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Sorafenib and TRC105 in Hepatocellular Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT01306058
First received: February 26, 2011
Last updated: November 20, 2014
Last verified: October 2014
  Purpose

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.


Condition Intervention Phase
Hepatoma
Liver Neoplasms
Adenoma, Liver Cell
Carcinoma, Hepatocellular
Liver Neoplasms, Experimental
Drug: TRC 105
Drug: Sorafenib
Phase 1
Phase 2

Study Type: Interventional
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)

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 44
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)
Arms Assigned Interventions
Experimental: 1
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 weeks
Drug: Sorafenib
400 mg bid continuously in a 28 days cycle

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Patients must have histopathological confirmation of hepatocellular carcinoma (HCC) by the Laboratory of Pathology of the 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.
  • 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.
    • AST/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 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 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 EGD. Mild gastritis is allowed.
  • QTc greater than 500 msec
  • 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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01306058

Contacts
Contact: Suzanne Fioravanti, R.N. (301) 594-6544 fioravas@mail.nih.gov
Contact: Tim F Greten, M.D. (301) 451-4723 gretentf@mail.nih.gov

Locations
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      
Sponsors and Collaborators
Investigators
Principal Investigator: Tim F Greten, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT01306058     History of Changes
Other Study ID Numbers: 110102, 11-C-0102
Study First Received: February 26, 2011
Last Updated: November 20, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Hepatocellular Carcinoma
TRC105
Sorafenib
Liver Cancer
Monoclonal Antibody

Additional relevant MeSH terms:
Adenoma, Liver Cell
Carcinoma
Carcinoma, Hepatocellular
Liver Neoplasms
Liver Neoplasms, Experimental
Neoplasms
Neoplasms, Experimental
Adenocarcinoma
Adenoma
Digestive System Diseases
Digestive System Neoplasms
Liver Diseases
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Glandular and Epithelial
Sorafenib
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protein Kinase Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on November 25, 2014