Durvalumab and Tremelimumab in Treating Patients with Liver Cancer Undergoing Drug-Eluting Bead Transarterial Chemoembolization
This phase II trial studies how well durvalumab and tremelimumab work in treating patients with liver cancer undergoing drug-eluting bead transarterial chemoembolization. Immunotherapy with monoclonal antibodies, such as durvalumab and tremelimumab, may help the body’s immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread.
- 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 has not received systemic or local treatment for new diagnosis of HCC (prior TACE is allowed). Recurrence from previous resected HCC is allowed as long as the recurrence has not been treated with systemic or local treatment
- HCC meeting Barcelona Clinic Liver Cancer (BCLC) stage B (intermediate stage), with tumor burden of a single lesion > 5 cm OR more than three lesions that are > 3 cm, without any vascular invasion seen on imaging, with measurable lesions on CT or MRI and without extrahepatic spread
- Disease that is technically amenable to DEB-TACE. Cases will be discussed at liver tumor board with interventional radiology. At least 1 measurable lesion, not previously irradiated, that can be accurately 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, and that is suitable for accurate repeated measurements as per modified Response Evaluation Criteria in Solid Tumors (RECIST) guidelines
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Body weight > 30 kg
- Child-Pugh score of A or early B (score =< 7) 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 >= 60,000/mm^3
- Albumin >= 2.8 g/dL
- Institutional normalized ratio (INR) =< 1.6 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 percutaneous liver biopsy
- 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 an investigational product during the last 6 months
- Any concurrent anticancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies) or receipt of the last dose =< 30 days prior to the baseline scan. Concurrent use of hormonal therapy for non–cancer-related conditions (e.g., hormone replacement therapy) is acceptable
- Patients who are being considered for a surgical resection or liver transplantation at the time of enrollment
- Patients with diffuse HCC, vascular invasion, or extrahepatic tumor
- Main portal vein thrombosis present on imaging
- History of hepatic encephalopathy within past 12 months or requirement for medications to prevent or control encephalopathy (e.g., no lactulose or rifaximin if used for purposes of hepatic encephalopathy)
- Ascites that require ongoing paracentesis, within 6 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 who are actively taking direct-acting antiviral treatment for hepatitis C virus (HCV) or who finished direct acting antiviral treatment within 6 months
- History of another primary malignancy except for: * Malignancy treated with curative intent and with no known active disease >= 5 years before the first dose of investigational product (IP) and of low potential risk for recurrence * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease * Adequately treated carcinoma in situ without evidence of disease
- 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 12 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 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
Locations & Contacts
Contact: Ana De Jesus-Acosta
Trial Objectives and Outline
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 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 assess the safety of combining DEB-TACE with durvalumab and tremelimumab in patients with intermediate stage of HCC.
V. 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).
OUTLINE: Patients are assigned to 1 of 2 cohorts.
COHORT A: 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.
COHORT B: Two weeks after initial standard of care DEB-TACE, patients receive tremelimumab IV over 60 minutes and durvalumab IV over 60 minutes. Treatment with tremelimumab repeats every 4 weeks for up to 4 cycles and 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 & Type
Johns Hopkins University / Sidney Kimmel Cancer Center
Ana De Jesus De Jesus Acosta
Secondary IDs NCI-2018-03653, CRMS-69872, IRB00179347
Clinicaltrials.gov ID NCT03638141