A Pilot Study of Combined Immune Checkpoint Inhibition in Combination With Ablative Therapies in Subjects With Hepatocellular Carcinoma (HCC) or Biliary Tract Carcinomas (BTC)
2 other identifiers
interventional
54
1 country
1
Brief 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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P25-P50 for phase_2
Started Jul 2016
Longer than P75 for phase_2
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
June 29, 2016
CompletedFirst Posted
Study publicly available on registry
July 4, 2016
CompletedStudy Start
First participant enrolled
July 5, 2016
CompletedPrimary Completion
Last participant's last visit for primary outcome
February 17, 2021
CompletedResults Posted
Study results publicly available
March 24, 2022
CompletedStudy Completion
Last participant's last visit for all outcomes
December 31, 2022
CompletedMarch 28, 2023
March 1, 2023
4.6 years
June 29, 2016
February 10, 2022
March 6, 2023
Conditions
Keywords
Outcome Measures
Primary Outcomes (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.
At 6 months
Secondary Outcomes (1)
Number of Grades 1-5 Adverse Events Related to Tremelimumab and Durvalumab
60 days after last treatment, an average of 44.89 months
Other Outcomes (1)
Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)
Date treatment consent signed to date off study, approximately 62 months and 3 days for the RFA/TACE group, and 27 months and 24 days for the RFA/CA group.
Study Arms (4)
1/A1-Durvalumab + Tremelimumab
EXPERIMENTALDurvalumab + Tremelimumab
2/A2 - Durvalumab + Tremelimumab + Trans-arterial Catheter Chemoembolization (TACE)
EXPERIMENTALDurvalumab + Tremelimumab + TACE
3/A3 - Durvalumab + Tremelimumab+ Radiofrequency Ablation (RFA)
EXPERIMENTALDurvalumab + Tremelimumab+ RFA
4/A4 - Durvalumab + Tremelimumab+ Cryoablation
EXPERIMENTALDurvalumab + Tremelimumab+ Cryoablation
Interventions
Flat dose of 1500 mg every 4 weeks.
Flat dose of 75 mg every 4 weeks for up to 4 doses.
TACE will be performed on Day 36 (+/-96hrs).
RFA will be performed on Day 36 (+/-96hrs).
Cryoablation will be performed on Day 36 (+/-96hrs).
Eligibility Criteria
You may qualify if:
- 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
- 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
- +8 more criteria
You may not qualify if:
- 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.
- 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 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.
- Patients with unhealed surgical wounds for more than 30 days.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (1)
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892, United States
Related Publications (5)
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.
PMID: 24201974BACKGROUNDBrahmer 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.
PMID: 22658128BACKGROUNDSangro 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.
PMID: 23466307BACKGROUNDMyojin 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.
PMID: 39965889DERIVEDMonge 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.
PMID: 38205877DERIVED
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Dr. Tim F. Greten
- Organization
- Principal Investigator
Study Officials
- PRINCIPAL INVESTIGATOR
Tim F Greten, M.D.
National Cancer Institute (NCI)
Publication Agreements
- PI is Sponsor Employee
- No
- Restrictive Agreement
- No
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- NIH
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Principal Investigator
Study Record Dates
First Submitted
June 29, 2016
First Posted
July 4, 2016
Study Start
July 5, 2016
Primary Completion
February 17, 2021
Study Completion
December 31, 2022
Last Updated
March 28, 2023
Results First Posted
March 24, 2022
Record last verified: 2023-03
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, SAP, ICF
- Time Frame
- Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol Genomic Data Sharing (GDS) plan for as long as database is active.
- Access Criteria
- Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI). Genomic data are made available via database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.
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).