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. An examination of the esophagus to look for problems with blood vessels will be completed in patients with a history of cirrhosis.
Participants will receive sorafenib tablets twice every day, in the morning and at night, with a full glass of water.
Participants will receive TRC 105 infusions once every two weeks on days 1 and 15 of a 28 day cycle.
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
Liver Neoplasms, Experimental
Drug: TRC 105
|Study Design:||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: Complete ] [ Designated as safety issue: Yes ]
- Phase II: To evaluate time to progression (TTP) for the combination of TR105 with sorafenib in HCC. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
- To evaluate overall response rate (ORR) as determined by both standard and EASL-modified RECIST criteria [ Time Frame: 2 years ] [ Designated as safety issue: No ]
- To evaluate the immunogenicity of TRC105 as measured by humanantichimeric antibody (HACA) and human antimouse antibodyformation [ Time Frame: 2 years ] [ Designated as safety issue: No ]
- To evaluate the safety of the combination of TRC105 and sorafenibin HCC. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
- To determine progression-free survival (PFS) and overall survival (OS) for TRC105 and sorafenib in HCC. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
- To perform correlative studies assessing 1) potential biomarkers ofresponse to angiogenic therapy, 2) changes in frequency andfunction of immune cells upon treatment and 3) molecularcharacterization of tumors. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
|Study Start Date:||February 2011|
|Estimated Study Completion Date:||September 2016|
|Estimated Primary Completion Date:||September 2016 (Final data collection date for primary outcome measure)|
15 mg/kg TRC105 IV every 2 weeks and 400 mg sorafenib PO twice per day
Drug: TRC 105
15 mg/kg IV every 2 weeksDrug: Sorafenib
400 mg bid continuously in a 28 days cycle
Hide Detailed Description
- 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 determine the estimate response rate according to RECIST criteria for the combination of TRC105 with sorafenib in HCC.
- 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 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 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
Please refer to this study by its ClinicalTrials.gov identifier: NCT01306058
|Contact: Donna E Mabry, C.R.N.P.||(301) email@example.com|
|Contact: Tim F Greten, M.D.||(301) firstname.lastname@example.org|
|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)|