A Phase I/II Study of TRC105 in Combination With Sorafenib in Hepatocellular Carcinoma (HCC)
- Worldwide, hepatocellular carcinoma (HCC) is the fifth most common malignancy with a
median survival of 6-9 months. The 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 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).
- Phase I: To establish the maximum tolerated dose (MTD) of TRC105 when given with
standard-dose sorafenib for HCC.
- Phase II: To evaluate time to progression (TTP) for the combination of TR105 with
sorafenib in HCC.
- To evaluate the safety of the combination of TRC105 and sorafenib in HCC.
- To evaluate the immunogenicity of TRC105 as measured by human antichimeric antibody
(HACA) and human antimouse antibody formation.
- To evaluate the overall response rate (ORR) for TRC105 and sorafenib in HCC as
determined by both standard and EASL-modified RECIST criteria.
- To determine progression-free survival (PFS) and overall survival (OS) for TRC105 and
sorafenib in HCC.
- To perform correlative studies assessing 1) potential biomarkers of response to
angiogenic therapy, 2) changes in frequency and function of immune cells with treatment
and 3) molecular characterization of tumors.
- 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).
- 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 is 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 will be taken orally at a dose of 400 mg twice
daily. TRC105 will be 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 will be escalated in cohorts of 3 to 6 patients up to a
maximum of 15 mg/kg every two weeks (see table below). Intra-patient dose escalation is
- Phase II: TRC105 will be administered as an intravenous infusion every two weeks at the
MTD defined in phase I. The sample size and interim stopping rule will be determined
using a Simon optimal two-stage design. In addition there will be stopping rules for
safety. If 10 or fewer of the initial 21 patients are progression-free after six 28-day
cycles (3 imaging assessments), then accrual will be terminated early and the trial
declared to have a negative result. If 11 or more of the initial 21 patients are
progression-free at 6 months, enrollment will continue to a total of 45 patients.
Cohort: -0; Sorafenib (mg PO twice daily): 400 bid; TRC105 (mg/kg 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
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Phase I: To establish the maximum tolerated dose (MTD) of TRC105 when given with standard-dose sorafenib for HCC.
Tim F Greten, M.D.
National Cancer Institute (NCI)
United States: Federal Government
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