Clinical Trials /

Study of Atezolizumab and Bevacizumab With Y-90 TARE in Patients With Unresectable Hepatocellular Carcinoma (HCC)

NCT04541173

Description:

This is an open-label, multi-center, randomized phase II study comparing the Y90 TARE followed by bevacizumab and atezolizumab treatment to the Y90 TARE treatment alone in unresectable intermediate stage HCC.

Related Conditions:
  • Hepatocellular Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Atezolizumab and Bevacizumab With Y-90 TARE in Patients With Unresectable Hepatocellular Carcinoma (HCC)
  • Official Title: A Randomized Phase II Study of Atezolizumab and Bevacizumab With Y-90 TARE in Patients With Unresectable Hepatocellular Carcinoma (HCC)

Clinical Trial IDs

  • ORG STUDY ID: GI19-405
  • NCT ID: NCT04541173

Conditions

  • Hepatocellular Carcinoma

Interventions

DrugSynonymsArms
AtezolizumabTecentriqArm B
BevacizumabAvastinArm B

Purpose

This is an open-label, multi-center, randomized phase II study comparing the Y90 TARE followed by bevacizumab and atezolizumab treatment to the Y90 TARE treatment alone in unresectable intermediate stage HCC.

Detailed Description

      Subjects will be randomized to Y-90 TARE alone (Arm A) or Y-90 TARE followed by the
      combination of atezolizumab and bevacizumab (Arm B). The first 10 subjects randomized to Arm
      B (Y-90 TARE + bevacizumab + atezolizumab) will be assessed for safety after two cycles. If
      there are no Grade ≥ 3 unexpected toxicities; possibly, probably or definitely related to
      TARE in combination with bevacizumab and atezolizumab the combination will be deemed safe and
      accrual will continue.

      Subjects randomized to receive bevacizumab and atezolizumab (Arm B) will start the
      combination of bevacizumab and atezolizumab 4 weeks (± 1 week) after TARE treatment. Full
      recovery from the procedure is required prior to systemic treatment:

        -  AST and ALT ≤ 5 x upper limit of normal (ULN) and total bilirubin ≤ 3 mg/dL

        -  Manifestations of post-embolization syndrome (e.g., fever, nausea, vomiting, and
           abdominal pain) have resolved to National Cancer Institute Common Terminology Criteria
           for Adverse Events, Version 5.0 Grade 1

        -  No significant medical events (e.g., gastrointestinal [GI] bleeding, cardiac events,
           hepatorenal syndrome) during or after the TARE procedure.

      These subjects will continue the study drugs for a total of 24 months from the TARE
      treatment, until intolerable toxicity or disease progression occur.
    

Trial Arms

NameTypeDescriptionInterventions
Arm AActive ComparatorTARE alone
    Arm BExperimentalTARE then Bevacizumab and Atezolizumab
    • Atezolizumab
    • Bevacizumab

    Eligibility Criteria

            Inclusion Criteria:
    
              1. Written informed consent and HIPAA authorization for release of personal health
                 information prior to registration. NOTE: HIPAA authorization may be included in the
                 informed consent or obtained separately. Patients must be willing and able to provide
                 written informed consent for this trial.
    
              2. Age ≥ 18 years at the time of consent.
    
              3. ECOG Performance Status of 0-1 at screening
    
              4. Histological or cytological evidence/confirmation per AJCC, 8th edition, of
                 hepatocellular carcinoma (HCC).
    
              5. Measurable disease by RECIST 1.1.
    
              6. Patients must have a Child-Pugh score of A.
    
              7. Patients must have at least Barcelona Clinic Liver Cancer (BCLC) stage B HCC and must
                 be outside of downstaging criteria (downstaging criteria are defined as: one lesion >
                 5 cm and </= 8 cm; two to three lesions each </= 5 cm; four to five lesions </= 3 cm
                 with a total tumor diameter of </= 8 cm); six lesions or more regardless of size;
                 and/or HCC peripheral vascular involvement of any size or number of tumor (segment
                 peripheral, vp1 and vp2 are allowed, but vp3 and vp4 are excluded). NOTE: absence of
                 extrahepatic spread, must be confirmed by computed tomography (CT) or magnetic
                 resonance imaging (MRI) scan of the chest, abdomen, and pelvis
    
              8. Archival tissue obtained within 6 months of registration is required. If archival
                 tissue is not available, subjects are not eligible.
    
              9. Patients must not be suitable for or amenable to transplant or resection.
    
             10. Patients may be treatment naive or have received any number of prior therapies except
                 systemic therapy. No prior systemic therapy is permitted. NOTE: Patients who received
                 prior local therapy (e.g., radiofrequency ablation, percutaneous ethanol or acetic
                 acid injection, cryoablation, high-intensity focused ultrasound) are eligible provided
                 the target lesion(s) have not been previously treated with local therapy or the target
                 lesion(s) within the field of local therapy have subsequently progressed in accordance
                 with RECIST 1.1. Prior TACE IS allowed if FLR is ≥ 40%.
    
             11. Patients must demonstrate adequate hepatic, bone marrow, and renal function as defined
                 in Table below. All screening labs should be performed within 14 days of treatment
                 initiation.
    
                   -  Absolute Neutrophil Count (ANC) ≥ 1,500 /μL
    
                   -  Hemoglobin (Hgb) ≥ 9 g/dL without transfusion or EPO dependency (within 7 days of
                      assessment)
    
                   -  Platelet count (Plt) ≥ 50,000 / μL
    
                   -  Serum creatinine OR Measured or calculated CrCl ≤ 1.5 X upper limit of normal
                      (ULN) OR ≥ 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN
    
                   -  Bilirubin ≤ 3.0 X ULN upper limit of normal (ULN)
    
                   -  Aspartate aminotransferase (AST) ≤ 5 X ULN for subjects with cancer in liver
    
                   -  Alanine aminotransferase (ALT) ≤ 5 X ULN for subjects with cancer in liver
    
                   -  Albumin > 2.5 mg/dL
    
                   -  Urine Protein ≤ 2 g
    
                   -  International Normalized Ratio (INR) or Prothrombin Time (PT) or Activated
                      Partial Thromboplastin Time (aPTT) ≤ 1.5 X ULN unless subject is receiving
                      anticoagulant therapy, in which case PT/aPTT must be within therapeutic range for
                      intended use of anticoagulants
    
             12. Negative HIV test at screening; NOTE: patients with a positive HIV test at screening
                 are eligible provided they are stable on anti-retroviral therapy, have a CD4 count >/=
                 200/µL, and have an undetectable viral load.
    
             13. Urine dipstick for proteinuria < 2+ (within 14 days prior to initiation of study
                 treatment) Patients discovered to have >/= 2+ proteinuria on dipstick urinalysis at
                 baseline should undergo a 24-hour urine collection and must demonstrate <1 g of
                 protein in 24 hours.
    
             14. Documented virology status of hepatitis, as confirmed by screening HBV and HCV
                 serology test : For patients with active hepatitis B virus (HBV): HBV DNA < 500 IU/mL
                 obtained within 28 days prior to initiation of study treatment, and Anti-HBV treatment
                 (per local standard of care; e.g., entecavir) for a minimum of 14 days prior to study
                 entry and willingness to continue treatment for the length of the study.
    
             15. Co-infection of HBV and HCV is an exclusion. Patients with a history of HCV infection
                 but who are negative for HCV RNA by PCR will be considered non-infected with HCV.
    
             16. Prior cancer treatment must be completed at least six months prior to registration and
                 the subject must have recovered from all reversible acute toxic effects of the regimen
                 (other than alopecia) to Grade ≤ 1 or baseline.
    
             17. Females of childbearing potential must have a negative serum pregnancy test within 14
                 days prior to registration. NOTE: Females are considered of child bearing potential
                 unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal
                 ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least
                 12 consecutive months.
    
             18. Females of childbearing potential must be willing to abstain from heterosexual
                 activity or to use 2 forms of effective methods of contraception from the time of
                 informed consent until 150 days after treatment discontinuation (Arm B). Males of
                 childbearing potential must be willing to abstain from heterosexual activity or to use
                 2 forms of effective methods of contraception from the time of informed consent until
                 210 days after treatment discontinuation (Arm B). The timeframe for female and male
                 subjects that randomize to Arm A is from the time of informed consent until 60 days
                 after treatment discontinuation.
    
             19. As determined by the enrolling physician or protocol designee, ability of the subject
                 to understand and comply with study procedures for the entire length of the study.
    
            Exclusion Criteria
    
              1. Have signs of liver failure, e.g. clinically significant ascites, encephalopathy, or
                 variceal bleeding within six months from enrollment.
    
              2. Prior bleeding event due to esophageal and/or gastric varices within 6 months prior to
                 initiation of study treatment. 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 within 6 months of prior to initiation of study treatment do not need
                 to repeat the procedure.
    
              3. Untreated or incompletely treated esophageal and/or gastric varices with bleeding or
                 high-risk for bleeding.
    
              4. Have evidence of excessive hepatopulmonary shunting (> 20% in 99mTc macro-aggregated
                 albumin scan) or angiographically demonstrable and non-occludable gastrointestinal
                 shunting, precluding from Y-90 treatment).
    
              5. Prior history of TACE or transarterial treatment via hepatic artery.
    
              6. Subject not a TARE candidate, as defined by a lung dose threshold for Y-90 of 30Gy and
                 an estimated (future liver remnants) FLR of < 40% at the time of forming the
                 comprehensive treatment plan.
    
              7. 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.
    
              8. Prior history of hypertensive crisis or hypertensive encephalopathy.
    
              9. 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.
    
             10. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
    
             11. Major surgery within 4 weeks prior to registration or anticipation of a major surgical
                 procedure during study.
    
             12. Have had prior transplant of any kind.
    
             13. Have active autoimmune disease that has required systemic treatment in the past 2
                 years (i.e. with use of disease modifying agents, corticosteroids, or
                 immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
                 physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency,
                 etc.) is not considered a form of systemic treatment. Have history of idiopathic
                 pulmonary fibrosis (including bronchiolitis obliterans with organizing pneumonia) or
                 evidence of active pneumonitis on screening chest CT scan.
    
             14. Have untreated central nervous system (CNS) metastatic disease (including spinal cord
                 and leptomeningeal disease). NOTE: Subjects with previously treated CNS metastases
                 that are radiographically and neurologically stable for at least 6 weeks and do not
                 require corticosteroids (of any dose) for symptomatic management are permitted to
                 enroll.
    
             15. Have unresolved toxicities from prior anticancer therapy, defined as having not
                 resolved to National Cancer Institute (NCI) CTCAE v5 grade 0 or 1 with the exception
                 of alopecia and laboratory values listed per the inclusion criteria. NOTE: Subjects
                 with irreversible toxicity that is not reasonably expected to be exacerbated by any of
                 the investigational products may be included (e.g., hearing loss) after consultation
                 with the sponsor-investigator.
    
             16. Diagnosed or treated for malignancy other than HCC, unless they meet one of the
                 following exceptions:
    
                   -  Malignancy treated with curative intent and with no known active disease present
                      for ≥ 2 years before registration and felt to be at low risk for recurrence by
                      the treating physician.
    
                   -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                      of disease.
    
                   -  Adequately treated cervical carcinoma in situ without evidence of disease.
    
             17. Have a known or suspected allergy to bevacizumab or atezolizumab or known
                 hypersensitivity to Chinese hamster ovary cell products or to any component of the
                 atezolizumab or bevacizumab formulation.
    
             18. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
                 recent peripheral arterial thrombosis) within 6 months prior to initiation of study
                 treatment.
    
             19. History of hemoptysis (≥ 2.5 mL of bright red blood per episode) within 1 month prior
                 to initiation of study treatment.
    
             20. Evidence of bleeding diathesis or significant coagulopathy (in the absence of
                 therapeutic anticoagulation).
    
             21. Current or recent (within 10 days of first dose of study treatment) use of aspirin (≥
                 325 mg/day) or treatment with dipyramidole, ticlopidine, clopidogrel, and cilostazol.
    
             22. Current or recent (within 10 days prior to study treatment start) use of full-dose
                 oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed
                 to prophylactic) purpose. NOTE: Prophylactic anticoagulation for the patency of venous
                 access devices is allowed provided the activity of the agent results in an INR < 1.5 x
                 ULN and aPTT is within normal limits within 14 days prior to initiation of study
                 treatment.
    
             23. Have an uncontrolled intercurrent illness including, but not limited to any of the
                 following:
    
                   -  Psychiatric illness/social situations that would limit compliance with study
                      requirements
    
                   -  Have any other disease, metabolic dysfunction, physical examination finding, or
                      clinical laboratory finding giving reasonable suspicion of a disease or condition
                      that contraindicates the use of an investigational drug or that may affect the
                      interpretation of the results or render the patient at high risk from treatment
                      complications.
    
                   -  Active alcohol use, drug use, or a psychiatric disease that would, in the opinion
                      of the sponsor-investigator or a sub-investigator (sub-I), prevent the subject
                      from complying with the study protocol and/or endanger the subject during their
                      participation in the study.
    
             24. 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. NOTE: 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.
    
             25. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the
                 mother is being treated on study).
    
             26. ave received a live vaccine within 30 days of the planned start of study therapy.
                 NOTE: Seasonal influenza vaccines for injection are generally inactivated flu vaccines
                 and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live
                 attenuated vaccines, and are not allowed.
    
             27. Have received or are receiving any investigational therapy within 28 days prior to the
                 first dose of bevacizumab and atezolizumab. NOTE: Subjects may be enrolled in an
                 observational (non-interventional) clinical study or in the follow-up period of an
                 interventional study.
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Progression free survival (PFS) by RECIST 1.1
    Time Frame:12 months
    Safety Issue:
    Description:PFS is defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first) according to RECIST v1.1

    Secondary Outcome Measures

    Measure:Incidence and severity of adverse events
    Time Frame:12 months
    Safety Issue:
    Description:Adverse events will be graded using CTCAE v5
    Measure:Progression free survival by mRECIST
    Time Frame:12 months
    Safety Issue:
    Description:• PFS is defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first) according to mRECIST
    Measure:Time to progression (TTP) by mRECIST
    Time Frame:12 months
    Safety Issue:
    Description:TTP is defined as the time from randomization to the first occurrence of disease progression according to RECIST v1.1 and mRECIST
    Measure:Overall Response Rate (ORR) by mRECIST
    Time Frame:12 months
    Safety Issue:
    Description:ORR is defined as a complete or partial response according to RECIST v1.1 or mRECIST
    Measure:Overall survival (OS)
    Time Frame:12 months
    Safety Issue:
    Description:OS is defined as the time from randomization to death from any cause.

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Aiwu Ruth He, MD

    Last Updated

    December 19, 2020