Sorafenib and TRC105 in Hepatocellular Cancer

Study Overview
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Brief Summary
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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
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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

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

Conditions
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Adenoma, Liver Cell, Hepatoma, Liver Neoplasms, Carcinoma, Hepatocellular, Liver Neoplasms, Experimental

Intervention / Treatment
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* Drug: TRC 105
* Drug: Sorafenib


Participation Criteria
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Eligibility Criteria
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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 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sorafenib & TRC105 in Hepatocellular CA<br>CA (cancer); 15 mg/kg TRC105 intravenous (IV) every 2 weeks and 400 mg sorafenib by mouth (PO) twice per day | Drug: TRC 105<br>* 15 mg/kg intravenous (IV) every 2 weeks<br>Drug: Sorafenib<br>* 400 mg twice a day (bid) continuously in a 28 days cycle<br>* Other names: Nexavar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 Outcome Measures

| Outcome Measure | 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. | 2 years | 
| 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 | 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. | 2 years | 
| Patients Who Developed Antidrug Antibodies | Patients who develop antidrug antibodies is measured by human anti-chimeric antibody (HACA) formation (e.g. immunogenicity of TRC105). | Cycle 1 Day 1, 28 days post end of study (up to 2 years) | 
| Immunogenicity of TRC105 as Measured by Human Anti-mouse Antibody (HAMA) Formation | 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. | Baseline and then 28 days following the end of the study treatment, approximately two years | 
| Number of Participants With Serious and Non-serious Adverse Events by Common Terminology Criteria in Adverse Events (CTCAE)v4.0 | 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. | 4 years and 10.5 months | 
| Number of Participants With Dose Limiting Toxicity (DLT) | 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. | First 28 days of treatment (cycle 1) | 
| Treatment-emergent Adverse Events | 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. | 4 years and 10.5 months | 
| Median Progression-free Survival (PFS) | 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). | up to 6 months | 
| Percentage of Participants With Progression Free Survival (PFS) at 3 and 6 Months | 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). | 3 and 6 months | 
| Median Overall Survival (OS) | 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. | up to 2 years | 
| Percentage of Participants With Overall Survival (OS) at 6 and 12 Months | Percentage of participants last known to be alive at 6 and 12 months. | 6 and 12 months | 
| Number of Participants With Stable Disease, Partial Response, and Progressive Disease on Phase I and Phase II of the Clinical Trial | 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). | Every 8 weeks, up to 180 days | 
| Area Under the Plasma Concentration | 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. | Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, and prior to start of TRC105 infusion | 
| Changes in Biomarkers Vascular Endothelial Growth Factor (VEGF) and Placenta Growth Factor (PIGF) | 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. | Cycle 1 day 1, cycle 1 day 15, cycle 2 day 1, or end of study, an average of 12 weeks | 
| Changes in Biomarker Cluster of Differentiation 105 (CD105) | 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. | Cycle 1 day 1, cycle 1 day 15, cycle 2 day 1, or end of study (eos), an average of 12 weeks | 
| Percentage Signal Change in Response on Magnetic Resonance Imaging (MRI) | 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. | Baseline and Cycle 1 Day 2 and Cycle 2 Day 1, an average of 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatocellular Carcinoma, TRC105, Sorafenib, Liver Cancer, Monoclonal Antibody