| Eligibility |
Inclusion Criteria:
Subject must meet all of the following applicable inclusion criteria to participate in this
study:
- Written informed consent and HIPAA authorization for release of personal health
information must be obtained either from the subject or their representative. See
protocol. NOTE: HIPAA authorization may be included in the informed consent or
obtained separately.
- Age = 18 years at the time of consent.
- ECOG Performance Status of 0-1.
- Locally advanced, metastatic, or unresectable hepatocellular carcinoma that has not
received prior systemic therapy. Note: if no prior histologic diagnosis exists, prefer
fresh biopsy if it is both safe and feasible. If fresh biopsy is not safe and
feasible, imaging criteria may be used for diagnosis as per AASLD criteria in
cirrhotic patients (please see www.aasld.org for up to date guidelines).
- Child Pugh Class B7 or B8 liver dysfunction or cirrhosis with the following
limitations:
- Bilirubin = 3 mg/dL
- Albumin = 2.8 g/dL
- INR = 1.7
- Absent to slight [CP=1 to 2] (no moderate [CP=3]) ascites (Also see exclusion
criteria).
- No clinically significant encephalopathy (Also see exclusion criteria).
- At least 1 untreated measurable lesion according to RECIST 1.1.
- Willingness to undergo fresh tumor biopsy at baseline if safe and feasible. Note:
archival tissue may be used at baseline provided histologic diagnosis was made and
sufficient tissue is available for NGS analysis.
- NGS analysis must be requested from archival tissue or fresh biopsy (if applicable) as
per standard of care. Foundation One CDX is the preferred platform. Prior NGS
sequencing results (including from another platform) will be accepted if NGS
sequencing was previously obtained (please see protocol).
- Demonstrate adequate bone marrow and organ function as defined below:
- Hematologic
- Absolute neutrophil count (ANC) = 1,000/mcL
- Lymphocyte count = 0.5 x 10^9/L (500uL)
- Hemoglobin = 90 g/L (9 g/dL)
- Platelet count = 70,000/mcL
- Renal
- Serum creatinine OR calculated* serum creatinine clearance (GFR can be used
in place of creatinine or creatinine clearance) = 1.5 x ULN OR = 30 mL/min
for participants with creatinine levels > 1.5 x institutional ULN *calculate
serum creatinine clearance using the standard Coccroft-Gault formula
- Urine protein: Urine dipstick for proteinuria < 2+ within 7 days prior to
start of study treatment *Patients with with = 2+ proteinuria on dipstick
analysis at baseline should undergo a 24-hour urine collection which must
demonstrate < 1g of protein in 24 hours.
- Hepatic
- AST (SGOT) and ALT (SGPT) = 8 x ULN
- Alkaline phosphastase (ALP) = 8 x ULN
- For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per
year during the treatment period and for at least 5 months after the last dose of
atezolizumab, or 6 months after the last dose of bevacizumab. See also the protocol
for definition of childbearing potential.
- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use
effective contraceptive measures. Men with female partners of childbearing potential
must remain abstinent or use a condom plus an additional contraceptive method that
together result in a failure rate of < 1% per year during the treatment period and for
6 months after the last dose of bevacizumab. With pregnant female partners, men must
remain abstinent or use a condom during the treatment period and for 6 months after
the last dose of bevacizumab to avoid exposing the embryo. See also the protocol for
additional information.
- As determined by the enrolling physician or protocol designee, ability of the subject
to understand a written informed consent document, and ability and willingness to
comply with study procedures for the entire length of the study. Patients with
impaired decision-making capacity (IDMC) who have a close caregiver or legally
authorized representative (LAR) and/or family member available are also eligible.
Exclusion Criteria:
Subjects meeting any of the criteria below may not participate in the study:
- Histologic diagnosis of fibrolamellar or sarcomatoid HCC or mixed
cholangiocarcinoma-HCC.
- Patients who have had chemotherapy, definitive radiation, biological cancer therapy,
or investigational agent/device within 21 days of first planned dose of study therapy
(within 14 days for palliative radiation). Patients who have had major surgery within
4 weeks of start of study therapy or anticipation of need for a major surgical
procedure during the study.
- Patients who have not recovered from adverse events due to prior anti-cancer therapy
(i.e., have residual toxicities > CTCAE Grade 1) with the exception of alopecia or
neuropathy.
- Patients who have received prior systemic therapy for HCC.
- Patients who have received prior immunotherapy.
- Patients with clinically meaningful ascites, defined as ascites requiring
non-pharmacologic intervention (e.g. paracentesis) to maintain symptomatic control
within 3 months prior to the first dose of study treatment. Note: Patients with
ascites meeting eligibility criteria who require pharmacologic intervention (e.g.
diuretics) to maintain symptomatic control and who have been on stable doses of
diuretics for 2 months prior to the first dose of study treatment are eligible.
- Patients with clinically meaningful encephalopathy, defined as a history of hepatic
encephalopathy within 6 months prior to first dose of study treatment or requirement
for medications to prevent or control encephalopathy (e.g. lactulose, rifaximin).
- Any of the following additional high-risk features:
- Patients with untreated or incompletely treated esophageal and/or gastric varices
with bleeding or high risk for bleeding. Note: Patients must undergo an
esophagogastroduodenoscopy (EGD), and all size of varices (small to large) must
be assessed and treated per local standard of care prior to enrollment. Patients
who have undergone an EGD with appropriate management of varices (if applicable)
within 6 months of prior to initiation of study treatment do not need to repeat
the procedure.
- History of esophageal and/or gastric hemorrhage within 3 months prior to study
treatment.
- History of hemoptysis (< 2.5 mL of bright red blood per episode) within 1 month
prior to study treatment.
- History of intracranial hemorrhage within 1 month prior to study treatment.
- History of abdominal or tracheoesophageal fistula, gastrointestinal (GI)
perforation, or intra-abdominal abscess within 6 months prior to initiation of
study treatment. Evidence of abdominal free air that is not explained by
paracentesis or recent surgical procedure.
- Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture
within 30 days prior to start of study treatment.
- Metastatic disease that involves major airways or blood vessels. Patients with
vascular invasion of the portal or hepatic veins may be enrolled.
- Significant vascular disease (e.g. aortic aneurysm requiring surgical repair) or
vasculitis within 6 months prior to initiation of study treatment.
- History of arterial thrombotic event (e.g. myocardial infarction, unstable
angina, cerebrovascular accident, or transient ischemic attack) within 6 months
prior to initiation of study treatment.
- Chronic or recent (within 10 days of first dose of study treatment) use of
aspirin > 325 mg/day, dipyramidaole, ticlopidine, clopidogrel, or dilostazol.
Note: Use of aspirin < 325 mg/day is allowed.
- History of venous thromboembolic event (e.g. deep vein thrombosis, pulmonary
embolism, portal vein thrombosis, or any other significant thromboembolism) must
be on a stable dose of anticoagulation for 1 month prior to initiation of study
treatment and must have completely treated varices.
- Use of Coumadin-like products or full dose oral or parenteral anticoagulants. Use
of prophylactic low dose anticoagulation, unfractionated heparin or LMWH is
allowed.
- Evidence of bleeding diathesis or significant coagulopathy (in the absence of
therapeutic anticoagulation).
- Core biopsy or other minor surgical procedure within 3 days prior to the first
dose of bevacizumab.
- History of intestinal obstruction. Note: Patients with previous intestinal
obstruction may be enrolled if they have received definitive treatment for
symptom resolution.
- History of inflammatory process within 6 months prior to start of study treatment
including but not limited to active peptic ulcer disease, diverticulitis or
colitis.
- Significant traumatic injury within 4 weeks prior to start of study treatment.
- Uncontrolled pleural effusion or pericardial effusion requiring frequent drainage
procedures (> once monthly). Patients with indwelling catheters (e.g. PleurX®)
are allowed.
- History of nephrotic or nephritic syndrome.
- Uncontrolled hypertension defined as systolic pressure = 150/90 in spite of
maximum anti-hypertensive therapy.
- Patients with untreated/uncontrolled CNS/leptomeningeal disease. Note: Patients with
asymptomatic, treated CNS disease are eligible if the treating physician determines
that immediate CNS specific treatment is not required and is unlikely to be required
during the first cycle of therapy and the following criteria are met:
- No evidence of interim progression between the completion of CNS-directed therapy
and the start of study enrollment.
- No stereotactic radiation or whole-brain radiation within 28 days prior to
randomization.
- No evidence of intracranial hemorrhage or spinal cord hemorrhage.
- Patients with active autoimmune disease requiring systemic corticosteroids greater
than the equivalent of prednisone 10 mg daily or other systemic immunosuppressive
medications including but not limited to: systemic lupus erythematosus, rheumatoid
arthritis, inflammatory bowel disease, colitis, vascular thrombosis associated with
antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Bell's palsy,
Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis,
or glomerulonephritis, with the following exceptions:
- Patients with a history of autoimmune hypothyroidism on thyroid replacement
hormone are eligible.
- Patients with Type 1 diabetes mellitus on an insulin regimen are eligible.
- Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with
dermatologic manifestations only are eligible provided: 1) rash covers < 10% of
body surface area (BSA), 2) disease is well controlled at baseline and requires
only low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone
butyrate 0.1%, flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate
0.05%).
- See protocol for a more comprehensive list of autoimmune diseases and immune
deficiencies.
- Patients receiving treatment with systemic immunosuppressive medications (including,
but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate,
thalidomide, and anti-tumor necrosis factor [TNF] agents) within 6 weeks must
discontinue these medications prior to starting protocol therapy, with the exception
of:
- Patients with active autoimmune disease managed with systemic corticosteroids
less than the equivalent of prednisone 10 mg daily.
- Patients who have received acute, low dose, systemic immunosuppressant
medications (e.g., a one-time dose of dexamethasone for nausea).
- The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone)
for patients with orthostatic hypotension and adrenocortical insufficiency.
- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of
active pneumonitis on screening chest computed tomography (CT) scan. Note: History of
radiation pneumonitis in the radiation field (fibrosis) is permitted.
- Patients who have undergone prior solid organ or bone marrow transplant with the
exception of patients with prior renal transplant for whom dialysis may be employed in
the event of graft rejection.
- Patients with serious active infection within 2 weeks prior to enrollment (e.g.
requiring hospitalization and/or intravenous [IV] antibiotics) infection within 2
weeks prior to enrollment, or currently receiving oral or IV antibiotics for the
treatment of infection. Patients receiving prophylactic antibiotics are eligible.
- Patients must have documented hepatitis virology status.
- Patients with active hepatitis B virus (HBV) infection must have a viral load <
500 IU/mL within 28 days prior to start of study treatment and be on suppressive
therapy (per local standard of care) for a minimum of 14 days prior to start of
study treatment and for the length of the study.
- Patients with co-infection with HBV and hepatitis C virus (HCV) are excluded.
Patients with a history of HCV infection but with negative HCV RNA by PCR are
considered non-infected with HCV.
- Patients with known human immunodeficiency virus (HIV) are allowed on study provided
they have:
- A stable regimen of highly active anti-retroviral therapy (HAART)
- No requirement for concurrent concurrent antibiotics or antifungal agents for the
prevention of opportunistic infection
- A CD4 count above 250 cells/mcL
- An undetectable HIV viral load on standard PCR-based testing
- Patients with uncontrolled intercurrent illness (e.g., including but not limited to
uncontrolled HTN [systolic BP = 150, diastolic BP = 100 despite optimal medical
management or history of hypertensive crisis or hypertensive encephalopathy],
symptomatic congestive heart failure [CHF], uncontrolled cardiac arrhythmia, or other
within 3 months prior to start of study treatment or psychiatric illness/social
situations or other conditions that would limit compliance with study requirements or
substantially increase risk of incurring AEs in the opinion of the treating
investigator.
- Patients with known concurrent malignancy that is expected to require active treatment
within two years or may interfere with the interpretation of the efficacy and safety
outcomes of this study in the opinion of the treating investigator. Note: Superficial
bladder cancer, nonmelanoma skin cancers, and low-grade prostate cancer not requiring
cytotoxic therapy should not exclude participation in this trial. Patients with CLL
may be enrolled if they do not require active chemotherapy and their hematologic,
renal and hepatic function meets criteria previously mentioned.
- Any other disease, metabolic dysfunction, physical examination finding, or clinical
laboratory finding that contraindicates the use of an investigational drug, may affect
the interpretation of the results, or may render the patient at high risk from
treatment complications in the opinion of the treating investigator.
- Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study
treatment.
- History of severe allergic anaphylactic reactions to chimeric or humanized antibodies
or fusion proteins or know hypersensitivity to Chinese hamster ovary cell products or
to any component of the atezolizumab or bevacizumab infusion.
- Uncontrolled tumor-related pain. NOTE: Patients requiring pain medication must be on a
stable regimen at study entry.
Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement)
amenable to palliative radiotherapy should be treated prior to enrollment. Patients should
be recovered from the effects of radiation. There is no required minimum recovery period.
- Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12
mg/dL or corrected serum calcium > ULN)
- Active tuberculosis
- Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including
anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
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