childs-Pugh A or B (7 points) cirrhosis only is allowed.

- Patients must have disease that is not amenable to potentially curative resection.

- Patients must have progressed on or been intolerant of prior sorafenib therapy.

- No history of bleeding varices (unless subsequent liver transplant). All patients must
have had endoscopic evaluation within 6 months of starting study.

- No history of bleeding varices in previous 1 year (unless subsequent liver transplant).
No anti-coagulation (except low-dose aspirin).

Design:

- This is a single-arm phase II study of TRC105 in patients with HCC.

- TRC105 will be administered as an intravenous infusion every two weeks. Patients will
be re-staged every 8 weeks.

- The primary endpoint of the study will be Time to Tumor Progression (TTP). The primary
purpose of this study is to evaluate the ability of TRC105 as a second line treatment
to improve upon the time to progression (TTP) of patients with refractory HCC.

- INCLUSION CRITERIA:

- Patients must have histopathological confirmation of Hepatocellular Carcinoma (HCC)
by the Laboratory of Pathology of the National Cancer Institute (NCI) prior to
entering this study.

Or

histopathological confirmation of carcinoma in the setting of clinical and radiological
characteristics which, together with the pathology, are highly suggestive of a diagnosis
of HCC.

- Patients must have disease that is not amenable to potentially curative resection or
ablative techniques. In addition, disease must not be amenable to transhepatic
arterial chemoembolization (TACE). Patients may have had prior TACE and had disease
progression following it. Patients must not be considered potential candidates for
liver transplantation. This determination will be made after hepatobiliary surgical
input at the NCI multidisciplinary conference.

- All patients enrolled will be required to have measurable disease.

- If liver cirrhosis is present, patient must have a Child-Pugh A classification.

- Patients must have progressed on or been intolerant of prior sorafenib therapy.

- Patients must with cirrhosis have had esophagogastric endoscopy within the previous 6
months prior to study entry for the assessment of varices. If the patient has not had
this done they must be willing to undergo this procedure prior to study entry.

- Age greater than or equal to 18 years

- Life expectancy of greater than 3 months.

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Patients must have normal organ and marrow function as defined below:

- Absolute neutrophil count greater than or equal to 1,500/mcL

- Platelets greater than or equal to 60,000/mcL

- Total bilirubin less than or equal to 3 times upper normal limits

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) less than or
equal to 10 times upper limit of normal

- Creatinine less than or equal to 1.5 times upper normal limits OR creatinine
clearance greater than or equal to 40 mL/min/1.73 m^2 for patients with
creatinine levels above institutional normal, as calculated by the Cockcroft
Gault formula.

- Patients must have recovered from any acute toxicity related to prior therapy,
including surgery. Toxicity should be less than or equal to grade 1 or returned to
baseline.

- Patients must not have other invasive malignancies within the past 3 years (with the
exception of non-melanoma skin cancers, carcinoma in situ of the cervix and
noninvasive bladder cancer).

- Enrolled patients must agree to use adequate contraception (hormonal or barrier
method of birth control; abstinence) prior to study entry, the duration of study
participation and 3 months after the end of the treatment.

- Patient must be able to understand and willing to sign a written informed consent
document.

EXCLUSION CRITERIA:

- Patients who have had chemotherapy, large field radiotherapy, or major surgery must
wait 4 weeks prior to entering the study (2 weeks is sufficient for targeted systemic
therapy provided toxicity has recovered to less than or equal to grade 1).

- Patients may not be receiving any anti-cancer agents not approved by the Food and
Drug Administration (FDA) within the past 4 weeks.

- Patients with known brain metastases will be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse
events.

- Proteinuria, as demonstrated by a 24 hour protein of greater than or equal to 2000
mg. Urine protein will be screened by urine protein-creatinine ratio (UPC). For urine
protein-to-creatinine (UPC) ratio > 1.0, a 24-hour urine protein will need to be
obtained and the level should be < 2000 mg for patient enrollment.

- Uncontrolled intercurrent illness including, but not limited to, hypertension
(systolic blood pressure (BP) 160, diastolic BP > 100), ongoing or active systemic
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia or psychiatric illness/social situations that would limit compliance with
study requirements.

- No anti-coagulation therapy is allowed with the exception of low-dose aspirin.

- No bleeding diathesis.

- Patients with a history of bleeding varices in previous 1 year are excluded (unless
patient has subsequently had a liver transplant). Those with gastric varices or
varices that are deemed as high risk by the endoscopist should be placed on
appropriate medical therapy as advised by the gastroenterologist.

- History of peptic ulcer disease or hemorrhagic gastritis within 6 months of TRC105
administration, unless patient has received adequate treatment for peptic ulcer
disease or hemorrhagic gastritis and has evidence of complete resolution documented
by esophagogastroduodenoscopy (EGD). Mild gastritis is allowed.

- Corrected QT interval (QTc) > 500 msec.

- Human immunodeficiency virus (HIV)-positive patients receiving anti-retroviral
therapy are excluded from this study due to the possibility of pharmacokinetic
interactions between antiretroviral medications and TRC105. HIV positive patients not
receiving antiretroviral therapy are excluded due to the possibility that TRC105 may
worsen their condition and the likelihood that the underlying condition may obscure
the attribution of adverse events with respect to TRC105.

- History of hypersensitivity reaction to human or mouse antibody products.

- Patients with a history of familial bleeding disorders.

- Patients with a history of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu
syndrome).

- Pregnancy and breast feeding are exclusion factors. Enrolled patients must agree to
use adequate contraception (hormonal or barrier method of birth control; abstinence)
prior to study entry, the duration of study participation and 3 months after the end
of the treatment.

INCLUSION OF WOMEN AND MINORITIES:

-Men and women of all races and ethnic groups are eligible for this trial.