Sorafenib and TRC105 in Hepatocellular Cancer

NCT01306058 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 11010211-C-0102
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Hepatoma; Liver Neoplasms; Adenoma, Liver Cell; Carcinoma, Hepatocellular; Liver Neoplasms, Experimental

Keywords

Hepatocellular Carcinoma; TRC105; Sorafenib; Liver Cancer; Monoclonal Antibody

Outcome Measures

Primary Outcomes (2)

• Phase I: Maximum Tolerated Dose (MTD) of TRC105 When Given With Standard-dose Sorafenib for Hepatocellular Cancer (HCC)

  MTD is the highest dose studied for which the incidence of DLT was less than 33%. DLT criteria included treatment-related grade 3 non-hematological toxicities or grade 4 hematological toxicities occurring within the first 28 days of treatment. Grade 3 electrolyte toxicities to be corrected to Grade 1 or less within 24 hours will be considered dose limiting (proteinuria \>3.5g/24 hour will be defined as a DLT). Drug-related Grade 4 hematological toxicity will be considered dose limiting. Toxicity requiring a dose reduction or a delay in treatment for \>7 days will be considered dose limiting. Other Grade 3 or higher toxicity related to TRC105 will be considered dose limiting.

  Completed in the first 28 days of treatment (cycle 1)

• Phase II: Time to Progression (TTP) for the Combination of TR105 With Sorafenib in Hepatocellular Cancer (HCC)

  TTP is the time between the first day of treatment to the day of disease progression. Progressive disease was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) and is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. (Note: the appearance of one or more new lesions is also considered progressions).

  2 years

Secondary Outcomes (16)

• Overall Response Rate (ORR) as Determined by the Standard Response Evaluation Criteria in Solid Tumors (RECIST) Criteria

  2 years

• Overall Response Rate (ORR) as Determined by the European Association for the Study of the Liver (EASL)-Modified Response Evaluation Criteria in Solid Tumors (RECIST) Criteria

  2 years

• Patients Who Developed Antidrug Antibodies

  Cycle 1 Day 1, 28 days post end of study (up to 2 years)

• Immunogenicity of TRC105 as Measured by Human Anti-mouse Antibody (HAMA) Formation

  Baseline and then 28 days following the end of the study treatment, approximately two years

• Number of Participants With Serious and Non-serious Adverse Events by Common Terminology Criteria in Adverse Events (CTCAE)v4.0

  4 years and 10.5 months

Study Arms (1)

Sorafenib & TRC105 in Hepatocellular CA

EXPERIMENTAL

CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day

Drug: TRC 105; Drug: Sorafenib

Interventions

TRC 105 DRUG

15 mg/kg intravenous (IV) every 2 weeks

Sorafenib & TRC105 in Hepatocellular CA

Sorafenib DRUG

400 mg twice a day (bid) continuously in a 28 days cycle

Also known as: Nexavar

Sorafenib & TRC105 in Hepatocellular CA

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.
• Eastern Cooperative Oncology Group (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.
• Aspartate aminotransaminase (AST)/alanine aminotransaminase (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.

You may not qualify if:

• 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 Food and Drug Administration (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 blood pressure (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 esophagogastroduodenoscopy (EGD). Mild gastritis is allowed.
• Corrected QT interval (QTc) greater than 500 msec
• Human immunodeficiency virus (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).
• Patients with unhealed wounds for more than 30 days.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000. Int J Cancer. 2001 Oct 15;94(2):153-6. doi: 10.1002/ijc.1440. No abstract available.

  PMID: 11668491 BACKGROUND

• Yoo HY, Patt CH, Geschwind JF, Thuluvath PJ. The outcome of liver transplantation in patients with hepatocellular carcinoma in the United States between 1988 and 2001: 5-year survival has improved significantly with time. J Clin Oncol. 2003 Dec 1;21(23):4329-35. doi: 10.1200/JCO.2003.11.137. Epub 2003 Oct 27.

  PMID: 14581446 BACKGROUND

• Palmer DH. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008 Dec 4;359(23):2498; author reply 2498-9. No abstract available.

  PMID: 19065750 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Carcinoma, Hepatocellular; Liver Neoplasms; Adenoma, Liver Cell; Liver Neoplasms, Experimental

Interventions

carotuximab; Sorafenib

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases; Adenoma; Neoplasms, Experimental

Intervention Hierarchy (Ancestors)

Phenylurea Compounds; Urea; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Dr. Tim Greten
• Organization: Principal Investigator

tim.greten@nih.hhs.gov

301-451-4723

Study Officials

• Tim F Greten, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: February 26, 2011
• First Posted: March 1, 2011
• Study Start: February 11, 2011
• Primary Completion: June 1, 2016
• Study Completion: June 9, 2017
• Last Updated: January 23, 2019
• Results First Posted: January 23, 2018

Record last verified: 2019-01

Locations

US (1)