Sorafenib and TRC105 in Hepatocellular Cancer

• Phase I: To establish the maximum tolerated dose (MTD) of TRC105 when given with standard-dose sorafenib for HCC. [ Time Frame: 6/30/2012 ] [ Designated as safety issue: Yes ]
• Phase II: To evaluate time to progression (TTP) for the combination of TR105 with sorafenib in HCC. [ Time Frame: 1/31/2014 ] [ Designated as safety issue: No ]

• To evaluate the safety [ Time Frame: 1/31/2014 ] [ Designated as safety issue: Yes ]
• To evaluate the immunogenicity [ Time Frame: 1/31/2014 ] [ Designated as safety issue: No ]
• To evaluate the overall response rate [ Time Frame: 1/31/2014 ] [ Designated as safety issue: No ]

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, and will have an examination of the esophagus to look for problems with blood vessels.

Participants will receive sorafenib tablets twice every day, in the morning and at night, with a full glass of water.

Participants will receive TRC105 infusions once every two weeks on days 1, 8, 15, and 22 of a 28-day cycle. Participants will also receive two doses of dexamethasone the day before the infusion to prevent possible side effects.

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 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

• Hepatoma
• Liver Neoplasms
• Adenoma, Liver Cell
• Carcinoma, Hepatocellular

• Drug: TRC 105
  Starting dose of 3mg/kg IV weekly with premedication regimen on days 1, 8, 15, and 22 of each cycle, dose escalation every 3 patients enrolled.
• Drug: Sorafenib
  400mg orally twice a day, every day of each cycle

• 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. No abstract available.
• 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. Epub 2003 Oct 27.
• Palmer DH. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008 Dec 4;359(23):2498; author reply 2498-9. No abstract available.

• 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 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 greater18 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 1,500/mcL without growth factor support within the past 30 days
  • Platelets greater than 60,000/mcL without transfusion support within the past 30 days
  • Hemoglobin greater than 10 g/dL without transfusion support within 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 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 are also excluded.
• 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.
• 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.