National Translational Science Network of Precision-based Immunotherapy for Primary Liver Cancer

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Brief Title

National Translational Science Network of Precision-based Immunotherapy for Primary Liver Cancer

Official Title

A National Translational Science Network of Precision-based Immunotherapy for Primary Liver Cancer (PLC)

Brief Summary


      Primary Liver Cancer is the second most common cause of cancer-related death worldwide. It is
      the cancer with the fastest rising incidence and mortality in the United States. Researchers
      want to learn more about liver cancer to help them design better treatments.


      To better understand liver cancer.


      People ages 18 and older who have liver cancer and had or are planning to have immune therapy


      Participants will be screened with a review of their medical records. They will be asked
      about their medical history and test results.

      Participants will come to the NIH Clinical Center. During this visit, their medical records,
      test results, imaging studies, and tissue samples (if available) will be gathered.
      Participants will learn the results of a test to see if they have any mutations known to be
      connected to cancer. They will learn if there are treatment options for them. Participants
      will give blood, urine, and stool samples or rectal swabs.

      Participants will not have follow-up visits just for this study. If they join another NIH
      research study and have visits for this other study, their medical records; test results; and
      blood, urine, and stool samples may be collected. This will occur about every 3 months. If
      they have a biopsy or surgery on another study or as part of treatment and there is leftover
      tissue, researchers would like to collect some of that tissue.

      Participants will be contacted every 6 months by phone or e-mail. They will be asked about
      their health. They will provide any medical records, test results, and imaging studies.

      Participants will be followed on this study for life.

Detailed Description


        -  Primary liver cancer (PLC) is the 2nd most common cause of cancer-related death
           worldwide and the one cancer with the fastest rising incidence and mortality in the U.S.
           PLC consists of two main histological subtypes, i.e., hepatocellular carcinoma (HCC) and
           cholangiocarcinoma (CCA), in which diagnoses and treatment decisions are solely based on
           their baseline clinical features. However, whether these subtypes are truly distinct or
           share some fundamental features which can be pursued to improve clinical management is
           currently unclear. In addition, chronic liver diseases, due to complex etiologies such
           as viral hepatitis, alcohol consumption, chemicals, parasites or dietary factors,
           underlie and contribute to liver damage, increasing the risk of HCC and CCA development
           and progression. Consequently, PLC is clinically and biologically heterogeneous which
           has impeded biological assessment and clinical treatment.

        -  Despite considerable efforts towards improving diagnosis and development of new
           treatment modalities, the improvement of PLC patient survival is minimal. For certain
           patients at early or intermediate disease stages, resection and percutaneous local
           ablation or Transarterial chemoembolization are available. However, the majority of
           patients present at advanced stages of disease, where the current gold standard of
           treatment is sorafenib, providing only a minimal improvement in survival time. PLC
           therefore remains among the most difficult-to-treat malignancies, with a 5-year survival
           rate of less than 15% in the United States. Thus, it is imperative that new treatment
           modalities are developed to limit cancer development and treat advanced PLC.

        -  Immunotherapy (IO) is a promising new approach in PLC treatment. Alterations of the
           immune system, a component of the revised hallmarks of cancer, is recognized as a
           central player in carcinogenesis and cancer progression. Thus, strategies to inhibit or
           re-direct the immune response to the presence of tumors are currently being employed or
           developed. Immune-checkpoint inhibitors have shown promise in clinical trials of several
           solid tumors. Of particular note are monoclonal antibody-based therapy to block
           immune-inhibitory molecules, including programmed cell death protein-1 (PD-1),
           programmed cell death 1 ligand 1 (PDL-1) and cytotoxic T lymphocyte antigen 4 (CTLA4),
           which block anti-tumor T cell activity. However, the capacity of these therapies to
           reduce incidence and progression of PLC are still relatively unknown. Currently, several
           trials are underway to study the impact of immune checkpoint inhibitors as single agents
           or in combination with targeted therapy, on PLC development and outcome. Initial
           findings from Phase I/II clinical trials of PLC are promising but suggest that only
           certain patients respond to such treatment regimens while others do not or suffer from
           resistance/relapse. At the moment, it is difficult to determine which patient may
           benefit from immune therapy, due in large part to the lack of large comprehensive
           studies, biobank resources of specimens and biospecimen collection in clinical trial
           protocols, which deter our ability to understand and define critical genomic or genetic
           factors that contribute to patient response. Hence, we plan to collect PLC patient
           specimens and clinical data from those undergoing immunotherapies at NIH Clinical Center
           and a few extramural clinical sites to develop predictors for (a) response or resistance
           to immunotherapy and (b) acquired resistance to immunotherapy.


      - To establish a biospecimen repository for genomic, genetic and epigenetic analysis to study
      the biology of PLC development and progression.


        -  Patients with histologically/ultrasound/imaging confirmed or suspicious lesions of HCC
           or CCA.

        -  Patients with planned or a history of at least 1 dose of immunotherapy for HCC or CCA

        -  Age >= 18 years old at date of study consent


        -  This will be a long-term multi-center study to comprehensively study patients with
           primary liver cancer (PLC).

        -  Participants will provide clinical information (including medical history, clinical
           tests, imaging studies and reports, surgical pathology reports, genetic test results).

        -  Tissue samples, blood, urine and fecal samples will be obtained from participants during
           this study.

        -  Broad spectrum of scientific experiments, including genomics, metabolome, microbiome and
           immune monitoring will be performed.

        -  Local physicians will be provided with test results of genomics panel evaluation
           (TruSight Oncology 500 (TSO-500).

        -  Since long-term follow-up of individuals with PLC is a major feature of the study, we
           intend to maintain active contact with study subjects for as long as possible. Patients
           will be followed throughout the course of their illnesses, with particular attention to
           patterns of disease recurrence and progression, response to therapies and duration of
           responses. National death index data can also be utilized to obtain patient outcome

Study Type


Primary Outcome

To establish a biospecimen repository for genomic, genetic and epigenetic analysis to study the biology of PLC development and progression

Secondary Outcome

 To estimate 3 years progression-free survival following immunotherapy for PLC


Hepatocellular Carcinoma

Study Arms / Comparison Groups

 1/ Cohort 1
Description:  Subjects with a diagnosis or suspicion of PLC


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Estimated Enrollment


Start Date

October 29, 2020

Completion Date

December 31, 2025

Primary Completion Date

December 31, 2025

Eligibility Criteria


          -  Patients with histologically/ultrasound/imaging confirmed or suspicious lesions of HCC
             or CCA.

          -  Patients with planned or a history of at least 1 dose of immunotherapy for HCC or CCA.

          -  Ability of subject or Legally Authorized Representative to understand and the
             willingness to sign a written informed consent document.

          -  Age greater than or equal to 18 years old at date of study consent.


        - Patients with known HIV infection (as these patients may have abnormal test results which
        may confound the endpoints of this study)




18 Years - N/A

Accepts Healthy Volunteers



Tim F Greten, M.D., (240) 760-6837, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Secondary IDs


Responsible Party


Study Sponsor

National Cancer Institute (NCI)

Study Sponsor

Tim F Greten, M.D., Principal Investigator, National Cancer Institute (NCI)

Verification Date

May 13, 2020