Neoplasms

All Conditions

Digestive System Diseases

Rare Diseases

Carcinoma

Cholangiocarcinoma

Carcinoma, Hepatocellular

Biliary Tract Neoplasms

Liver Neoplasms

Bile Duct Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Bile Duct Diseases

Biliary Tract Diseases

Bile Duct Cancer

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Durvalumab

Immunoglobulins

Chlorotrianisene

Tremelimumab

Antineoplastic Agents, Immunological

Flat dose of 75 mg every 4 weeks for up to 4 doses.

TACE will be performed on Day 36 (+/-96hrs).

Trans-arterial Catheter Chemoembolization (TACE)

RFA will be performed on Day 36 (+/-96hrs).

Radiofrequency Ablation (RFA)

Cryoablation will be performed on Day 36 (+/-96hrs).

Cryoablation

Tim F Greten, M.D.

BACKGROUND:

* Various tumor ablative procedures and techniques have been shown to result in immunogenic cell death and induction of a peripheral immune response. The term ablative therapies applies to trans-arterial catheter chemoembolization (TACE), radiofrequency ablation (RFA) and cryoablation (CA).
* The underlying hypothesis of this study is that the effect of immune checkpoint inhibition can be enhanced by TACE, CA and RFA in patients with advanced hepatocellular carcinoma (HCC) and biliary tract carcinomas (BTC). We have already demonstrated proof of principle as well as safety and feasibility of this approach with anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) therapy.
* Based on the concept of programmed death-ligand 1 (PDL1)-mediated adaptive resistance and the emerging role of programmed cell death protein 1 (PD1) therapy in HCC, we would like to evaluate the combination of tremelimumab and durvalumab (with ablative therapies) in HCC and BTC.

Objectives:

- To preliminarily evaluate the 6-month progression free survival (PFS) of combining tremelimumab and durvalumab in patients with advanced HCC (either alone or with cryoablation, TACE or RFA) and in patients with advanced biliary tract carcinoma (BTC) (either alone or with cryoablation or RFA).

ELIGIBILITY:

* Histologically or cytologically confirmed diagnosis of HCC or biliary tract carcinoma 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).
* Childs-Pugh A/B7 cirrhosis only is allowed. If patient does not have cirrhosis, this limitation does not apply.
* Patients must have disease that is not amenable to potentially curative resection, radiofrequency ablation, or liver transplantation.

DESIGN:

We will evaluate the combination of tremelimumab and durvalumab (with ablative therapies) in cohorts A (HCC; N=40) and B (BTC; N=30). The first N=10 patients in both cohorts will receive tremelimumab and durvalumab only (i.e. No interventional radiologic procedures).

* A: Advanced HCC, BCLC# Stage B/C

  * N= 1st 10 pts: No ablative procedure Cryoablation/RFA/TACE##
  * Tremelimumab 75mg flat dose every (q)28 days for 4 doses; Durvalumab 1500mg flat dose q28 days until end of study (EOS)###
  * 40 total: 10 trem+ dur alone; 10 trem+ dur + TACE; 10 trem + dur + RFA; 10 trem + dur + cryo
* B: Intra/extra-hepatic cholangiocarcinoma

  * N= 1st 10 patients (pts): No ablative procedure; RFA/ cryoablation
  * Tremelimumab 75mg flat dose q28 days for 4 doses; Durvalumab 1500mg flat dose q28 days until EOS###
  * 30 total: 10 trem+ dur alone; 10 trem + dur + RFA; 10 trem

    * BCLC = Barcelona clinic liver cancer staging system

      * For BCLC stage B patients TACE may be repeated as per standard of care

        * EOS = End of study treatment or meeting any of the off-treatment or off study criteria.

BACKGROUND:

* Various tumor ablative procedures and techniques have been shown to result in immunogenic cell death and induction of a peripheral immune response. The term ablative therapies applies to trans-arterial catheter chemoembolization (TACE), radiofrequency ablation (RFA) and cryoablation (CA).
* The underlying hypothesis of this study is that the effect of immune checkpoint inhibition can be enhanced by TACE, CA and RFA in patients with advanced hepatocellular carcinoma (HCC) and biliary tract carcinomas (BTC). We have already demonstrated proof of principle as well as safety and feasibility of this approach with anti-CTLA4 therapy.
* Based on the concept of PDL1-mediated adaptive resistance and the emerging role of PD1 therapy in HCC, we would like to evaluate the combination of tremelimumab and durvalumab (with ablative therapies) in HCC and BTC.

Objectives:

- To preliminarily evaluate the 6-month progression free survival (PFS) of combining tremelimumab and durvalumab in patients with advanced HCC (either alone or with cryoablation, TACE or RFA) and in patients with advanced biliary tract carcinoma (BTC) (either alone or with cryoablation or RFA).

ELIGIBILITY:

* Histologically or cytologically confirmed diagnosis of HCC or biliary tract carcinoma 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).
* Childs-Pugh A/B7 cirrhosis only is allowed. If patient does not have cirrhosis, this limitation does not apply.
* Patients must have disease that is not amenable to potentially curative resection, radiofrequency ablation, or liver transplantation.

DESIGN:

We will evaluate the combination of tremelimumab and durvalumab (with ablative therapies) in cohorts A1 (HCC; Barcelona clinic liver cancer staging system (BCLC) stage C; N=10), A2 (HCC; BCLC stages B/C; N=30) and B (BTC; N=30). The patients in cohort A1 and first 10 patients in cohort B will receive tremelimumab and durvalumab only (i.e. no interventional radiologic procedures).

A Pilot Study of Combined Immune Checkpoint Inhibition in Combination With Ablative Therapies in Subjects With Hepatocellular Carcinoma (HCC) or Biliary Tract Carcinomas (BTC)

All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request.

In addition, all large scale genomic sequencing data will be shared with subscribers to database of Genotypes and Phenotypes (dbGaP).

Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for 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.

PFS is the median amount of time subject survives without disease progression 6 months after treatment. Progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) and is defined as the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.

Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE)v4.0. Grade 1 is mild, grade 2 is moderate, grade 3 is severe, grade 4 is life-threatening, and grade 5 is death related to adverse event.

National Cancer Institute (NCI)

Principal Investigator

RFA/TACE Tremelimumab (trem) 75mg flat dose every (q)28 days for 4 doses and Durvalumab (dur) 1500mg flat dose q28 days until end of study.

30 total (e.g. Per the study design, this is the number of participants we planned to treat): 10 trem+ dur alone; 10 trem + dur + RFA; 10 trem + dur + cryoablation

Radiofrequency Ablation/Trans-arterial Catheter Chemoembolization (RFA/TACE)

Tremelimumab (trem) 75mg flat dose every (q)28 days for 4 doses and Durvalumab (dur) 1500mg flat dose q28 days until end of study.

30 total (e.g. Per the study design, this is the number of participants we planned to treat): 10 trem+ dur alone; 10 trem + dur + RFA; 10 trem + dur + cryoablation

Radiofrequency Ablation/Cryoablation (RFA/CA)

Enrolled But Not Treated

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Tim F. Greten

6 Month Progression Free Survival (PFS)

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Number of Grades 1-5 Adverse Events Related to Tremelimumab and Durvalumab

Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)

Overall Study

Spots Global Cancer Trial Database for combination of tremelimumab and durvalumab