Tremelimumab With Chemoembolization or Ablation for Liver Cancer

Study Overview
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Brief Summary
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Background: - Tremelimumab is a cancer treatment drug that helps the immune system recognize and destroy cancer cells. Researchers want to see if it can be used to treat advanced liver cancer. The drug will be given with one of two types of treatment for liver cancer. The first type, transarterial catheter chemoembolization (TACE), injects chemotherapy drugs into the tumor through the main blood vessel that is feeding it. That blood vessel is then closed off to help keep the drugs in the tumor longer. The second type, radiofrequency ablation (RFA), uses a heated probe to destroy the tumor tissue. Researchers want to study how safe and effective these treatments are with the study drug. Objectives: - To test the safety and effectiveness of Tremelimumab with TACE or RFA for advanced liver cancer. Eligibility: - Individuals at least 18 years of age who have advanced liver cancer that has not responded to other treatments.

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. For patients with advanced disease sorafenib is the only approved drug and this has limited benefit. Tremelimumab is a monoclonal antibody against cytotoxic T-lymphocyte-associated protein 4 (CTLA4). Anti-CTLA4 therapy has been shown to enhance anti-tumor immunity by blocking tumor-induced immune suppression of cytotoxic T cells. Various tumor ablative procedures and techniques have been shown to result in immunogenic cell death and induction of a peripheral immune response. Both transarterial catheter chemoembolization (TACE) and radiofrequency ablation (RFA) have been shown to do this, as well as cryoablation and external beam radiation. The underlying hypothesis of this study is that the effect of anti-CTLA4 treatment can be enhanced by TACE or RFA in patients with advanced hepatocellular carcinoma. We will also evaluate this in the context of cryoablation and radiation in hepatocellular carcinoma (HCC) and RFA in cholangiocarcinoma. Objective: To assess the safety and feasibility of combining Tremelimumab with trans-arterial catheter chemoembolization (TACE) radiofrequency ablation (RFA), or cryoablation in patients with advanced HCC. Eligibility: Histologically or cytologically confirmed diagnosis of HCC. Childs-Pugh A/B7 cirrhosis only is allowed. If patient does not have cirrhosis, this limitation does not apply. Barcelona Clinic Liver Cancer (BCLC) Stage B and C patients. Patients must have disease that is not amenable to potentially curative resection, radiofrequency ablation, or liver transplantation.

Official Title
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A Pilot Study of Tremelimumab - A Monoclonal Antibody Against CTLA-4 in Combination With Trans-Arterial Catheter Chemoembolization (TACE), Radiofrequency Ablation (RFA), or Cryoablation in Subjects With Hepatocellular Carcinoma (HCC) or Biliary Tract Carcinomas (BTC)

Conditions
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Heptocellular Cancer, Biliary Tract Neoplasms, Liver Cancer, Hepatocellular Carcinoma, Biliary Cancer

Intervention / Treatment
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* Drug: Tremelimumab
* Procedure: RFA
* Procedure: TACE
* Procedure: Cryoablation


Participation Criteria
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Eligibility Criteria
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-INCLUSION CRITERIA: Patients must have histopathological confirmation of hepatocellular carcinoma (HCC) or (Cohort E only) biliary tract carcinoma (BTC) 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 (or biliary tract carcinoma in Cohort E). Fibrolammelar variant is also allowed. For cohort E, the term BTC includes intraor extrahepatic cholangiocarcinoma, gallbladder cancer or ampullary cancer, as long as there is an intrahepatic component amenable to radiofrequency ablation (RFA). Patients must have disease that is not amenable to potentially curative resection, transplantation or ablation. For Cohorts A, C and D patients must have progressed on, been intolerant to, or refused prior sorafenib therapy. Cohort E patients must have received at least one line of chemotherapy for BTC. Disease must be technically amenable to transhepatic arterial chemoembolization (TACE), radiofrequency ablation (RFA) or cryoablation. Each case will be discussed at gastrointestinal (GI) tumor board with interventional radiology. Patients must have evaluable disease. If liver cirrhosis is present, patient must have a Child-Pugh A/B7 classification. 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: leukocytes greater than or equal to 3,000/mcL absolute neutrophil count greater than or equal to 1,000/mcL platelets greater than or equal to 60,000/mcL total bilirubin, If cirrhosis present: Part of Child Pugh requirement. If no cirrhosis: Bili should be less than or equal to 2 times upper limit of normal (ULN) Serum albumin, If cirrhosis present: Part of Child Pugh requirement. If no cirrhosis: albumin should be greater than or equal to 2.5g/dl Patients are eligible with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) up to 5 times ULN. creatinine, less than 1.5 times institution upper limit of normal OR creatinine clearance greater than or equal to 45 mL/min/1.73 m(2), as calculated below, for patients with creatinine levels above institutional normal 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, non-invasive bladder cancer or localized prostate cancer for whom systemic therapy is not required). Patient must be able to understand and willing to sign a written informed consent document. EXCLUSION CRITERIA: Patients who have had standard of care chemotherapy, large field radiotherapy, or major surgery must wait 2 weeks prior to entering the study. For recent experimental therapies a 28 day period of time must elapse before treatment. Patients who have undergone prior liver transplantation are ineligible. 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. Uncontrolled intercurrent illness including, but not limited to, ongoing or active systemic infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia (excluding insignificant sinus bradycardia and sinus tachycardia) or psychiatric illness/social situations that would limit compliance with study requirements. History of chronic autoimmune disease (e.g., Addison's disease, multiple sclerosis, Graves disease, Hashimoto's thyroiditis, rheumatoid arthritis, hypophysitis, etc.) with symptomatic disease within the 3 years before randomization. Note: Active vitiligo or a history of vitiligo will not be a basis for exclusion. Dementia or significantly altered mental status that would prohibit the understanding or rendering of Information and Consent and compliance with the requirements of the protocol. Diverticulitis (either active or history of) within the past 2 years. Note that diverticulosis is permitted. Active or history of inflammatory bowel disease (colitis, Crohn's), irritable bowel disease, celiac disease, or other serious, chronic, gastrointestinal conditions associated with diarrhea. Active or history of systemic lupus erythematosus or Wegener's granulomatosis. Currently receiving immunosuppressive doses of steroids or other immunosuppressive medications (inhaled and topical steroids are permitted) History of sarcoidosis syndrome Patients should not be vaccinated with live attenuated vaccines within 1 month of starting Tremelimumab treatment. 12 Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) 13. HIV-positive patients receiving anti-retroviral therapy are excluded from this study due to the possibility of pharmacokinetic interactions between antiretroviral medications and Tremelimumab. HIV positive patients not receiving antiretroviral therapy are excluded due to the possibility that Tremelimumab may worsen their condition and the likelihood that the underlying condition may obscure the attribution of adverse events. 14. History of hypersensitivity reaction to human or mouse antibody products. 15. Pregnancy and breast feeding are exclusion factors. The effects of Tremelimumab on the developing human fetus are unknown. 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. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. 16. Patients with unhealed surgical wounds for more than 30 days.

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pilot 1/Arm A1-Tremelimumab + RFA or TACE<br>Escalating doses of Tremelimumab + Radiofrequency Ablation (RFA) or Transarterial Catheter Chemoembolization (TACE) | Drug: Tremelimumab<br>* 3.5 mg/kg or 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years<br>* Other names: Ticilimumab;Procedure: RFA<br>* Performed on Day 36<br>* Other names: Radiofrequency Ablation;Procedure: TACE<br>* Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated)<br>* Other names: Transarterial Catheter Chemoembolization;|
| Experimental: 2/Arm A2 - Tremelimumab + RFA or TACE<br>Tremelimumab + Radiofrequency Ablation (RFA) or Transarterial Catheter Chemoembolization (TACE) | Drug: Tremelimumab<br>* 3.5 mg/kg or 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years<br>* Other names: Ticilimumab;Procedure: RFA<br>* Performed on Day 36<br>* Other names: Radiofrequency Ablation;Procedure: TACE<br>* Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated)<br>* Other names: Transarterial Catheter Chemoembolization;|
| Experimental: 3/Arm B - Tremelimumab + TACE<br>Tremelimumab + Transarterial Catheter Chemoembolization (TACE) | Drug: Tremelimumab<br>* 3.5 mg/kg or 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years<br>* Other names: Ticilimumab;Procedure: TACE<br>* Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated)<br>* Other names: Transarterial Catheter Chemoembolization;|
| Experimental: 4/Arm C (never opened)<br>Tremelimumab + Radiofrequency Ablation (RFA) or Transarterial Catheter Chemoembolization (TACE) | Drug: Tremelimumab<br>* 3.5 mg/kg or 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years<br>* Other names: Ticilimumab;Procedure: TACE<br>* Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated)<br>* Other names: Transarterial Catheter Chemoembolization;Procedure: Cryoablation<br>* Performed on Day 36<br>|
| Experimental: 5/Arm D - Tremelimumab + Cryoablation<br>Tremelimumab + Cryoablation | Drug: Tremelimumab<br>* 3.5 mg/kg or 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years<br>* Other names: Ticilimumab;Procedure: Cryoablation<br>* Performed on Day 36<br>|
| Experimental: 6/Arm E - Tremelimumab + RFA<br>Tremelimumab + Radiofrequency Ablation (RFA) | Drug: Tremelimumab<br>* 3.5 mg/kg or 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years<br>* Other names: Ticilimumab;Procedure: RFA<br>* Performed on Day 36<br>* Other names: Radiofrequency Ablation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Serious and Non-Serious Adverse Events Regardless of Attribution | 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. | Date treatment consent signed to date off study, approximately 44 months and 5 days for 1/Arm A1; 49 months and 26 days for 2/Arm A2; 1 month and 26 days for 3/Arm B; 30 months and 20 days for 5/Arm D; and 34 months and 25 days for 6/Arm E. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Best Response | Best response was assessed by the combined Response Evaluation Criteria in Solid Tumors (RECIST and the Modified Immune-Related Response Criteria (irRC). Complete Response (CR) is disappearance of all target lesions. Any patjhological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. 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. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. Progressive Disease (PD) is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if it is the smallest on study). The appearance of one or more lesions is also considered progressions. | Start of study, baseline target lesions until disease progression occurs with 20% increase of target lesions or appearance of new lesions, up to 13.1 months | 
| Progression Free Survival (PFS) | Progression free survival is defined as the amount of time a subject survives without disease progression after treatment. Progression is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if it is the smallest on study). The appearance of one or more lesions is also considered progressions. | Progression free survival is time patients were off treatment until death. For all cohorts progression free survival ranged from 3.4 months to 8.6 months | 
| Overall Survival | Overall survival is defined as the amount of time a subject survives after therapy. | From the time of initial treatment consent until date of death for each patient. Overall survival ranged from 6 months to 13.1 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Blocking of Immune Suppression, Monoclonal Antibody, Immunotherapy, Ablative Therapy