Sorafenib and TRC105 in Hepatocellular Cancer
Condition: Hepatoma; Liver Neoplasms; Adenoma, Liver Cell; Carcinoma, Hepatocellular; Liver Neoplasms, Experimental
MeSH terms: Carcinoma; Neoplasms; Adenoma; Carcinoma, Hepatocellular; Liver Neoplasms; Neoplasms, Experimental; Adenoma, Liver Cell; Liver Neoplasms, Experimental
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Background:

      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.

      Objectives:

      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.

      Eligibility:

      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.

      Design:

      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.
    

Detailed description: 
      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
    

Intervention name(s): TRC 105; Sorafenib
Intervention type(s): Drug; Drug
Intervention description(s): 15 mg/kg intravenous (IV) every 2 weeks; 400 mg twice a day (bid) continuously in a 28 days cycle
Other intervention name(s): Nexavar
Intervention MeSH terms: Sorafenib
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Hepatocellular Carcinoma; TRC105; Sorafenib; Liver Cancer; Monoclonal Antibody