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Atezolizumab and Bevacizumab Pre-Liver Transplantation for Patients With Hepatocellular Carcinoma Beyond Milan Criteria

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05185505
Recruitment Status : Not yet recruiting
First Posted : January 11, 2022
Last Update Posted : January 11, 2022
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
Maen Abdelrahim, MD, PhD, Pharm.B, The Methodist Hospital Research Institute

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Hepatocellular Carcinoma Hepatocellular Cancer Drug: Atezolizumab Drug: Bevacizumab Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Atezolizumab and Bevacizumab Pre-Liver Transplantation for Patients With Hepatocellular Carcinoma Beyond Milan Criteria: A Feasibility Study
Estimated Study Start Date : March 17, 2022
Estimated Primary Completion Date : June 17, 2026
Estimated Study Completion Date : December 17, 2026

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Atezolizumab + Bevacizumab
Patients will receive transarterial chemoembolization (TACE) every 3 months, with a maximum of 4 treatments, plus atezolizumab combined with bevacizumab.
Drug: Atezolizumab
1200 mg administered every three weeks for up to 6 months (up to 8 cycles) during the liver transplant waiting period
Other Name: Tecentriq

Drug: Bevacizumab
15 mg/kg administered every three weeks for up to 6 months (up to 8 cycles) during the liver transplant waiting period
Other Name: Avastin




Primary Outcome Measures :
  1. Proportion of Patients Receiving Liver Transplant Experiencing Acute Rejection [ Time Frame: Within 1 year after liver transplant ]
    The proportion of liver transplant patients who have acute allograft rejection


Secondary Outcome Measures :
  1. Proportion of participants who experience treatment-emergent adverse events [ Time Frame: Within 90 days of study drug administration ]
    Number of patients who experience an FDA-defined adverse event due to the experimental treatment

  2. Objective Response Rate [ Time Frame: 6 months post study drug initiation ]
    Combined incidence of partial response and complete response of tumors to therapy per RECIST criteria

  3. Proportion of participants who are removed from the liver transplant waiting list after initiating the atezolizumab/bevacizumab therapy [ Time Frame: Through study completion, up to 4 years ]
    Number of participants who had been on the liver transplant waitlist but are removed

  4. The proportion of participants who proceed to liver transplantation [ Time Frame: Through study completion, up to 4 years ]
    Participants who receive a liver transplant

  5. Proportion of the liver explant tissue containing necrotic tumors [ Time Frame: Through study completion, up to 4 years ]
    Number of livers explanted during liver transplant that are found to contain necrotic tumors via pathology

  6. Recurrence-free survival in patients receiving a liver transplant [ Time Frame: Within 1 year after liver transplant ]
    Measure of how many patients experience hepatocellular carcinoma recurrence

  7. Overall survival after liver transplant [ Time Frame: Study enrollment to 1 year after liver transplant, time of liver transplant to 1 year after liver transplant ]
    Number of patients who are still alive after receiving a liver transplant (taking into account death of any cause)

  8. Tumor biomarkers [ Time Frame: 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 ]
    Measurement of alpha fetoprotein tumor biomarker from blood samples

  9. Immune Cell Biomarkers [ Time Frame: 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 ]
    Measurement of biomarkers in immune cells gathered via blood samples: 1) PD-L1+ in CD4+ and CD8+ cells and 2) FOXP3, CD127, and IL-8 in T regulatory cells



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female, aged ≥18 years old at the time of signing Informed Consent Form
  2. Measurable or evaluable disease per RECIST v1.1 or mRECIST of unresectable HCC outside of Milan criteria
  3. 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.
  4. Prior remote LRT is allowed if new lesions or local disease recurrence are present
  5. Must be eligible for liver transplantation, defined in Section 10.4
  6. Eligible and suited to receive TACE procedure(s)
  7. Child-Pugh score ≤A6
  8. Eastern Cooperative Oncology Group (ECOG) score 0-1
  9. Life expectancy of ≥ 6 months
  10. Adequate hematological and end-organ function, defined by the following laboratory test results obtained within 14 days prior to study initiation:

    1. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
    2. Lymphocyte count ≥ 0.5 x 10^9/L (500/uL)
    3. Platelet count > 75 x 109/L
    4. Hemoglobin > 9 g/dL
    5. Total bilirubin < 1.5 x upper limit of normal (ULN)
    6. Aspartate transaminase (AST),alanine aminotransferase (ALT), and alkaline phosphatase (ALP) < 2.5 x ULN
    7. Serum albumin > 2.7 g/dL
    8. Serum creatinine < 1.5x ULN or calculated creatinine clearance < 50 ml/min
    9. Urine dipstick for proteinuria ≥ 2+ unless a 24-hour urine protein < 1 g of protein is demonstrated
    10. 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.
  11. 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 8.7.1.2.
  12. No history of hemoptysis (≥ 1/2 teaspoon of bright red blood per episode) within 1 month of study enrollment
  13. Negative HIV test at screening or transplant workup
  14. Negative hepatitis B surface antigen (HBsAg) test at screening or transplant workup
  15. 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.
  16. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, as defined below:

    1. 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.
    2. 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.
    3. 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.
    4. 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.
  17. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below:

    1. 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.
    2. 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.
  18. Stated willingness to comply with all study procedures and availability for the duration of the study
  19. Women of childbearing potential must have a negative serum or urine pregnancy test result within 14 days prior to initiation of study treatment.

Exclusion Criteria:

  1. Known fibrolamellar HCC, sacromatoid HCC, or mixed cholangiocarcinoma and HCC
  2. Previous systemic therapy for HCC prior to study enrollment
  3. Planned or prior multi-organ transplant or prior solid organ or allogeneic stem cell transplantation
  4. History of Grade ≥4 venous thromboembolism
  5. 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.
  6. Moderate or severe ascites
  7. History of hepatic encephalopathy
  8. Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg)
  9. History of hypertensive crisis or hypertensive encephalopathy
  10. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months prior to drug administration
  11. 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
  12. History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (i.e., in the absence of therapeutic anticoagulation)
  13. 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.

  14. 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
  15. 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.
  16. Serious, non-healing wound, active ulcer, or untreated bone fracture
  17. Other malignancy within 5 years prior to randomization, except for localized cancer in situ, such as basal or squamous cell skin cancer
  18. 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.
  19. 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.

  20. 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

  21. Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN)
  22. 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
  23. 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.
  24. Active tuberculosis
  25. 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
  26. 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
  27. Current treatment with anti-viral therapy for HBV
  28. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
  29. 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
  30. 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.
  31. History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
  32. Known allergy or hypersensitivity to any component of the Atezlizumab and Bevacizumab formulation, such as a known hypersensitivity to Chinese hamster ovary cell products
  33. Inability to comply with study and/or follow-up procedures
  34. 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.
  35. 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
  36. History of leptomeningeal disease
  37. Evidence of abdominal free air that is not explained by paracentesis or recent surgical procedure
  38. 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.
  39. Chronic daily treatment with a nonsteroidal anti-inflammatory drug (NSAID). Occasional use of NSAIDs for the symptomatic relief of medical conditions such as headache or fever is allowed
  40. Uncontrolled tumor-related pain

    • Patients requiring pain medication must be on a stable regimen at study entry.
    • Symptomatic lesions (eg, 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05185505


Contacts
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Contact: Darrel Cleere, BSN 713-441-6232 dwcleere@houstonmethodist.org
Contact: Shondra Word 713-441-5122 sword@houstonmethodist.org

Locations
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United States, Texas
Houston Methodist Research Institute
Houston, Texas, United States, 77030
Contact: Darrel W Cleere, BSN    713-515-8380    dwcleere@houstonmethodist.org   
Contact: Beatriz Efron, BSN    713-363-8890    befron@houstonmethodist.org   
Principal Investigator: Maen Abdelrahim, MD         
Sponsors and Collaborators
The Methodist Hospital Research Institute
Genentech, Inc.
Additional Information:
Publications:
Tecentriq [Package Insert]. South San Francisco, CA: Genentech, Inc.; 2020.
Avastin [Package Insert]. South San Francisco, CA: Genentech, Inc.; 2020.
Finn RS, Qin S, Ikeda M, et al. Imbrave150: Updated Overall Survival (Os) Data from a Global, Randomized, Open-Label Phase Iii Study of Atezolizumab (Atezo) + Bevacizumab (Bev) Versus Sorafenib (Sor) in Patients (Pts) with Unresectable Hepatocellular Carcinoma (Hcc). Journal of Clinical Oncology. 2021;39(3_suppl):267-267.
Opdivo [Package Insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2018.
Ravelli A, Minoia F, Davi S, Horne A, Bovis F, Pistorio A, Arico M, Avcin T, Behrens EM, De Benedetti F, Filipovic L, Grom AA, Henter JI, Ilowite NT, Jordan MB, Khubchandani R, Kitoh T, Lehmberg K, Lovell DJ, Miettunen P, Nichols KE, Ozen S, Pachlopnik Schmid J, Ramanan AV, Russo R, Schneider R, Sterba G, Uziel Y, Wallace C, Wouters C, Wulffraat N, Demirkaya E, Brunner HI, Martini A, Ruperto N, Cron RQ; Paediatric Rheumatology International Trials Organisation; Childhood Arthritis and Rheumatology Research Alliance; Pediatric Rheumatology Collaborative Study Group; Histiocyte Society. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative. Arthritis Rheumatol. 2016 Mar;68(3):566-76. doi: 10.1002/art.39332. Epub 2016 Feb 9.

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Responsible Party: Maen Abdelrahim, MD, PhD, Pharm.B, Associate Professor of Medicine in Oncology, Houston Methodist Academic Institute, The Methodist Hospital Research Institute
ClinicalTrials.gov Identifier: NCT05185505    
Other Study ID Numbers: PRO00032239
ML43352 ( Other Grant/Funding Number: Genentech, Inc. )
First Posted: January 11, 2022    Key Record Dates
Last Update Posted: January 11, 2022
Last Verified: January 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Maen Abdelrahim, MD, PhD, Pharm.B, The Methodist Hospital Research Institute:
Bevacizumab
atezolizumab
Neoadjuvant Therapy
Liver Neoplasms
Liver Transplantation
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Hepatocellular
Liver Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Bevacizumab
Atezolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors