TRC105 for Liver Cancer That Has Not Responded to Sorafenib

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01375569
• Collaborator: (none)
• Enrollment: 11
• Location: 1
• Arm: 1
• Actual Duration (Months): 53.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Background:

• TRC105 is an experimental cancer drug. It is designed to slow or stop the growth of tumors. It does this by preventing the growth of new blood vessels that feed these tumors. People with hepatocellular carcinoma (or liver cancer) sometimes do not respond to standard treatments. This includes the cancer drug sorafenib.

Objectives:

• To test the safety and effectiveness of TRC105 to treat liver cancer that has not responded to standard therapy.

Eligibility:

• People at least 18 years of age who have hepatocellular carcinoma (or liver cancer) that has not responded to standard therapy. Participants also will not be eligible for a liver transplant.

• No anticoagulation therapy is allowed with the exception of low-dose aspirin.

• No history of bleeding disorders, peptic ulcer disease or gastritis.

Design:

• Participants will have a physical exam and medical history. They will also have blood and urine tests, and imaging studies.

• Participants will receive TRC105 once a week. They will also have two daily doses of a steroid the day before each treatment. This will help prevent known side effects.

• Participants will be monitored with blood and urine tests. They will also have imaging studies every two months to study the effect of the drug on tumor growth.

• Participants will continue to have TRC105 as long as they do not have severe side effects and their liver cancer stops growing or shrinks. After stopping TRC105, they will have yearly visits with physical exams and blood tests.

Condition or Disease	Intervention/Treatment	Phase
Hepatocellular Carcinoma; Hepatocellular Cancer; Carcinoma, Hepatocellular	Drug: TRC105	Phase 2

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. There is no standard therapy for patients whose disease has progressed despite Sorafenib therapy.

• TRC105 is a chimeric, anti-angiogenic monoclonal antibody that binds CD105, a transmembrane receptor overexpressed 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:

-To evaluate time to tumor progression (TTP) for TRC105 in HCC.

Secondary:

• To evaluate safety of TRC105 in HCC.

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

• To evaluate anti-tumor response as determined by standard and European Association for the Study of the Liver (EASL) -modified Response Evaluation Criteria in Solid Tumors (RECIST) response criteria.

• To perform correlative studies assessing potential biomarkers of response to TRC105.

Eligibility:

• Histologically or cytologically confirmed diagnosis of HCC.

• Childs-Pugh A or B (7 points) cirrhosis only is allowed.

• Patients must have disease that is not amenable to potentially curative resection.

• Patients must have progressed on or been intolerant of prior sorafenib therapy.

• No history of bleeding varices (unless subsequent liver transplant). All patients must have had endoscopic evaluation within 6 months of starting study.

• No history of bleeding varices in previous 1 year (unless subsequent liver transplant). No anti-coagulation (except low-dose aspirin).

Design:

• This is a single-arm phase II study of TRC105 in patients with HCC.

• TRC105 will be administered as an intravenous infusion every two weeks. Patients will be re-staged every 8 weeks.

• The primary endpoint of the study will be Time to Tumor Progression (TTP). The primary purpose of this study is to evaluate the ability of TRC105 as a second line treatment to improve upon the time to progression (TTP) of patients with refractory HCC.

Study Design

• Study Type: Interventional
• Actual Enrollment: 11 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of TRC105 in Patients With Hepatocellular Carcinoma (HCC) Who Have Progressed on Sorafenib
• Actual Study Start Date: Jun 22, 2011
• Actual Primary Completion Date: Feb 1, 2014
• Actual Study Completion Date: Dec 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TRC105 in Liver Cancer TRC105 is an experimental cancer drug designed to slow or stop the growth of tumors. It does this by preventing the growth of new blood vessels that feed these tumors. This drug is being used to test the safety and effectiveness to treat liver cancer that has not responded to standard therapy. TRC105 will be given as an intravenous infusion every two weeks.	Drug: TRC105

Outcome Measures

Primary Outcome Measures

1. Time to Tumor Progression (TTP) for TRC105 in Hepatocellular Carcinoma (HCC). [2 years]

   Time to tumor progression is defined as the proportion of participants who are progression free after 4 months on study. Progression is defined by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Progression is 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).

Secondary Outcome Measures

1. Count of Participants With Adverse Events [25 months, 15 days]

   here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• INCLUSION CRITERIA:

• 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

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 transhepatic arterial chemoembolization (TACE). Patients may have had prior TACE and had disease progression following it. Patients must not be considered potential candidates for liver transplantation. This determination will be made after hepatobiliary surgical input at the NCI multidisciplinary conference.

• All patients enrolled will be required to have measurable disease.

• If liver cirrhosis is present, patient must have a Child-Pugh A classification.

• Patients must have progressed on or been intolerant of prior sorafenib therapy.

• Patients must with cirrhosis 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

• Total bilirubin less than or equal to 3 times upper normal limits

• Aspartate aminotransferase (AST)/alanine aminotransferase (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 40 mL/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 3 years (with the exception of non-melanoma skin cancers, carcinoma in situ of the cervix and noninvasive bladder cancer).

• 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.

• Patient must be able to understand and willing to sign a written informed consent document.

EXCLUSION CRITERIA:

• Patients who have had chemotherapy, large field radiotherapy, or major surgery must wait 4 weeks prior to entering the study (2 weeks is sufficient for targeted systemic therapy provided toxicity has recovered to less than or equal to grade 1).

• Patients may not be receiving any anti-cancer 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 urine protein-to-creatinine (UPC) ratio > 1.0, a 24-hour urine protein will need to be obtained and the level should be < 2000 mg for patient enrollment.

• Uncontrolled intercurrent illness including, but not limited to, hypertension (systolic blood pressure (BP) 160, diastolic BP > 100), 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 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.

• Corrected QT interval (QTc) > 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 TRC105. HIV positive patients not receiving antiretroviral therapy are excluded due to the possibility that TRC105 may worsen their condition and the likelihood that the underlying condition may obscure the attribution of adverse events with respect to 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.

INCLUSION OF WOMEN AND MINORITIES:

-Men and women of all races and ethnic groups are eligible for this trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Tim F Greten, M.D., National Cancer Institute (NCI)

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008 Jul 24;359(4):378-90. doi: 10.1056/NEJMoa0708857.
• 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.
• 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. Epub 2003 Oct 27.

• Responsible Party: Tim Greten, M.D., Principal Investigator, National Institutes of Health Clinical Center (CC)
• ClinicalTrials.gov Identifier: NCT01375569
• Other Study ID Numbers: 110181; 11-C-0181
• First Posted: Jun 17, 2011
• Last Update Posted: Jul 28, 2017
• Last Verified: Jun 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Tim Greten, M.D., Principal Investigator, National Institutes of Health Clinical Center (CC): CD105; Monoclonal Antibody; Anti-Angiogenic; Chimeric; Apoptosis; Liver Cancer
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Hepatocellular; Liver Neoplasms

Study Results

Participant Flow

Arm/Group Title	TRC105 in Liver Cancer
Arm/Group Description	TRC105 is an experimental cancer drug designed to slow or stop the growth of tumors. It does this by preventing the growth of new blood vessels that feed these tumors. This drug is being used to test the safety and effectiveness to treat liver cancer that has not responded to standard therapy. TRC105 will be given as an intravenous infusion every two weeks.
Period Title: Overall Study
STARTED	11
COMPLETED	11
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	TRC105 in Liver Cancer
Arm/Group Description	TRC105 is an experimental cancer drug designed to slow or stop the growth of tumors. It does this by preventing the growth of new blood vessels that feed these tumors. This drug is being used to test the safety and effectiveness to treat liver cancer that has not responded to standard therapy. TRC105 will be given as an intravenous infusion every two weeks.
Overall Participants	11
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	10 90.9%
>=65 years	1 9.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.46 (12.8)
Sex: Female, Male (Count of Participants)
Female	2 18.2%
Male	9 81.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	11 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 9.1%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	5 45.5%
White	5 45.5%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	11 100%

Outcome Measures

1. Primary Outcome

Title	Time to Tumor Progression (TTP) for TRC105 in Hepatocellular Carcinoma (HCC).
Description	Time to tumor progression is defined as the proportion of participants who are progression free after 4 months on study. Progression is defined by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Progression is 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).
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	TRC105 in Liver Cancer
Arm/Group Description	TRC105 is an experimental cancer drug designed to slow or stop the growth of tumors. It does this by preventing the growth of new blood vessels that feed these tumors. This drug is being used to test the safety and effectiveness to treat liver cancer that has not responded to standard therapy. TRC105 will be given as an intravenous infusion every two weeks.
Measure Participants	11
Mean (Full Range) [Weeks]	12

2. Secondary Outcome

Title	Count of Participants With Adverse Events
Description	here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.
Time Frame	25 months, 15 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	TRC105 in Liver Cancer
Arm/Group Description	TRC105 is an experimental cancer drug designed to slow or stop the growth of tumors. It does this by preventing the growth of new blood vessels that feed these tumors. This drug is being used to test the safety and effectiveness to treat liver cancer that has not responded to standard therapy. TRC105 will be given as an intravenous infusion every two weeks.
Measure Participants	11
Count of Participants [Participants]	11 100%

Adverse Events

Time Frame	25 months, 15 days
Arm/Group Title	TRC105 in Liver Cancer
Arm/Group Description	TRC105 is an experimental cancer drug designed to slow or stop the growth of tumors. It does this by preventing the growth of new blood vessels that feed these tumors. This drug is being used to test the safety and effectiveness to treat liver cancer that has not responded to standard therapy. TRC105 will be given as an intravenous infusion every two weeks.
All Cause Mortality
	TRC105 in Liver Cancer
	Affected / at Risk (%)	# Events
Total	0/11 (0%)
Serious Adverse Events
	TRC105 in Liver Cancer
	Affected / at Risk (%)	# Events
Total	5/11 (45.5%)
Cardiac disorders
Myocardial infarction	1/11 (9.1%)	1
Hepatobiliary disorders
Hepatic failure	1/11 (9.1%)	1
Infections and infestations
Lung infection	1/11 (9.1%)	2
Investigations
Aspartate aminotransferase increased	1/11 (9.1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	1/11 (9.1%)	1
Nervous system disorders
Encephalopathy	1/11 (9.1%)	1
Other (Not Including Serious) Adverse Events
	TRC105 in Liver Cancer
	Affected / at Risk (%)	# Events
Total	11/11 (100%)
Blood and lymphatic system disorders
Anemia	7/11 (63.6%)	23
Cardiac disorders
Chest pain - cardiac	1/11 (9.1%)	1
Sinus tachycardia	2/11 (18.2%)	2
Eye disorders
Blurred vision	1/11 (9.1%)	1
Eye disorders - Other, specify (eye itchiness and redness)	1/11 (9.1%)	1
Gastrointestinal disorders
Abdominal pain	1/11 (9.1%)	1
Ascites	2/11 (18.2%)	3
Constipation	2/11 (18.2%)	2
Dry mouth	1/11 (9.1%)	1
Dyspepsia	1/11 (9.1%)	1
Gingival pain	1/11 (9.1%)	1
Hemorrhoidal hemorrhage	1/11 (9.1%)	1
Nausea	3/11 (27.3%)	3
Oral hemorrhage	3/11 (27.3%)	5
Rectal hemorrhage	1/11 (9.1%)	1
Vomiting	2/11 (18.2%)	3
General disorders
Edema limbs	6/11 (54.5%)	6
Fatigue	4/11 (36.4%)	5
Fever	2/11 (18.2%)	5
Infusion related reaction	2/11 (18.2%)	2
Pain	4/11 (36.4%)	9
Infections and infestations
Gallbladder infection	1/11 (9.1%)	1
Infections and infestations - Other, specify (oral thrush)	2/11 (18.2%)	2
Investigations
Activated partial thromboplastin time prolonged	4/11 (36.4%)	6
Alanine aminotransferase increased	6/11 (54.5%)	13
Alkaline phosphatase increased	8/11 (72.7%)	14
Aspartate aminotransferase increased	9/11 (81.8%)	27
Blood bilirubin increased	9/11 (81.8%)	19
CPK increased	1/11 (9.1%)	1
Creatinine increased	1/11 (9.1%)	4
Lymphocyte count decreased	6/11 (54.5%)	17
Neutrophil count decreased	1/11 (9.1%)	3
Platelet count decreased	5/11 (45.5%)	6
Serum amylase increased	2/11 (18.2%)	6
Weight loss	1/11 (9.1%)	1
White blood cell decreased	2/11 (18.2%)	2
Metabolism and nutrition disorders
Anorexia	2/11 (18.2%)	3
Dehydration	1/11 (9.1%)	1
Hypercalcemia	1/11 (9.1%)	3
Hyperkalemia	1/11 (9.1%)	1
Hypermagnesemia	2/11 (18.2%)	4
Hypoalbuminemia	7/11 (63.6%)	20
Hypomagnesemia	2/11 (18.2%)	2
Hyponatremia	7/11 (63.6%)	12
Hypophosphatemia	2/11 (18.2%)	2
Musculoskeletal and connective tissue disorders
Chest wall pain	1/11 (9.1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	1/11 (9.1%)	1
Nervous system disorders
Dizziness	1/11 (9.1%)	1
Dysgeusia	1/11 (9.1%)	1
Headache	7/11 (63.6%)	15
Somnolence	1/11 (9.1%)	1
Psychiatric disorders
Insomnia	1/11 (9.1%)	1
Reproductive system and breast disorders
Vaginal hemorrhage	1/11 (9.1%)	1
Respiratory, thoracic and mediastinal disorders
Cough	2/11 (18.2%)	3
Dyspnea	3/11 (27.3%)	3
Epistaxis	7/11 (63.6%)	11
Nasal congestion	2/11 (18.2%)	2
Pneumonitis	1/11 (9.1%)	1
Productive cough	1/11 (9.1%)	1
Respiratory, thoracic and mediastinal disorders - Other, specify (hemoptysis)	2/11 (18.2%)	2
Sore throat	1/11 (9.1%)	1
Skin and subcutaneous tissue disorders
Hyperhidrosis	2/11 (18.2%)	3
Telangiectasia	1/11 (9.1%)	1
Vascular disorders
Flushing	1/11 (9.1%)	1
Hypertension	1/11 (9.1%)	1
Thromboembolic event	1/11 (9.1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.