TRC105 and Sorafenib Tosylate in Treating Patients with Liver Cancer

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Basic Trial Information

PhaseTypeAgeTrial IDs
Phase II, Phase IBiomarker/Laboratory analysis, Treatment18 and over11-C-0102
NCI-2013-01477, 110102, 339029, P10766, NCT01306058

Trial Description

Summary

This phase I/II trial studies the side effects and best dose of TRC105 (anti-endoglin chimeric monoclonal antibody TRC105) and to see how well it works when given together with sorafenib tosylate in treating patients with liver cancer. Monoclonal antibodies, such as anti-endoglin chimeric monoclonal antibody TRC105, may interfere with the ability of tumor cells to grow and spread. Sorafenib tosylate may stop the growth of liver cancer by blocking blood flow to the tumor. Giving anti-endoglin chimeric monoclonal antibody TRC105 with sorafenib tosylate may be an effective treatment for liver cancer.

Further Study Information

PRIMARY OBJECTIVES:

I. To establish the maximum tolerated dose (MTD) for TRC105 when given with sorafenib (sorafenib tosylate) in hepatocellular carcinoma (HCC). (Phase I)

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. (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate the safety of the combination of TRC105 and sorafenib in HCC.

II. To evaluate the immunogenicity of TRC105 as measured by human antichimeric antibody (HACA) and human antimouse antibody formation.

III. To evaluate overall response rate (ORR) as determined by both standard and European Association for the Study of the Liver (EASL)-modified RECIST criteria.

IV. To determine progression-free survival (PFS) and overall survival (OS) for TRC105 and sorafenib in HCC.

V. To perform correlative studies assessing, 1) potential biomarkers of response to angiogenic therapy, 2) changes in frequency and function of immune cells upon treatment and 3) molecular characterization of tumors.

OUTLINE: This is a phase I, dose-escalation study of anti-endoglin monoclonal antibody TRC105 followed by a phase II study.

Patients receive anti-endoglin chimeric monoclonal antibody TRC105 intravenously (IV) over 1-4 hours on days 1 and 15 and sorafenib tosylate orally (PO) twice daily (BID) on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up annually.

Eligibility Criteria

Inclusion Criteria:

PHASE I: Prior systemic therapy with sorafenib is allowed

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 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

PHASE II: All patients will be required to have measurable disease

PHASE I: Patients may have measurable or evaluable disease only

Creatinine =< 1.5 x upper normal limits OR creatinine clearance >= 40 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal, as calculated by the Cockcroft Gault formula

Eastern Cooperative Oncology Group (ECOG) performance status 0-2

Absolute neutrophil count >= 1,500/mcL

Total bilirubin =< 3 mg/dl

Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 10 × upper limit of normal

Platelets >= 60,000/mcL without transfusion support within the past 30 days

Patients must have recovered from any acute toxicity related to prior therapy, including surgery; toxicity should be =< grade 1 or returned to baseline

Patients must have histopathological confirmation of hepatocellular carcinoma (HCC) by the Laboratory of Pathology of the National Cancer Institute (NCI) prior to entering this study OR

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 or B (7 points) 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

PHASE II: Prior systemic therapy with sorafenib is allowed

Life expectancy of greater than 3 months

Exclusion Criteria:

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 a history of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)

Corrected QT (QTc) interval > 500 msec

Patients with known brain metastases will be excluded from this clinical trial

Patients may not be receiving any agents not approved by the Food and Drug Administration (FDA) within the past 4 weeks

Patients who have had chemotherapy (other than sorafenib treatment), large field radiotherapy, or major surgery must wait 4 weeks prior to entering the study

Proteinuria, as demonstrated by a 24-hour protein of >= 2000 mg; urine protein will be screened by urine protein-creatinine ratio (UPC); for UPC ratio > 1.0, a 24-hour urine protein will need to be obtained and the level should be < 2000 mg for patient enrollment

Patients with unhealed wounds for more than 30 days

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 hemorrhagic gastritis within 6 months of TRC105 administration, unless patient has received adequate treatment for peptic ulcer disease or hemorrhagic gastritis and has evidence of complete resolution documented by esophagogastroduodenoscopy (EGD); mild gastritis is allowed

History of hypersensitivity reaction to human or mouse antibody products

Patients with a history of familial bleeding disorders

Uncontrolled intercurrent illness including, but not limited to, hypertension (systolic blood pressure [BP] > 140, diastolic BP > 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

Human immunodeficiency virus (HIV)-positive patients receiving anti-retroviral therapy are excluded from this study; HIV positive patients not receiving antiretroviral therapy are excluded

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

NCI - Center for Cancer Research

  • National Cancer Institute
Tim F. Greten, Principal Investigator

Trial Sites

U.S.A.

Maryland
Bethesda

Mark O Hatfield-Warren Grant Magnuson Clinical Center

Tim F. Greten
Ph: 301-451-4723
Email: gretentf@mail.nih.gov

Tim F. Greten
Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01306058

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.