Background:
- Worldwide, hepatocellular carcinoma (HCC) is the fourth most common cause of cancer
related death with a median survival of 6-9 months.
- Biliary tract carcinoma (BTC) is relatively uncommon and includes cancers of the
gallbladder and intra- and extra-hepatic biliary ductal system, although periampullary
tumors are often considered part of this group as well.
- A class of agents that in the recent years has been at the epicenter of immunotherapy
approaches in gastrointestinal malignancies 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.
- Tremelimumab is a-uman IgG2 mAb directed against CTLA-4. Tremelimumab blocks the
inhibitory effect of CTLA-4, and therefore enhances T cell activation.
- 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
consequently arrest the tumor growth by depriving essential nutrients and oxygen.
- TACE has been shown to induce anti-tumor immunity.
- Early phase studies have shown that anti-VEGF treatment with bevacizumab in combination
with TACE decreases neovascular formation.
- We have previously shown that 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.
Objectives:
- To evaluate the 6-month progression free survival (PFS) in patients with advanced HCC
BCLC stage B treated with bevacizumab, durvalumab, tremelimumab and TACE.
- To evaluate the 6-month PFS in patients with BTC and HCC BCLC stage C treated with
bevacizumab, durvalumab and tremelimumab.
Eligibility:
- Histopathological confirmation of HCC or BTC 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 BTC.
- Patients must have evaluable or measurable disease per RECIST 1.1.
- Patients must have disease that is not amenable to potentially curative resection,
radiofrequency ablation, or liver transplantation.
Design:
-This is an open label Phase II trial conducted to evaluate efficacy of
durvalumab, bevacizumab and tremelimumab combined treatment in patients with advanced HCC
BCLC stage C or BTC and efficacy of durvalumab, bevacizumab, tremelimumab and TACE combined
treatment in patients with advanced HCC BCLC stage B.
- Initially 3-6 patients with HCC BCLC Stage C or BTC will be enrolled into safety run-in
of Arm
1 to determine the safety of combined treatment of durvalumab, bevacizumab and
tremelimumab.
- Once safety has been determined, subsequent patients with HCC BCLC Stage C and BTC will
be enrolled in Arm 1 and patients with HCC BCLC Stage B will start enrollment into Arm
2,
consistent of durvalumab, bevacizumab, tremelimumab and multiple TACE procedures.
-Treatment will continue until progression or unbearable toxicity.
- INCLUSION CRITERIA:
- Patients must have:
- histopathological confirmation of HCC (Cohorts 1 and 3)
OR
- histopathological confirmation of BTC 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 BTC (Cohort 2).
- Patients should have have progressed on standard of care chemotherapy or been
intolerant of or refused standard treatment.
- 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 (Cohort 3)
- Patients must have lesions accessible for biopsy and be willing to undergo pre-
and posttreatment biopsies
- ECOG performance status of 0 to 1
- If liver cirrhosis is present, patient must have a Child-Pugh score <7
- Subjects with HCC must have BCLC C (Cohort 1) or BCLC B (Cohort 3)
- 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
- 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) at the
study entry and for the duration of study treatment 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.
- 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
- Patient must be able to understand and willing to sign a written informed consent
document.
EXCLUSION CRITERIA:
- Patients who have had standard-of-care anti-cancer therapy or therapy with
investigational agents (e.g. chemotherapy, endocrine therapy, targeted therapy,
biologic therapy, tumor embolization, monoclonal antibodies or other investigation
agents) or large field radiotherapy within 4 weeks prior to treatment initiation.
- Major surgery within 6 weeks prior to treatment initiation. Minor procedures (e.g.
port placement, endoscopy with intervention) within 2 weeks prior to treatment
initiation.
- Active central nervous system metastases and/or carcinomatous meningitis. Patients
with known active 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).
- A prior bleeding event due to esophageal and/or gastric varices within 6 months prior
to initiation of study treatment.
- Inadequately controlled arterial hypertension (defined as systolic blood pressure (BP)
> 150 mmHg and/or diastolic blood pressure > 100 mmHg), based on an average of 3 BP
readings on 2 sessions. Note: anti-hypertensive therapy to achieve these parameters is
allowable.
- Prior history of hypertensive crisis or hypertensive encephalopathy
- Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
recent peripheral arterial thrombosis) within 6 months prior to initiation of study
treatment
- Evidence of bleeding diathesis or significant coagulopathy (with or without current
therapeutic anticoagulation).
- Recent (within 10 days of first dose of study treatment) use of aspirin
- Thromboembolic event within 6 months of initiation of study treatment (including
cerebrovascular accident (CVA) and myocardial infarction (MI).
- History of hemoptysis (>2.5 mL of bright red blood per episode) within 1 month prior
to treatment initiation.
- 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 any monoclonal antibody.
- Congestive heart failure, transmural myocardial infarction, angina pectoris requiring
medication, clinically significant valvular disease, high-risk arrhythmia within 12
months prior to treatment initiation. Prior history of hypertensive crisis or
hypertensive encephalopathy.
- Prior invasive malignancies within the past 5 years prior to treatment initiation
(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
initiation of study treatment.
- 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 initiation
of study treatment. 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 initiation of study
treatment. Note that diverticulosis is permitted.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection or psychiatric illness/social situations that may impair the patient s
tolerance of study treatments.
- Received any live vaccine within the last 30 days before treatment initiation.
- 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 tremelimumab, durvalumab and bevacizumab, breastfeeding
should be discontinued if the mother is treated with study drugs.
