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Biliary Tract NeoplasmsPhase 2NCT02821754

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

A Phase 2 study testing Durvalumab, Tremelimumab and Trans-arterial Catheter Chemoembolization (TACE) in people with Biliary Tract Neoplasms and Liver Cancer, run by National Cancer Institute (NCI) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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). Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Durvalumab, Tremelimumab and Trans-arterial Catheter Chemoembolization (TACE)
Type of treatment
Surgery or procedure
Could I receive a placebo?
No, everyone receives an active treatment
How many people
54 participants
Where
1 siteUnited States
Study dates
5 Jul 2016to 31 Dec 2022
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients must have histopathological confirmation of hepatocellular carcinoma (HCC) or 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). Fibrolamellar variant is also allowed. The term BTC includes intra or extrahepatic cholangiocarcinoma, gallbladder cancer or ampullary cancer.
  • Patients must have disease that is not amenable to potentially curative resection, transplantation or ablation. HCC patients must have progressed on, been intolerant to, or refused prior sorafenib therapy. Patients with BTC must have received, been intolerant of or refused at least one line of chemotherapy.
  • Patients must have multiple tumor lesions (at least 2): one for the ablation procedure and another for evaluation located outside the proposal ablation zone.
  • Disease must be technically amenable to transhepatic arterial chemoembolization (TACE) (HCC patients only), 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 18 years or older
Show all 23Show fewer
  • 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: bilirubin should be less than or equal to 2 x upper limit of normal (ULN)
  • serum albumin If cirrhosis present: Part of Child Pugh requirement; If no cirrhosis: albumin should be less than or equal to 2.5g/dl
  • patients are eligible with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) up to 5 x ULN.
  • creatinine < 1.5x institution upper limit of normal OR creatinine clearance greater than or equal to 45 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • 9. 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.
  • 10. 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).
  • 11. Patient must be able to understand and willing to sign a written informed consent document.
  • 12. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
  • Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
  • Women greater than or equal to 50 years of age would be considered post-menopausal if they have been
  • amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy. Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
  • 13. Body weight greater than 30kg

Who cannot join

  • 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.
Show all 14Show fewer
  • 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 30 days of starting durvalumab or tremelimumab treatment.
  • Has a known history of Human Immunodeficiency Virus (HIV). 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.
  • History of hypersensitivity reaction to human or mouse antibody products.
  • 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 prior to study entry, the duration of study participation and 6 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.
  • Patients with unhealed surgical wounds for more than 30 days.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • National Institutes of Health Clinical Center

    Bethesda, Maryland, 20892

Other trials in United States

About this study

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.
Read more

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.
Read the detailed description

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).

Being tested
Durvalumab, Tremelimumab, Trans-arterial Catheter Chemoembolization (TACE), Radiofrequency Ablation (RFA), Cryoablation
Keywords
PDL1-Mediated Adaptive Resistance, Monoclonal Antibody, CTLA-4, Ablative Therapy, Combination of Tremelimumab and Durvalumab
Medical subject headings
Biliary Tract Neoplasms, Liver Neoplasms, Carcinoma, Hepatocellular, Cholangiocarcinoma, Bile Duct Neoplasms, Diabetes Mellitus, Insulin-Dependent, 12

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • DurvalumabDrug

    Also called Imfinzi

    Flat dose of 1500 mg every 4 weeks.

  • TremelimumabDrug

    Also called Ticilimumab

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

  • Trans-arterial Catheter Chemoembolization (TACE)Procedure or surgery

    Also called TACE

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

  • Radiofrequency Ablation (RFA)Procedure or surgery

    Also called RFA

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

  • CryoablationProcedure or surgery

    Also called Cryosurgery

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

Study groups in NCT02821754
Study groupRoleWhat they receive
1/A1-Durvalumab + TremelimumabExperimentalDurvalumab + Tremelimumab
Receives: Drug: Durvalumab; Drug: Tremelimumab
2/A2 - Durvalumab + Tremelimumab + Trans-arterial Catheter Chemoembolization (TACE)ExperimentalDurvalumab + Tremelimumab + TACE
Receives: Drug: Durvalumab; Drug: Tremelimumab; Procedure: Trans-arterial Catheter Chemoembolization (TACE)
3/A3 - Durvalumab + Tremelimumab+ Radiofrequency Ablation (RFA)ExperimentalDurvalumab + Tremelimumab+ RFA
Receives: Drug: Durvalumab; Drug: Tremelimumab; Procedure: Radiofrequency Ablation (RFA)
4/A4 - Durvalumab + Tremelimumab+ CryoablationExperimentalDurvalumab + Tremelimumab+ Cryoablation
Receives: Drug: Durvalumab; Drug: Tremelimumab; Procedure: Cryoablation

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 6 Month Progression Free Survival (PFS)

    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.

    Measured: At 6 months

Secondary outcomes (1)

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

    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.

    Measured: 60 days after last treatment, an average of 44.89 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted4 Jul 2016 (estimated)
  2. Study start5 Jul 2016
  3. Primary completion17 Feb 2021
  4. Study completion31 Dec 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
54 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02821754
Sponsor's protocol ID
160135
Other IDs
16-C-0135
Status last verified
Mar 2023
First submitted
29 Jun 2016
Last updated
28 Mar 2023
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: 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).

Publications

  • Duffy AG, Greten TF. Immunological off-target effects of standard treatments in gastrointestinal cancers. Ann Oncol. 2014 Jan;25(1):24-32. doi: 10.1093/annonc/mdt349. Epub 2013 Nov 7.

    PubMed 24201974

  • Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012 Jun 28;366(26):2455-65. doi: 10.1056/NEJMoa1200694. Epub 2012 Jun 2.

    PubMed 22658128

  • Sangro B, Gomez-Martin C, de la Mata M, Inarrairaegui M, Garralda E, Barrera P, Riezu-Boj JI, Larrea E, Alfaro C, Sarobe P, Lasarte JJ, Perez-Gracia JL, Melero I, Prieto J. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol. 2013 Jul;59(1):81-8. doi: 10.1016/j.jhep.2013.02.022. Epub 2013 Mar 4.

    PubMed 23466307

  • Myojin Y, Babaei S, Trehan R, Hoffman C, Kedei N, Ruf B, Benmebarek MR, Bauer KC, Huang P, Ma C, Monge C, Xie C, Hrones D, Duffy AG, Armstrong P, Kocheise L, Desmond F, Buchalter J, Galligan M, Cantwell C, Ryan R, McCann J, Bourke M, Mac Nicholas R, McDermott R, Awosika J, Cam M, Krebs R, Budhu A, Revsine M, Figg WD, Kleiner DE, Redd B, Wood BJ, Wang XW, Korangy F, Claassen M, Greten TF. Multiomics analysis of immune correlatives in hepatocellular carcinoma patients treated with tremelimumab plus durvalumab. Gut. 2025 May 7;74(6):983-995. doi: 10.1136/gutjnl-2024-334026.

    PubMed 39965889

  • Monge C, Xie C, Myojin Y, Coffman-D'Annibale KL, Hrones D, Brar G, Wang S, Budhu A, Figg WD, Cam M, Finney R, Levy EB, Kleiner DE, Steinberg SM, Wang XW, Redd B, Wood BJ, Greten TF. Combined immune checkpoint inhibition with durvalumab and tremelimumab with and without radiofrequency ablation in patients with advanced biliary tract carcinoma. Cancer Med. 2024 Feb;13(3):e6912. doi: 10.1002/cam4.6912. Epub 2024 Jan 11.

    PubMed 38205877

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Durvalumab, Tremelimumab and Trans-arterial Catheter Chemoembolization (TACE) in people with Biliary Tract Neoplasms and Liver Cancer, run by National Cancer Institute (NCI) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 23 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 28 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 24 Mar 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

6 Month Progression Free Survival (PFS) (time frame: At 6 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02821754, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Mar 2023.

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