Know Cancer

or
forgot password

A Phase I/II Study of TRC105 in Combination With Sorafenib in Hepatocellular Carcinoma (HCC)


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Hepatoma, Liver Neoplasms, Adenoma, Liver Cell, Carcinoma, Hepatocellular

Thank you

Trial Information

A Phase I/II Study of TRC105 in Combination With Sorafenib in Hepatocellular Carcinoma (HCC)


Background:

- Worldwide, hepatocellular carcinoma (HCC) is the fifth most common malignancy with a
median survival of 6-9 months. The SHARP study established sorafenib as a standard
consideration in this disease and set the bar for future studies of systemic therapy.

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

- Phase I: To establish the maximum tolerated dose (MTD) of TRC105 when given with
standard-dose sorafenib for HCC.

- Phase II: To evaluate time to progression (TTP) for the combination of TR105 with
sorafenib in HCC.

Secondary:

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

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

- To evaluate the overall response rate (ORR) for TRC105 and sorafenib in HCC as
determined by both standard and EASL-modified RECIST criteria.

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

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

Eligibility:

- Histologically or cytologically confirmed diagnosis of HCC.

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

- Patients must have disease that is not amenable to potentially curative resection,
radiofrequency ablation, or liver transplantation.

- In phase I, prior systemic therapy is allowed.

- In phase II, prior systemic therapy for HCC (including sorafenib) is allowed.

- No history of bleeding varices in previous 1 year (unless subsequent liver transplant).

- No anti-coagulation (except low-dose aspirin).

Design:

- TRC105 will be administered intravenously every two weeks, on days 1 and 15 of each 28
day cycle. Sorafenib will be self-administered twice daily by mouth.

- Phase 1: The first part of this study is a standard 3+3 dose escalation phase I study
with the primary objective of establishing MTD for TRC105 when given in combination
with standard-dose sorafenib. Sorafenib will be taken orally at a dose of 400 mg twice
daily. TRC105 will be administered as an intravenous infusion every two weeks. Patients
will be restaged including imaging studies to assess for response and progression every
8 weeks. The TRC105 dose will be escalated in cohorts of 3 to 6 patients up to a
maximum of 15 mg/kg every two weeks (see table below). Intra-patient dose escalation is
not allowed.

- Phase II: TRC105 will be administered as an intravenous infusion every two weeks at the
MTD defined in phase I. The sample size and interim stopping rule will be determined
using a Simon optimal two-stage design. In addition there will be stopping rules for
safety. If 10 or fewer of the initial 21 patients are progression-free after six 28-day
cycles (3 imaging assessments), then accrual will be terminated early and the trial
declared to have a negative result. If 11 or more of the initial 21 patients are
progression-free at 6 months, enrollment will continue to a total of 45 patients.

Cohort: -0; Sorafenib (mg PO twice daily): 400 bid; TRC105 (mg/kg IV weekly): 1

Cohort: 1; Sorafenib (mg PO twice daily): 400 bid; TRC105 (mg/kg IV weekly): 3

Cohort: 2; Sorafenib (mg PO twice daily): 400 bid; TRC105 (mg/kg IV weekly): 6

Cohort: 3; Sorafenib (mg PO twice daily): 400 bid; TRC105 (mg/kg IV weekly): 10

Cohort: 4; Sorafenib (mg PO twice daily): 400 bid; TRC105 (mg/kg IV weekly): 15

Inclusion 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.

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Phase I: To establish the maximum tolerated dose (MTD) of TRC105 when given with standard-dose sorafenib for HCC.

Outcome Time Frame:

6/30/2012

Safety Issue:

Yes

Principal Investigator

Tim F Greten, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

110102

NCT ID:

NCT01306058

Start Date:

February 2011

Completion Date:

January 2014

Related Keywords:

  • Hepatoma
  • Liver Neoplasms
  • Adenoma, Liver Cell
  • Carcinoma, Hepatocellular
  • Hepatocellular Carcinoma
  • TRC105
  • Sorafenib
  • Liver Cancer
  • Monoclonal Antibody
  • Adenoma
  • Neoplasms
  • Carcinoma
  • Liver Neoplasms
  • Carcinoma, Hepatocellular
  • Adenoma, Liver Cell

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892