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Carcinoma, Hepatocellular

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Neoplasms, Experimental

Adenoma, Liver Cell

Liver Neoplasms, Experimental

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

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Sorafenib

Protein Kinase Inhibitors

Enzyme Inhibitors

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

TRC 105

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

Tim F Greten, M.D.

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.

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

Sorafenib and TRC105 in Hepatocellular Cancer

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

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).

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.

Overall response (Complete Response (CR) + Partial Response (PR) was assessed by the European Association for the Study of the Liver (EASL)-modified 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.

Patients who develop antidrug antibodies is measured by human anti-chimeric antibody (HACA) formation (e.g. immunogenicity of TRC105).

A 5mL blood sample will be collected to assess immunogenicity. Immunogenicity will be measured by the enzyme-linked immunosorbent assay (ELISA) and expressed in titres. The higher the titre, the higher the formation of HAMA antibody in the blood. A higher concentration of HAMA (higher titre result) is a negative finding. A higher level means the drug elimination is faster and the TRC 105 is then less effective. Lower level is 0-2 titre. Any value above 2 titre would be a positive HAMA result. The HAMA ( Human anti-mouse antibody) measurement at 28 days post treatment levels provides information as to the rate of drug elimination and effectiveness. Patients with 0 to \< 2.0 titre. eliminates the TRC 105 slower and the drug may be more effective than patients who have a low(\>2.0 titres) or high level of HAMA. Higher levels of HAMA reflect the TRC 105 elimination from the body faster and the drug potentially not as effective as negative HAMA titres.

Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

DLT was assessed by the Common Terminology Criteria in Adverse Events (CTCAE) v4.0. 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.

Here are the number of treatment-emergent adverse events categorized by Any grade, Grade 3, Grade 4 and Grade 5 adverse events. Adverse events was assessed by the Common Terminology Criteria in Adverse Events (CTCAE) v4.0. Grade 1 is mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 is moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL) (e.g. preparing meals, shopping for groceries or clothes). Grade 3 is severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL (e.g. bathing, dressing and undressing). Grade 4 is life-threatening consequences; urgent intervention indicated. Grade 5 is death related to adverse event.

PFS was calculated from the on-study date until date of progression, death, or an event that would render the patient inevaluable for further follow-up (liver dysfunction), or end of study. Probabilities were determined using the Kaplan-Meier method. 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).

Percentage of participants who were progression free at 3 and 6 months. 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).

OS was calculated from the on-study date until the date of death or the date the patient was last known to be alive. Probabilities were determined using the Kaplan-Meier method.

Percentage of participants last known to be alive at 6 and 12 months.

Response is defined as per the Response Evaluation Criteria in Solid Tumors (RECIST). Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. To be assigned a confirmed PR, changes in tumor measurements must be confirmed by repeat assessments that should be performed at least 4 weeks after the criteria for response are first met. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum of diameters on study. PD 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. 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).

Mean peak TRC105 serum trough concentrations were plotted over time by dose level to assess accumulation. (e.g. drug absorption). The lower limit of quantification (LLOQ) is 200 ng/mL.

Plasma biomarker tests were performed for VEGF and PIGF using assay plates from Meso-Scale Discovery according to the product manual. The concentrations of the cytokines were determined with recombinant standards. Changes in biomarkers were determined by a Wilcoxon signed rank test.

Blood samples were collected and analyzed by the enzyme-linked immunosorbent assay (ELISA). Serum samples were measured using a validated ELISA with a lower limit of quantification (LLOQ) of 200 ng/ml. Soluble endoglin was only assessed in patient samples without detectable TRC105 concentrations.

The perfusion of tumors was evaluated and analysis of normalized signal intensity in unenhanced and enhanced MRIs at each time point with calculation of measured percentage of signal change to reflect tumor vascularity. Signal change and signal intensity is defined as the Initial Area Under the Gd Curve measured over 60 seconds (IAUC60) and the Transport Constant (Ktrans) and the difference in these values relative to baseline.

National Cancer Institute (NCI)

Principal Investigator

16 deaths are not included in the serious adverse event table because this study was originally not under the death related to disease serous adverse event. The deaths were reported in the continuing reviews.

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

Sorafenib & TRC105 in Hepatocellular CA

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Hepatitis B Virus (HBV)

Hepatitis C Virus (HCV)

Cryptogenic

Hematochromatosis

Hepatitis B virus is a viral infection that affects the liver. Hepatitis C virus is a virus spread by infected blood (e.g. share needles). Crytogenic means the cause of the disease is unknown. Hematochromatosis is an iron disorder in which the body has an excess of iron in the blood.

One patient was enrolled and signed consent but developed rapid disease progression and did not receive any treatment. One patient developed a fatal myocardial infarction.

Participant Etiology of Hepatocellular Cancer (HCC)

Child Pugh Score - 5

Child Pugh Score - 6

Child Pugh Score - 7

The Modified Child-Pugh classifies the severity of liver disease according to the degree of ascites, plasma concentrations of bilirubin and albumin, the prothrombin time and degree of encephalopathy. A total score of 5-6 is considered grade A (well-compensated disease); 7-9 grade B (significant functional compromise) and 10-15 is grade C (decompensated disease). NA = not all patients had cirrhosis. You only do a Pugh Score if cirrhosis is present.

Baseline Child Pugh Score

Extrahepatic is defined as disease outside of the liver.

Number of Participants with Extrahepatic disease

No prior intervention

≥2 locoregional procedures

Previous TACE

Surgery

Ablation

Radioembolization

Transplant

Of note, some patients received more than one prior therapeutic intervention. Transcatheter arterial chemoembolization (TACE) is performed to restrict blood flow. Ablation is a procedure to destroy cardiac tissue. Radioembolization is a combination of embolization and radiation therapy to treat liver cancer. Locoregional is a recurrence of cancer at the same original site of disease. Transplant refers to a liver transplant.

Prior Therapies

Number of Participants with Liver Cirrhosis

Grade 0

Grade 1

ECOG Grade 0 is normal activity. Fully active, able to carry on all-pre-disease performance without restriction. Grade 1 is symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature. Grade 2 is in bed \<50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work activities. Grade 3 is in bed \>50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. Grade 4 is 100% bedridden. Completely disabled. Grade 5 is dead.

Eastern Cooperative Oncology Group (ECOG) Performance Status

Hepatocellular Cancer (HCC)

Fibrolamellar

HCC is liver cancer usually found in patients with cirrhosis or liver disease. Fibolamellar is a rare form of HCC. The tumor cells are mixed with fibrous layers.

Participants with Hepatocellular Cancer & Fibrolamellar

Dr. Tim Greten

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.

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

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

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

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

11/27 were analyzed because only 11 patients were evaluable at the highest dose level given to patients.

Patients Who Developed Antidrug Antibodies

Baseline

no evidence of HAMA 28 days post treatment

Low level of HAMA 28 days post treatment

High level of HAMA 28 days post treatment

9/20, 8/20, and 3/20 participants were evaluable for the noted time periods below.

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

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

Number of Participants With Dose Limiting Toxicity (DLT)

Any Grade Headache

Any Grade Epistaxis

Any Grade Increased aspartate aminotransaminase

Grade 3 Increased aspartate aminotransaminase

Any Grade Rash, other

Grade 3 Rash, other

Any Grade Hypophosphatemia

Grade 3 Hypophosphatemia

Any Grade Hypoalbuminemia

Grade 3 Hypoalbuminemia

Any Grade Anemia

Grade 3 Anemia

Any Grade Fatigue

Any Grade Increased alkaline phosphatase

Grade 3 Increased alkaline phosphatase

Any Grade Diarrhea

Grade 3 Diarrhea

Any Grade Increased blood bilirubin

Grade 3 Increased blood bilirubin

Grade 4 Increased blood bilirubin

Any Grade Nausea

Any Grade Increased alanine transaminase

Any Grade Oral mucositis/pain

Any Grade Thrombocytopenia

Grade 3 Thrombocytopenia

Any Grade Amylase

Grade 3 Amylase

Grade 4 Amylase

Any Grade Abdominal pain

Any Grade Hand-foot skin reaction

Grade 3 Hand-foot skin reaction

Any Grade Infusion reaction

Grade 3 infusion reaction

Any Grade Neutropenia

Any Grade Weight loss

Any Grade Hypertension

Grade 3 Hypertension

Any Grade Vomiting

Any Grade Hypomagnesemia

Any Grade Alopecia

Any Grade Insomnia

Any Grade Constipation

Grade 3 Intracranial hemorrhage

Grade 5 Myocardial ischemia

Grade 4 Lipase

Any Grade Hyperglycemia

Grade 3 Hyperglycemia

Grade 4 Hyperuricemia

25/27 analyzed. One patient developed a fatal myocardial infarction and one patient developed a grade 3 cerebral tumor hemorrhage.

Treatment-emergent Adverse Events

Median Progression-free Survival (PFS)

3 month PFS

6 month PFS

Percentage of Participants With Progression Free Survival (PFS) at 3 and 6 Months

Median Overall Survival (OS)

6 month OS

12 month OS

Percentage of Participants With Overall Survival (OS) at 6 and 12 Months

Phase I - Stable disease

Phase I - Progressive disease

Phase I - Partial response

Phase 2 - Stable disease

Phase 2 - Partial response

Phase 2 - Progressive disease

7/27 participants were not evaluable (1 was not evaluable, 1 patient had dose limiting toxicity myocardial infarction, 1 could not tolerate sorafenib, 1 infusion reaction to TRC105 during first dose, 1 early progressive disease, 1 side effects, and 1 off due to severe skin toxicity).

Number of Participants With Stable Disease, Partial Response, and Progressive Disease on Phase I and Phase II of the Clinical Trial

Dose level 1

Dose level 2

Dose level 3

Dose level 4

Area Under the Plasma Concentration

VEGF cycle 1 day 1

PIGF cycle 1 day 1

VEGF cycle 1 day 15

PIGF cycle 1 day 15

VEGF cycle 2 day 1

PIGF cycle 2 day 1

VEGF end of study (eos)

PIGF end of study (eos)

Changes in Biomarkers Vascular Endothelial Growth Factor (VEGF) and Placenta Growth Factor (PIGF)

Cycel 1 Day 1

Cycle 1 Day 15

Cycel 2 day 1

End of study (eos)

Changes in Biomarker Cluster of Differentiation 105 (CD105)

This analysis was not done as magnetic resonance imaging (MRI) scans not performed as planned.

Percentage Signal Change in Response on Magnetic Resonance Imaging (MRI)

Overall Study

Spots Global Cancer Trial Database for liver neoplasms, experimental