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

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.

Study Overview

• Status: Completed
• Conditions: Hepatocellular Carcinoma; Cholangiocarcinoma; Bile Duct Cancer; Biliary Tract Neoplasms; Liver Cancer
• Intervention / Treatment: Drug: Durvalumab; Drug: Tremelimumab; Procedure: Trans-arterial Catheter Chemoembolization (TACE); Procedure: Radiofrequency Ablation (RFA); Procedure: Cryoablation

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).

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• INCLUSION CRITERIA:

  1. 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.
  2. 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.
  3. Patients must have multiple tumor lesions (at least 2): one for the ablation procedure and another for evaluation located outside the proposal ablation zone.
  4. 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.
  5. If liver cirrhosis is present, patient must have a Child-Pugh A/B7 classification
  6. Age 18 years or older
  7. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  8. 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

EXCLUSION CRITERIA:

1. 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.
2. Patients who have undergone prior liver transplantation are ineligible.
3. 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.
4. 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.
5. 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.
6. 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.
7. Diverticulitis either active or history of within the past 2 years. Note that diverticulosis is permitted.
8. 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)
9. History of sarcoidosis syndrome
10. Patients should not be vaccinated with live attenuated vaccines within 30 days of starting durvalumab or tremelimumab treatment.
11. 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.
12. History of hypersensitivity reaction to human or mouse antibody products.
13. 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.
14. Patients with unhealed surgical wounds for more than 30 days.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1/A1-Durvalumab + Tremelimumab; Durvalumab + Tremelimumab	Drug: Durvalumab; Flat dose of 1500 mg every 4 weeks.; Other Names: Imfinzi; Drug: Tremelimumab; Flat dose of 75 mg every 4 weeks for up to 4 doses.; Other Names: Ticilimumab
Experimental: 2/A2 - Durvalumab + Tremelimumab + Trans-arterial Catheter Chemoembolization (TACE); Durvalumab + Tremelimumab + TACE	Drug: Durvalumab; Flat dose of 1500 mg every 4 weeks.; Other Names: Imfinzi; Drug: Tremelimumab; Flat dose of 75 mg every 4 weeks for up to 4 doses.; Other Names: Ticilimumab; Procedure: Trans-arterial Catheter Chemoembolization (TACE); TACE will be performed on Day 36 (+/-96hrs).; Other Names: TACE
Experimental: 3/A3 - Durvalumab + Tremelimumab+ Radiofrequency Ablation (RFA); Durvalumab + Tremelimumab+ RFA	Drug: Durvalumab; Flat dose of 1500 mg every 4 weeks.; Other Names: Imfinzi; Drug: Tremelimumab; Flat dose of 75 mg every 4 weeks for up to 4 doses.; Other Names: Ticilimumab; Procedure: Radiofrequency Ablation (RFA); RFA will be performed on Day 36 (+/-96hrs).; Other Names: RFA
Experimental: 4/A4 - Durvalumab + Tremelimumab+ Cryoablation; Durvalumab + Tremelimumab+ Cryoablation	Drug: Durvalumab; Flat dose of 1500 mg every 4 weeks.; Other Names: Imfinzi; Drug: Tremelimumab; Flat dose of 75 mg every 4 weeks for up to 4 doses.; Other Names: Ticilimumab; Procedure: Cryoablation; Cryoablation will be performed on Day 36 (+/-96hrs).; Other Names: Cryosurgery

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	60 days after last treatment, an average of 44.89 months

Other Outcome Measures

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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): July 5, 2016
• Primary Completion (Actual): February 17, 2021
• Study Completion (Actual): December 31, 2022

Study Registration Dates

• First Submitted: June 29, 2016
• First Submitted That Met QC Criteria: July 1, 2016
• First Posted (Estimate): July 4, 2016

Study Record Updates

• Last Update Posted (Actual): March 28, 2023
• Last Update Submitted That Met QC Criteria: March 6, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Monoclonal Antibody; CTLA-4; Ablative Therapy; PDL1-Mediated Adaptive Resistance; Combination of Tremelimumab and Durvalumab
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Biliary Tract Diseases; Bile Duct Diseases; Carcinoma; Carcinoma, Hepatocellular; Cholangiocarcinoma; Biliary Tract Neoplasms; Bile Duct Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Durvalumab; Tremelimumab
• Other Study ID Numbers: 160135; 16-C-0135

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

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).

IPD Sharing 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.

IPD Sharing 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.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No