- Worldwide, hepatocellular carcinoma (HCC) is the fifth most common malignancy with a
median survival of 6-9 months.
- A class of agents that in the recent years has been at the epicenter of immunotherapy
approaches in HCC are the monoclonal antibodies (mAbs) against the immune checkpoint
inhibitors CTLA4, PD-1 and PD-L1.
- Durvalumab is a human monoclonal antibody of the immunoglobulin G1 kappa (IgG1 )
subclass. Durvalumab inhibits binding of programmed cell death ligand 1 (PD-L1) to
programmed cell death 1 (PD-1) and CD80. Anti-PD-L1 antibodies directly target tumor
cells and are expected to have less adverse events in comparison with anti-PD-1
antibodies that target effector T-cells in the tumor microenvironment.
- Angiogenesis is defined as the formation of new blood capillaries, which is a complex
process that promotes vascular endothelial growth factor (VEGF) and other proangiogenic
factor expression, thus enhancing metastasis. Inhibition of VEGF function by bevacizumab
can lead to the inhibition of the new blood vessels formation surrounding a tumor, and
consequenly arrest the tumor growth by depriving essential nutrients and oxygen.
- TACE has been shown to induce anti-tumor immunity.
- Early phase study has showed anti-VEGF bevacizumab with TACE diminishes
-We have previously shown that the locoregional therapies can be safely combined with immune
checkpoint blockade. There are also preclinical data suggesting that anti-VEGF therapy may
target myeloid cells with suppressor activity.
-To evaluate 6-month progression free survival (PFS) in patients with advanced HCC treated
with bevacizumab, durvalumab and TACE.
- Histopathological confirmation of HCC 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
- HCC of intermediate (B) or advanced (C) stage per Barcelona Clinic Liver Cancer (BCLC)
- Patients must have disease that is not amenable to potentially curative resection,
radiofrequency ablation, or liver transplantation.
-This is an open label Phase II trial conducted to evaluate efficiency of durvalumab,
bevacizumab and TACE combined treatment in patients with advanced HCC.
- Initially 6 patients with BCLC Stage C will be enrolled into safety run-in of Arm 1 to
determine the safety of combined treatment, including one TACE.
- Once safety has been determined, subsequent patients will be enrolled in Arm 1 (patients
with BCLC Stage C) and Arm 2, including more than one TACE (patients with BCLC Stage B).
- Treatment will continue until progression or unbearable toxicity.
- INCLUSION CRITERIA:
- Patients must have:
- Histopathological confirmation of HCC by the NCI Laboratory of Pathology
- Histopathological confirmation of carcinoma by the NCI Laboratory of Pathology in the
setting of clinical and radiological characteristics which, together with the
pathology, are highly suggestive of a diagnosis of HCC.
- Patients should have received at least one line of systemic therapy including but
not limited to sorafenib, lenvatinib, regorafenib and/or immune checkpoint
inhibitor therapy with evidence of disease progression clinically or
radiographically as deemed by investigator or refused standard-of-care therapy.
- Patients must have disease that is not amenable to potentially curative
resection, radiofrequency ablation, or liver transplantation
- Patients must have evaluable or measurable disease per RECIST 1.1
- Patients must have at least one lesion accessible for TACE
- Patients must have lesions accessible for biopsy and be willing to undergo pre-
and posttreatment biopsies
- Patients with cirrhosis must have had esophagogastric endoscopy within the
previous 6 months prior to enrollment for the assessment of varices. If
participants have not had this done, they must be willing to undergo this
procedure prior to study enrollment. Varices must be reviewed and managed by the
gastroenterologist performing endoscopy and deemed as not high risk for bleeding.
- ECOG performance status of 0 to 1
- If liver cirrhosis is present, patient must have a Child-Pugh score <7
- BCLC C (Cohort 1) or BCLC B (Cohort 2)
- Patients must have normal organ and marrow function as defined below:
- 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 XULN
- ALT or AST up to 5 x ULN
- Creatinine OR measured or calcutated Creatinine clearance (crCl) (eGFR may Also be
used in place of CrCl) A: less than the institutional limit of normal OR greater than
or equal to 45/mL/1.73 m^2 for participant with creatinine levels greater than or
equal to 1.5 X institutional ULN
- No proteinuria: Urine dipstick <2. Patients discovered to have greater than or equal
to 2 + proteinuria on dipstick analysis should undergo a 24-hour urine collection and
must demonstrate less than or equal to 1g of protein in 24 hours to be eligible
- Coagulation: PT/aPTT within normal range (Isolated prolonged aPTT with positive LAC
will have hematologist clearance before enrollment)
- Age greater than or equal to 18 years
- Patients must have recovered from any acute toxicity related to prior therapy,
including surgery. Toxicity should be less than or equal to grade 1.
- The effects of study drugs on the developing human fetus are unknown. For this
reason, women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to
study entry and for the duration of study participation and up to 90 days after
the last dose of the study drug(s). 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.
- Patient must be able to understand and willing to sign a written informed consent
- HBV infected subjects must be on antivirals and have HBV DNA <100IU/mL. HCV
infected subjects can be enrolled with close HCV RNA level monitoring
- Body weight >30kg
- Systemic anti-cancer treatment or radiotherapy within 4 weeks of enrollment.
- Major surgery within 6 weeks of enrollment. Minor procedures (e.g. port placement,
endoscopy with intervention) within 4 weeks of enrollment.
- Active central nervous system metastases and/or carcinomatous meningitis. 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
- Metastatic disease that involves major airways or blood vessels, or centrally located
mediastinal tumor masses.
- Medical condition that requires chronic systemic steroid therapy, or any other form of
immunosuppressive medication (inhaled and topical steroids are permitted).
- Chronic daily treatment with a non-steroidal anti-inflammatory drug (NSAID).
- Patients with a history of bleeding varices within 1 year of enrollment.
- Thromboembolic event within 6 months of enrollment (including cerebrovascular accident
(CVA) and myocardial infarction (MI).
- Evidence of bleeding diathesis or significant coagulopathy (with or without current
- History of hemoptysis (>1/2 teaspoon of bright red blood per episode) within 1 month
- Serious, non-healing wound, active ulcer, or untreated bone fracture.
- HIV-positive patients are excluded because HIV causes complicated immune deficiency
and study treatment can pose more risks for these patients.
- History of severe hypersensitivity reaction to another monoclonal antibody.
- Congestive heart failure, baseline LVEF <50%, transmural myocardial infarction,
uncontrolled hypertension (defined as systolic blood pressure > 140 mmHg and/or
diastolic blood pressure > 90 mmHg), angina pectoris requiring medication, clinically
significant valvular disease, high-risk arrhythmia within 12 months of enrollment.
Prior history of hypertensive crisis or hypertensive encephalopathy.
- Prior invasive malignancies within the past 5 years of enrollment (with the exception
of non-melanoma skin cancers, non-invasive bladder cancer or localized prostate cancer
for whom systemic therapy is not required)
- Active or history of inflammatory bowel disease (colitis, Crohn s), irritable bowel
disease, celiac disease, or other serious, chronic, gastrointestinal conditions
associated with diarrhea.
- History of abdominal fistula or gastrointestinal perforation within 6 months prior to
- History of chronic autoimmune disease (e.g., Addison s disease, multiple sclerosis,
Graves disease, Hashimoto s thyroiditis, rheumatoid arthritis, hypophysitis, systemic
lupus erythematosus, Wegener s granulomatosis, sarcoidosis syndrome etc.) or other
connective tissue diseases with symptomatic disease within the 3 years of enrollment.
Note: Active vitiligo or a history of vitiligo will not be a basis for exclusion.
- Diverticulitis either active or history of within 2 years of enrollment. Note that
diverticulosis is permitted.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that may impair the patient s
tolerance of study treatments.
- Received any live vaccine within the last 30 days.
- Patients who have undergone prior liver transplantation.
- Pregnant women are excluded from this study because durvalumab s and bevacizumab s
potential for teratogenic or abortifacient effects is unknown. Because there is an
unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with durvalumab and bevacizumab, breastfeeding should be
discontinued if the mother is treated with study drugs.