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

Summary

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.

Conditions

• Biliary Tract Neoplasms
• Liver Cancer
• Hepatocellular Carcinoma
• Cholangiocarcinoma
• Bile Duct Cancer

Interventions

DRUG

Durvalumab

Flat dose of 1500 mg every 4 weeks.

DRUG

Tremelimumab

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

PROCEDURE

Trans-arterial Catheter Chemoembolization (TACE)

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

PROCEDURE

Radiofrequency Ablation (RFA)

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

PROCEDURE

Cryoablation

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

Sponsors & Collaborators

• National Cancer Institute (NCI)

  lead NIH

Principal Investigators

• Tim F Greten, M.D. · National Cancer Institute (NCI)

Study Design

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2016-07-05

Primary Completion

2021-02-17

Completion

2022-12-31

FDA Drug

Yes

Countries

• United States

Study Locations