Sorafenib and TRC105 in Hepatocellular Cancer | NCT01306058

ID	Type	Description	Link
11-C-0102

Description Module

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.

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.
TRC105 is a chimeric anti-angiogenic monoclonal antibody that binds cluster of differentiation 105 (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 determine the estimate response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria for the combination of TRC105 with sorafenib in HCC.

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 was 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 is taken orally at a dose of 400 mg twice daily. TRC105 is 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 was escalated in cohorts of 3 to 6 patients up to a maximum of 15 mg/kg every two weeks. Intra-patient dose escalation was not allowed.
Phase II: TRC105 will be administered as an intravenous infusion every two weeks at the recommended phase II dose, 15 mg/kg of TRC105 ever two weeks in combination with standard dose sorafenib, defined in phase I. The sample size and interim stopping rule will be determined using a Simon optimal two-stage design. The first stage will initially enroll 6 evaluable patients, and if 0 of the 6 have a clinical response, then no further patients will be accrued. If 1 or more of the first 6 patients has a clinical response, then accrual would continue until a total of 23 patients have been enrolled. As it may take several weeks to determine if a patient has experienced a response, a temporary pause in the accrual may be necessary to ensure that enrollment to the second stage is warranted. If there are 1 to 2 clinical responses in 23 patients, this would be an uninterestingly low response rate. If there were 3 or more complete responses in 23 patients (13.0%), this would be sufficiently interesting to warrant further study in later trials. Under the null hypothesis (5% response rate), the probability of early termination is 73.5%.

Cohort: -0; Sorafenib (mg by mouth (PO) twice daily): 400 bid; TRC105 (mg/kg intravenous (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

Label	Type	Description	Intervention Names
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

Name	Type	Description	Arm Group Labels	Other Names
TRC 105	Drug	15 mg/kg intravenous (IV) every 2 weeks	Sorafenib & TRC105 in Hepatocellular CA

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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

Measure	Description	Time Frame
Overall Response Rate (ORR) as Determined by the Standard Response Evaluation Criteria in Solid Tumors (RECIST) Criteria	Overall response (Complete Response (CR) + Partial Response (PR) was assessed by the Standard Response Evaluation Criteria in Solid Tumors (RECIST) criteria for target lesions and assessed by magnetic resonance imaging (MRI). CR is disappearance of all target lesions. PR is at least a 30% decrease in the sum of the longest diameter of target lesions.

Eligibility Module

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.

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.
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 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).
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.

Name	Affiliation	Role
Tim F Greten, M.D.	National Cancer Institute (NCI)	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
National Institutes of Health Clinical Center, 9000 Rockville Pike		Bethesda	Maryland	20892	United States

PubMed Identifier	Type	Citation	Retractions
11668491	Background	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.
14581446	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.

Label	URL
NIH Clinical Center Detailed Web Page	View source

ID	Title	Description
FG000	Sorafenib & TRC105 in Hepatocellular CA	CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day TRC 105: 15 mg/kg IV every 2 weeks Sorafenib: 400 mg twice a day (bid) continuously in a 28 days cycle

ID	Title	Description
BG000	Sorafenib & TRC105 in Hepatocellular CA	CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day TRC 105: 15 mg/kg IV every 2 weeks Sorafenib: 400 mg twice a day (bid) continuously in a 28 days cycle

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Categorical			Count of Participants

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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.

24/27 analyzed. One patient signed consent but developed rapid disease progression and did not receive any treatment. One patient developed a fatal myocardial infarction and one patient developed a grade 3 cerebral tumor hemorrhage.

Posted

Number

mg/kg

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

ID	Title	Description

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Sorafenib & TRC105 in Hepatocellular CA	CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day TRC 105: 15 mg/kg IV every 2 weeks Sorafenib: 400 mg twice a day (bid) continuously in a 28 days cycle

ID	Term
D006528	Carcinoma, Hepatocellular
D008113	Liver Neoplasms
D018248	Adenoma, Liver Cell
D008114	Liver Neoplasms, Experimental

ID	Term
D000230	Adenocarcinoma
D002277	Carcinoma
D009375	Neoplasms, Glandular and Epithelial
D009370	Neoplasms by Histologic Type

ID	Term
C579557	carotuximab
D000077157	Sorafenib

ID	Term
D010671	Phenylurea Compounds
D014508	Urea
D000577	Amides
D009930	Organic Chemicals