Trial Title:
LOcoregional Vs Systemic Therapy in Patients with BCLC Stage B HCC
NCT ID:
NCT05537402
Condition:
Hepatocellular Carcinoma
Conditions: Official terms:
Carcinoma
Carcinoma, Hepatocellular
Bevacizumab
Atezolizumab
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Intervention model description:
Patients will be randomly assigned to one of two study arms:
Arm A: Atezolizumab and bevacizumab or Arm B: Locoregional therapy with TACE or TARE as
determined by local site. Randomization will occur on 1:1 ratio through permuted-block
randomization method and will be stratified.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Atezolizumab and bevacizumab
Description:
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of
each 21-day cycle and Bevacizumab will be administered by IV infusion at a dose of 15
mg/kg on Day 1 of each 21-day cycle
Arm group label:
Arm A: Atezolizumab and bevacizumab
Intervention type:
Radiation
Intervention name:
transarterial chemoembolization (TACE) or transarterial radioembolization (TARE
Description:
TACE cycles occur every 8 weeks +/- 7 days OR TARE cycles occur every 12 weeks +/- 7 days
Arm group label:
Arm B: Locoregional therapy with TACE or TARE
Summary:
The purpose of this research study is to compare the effectiveness and safety of two
standard of care treatments in people who have been diagnosed with hepatocellular
carcinoma (HCC).This research study is being done to compare atezolizumab/bevacizumab to
locoregional therapy with either transarterial chemoembolization (TACE) or transarterial
radioembolization (TARE).
Detailed description:
To evaluate the efficacy and safety of atezolizumab and bevacizumab compared to
locoregional therapy (TACE or TARE) in patients with intermediate-stage HCC. The primary
outcome is progression-free survival, which will be compared between two arms using
stratified log-rank tests, adjusting the effect of stratification variables between two
study arms. Cox regression analysis will be done to see if there are significant
differences in PFS, controlling for the effects of confounding variables between the two
study arms.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Patients with confirmed HCC by imaging (LI-RADS 5) or histopathology
2. Treatment-naïve, liver localized (intermediate-stage), i.e., beyond Milan Criteria
(one tumor ≤5 cm, or two to three tumors, each ≤3 cm) and not amenable to curative
surgery, liver transplantation, or local ablation and no evidence of extrahepatic
disease or vascular invasion.
3. Child Pugh class A
4. Age ≥18 years at time of screening
5. ECOG Performance Status 0 or 1
6. Patients with HBV infection, which is characterized by positive hepatitis B surface
antigen (HBsAg) and/or hepatitis B core antibodies (anti-HBcAb) with detectable HBV
NA (≥10 IU/ml or above the limit of detection per local lab standard), must be
treated with antiviral therapy, as per institutional practice. HBV antiviral therapy
must be initiated prior to randomization and patients must remain on antiviral
therapy for the study duration and for 6 months after the last dose of study
medication.
Patients who test positive for anti-hepatitis B core (HBc) with undetectable HBV DNA
(<10 IU/ml or under the limit of detection per local lab standard) are not required
to start antiviral therapy prior to randomization. These subjects will be tested at
every cycle to monitor HBV DNA levels and initiate antiviral therapy if HBV DNA is
detected (≥10 IU/ml or above the limit of detection per local lab standard). HBV DNA
detectable subjects must initiate and remain on antiviral therapy for the study
duration and for 6 months after the last dose of study medication.
7. Patients with HCV infection, defined by presence of detectable antibody or RNA,
should have management of this disease per local institutional practice throughout
the study.
8. At least 1 measurable intrahepatic lesion suitable for repeat assessments according
to the following mRECIST criteria: • Liver lesions that show typical features of HCC
on IV contrast-enhanced CT or MRI scans, ie, hypervascularity in the arterial phase
with washout in the portal or the late venous phase
- Viable, non-necrotic portion (arterial phase IV contrast-enhancing) that can be
accurately measured at baseline as ≥10 mm in the longest diameter
9. Adequate organ and marrow function at enrollment as defined below:
(a) Hemoglobin ≥9.0 g/dL Patients may be transfused to meet this criterion. (b)
Absolute neutrophil count ≥1500/μL (c) Platelet count ≥75000/μL (d) Total bilirubin
≤3 × the upper limit of normal (ULN) (e) Alanine aminotransferase (ALT) and
aspartate aminotransferase (AST) ≤5 × ULN (f) Albumin ≥2.8 g/dL (g) Lymphocyte count
≥0.5 X 109/L (500/µL) (h) 2+ proteinuria or less urine dipstick reading or normal UA
with less than 100 mg/dL protein (i) Calculated creatinine clearance (CL) ≥30 mL/min
as determined by Cockcroft-Gault (using actual body weight) or 24-hour urine
creatinine CL (j) For patients not receiving therapeutic anticoagulation: INR or
aPTT ≤2 × ULN
10. Upper endoscopy to evaluate varices and risk of bleeding is required within one year
prior to randomization
11. Negative HIV test at screening
12. All men, as well as women of child-bearing potential must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) for the
duration of study participation, and for 6 months following completion of therapy.
Women must refrain from donating eggs during this same period. Should a woman become
pregnant or suspect she is pregnant while participating in this study, she should
inform her treating physician immediately.
• A female of child-bearing potential is any woman (regardless of sexual
orientation, marital status, having undergone a tubal ligation, or remaining
celibate by choice) who meets the following criteria:
- Has not undergone a hysterectomy or bilateral oophorectomy; or
- Has not been naturally postmenopausal for at least 12 consecutive months (i.e.,
has had menses at any time in the preceding 12 consecutive months).
13. Ability to understand and the willingness to sign a written informed consent.
Exclusion Criteria:
1. Chemotherapy, radiotherapy, or other cancer therapy within 3 months prior to
starting study treatment.
2. Any prior immunotherapy for malignancy.
3. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
4. Patients with infiltrative-type HCC
5. Definite macrovascular invasion or distant metastatic disease at randomization
6. Clinically significant ascites, requiring non-pharmacological intervention (e.g.,
paracentesis) to maintain control within past 6 months
7. History of hepatic encephalopathy within past 6 months
8. Actively listed or under evaluation for liver transplantation
9. Prior bleeding event due to untreated or incompletely treated esophageal and/or
gastric varices within 6 months prior to randomization
10. History or evidence of inherited bleeding diathesis or significant coagulopathy at
risk of bleeding (i.e., in the absence of therapeutic anticoagulation).
11. Prior treatment with CD137 agonists or immune checkpoint blockade therapies,
including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
12. Treatment with investigational therapy within 28 days prior to initiation of study
treatment
13. 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
14. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation
of study treatment Patients receiving prophylactic antibiotics (e.g., to prevent a
urinary tract infection or chronic obstructive pulmonary disease exacerbation) are
eligible for the study.
15. Active tuberculosis
16. 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
17. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
18. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures (once monthly or more frequently)
19. Patients with indwelling catheters (e.g., PleurX®) are allowed.
20. Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium >
12 mg/dL or corrected serum calcium > ULN)
21. History or evidence upon physical or neurological examination of central nervous
system dysfuction
22. Current or recent (< 10 days prior to initiation of study treatment) use of aspirin
(> 325 mg/day), or clopidogrel (> 75 mg/day) Note: The use of full-dose oral or
parenteral anticoagulants for therapeutic purpose is permitted as long as the INR
and/or aPTT is within therapeutic limits (according to institution standards) within
7 days prior to initiation of study treatment and the patient has been on a stable
dose of anticoagulants for ≥ 2 weeks prior to initiation of study treatment.
Prophylactic use of anticoagulants is allowed. However, the use of direct oral
anticoagulant therapies such as dabigatran (Pradaxa®) and rivaroxaban (Xarelto®) is
not recommended due to bleeding risk.
23. History of leptomeningeal disease
24. Uncontrolled tumor-related pain. Patients requiring pain medication should be on
stable regimen prior to study entry.
25. Active or history of autoimmune disease or immune deficiency, including, but not
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré
syndrome, or multiple sclerosis, with the following exceptions: Patients with a
history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone
are eligible for the study.
Patients with controlled Type 1 diabetes mellitus who are on an insulin are eligible
for the study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis are
excluded) are eligible for the study provided all of following conditions are met:
- Rash must cover <10% of body surface area.
- Disease is well controlled at baseline and requires only low-potency topical
corticosteroids.
- There is no occurrence of acute exacerbations of the underlying condition
requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids,
biologic agents, oral calcineurin inhibitors, or high-potency or oral
corticosteroids within the 12 months prior to Day 1 of Cycle 1.
26. Systemic immunostimulatory agents (including, but not limited to, IFNs and IL-2) are
prohibited within 4 weeks or 5 drug-elimination half-lives (whichever is longer)
prior to initiation of study treatment and during study treatment.
27. History of hypertensive crisis or hypertensive encephalopathy.
28. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
recent arterial thrombosis) within 6 months prior to randomization.
29. History of arterial thrombotic event, including myocardial infarction, unstable
angina, cerebrovascular accident, or transient ischemic attack, within 6 months
prior to randomization.
30. History of grade ≥4 venous thromboembolism.
31. Non-healing wound, active ulcer, or bone fracture. Patients with granulating
incisions healing by secondary intention with no evidence of facial dehiscence or
infection are eligible but require wound examinations every 3 weeks.
32. History of abdominal fistula or GI perforation, non-healed gastric ulcer that is
refractory to treatment, or active GI bleeding within 6 months prior to enrollment.
33. History of grade ≥ 2 hemoptysis (defined as ≥ 2.5 mL of bright red blood per
episode) within one month of screening
34. Core biopsy or other minor surgical procedure, excluding vascular access device,
within 7 days prior to initiation of study treatment.
35. Surgical procedure (including open biopsy, surgical resection, wound revision, or
any other major surgery involving entry into a body cavity) or significant traumatic
injury within 28 days prior to initiation of study treatment, or anticipation of
need for major surgical procedure during the course of the study (Note: Biopsy and
endoscopy are not considered surgery so would not be exclusion criteria)
36. Uncontrolled hypertension defined by a systolic pressure >150 mmHg or diastolic
pressure >90 mmHg, with or without antihypertensive medication. Patients with
initial blood pressure (BP) elevations are eligible if initiation or adjustment of
antihypertensive medication lowers pressure to meet entry criteria.
37. History of allogeneic stem cell or organ transplantation
38. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
infection (except for noted HBV or HCV as detailed above), symptomatic congestive
heart failure, poorly controlled diabetes mellitus, unstable angina pectoris,
uncontrolled cardiac arrhythmia, active Interstitial Lung Disease (ILD), serious
chronic GI conditions associated with diarrhea, or psychiatric illness/social
situations that would limit compliance with study
39. History of another primary malignancy except for
- Malignancy treated with curative intent and with no known active disease ≥1
year before randomization 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
40. History of active primary immunodeficiency.
41. Patients co-infected with HBV and hepatitis D virus (HDV). (HBV infection is defined
above; HDV positive infection is indicated by the presence of anti-HDV antibodies).
42. Treatment with a live, attenuated vaccine (e.g., FluMist®) within 4 weeks prior to
Day 1 of Cycle 1, or anticipation of need for such a vaccine during atezolizumab
treatment or within 5 months after the final dose of atezolizumab.
43 Subjects must have recovered from prior treatment-related toxicities to grade 1 or
baseline (excluding alopecia and clinically stable toxicities requiring ongoing medical
management).
44. Subjects may not be receiving any other investigational agents for the treatment of
the cancer under study.
45. History of allergic reactions attributed to compounds of similar chemical or
biologic composition to atezolizumab or bevacizumab or other agents used in study.
46. Subjects must not be pregnant or breastfeeding during the study treatment, or have
the intention of becoming pregnant during the study treatment or within 6 months
after the final dose of study treatment due to the potential for congenital
abnormalities and the potential of this regimen to harm nursing infants. Women of
childbearing potential must have a negative serum or urine pregnancy test result
within 14 days prior to initiation of study treatment.
47. Treatment with systemic immunosuppressive medication (including, but not limited to,
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
anti-TNF-a agents) within 2 weeks prior to initiation of study treatment, or
anticipation of need for systemic immunosuppressive medication during study
treatment, with the following exceptions: Patients who received acute, low-dose
systemic immunosuppressant medication or a one-time pulse dose of systemic
immunosuppressant medication (e.g., 48 hours of Patients who receive
mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive
pulmonary disease (COPD) or asthma, or low-dose corticosteroids for
48. History of severe allergic anaphylactic reactions to chimeric or humanized
antibodies or fusion proteins.
49. Known hypersensitivity to Chinese hamster ovary cell products or to any component of
the atezolizumab formulation.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
Address:
City:
Dallas
Zip:
75390
Country:
United States
Status:
Recruiting
Contact:
Last name:
Clinical Research Office -Simmons Cancer Center
Phone:
214-648-7097
Start date:
September 27, 2023
Completion date:
January 1, 2028
Lead sponsor:
Agency:
University of Texas Southwestern Medical Center
Agency class:
Other
Collaborator:
Agency:
Genentech, Inc.
Agency class:
Industry
Source:
University of Texas Southwestern Medical Center
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05537402
