Clinical trial NCT01375569: TRC105 for Liver Cancer That Has Not Responded to Sorafenib
Official title: A Phase II Study of TRC105 in Patients With Hepatocellular Carcinoma (HCC) Who Have Progressed on Sorafenib
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hepatocellular Carcinoma
Hepatocellular Cancer
Carcinoma, Hepatocellular
Keywords: CD105
Monoclonal Antibody
Anti-Angiogenic
Chimeric
Apoptosis
Liver Cancer
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2011-06-17
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: * 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.

Primary outcomes:
measure: Time to Tumor Progression (TTP) for TRC105 in Hepatocellular Carcinoma (HCC).
timeFrame: 2 years
Secondary outcomes:
measure: Count of Participants With Adverse Events
timeFrame: 25 months, 15 days
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Tim F Greten, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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, Haussinger 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.