Sorafenib and TRC105 in Hepatocellular Cancer

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.

- TRC105 is a chimeric anti-angiogenic monoclonal antibody that binds cluster of
differentiation 105 (CD105), a transmembrane receptor selectively expressed 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:

- Phase I: To establish the maximum tolerated dose (MTD) of TRC105 when given with
standard-dose sorafenib for HCC.

- Phase II:To determine the estimate response rate according to Response Evaluation
Criteria in Solid Tumors (RECIST) criteria for the combination of TRC105 with sorafenib
in HCC.

Eligibility:

- Histologically or cytologically confirmed diagnosis of HCC.

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

- Patients must have disease that is not amenable to potentially curative resection,
radiofrequency ablation, or liver transplantation.

- In phase I, prior systemic therapy is allowed.

- In phase II, prior systemic therapy for HCC (including sorafenib) is allowed.

- No history of bleeding varices in previous 1 year (unless subsequent liver transplant).

- No anti-coagulation (except low-dose aspirin).

Design:

- TRC105 will be administered intravenously every two weeks, on days 1 and 15 of each 28
day cycle. Sorafenib will be self-administered twice daily by mouth.

- Phase 1: The first part of this study was a standard 3+3 dose escalation phase I study
with the primary objective of establishing MTD for TRC105 when given in combination with
standard-dose sorafenib. Sorafenib is taken orally at a dose of 400 mg twice daily.
TRC105 is administered as an intravenous infusion every two weeks. Patients will be
restaged including imaging studies to assess for response and progression every 8 weeks.
The TRC105 dose was escalated in cohorts of 3 to 6 patients up to a maximum of 15 mg/kg
every two weeks. Intra-patient dose escalation was not allowed.

- Phase II: TRC105 will be administered as an intravenous infusion every two weeks at the
recommended phase II dose, 15 mg/kg of TRC105 ever two weeks in combination with
standard dose sorafenib, defined in phase I. The sample size and interim stopping rule
will be determined using a Simon optimal two-stage design. The first stage will
initially enroll 6 evaluable patients, and if 0 of the 6 have a clinical response, then
no further patients will be accrued. If 1 or more of the first 6 patients has a clinical
response, then accrual would continue until a total of 23 patients have been enrolled.
As it may take several weeks to determine if a patient has experienced a response, a
temporary pause in the accrual may be necessary to ensure that enrollment to the second
stage is warranted. If there are 1 to 2 clinical responses in 23 patients, this would be
an uninterestingly low response rate. If there were 3 or more complete responses in 23
patients (13.0%), this would be sufficiently interesting to warrant further study in
later trials. Under the null hypothesis (5% response rate), the probability of early
termination is 73.5%.

Cohort: -0; Sorafenib (mg by mouth (PO) twice daily): 400 bid; TRC105 (mg/kg intravenous (IV)
weekly): 1

Cohort: 1; Sorafenib (mg PO twice daily): 400 bid; TRC105 (mg/kg IV weekly): 3

Cohort: 2; Sorafenib (mg PO twice daily): 400 bid; TRC105 (mg/kg IV weekly): 6

Cohort: 3; Sorafenib (mg PO twice daily): 400 bid; TRC105 (mg/kg IV weekly): 10

Cohort: 4; Sorafenib (mg PO twice daily): 400 bid; TRC105 (mg/kg IV weekly): 15

- 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 or have progressed
on transhepatic arterial chemoembolization (TACE). Patients must not be considered
potential candidates for liver transplantation. This determination will be made after
hepatobiliary surgical input at the NCI multidisciplinary conference.

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

- Patients with cirrhosis must 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 without transfusion support within
the past 30 days

- Total bilirubin less than or equal to 3 mg/dl.

- Aspartate aminotransaminase (AST)/alanine aminotransaminase (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 40mL/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 5 years (with the
exception of non-melanoma skin cancers or non-invasive bladder cancer).

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

Additional Inclusion Criteria for PHASE I Portion:

- Patients may have measurable or evaluable disease only.

- Prior therapy: prior systemic therapy with sorafenib is allowed.

Additional Inclusion Criteria for PHASE II Portion:

- All patients will be required to have measurable disease.

- Prior therapy: prior systemic therapy with sorafenib is allowed.

EXCLUSION CRITERIA:

- Patients who have had chemotherapy (other than sorafenib treatment), large field
radiotherapy, or major surgery must wait 4 weeks prior to entering the study.

- Patients may not be receiving any 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 UPC ratio
greater than 1.0, a 24-hour urine protein will need to be obtained and the level
should be less than 2000 mg for patient enrollment.

- Uncontrolled intercurrent illness including, but not limited to, hypertension
(systolic blood pressure (BP) greater than 140, diastolic BP greater than 90), 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 gastritis within 6 months of TRC105 administration,
unless patient has received adequate treatment for peptic ulcer disease and has
evidence of complete resolution documented by esophagogastroduodenoscopy (EGD). Mild
gastritis is allowed.

- Corrected QT interval (QTc) greater than 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 sorafenib or TRC105. HIV positive patients not
receiving antiretroviral therapy are excluded due to the possibility that sorafenib or
TRC105 may worsen their condition and the likelihood that the underlying condition may
obscure the attribution of adverse events with respect to sorafenib or 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.

- Patients with unhealed wounds for more than 30 days.

INCLUSION OF WOMEN AND MINORITIES:

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