Sorafenib and TRC105 in Hepatocellular Cancer
Sorafenib is a drug that has been approved to treat kidney and liver cancer (hepatocellular carcinoma, or HCC) and has been shown to prolong survival in patients with HCC. It works by slowing the spread of cancer cells, but it does not fully prevent the cancer from growing again. Researchers are interested in combining sorafenib with the experimental drug TRC105, which has been designed to block the growth of blood vessels that lead to tumor growth, in order to determine whether this drug combination stops tumor growth and reduces tumor size better than sorafenib alone.
To determine the safety and effectiveness of the combination of sorafenib and TRC105 as a treatment for hepatocellular cancer that has not responded to other treatments.
Individuals at least 18 years of age who have been diagnosed with hepatocellular cancer that has not responded to other treatments, and who are not considered to be candidates for liver transplantation. Patients cannot be receiving anticoagulant therapy with the exception of low dose aspirin. No history of bleeding problems or peptic ulcer disease.
Participants will be screened with a full medical history and physical examination, blood and urine tests, and tumor imaging studies. Participants will have a tumor biopsy or provide previously collected tumor tissue for study, and will have an examination of the esophagus to look for problems with blood vessels.
Participants will receive sorafenib tablets twice every day, in the morning and at night, with a full glass of water.
Participants will receive TRC105 infusions once every two weeks on days 1, 8, 15, and 22 of a 28-day cycle. Participants will also receive two doses of dexamethasone the day before the infusion to prevent possible side effects.
At each visit during the first cycle, participants will have a physical examination and blood tests. Participants will continue to have blood tests and a urine test every cycle to monitor the effects of treatment, including tests of kidney function. Participants will have imaging studies after every two cycles to evaluate the results of treatment, and may also provide tumor samples for study.
Treatment will continue as long as the tumor does not grow and side effects remain tolerable.
Adenoma, Liver Cell
Drug: TRC 105
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase I/II Study of TRC105 in Combination With Sorafenib in Hepatocellular Carcinoma (HCC)|
- Phase I: To establish the maximum tolerated dose (MTD) of TRC105 when given with standard-dose sorafenib for HCC. [ Time Frame: 6/30/2012 ] [ Designated as safety issue: Yes ]
- Phase II: To evaluate time to progression (TTP) for the combination of TR105 with sorafenib in HCC. [ Time Frame: 1/31/2014 ] [ Designated as safety issue: No ]
- To evaluate the safety [ Time Frame: 1/31/2014 ] [ Designated as safety issue: Yes ]
- To evaluate the immunogenicity [ Time Frame: 1/31/2014 ] [ Designated as safety issue: No ]
- To evaluate the overall response rate [ Time Frame: 1/31/2014 ] [ Designated as safety issue: No ]
|Study Start Date:||February 2011|
|Estimated Study Completion Date:||February 2015|
|Estimated Primary Completion Date:||February 2015 (Final data collection date for primary outcome measure)|
Drug: TRC 105
- 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 not allowed.
- 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
|Contact: Suzanne Fioravanti, R.N.||(301) firstname.lastname@example.org|
|Contact: Tim F Greten, M.D.||(301) email@example.com|
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office (888) NCI-1937|
|Principal Investigator:||Tim F Greten, M.D.||National Cancer Institute (NCI)|