Durvalumab and Tremelimumab in Treating Patients with Liver Cancer Undergoing Drug-Eluting Bead Transarterial Chemoembolization
- Written informed consent and any locally-required authorization (e.g., Health Insurance Portability and Accountability Act [HIPAA] in the United States of America [USA], European Union [EU] Data Privacy Directive in the EU) obtained from the patient prior to performing any protocol-related procedures, including screening evaluations
- Patients with new diagnosis of HCC either by high-resolution imaging (triple-phase computed tomography [CT] or magnetic resonance imaging [MRI]) and/or by tumor biopsy
- Patient is not on systemic treatment for diagnosis of HCC. Prior local therapy (e.g. TACE, radioembolization, radiation) is allowed if treatment was more than 1 month prior to enrollment with evidence of viable HCC or recurrence. Patients who were on tyrosine-kinase inhibitors (sorafenib, regorafenib, lenvatinib) or other systemic treatments for HCC but considered non-responders or intolerant to treatment are allowed to participate
- HCC meeting Barcelona Clinic Liver Cancer (BCLC) stage B (intermediate stage), with measurable lesions on CT or MRI and without extrahepatic spread. Patients with BCLC stage A not considered candidates for transplant or surgery at the time of enrollment can participate if committed to remain on study for 6 months prior to consideration for alternative local therapies
- Disease that is technically amenable to DEB-TACE. Cases will be discussed with interventional radiology. At least 1 measurable lesion, that can be measured at baseline as >= 10 mm in the longest diameter (except lymph nodes, which must have a short axis >= 15 mm) with CT or MRI
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Body weight > 30 kg
- Child-Pugh score of A or early B (score =< 8) without clinically significant ascites. Trace or small amounts of radiographic ascites without prior concern for malignant ascites or not associated with peritoneal carcinomatosis may be approved by the Protocol Chair
- Aspartate aminotransferase (AST) alanine aminotransferase (ALT) =< 5 x upper limit of normal (ULN) (pre-treatment)
- Total bilirubin: If cirrhosis present: Part of Child Pugh requirement. If no cirrhosis present: total bilirubin =< 2 mg/dL
- Absolute neutrophil count of >= 1,000/mm^3
- Hemoglobin >= 9.0 g/dL
- Platelets >= 75,000/mm^3
- Albumin >= 2.5 g/dL
- Institutional normalized ratio (INR) =< 1.8 mg/dL
- Creatinine =< 2.0 or calculated creatinine clearance > 50 mL/minute * Measured creatinine clearance (CL) > 40 mL/min or calculated creatinine clearance CL > 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance
- 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 >= 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)
- Patient 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
- Patient who is willing to get tumor biopsies per the study schedule
- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
- Participation in another clinical study with last dose of an investigational product =< 30 days prior to start of study treatment
- Any concurrent anticancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumour embolization, monoclonal antibodies) or receipt of the last dose =< 30 days prior to start of study treatment (TACE). Concurrent use of hormonal therapy for non–cancer-related conditions (e.g., hormone replacement therapy) is acceptable
- Patients with vascular invasion or extrahepatic tumor
- Main portal vein tumor-related thrombosis present on imaging. Non-tumor related thrombosis is allowed
- Uncontrolled hepatic encephalopathy at time of enrollment
- Ascites that require ongoing paracentesis, within 4 weeks prior to the first scheduled dose, to control symptoms
- Any contraindications for embolization, including hepatofugal blood flow or portosystemic shunt
- Patients with detectable hepatitis B virus (HBV) viral load without active anti-viral treatment * Patients with positive hepatitis B (HepB) surface antigen (HBsAg) and/or HepB core antibodies (anti-HBc) with detectable HBV DNA (>= 10 IU/mL or above the limit of detection per local lab standard) are permitted on study if they are being treated with antiviral therapy to ensure adequate viral suppression (HBV DNA =< 2000 IU/mL) prior to enrollment. Patients who test positive for anti-HBc with undetectable HBV DNA (< 10 IU/ml or under the limit of detection per local lab standard) do not require antiviral therapy prior to enrollment
- Any prior or concurrent malignancy or myeloproliferative disorder whose natural history or treatment has the potential to interfere with safety or efficacy assessment of this study’s investigational drug. Patients with a previous non-HCC malignancy without evidence of disease for > 5 years will be allowed to enter the trial
- History of leptomeningeal carcinomatosis
- History of active primary immunodeficiency
- Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis [TB] testing in line with local practice), or human immunodeficiency virus (positive human immunodeficiency virus [HIV] 1/2 antibodies)
- Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) grade >= 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria: * Patients with grade >= 2 neuropathy will be evaluated on a case-by-case basis after consultation with the study physician * Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the study physician
- Active or prior documented gastrointestinal (GI) variceal bleed or history of upper GI bleeding, ulcers, or esophageal varices with bleeding within 6 months; adequate endoscopic therapy according to institutional standards is required for patients with history of esophageal variceal bleeding or assessed as high risk for esophageal variceal by the treating investigator
- Major surgical procedure (as defined by the investigator) within 28 days prior to the first dose of investigational product (IP). Note: Local surgery of isolated lesions for palliative intent is acceptable
- Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. The following are exceptions to this criterion: * Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) * Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent * Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
- Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc])
- Patients with hypothyroidism (e.g., following Hashimoto syndrome) who are not stable on hormone replacement
- Any chronic skin condition that require systemic therapy
- History of allogenic organ transplantation
- History of pericarditis, cardiomyopathy or current use of defibrillator
- Patients with celiac disease not controlled by diet alone
- Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring adverse event (AE)s or compromise the ability of the patient to give written informed consent
- Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP
- Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy or 180 days after the last dose of durvalumab + tremelimumab combination therapy
- Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
- Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment
- Patients who have received prior anti–PD-1, anti–PD-L1 or anti–CTLA-4 including durvalumab and tremelimumab
- Judgment by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements
I. To evaluate the objective response rate (ORR) of patients with intermediate stage hepatocellular carcinoma (HCC) treated with anti-CTLA-4 (tremelimumab) and anti-PD-L1 (durvalumab) with transarterial chemoembolization (drug-eluting bead [DEB]-TACE), according to modified response evaluation criteria in solid tumors (mRECIST).
I. To assess the safety of combining DEB-TACE with durvalumab and tremelimumab in patients with intermediate stage HCC.
I. To evaluate progression-free survival (PFS) and 6-month PFS of patients treated with the combination of durvalumab and tremelimumab with DEB-TACE.
II. To evaluate the tumor response of non-targeted lesion evaluated by objective response (mRECIST).
III. To evaluate a 2 year overall survival (OS) of patients treated with the combination of durvalumab and tremelimumab with DEB-TACE.
IV. To determine the effect of combined immune checkpoint and DEB-TACE versus DEB-TACE only on tumor microenvironment by comparing pre- and post-treatment tissue samples and peripheral blood tumor biomarkers including T cell receptor repertoire and circulating tumor cells/circulating tumor deoxyribonucleic acid (DNA).
V. To explore potential molecular determinants of response, progression, and disease stability using next generation sequencing and other sequencing techniques.
Two weeks after initial standard of care DEB-TACE, patients receive tremelimumab intravenously (IV) over 60 minutes and durvalumab IV over 60 minutes. Treatment with durvalumab repeats every 4 weeks for up to 13 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 90 days.
Trial Phase Phase II
Trial Type Treatment
Johns Hopkins University / Sidney Kimmel Cancer Center
Ana De Jesus De Jesus Acosta
- Primary ID J18118
- Secondary IDs NCI-2018-03653, IRB00179347, CRMS-69872
- Clinicaltrials.gov ID NCT03638141