Atezolizumab and Bevacizumab Pre-Liver Transplantation for Patients With Hepatocellular Carcinoma Beyond Milan Criteria: A Feasibility Study
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- Proportion of Patients Receiving Liver Transplant Experiencing Acute Rejection
研究概览
简要总结
Patients with hepatocellular carcinoma (HCC) beyond Milan Criteria (MC) who are transplant-eligible will be treated with 6 months of neoadjuvant/downstaging atezolizumab plus bevacizumab while receiving standard of care transarterial chemoembolization (TACE). We hypothesize that atezolizumab and bevacizumab can appropriately bridge patients with HCC beyond MC to transplantation and not increase the risk of 1-year post-transplant rejection.
详细描述
Hepatocellular carcinoma (HCC) represents the second most common cause of cancer-related death and accounts for over 80% of primary liver cancers worldwide.(1) Curative treatment options include surgical resection in patients with well compensated liver function and radio frequency ablation in small tumors. However, in 90% of patients, HCC occurs in the setting of cirrhosis(2) where optimal management remains liver transplantation (LT) with 5-year survival rates of approximately 80%.(3) Despite the success of LT in treating HCC, only a small portion of patients fit into standard Milan Criteria to receive a LT due to 1) advanced-stage disease and/or large tumor size preventing/delaying organ allocation and 2) a lack of neoadjuvant (bridging) therapies that can effectively down-stage or delay tumor progression for patients while on the LT waiting list. The proposed clinical trial will evaluate the feasibility of using a combination of the chemotherapeutic interventions atezolizumab(4) and bevacizumab(5) in a group of patients with HCC who have tumors beyond the Milan Criteria (in brief, 5 - 10 cm), in order to appropriately bridge them to liver transplantation without increasing the risk of graft rejection within 1-year post-LT.
Globally, Milan Criteria (MC),(6) defined as one single tumor < 5cm or 3 tumors < 3cm, is the most commonly recognized criteria for selecting patients for deceased donor LT. However, it is increasingly recognized that these criteria may be restrictive and not always reflect biology of the disease.(3) Variable extended strategies have been employed including the i) extended Toronto Criteria(7) (where no limitation in tumor burden is imposed provided the tumor is not poorly differentiated and there is no evidence of extrahepatic disease or vascular invasion), ii) Ontario criteria, where patients are eligible based on Total Tumor Volume (TTV, ≤ 145cm^3) and alpha fetoprotein (AFP < 1000 ng/mL), or iii) University of California San Francisco criteria (tumor size ≤6.5 cm) and beyond.
A number of centers have implemented downstaging strategies incorporating AFP dynamics to help select who may benefit.(8) Despite similar survival in patients beyond MC successfully receiving a transplant,(7) a considerably higher rate of drop-off from the waiting list exists and survival in this population is particularly poor.(9) Downstaging patients to MC and transplant most commonly involves locoregional therapies (LRT); however, for patients who do not reach transplant, the long term survival after receiving systemic treatments is low.
The IMbrave150 study of atezolizumab and bevacizumab versus sorafenib demonstrated response rates of 29.8% vs 12%, respectively, and median overall survival of 19.8 months in the combination arm versus 13.4 months in the sorafenib alone arm (HR 0.66, 95% CI 0.52, 0.85; p=0.0009).(10) The synergistic effect of an antiangiogenic plus immune checkpoint inhibitor (CPI) can reactivate the intra-tumoral trafficking of cytotoxic T cells and create a favorable immune microenvironment for CPI antitumoral activity.(11)
This study has now shifted the treatment paradigm in HCC, suggesting a new standard of care in intermediate stage HCC refractory to local therapies and those with advanced stage disease eligible for first line treatment.(12) This data highlights the importance of systemic treatment in the management of HCC and challenges historical treatment paradigms. It further emphasizes the need to maintain liver function so that patients can receive systemic therapies.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female, aged ≥18 years old at the time of signing Informed Consent Form
- •Measurable or evaluable disease per RECIST v1.1 or mRECIST of unresectable HCC outside of Milan criteria
- •Histologically proven HCC, without extrahepatic disease. Patients who consent to a fresh tissue biopsy, and under the discretion of the Investigators, will provide a baseline biopsy sample for diagnosis and correlative studies. Archival tumor tissue may be used to confirm HCC in patients who do not consent to a fresh tissue biopsy.
- •Prior remote LRT is allowed if new lesions or local disease recurrence are present
- •Must be eligible for liver transplantation, defined in Section 10.4
- •Eligible and suited to receive TACE procedure(s)
- •Child-Pugh score ≤A6
- •Eastern Cooperative Oncology Group (ECOG) score 0-1
- •Life expectancy of ≥ 6 months
- •Adequate hematological and end-organ function, defined by the following laboratory test results obtained within 14 days prior to study initiation:
- •Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
- •Lymphocyte count ≥ 0.5 x 10^9/L (500/uL)
- •Platelet count > 75 x 109/L
- •Hemoglobin > 9 g/dL
- •Total bilirubin < 1.5 x upper limit of normal (ULN)
- •Aspartate transaminase (AST),alanine aminotransferase (ALT), and alkaline phosphatase (ALP) < 2.5 x ULN
- •Serum albumin > 2.7 g/dL
- •Serum creatinine < 1.5x ULN or calculated creatinine clearance < 50 ml/min
- •Urine dipstick for proteinuria ≥ 2+ unless a 24-hour urine protein < 1 g of protein is demonstrated
- •International normalized ratio (INR) ≤ 1.5 or partial thromboplastin time (PTT) ≤ 1.5 x ULN for patients not receiving anti-coagulation. The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or PTT is within therapeutic limits (according to the medical standard of the enrolling institution) and the patient has been on a stable dose of anticoagulants for at least two weeks prior to the first study treatment.
- •No evidence of a Grade 2 or higher esophageal and/or gastric varices. Patients must have an esophagogastroduodenoscopy (EGD) within 6 months prior to initiating the study treatment. See Section 8.7.1.
- •No history of hemoptysis (≥ 1/2 teaspoon of bright red blood per episode) within 1 month of study enrollment
- •Negative HIV test at screening or transplant workup
- •Negative hepatitis B surface antigen (HBsAg) test at screening or transplant workup
- •Negative total hepatitis B core antibody (HBcAb) test at screening or transplant workup, or positive total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening or transplant workup. The HBV DNA test will be performed only for patients who have a negative HBsAg test and a positive total HBcAb test.
- •For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, as defined below:
- •Women must remain abstinent or use contraceptive methods with a failure rate of <1% per year during the treatment period and for 6 months after the final dose of atezolizumab/bevacizumab Females who receive a LT are required to maintain abstinence or contraception until the End of Study.
- •A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). The definition of childbearing potential may be adapted for alignment with local guidelines or requirements.
- •Examples of contraceptive methods with a failure rate of <1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
- •The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (eg, calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception.
- •For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below:
- •With a female partner of childbearing potential or pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 6 months after the final dose of atezolizumab/bevacizumab to avoid exposing the embryo. Men must refrain from donating sperm during this same period. Males who receive a LT are required to maintain these criteria until the End of Study.
- •The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (eg, calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of preventing drug exposure.
- •Stated willingness to comply with all study procedures and availability for the duration of the study
- •Women of childbearing potential must have a negative serum or urine pregnancy test result within 14 days prior to initiation of study treatment.
排除标准
- •Known fibrolamellar HCC, sacromatoid HCC, or mixed cholangiocarcinoma and HCC
- •Previous systemic therapy for HCC prior to study enrollment
- •Planned or prior multi-organ transplant or prior solid organ or allogeneic stem cell transplantation
- •History of Grade ≥4 venous thromboembolism
- •History or evidence upon physical or neurological examination of central nervous system (eg seizures) unrelated to cancer unless adequately treated with standard medical therapy. Anticonvulsants (stable dose) are allowed.
- •Moderate or severe ascites
- •History of hepatic encephalopathy
- •Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg)
- •History of hypertensive crisis or hypertensive encephalopathy
- •Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months prior to drug administration
- •Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
- •History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (i.e., in the absence of therapeutic anticoagulation)
- •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 Treatment Phase of the study
- •Core biopsy or other minor surgical procedure, excluding placement of a vascular access device within 7 days prior to initiation of study treatment. Placement of a vascular access device should be at least 2 days prior to initiation of study treatment.
- •History of abdominal fistula, gastrointestinal (GI) perforation, intra-abdominal abscess, grade 2 or higher untreated esophageal or gastric varices or active GI bleeding within 6 months prior to treatment
- •Untreated or incompletely treated esophageal and/or gastric varices with bleeding or high risk for bleeding. 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 within 6 months prior to initiating the study treatment do not need to repeat the procedure.
- •Serious, non-healing wound, active ulcer, or untreated bone fracture
- •Other malignancy within 5 years prior to randomization, except for localized cancer in situ, such as basal or squamous cell skin cancer
- •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 a PTT is within therapeutic limits (according to institution standards) within 14 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.
- •Pregnancy (positive pregnancy test) or lactation, or intention of becoming pregnant during study treatment or within 6 months after the final dose of study drugs
- •o Women of childbearing potential must have a negative serum or urine pregnancy test result within 28 days prior to initiation of study treatment.
- •Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
- •Patients with indwelling catheters (e.g., PleurX®) are allowed
- •Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN)
- •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 eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (eg, patients with psoriatic arthritis are excluded) are eligible for the study provided all 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
- •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 previous 12 months
- •History of idiopathic pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
- •Active tuberculosis
- •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
- •Treatment with a live, attenuated vaccine (e.g., FluMist®) within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of atezolizumab
- •Current treatment with anti-viral therapy for HBV
- •Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
- •Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment
- •Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-α agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during the Treatment Phase, 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 corticosteroids for a contrast allergy) are eligible for the study after Principal Investigator confirmation has been obtained.
- •Patients who received mineralocorticoids (eg, fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.
- •History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
- •Known allergy or hypersensitivity to any component of the Atezlizumab and Bevacizumab formulation, such as a known hypersensitivity to Chinese hamster ovary cell products
- •Inability to comply with study and/or follow-up procedures
- •Active infection requiring IV antibiotics within 2 weeks prior to initiation.
- •Note: Placement of a vascular access device should be at least 2 days 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.
- •Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
- •History of leptomeningeal disease
- •Evidence of abdominal free air that is not explained by paracentesis or recent surgical procedure
- •History of intra-abdominal inflammatory process within 6 months prior to initiation of study treatment, including but not limited to active peptic ulcer disease, diverticulitits, or colitis.
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研究组 & 干预措施
Atezolizumab + Bevacizumab
Patients will receive transarterial chemoembolization (TACE) every 3 months, with a maximum of 4 treatments, plus atezolizumab combined with bevacizumab.
干预措施: Atezolizumab (Drug)
Atezolizumab + Bevacizumab
Patients will receive transarterial chemoembolization (TACE) every 3 months, with a maximum of 4 treatments, plus atezolizumab combined with bevacizumab.
干预措施: Bevacizumab (Drug)
结局指标
主要结局
Proportion of Patients Receiving Liver Transplant Experiencing Acute Rejection
时间窗: Within 1 year after liver transplant
The proportion of liver transplant patients who have acute allograft rejection
次要结局
- Tumor biomarkers(At enrollment; at time of first dose of atezolizumab/bevacizumab; 3, 6, 9, 12, 15, 18, 21, 24, 30, 39 weeks after first dose; at time of liver transplant; 1, 6, and 12 months after liver transplant)
- Proportion of participants who experience treatment-emergent adverse events(Within 90 days of study drug administration)
- Proportion of participants who are removed from the liver transplant waiting list after initiating the atezolizumab/bevacizumab therapy(Through study completion, up to 4 years)
- The proportion of participants who proceed to liver transplantation(Through study completion, up to 4 years)
- Recurrence-free survival in patients receiving a liver transplant(Within 1 year after liver transplant)
- Overall survival after liver transplant(Study enrollment to 1 year after liver transplant, time of liver transplant to 1 year after liver transplant)
- Immune Cell Biomarkers(At enrollment; at time of first dose of atezolizumab/bevacizumab; 3, 6, 9, 12, 15, 18, 21, 24, 30, 39 weeks after first dose; at time of liver transplant; 1, 6, and 12 months after liver transplant)
- Objective Response Rate(6 months post study drug initiation)
- Proportion of the liver explant tissue containing necrotic tumors(Through study completion, up to 4 years)
研究者
Maen Abdelrahim, MD, PhD, Pharm.B
Associate Professor of Medicine in Oncology, Houston Methodist Academic Institute
The Methodist Hospital Research Institute