xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT06006286</url>
    </required_header>
    <id_info>
      <org_study_id>2023-0208</org_study_id>
      <secondary_id>NCI-2023-06581</secondary_id>
      <nct_id>NCT06006286</nct_id>
    </id_info>
    <brief_title>A Study Evaluating Atezolizumab and Bevacizumab Plus ADI-PEG 20 in Patients With Locally Advanced / Metastatic Hepatocellular Carcinoma</brief_title>
    <official_title>A Pilot Study Evaluating Atezolizumab and Bevacizumab Plus ADI-PEG 20 in Patients With Locally Advanced / Metastatic Hepatocellular Carcinoma</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>M.D. Anderson Cancer Center</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>M.D. Anderson Cancer Center</source>
    <oversight_info>
      <has_dmc>Yes</has_dmc>
      <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        To learn about the safety and tolerability of atezolizumab, bevacizumab, and ADI-PEG 20 when&#xD;
        given in combination to patients with locally advanced or metastatic liver cancer&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Primary Objectives:&#xD;
  &#xD;
        --To evaluate the safety and tolerability of treatment with atezolizumab and bevacizumab +&#xD;
        ADI-PEG 20 in Patients with Locally Advanced/ Metastatic Hepatocellular Carcinoma.&#xD;
  &#xD;
        Secondary Objectives:&#xD;
  &#xD;
        --To assess the pathologic response rate including pathologic complete response (pCR) per&#xD;
        RECIST and degree of necrosis (&gt;50% in tumor volume) with atezolizumab and bevacizumab +&#xD;
        ADI-PEG 20 in treatment-naïve locally advanced or metastatic HCC.&#xD;
  &#xD;
        Exploratory Objectives:&#xD;
  &#xD;
        --To assess the immunological/biomarker changes (pre- vs. post-treatment) in tumor tissues&#xD;
        and peripheral blood in response to atezolizumab and bevacizumab + ADI-PEG 20 in HCC therapy&#xD;
        and explore any potential association between these biomarker measures and antitumor&#xD;
        response.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">February 28, 2024</start_date>
    <completion_date type="Anticipated">May 20, 2025</completion_date>
    <primary_completion_date type="Anticipated">May 20, 2025</primary_completion_date>
    <phase>Phase 1/Phase 2</phase>
    <study_type>Interventional</study_type>
    <study_design_info>
      <allocation>N/A</allocation>
      <intervention_model>Single Group Assignment</intervention_model>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0</measure>
      <time_frame>through study completion; an average of 1 year</time_frame>
    </primary_outcome>
    <number_of_arms>1</number_of_arms>
    <enrollment type="Anticipated">10</enrollment>
    <condition>Metastatic Hepatocellular Carcinoma</condition>
    <arm_group>
      <arm_group_label>ADI-PEG20/ATEZO/BEV</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Participants will first receive the study drug combination for up to 12 weeks. If participants have stable disease or a partial response to the study drug after 12 weeks, participants may continue to receive ADI-PEG 20 for up to 2 years of total dosing, and participants may continue to receive atezolizumab and bevacizumab indefinitely (no limit)</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Atezolizumab</intervention_name>
      <description>Given by IV (vein)</description>
      <arm_group_label>ADI-PEG20/ATEZO/BEV</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Bevacizumab</intervention_name>
      <description>Given by IV (vein)</description>
      <arm_group_label>ADI-PEG20/ATEZO/BEV</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>ADI-PEG 20</intervention_name>
      <description>Given by Injection (inj)</description>
      <arm_group_label>ADI-PEG20/ATEZO/BEV</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            1. Ability to understand and the willingness to sign a written informed consent document&#xD;
               for participation in this trial&#xD;
  &#xD;
            2. Willingness to sign a written informed consent document to participate in laboratory&#xD;
               protocol PA13-0291 for the testing of biomarkers as described in this clinical&#xD;
               protocol.&#xD;
  &#xD;
            3. ≥ 18 years of age&#xD;
  &#xD;
            4. Histologically confirmed HCC (documentation of original biopsy for diagnosis is&#xD;
               acceptable if tumor tissue is unavailable) or clinical diagnosis by AASLD (American&#xD;
               Association for the Study for Liver Diseases) criteria in cirrhotic subjects (presence&#xD;
               of nonrim arterial phase hyperenhancement relative to the liver parenchyma with venous&#xD;
               washout for tumors &gt; 1 cm). For subjects without cirrhosis, histological confirmation&#xD;
               is mandatory.&#xD;
  &#xD;
               The determination of cirrhosis status will ultimately lie in the clinical judgment of&#xD;
               the surgical oncologist and medical oncologist involved in the care of the patient.&#xD;
  &#xD;
            5. Locally advanced or metastatic disease.&#xD;
  &#xD;
            6. Measurable disease defined as a lesion that can be accurately measured in at least one&#xD;
               dimension (longest diameter to be recorded) and measures ≥ 15 mm with conventional&#xD;
               techniques or ≥ 10 mm with more sensitive techniques such as magnetic resonance&#xD;
               imaging (MRI) or spiral computed tomography (CT) scan.&#xD;
  &#xD;
            7. Eastern Cooperative Oncology Group performance status (ECOG PS) score ≤ 1.&#xD;
  &#xD;
            8. Child-Turcotte-Pugh Score A.&#xD;
  &#xD;
            9. Record of treated or absence of esophageal varices by esophagogastroduodenoscopy&#xD;
               within 6 months of initiating treatment.&#xD;
  &#xD;
           10. Adequate organ and marrow function (as defined below) within 14 days of the first dose&#xD;
               of study drug:&#xD;
  &#xD;
                 -  Absolute neutrophil count ≥ 1,500/μL&#xD;
  &#xD;
                 -  Platelets ≥100,000/μL&#xD;
  &#xD;
                 -  Hemoglobin &gt; 9.0 g/dL (may be transfused or receive epoetin alfa [e.g., Epogen®]&#xD;
                    to maintain or exceed this level)&#xD;
  &#xD;
                 -  Total bilirubin ≤ 1.5 x ULN with the following exception:&#xD;
  &#xD;
                    - Patients with known Gilbert disease: serum bilirubin ≤ 3 x ULN&#xD;
  &#xD;
                 -  Estimated creatinine clearance &gt;40mL/min.&#xD;
  &#xD;
                 -  Aspartate transaminase (AST) (SGOT) and/or alanine transaminase (ALT) (SGPT) ≤ 5&#xD;
                    X institutional ULN&#xD;
  &#xD;
                 -  Documented virology status of hepatitis, as confirmed by screening HBV and HCV&#xD;
                    tests for patients with active HBV: HBV DNA ≤ 500 IU/mL during screening,&#xD;
                    initiation of anti-HBV treatment at least 14 days prior to randomization and&#xD;
                    willingness to continue anti-HBV treatment during the study (per local standard&#xD;
                    of care: e.g., entecavir)&#xD;
  &#xD;
                 -  UA with protein less than 2+&#xD;
  &#xD;
                 -  Serum uric acid ≤10 mg/dL (595 μmol/L) (with or without medication control).&#xD;
  &#xD;
           11. Negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent&#xD;
               units of HCG) within 24 hours prior to the start of study drug and every 4 weeks while&#xD;
               taking atezolizumab and bevacizumab (for women of childbearing potential [WOCBP]).&#xD;
  &#xD;
           12. Not breastfeeding&#xD;
  &#xD;
           13. The effects of ADI-PEG 20 on the developing human fetus are unknown. For this reason,&#xD;
               women of child-bearing potential (WOCBP) and men who are sexually active with WOCBP&#xD;
               must agree to use adequate contraception (hormonal or barrier method of birth control;&#xD;
               abstinence) prior to study entry, for the duration of study participation and for a&#xD;
               total of 12 (women) or 7 (men who are sexually active with WOCBP) months after the&#xD;
               completion of API-PEG 20 (Refer to Pregnancy Assessment Policy MD Anderson&#xD;
               Institutional Policy # CLN1114). This includes all female patients, between the onset&#xD;
               of menses (as early as 8 years of age) and 55 years unless the patient presents with&#xD;
               an applicable exclusionary factor which may be one of the following:&#xD;
  &#xD;
                 -  Postmenopausal (no menses in greater than or equal to 12 consecutive months).&#xD;
  &#xD;
                 -  History of hysterectomy or bilateral salpingo-oophorectomy.&#xD;
  &#xD;
                 -  Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range,&#xD;
                    who have received Whole Pelvic Radiation Therapy).&#xD;
  &#xD;
                 -  History of bilateral tubal ligation or another surgical sterilization procedure.&#xD;
  &#xD;
          Approved methods of birth control are as follows: Hormonal contraception (i.e. birth&#xD;
          control pills, injection, implant, transdermal patch, vaginal ring), Intrauterine device&#xD;
          (IUD), Tubal Ligation or hysterectomy, Subject/Partner post vasectomy, Implantable or&#xD;
          injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for&#xD;
          the total duration of the trial and the drug washout period is an acceptable practice;&#xD;
          however periodic abstinence, the rhythm method, and the withdrawal method are not&#xD;
          acceptable methods of birth control. Should a woman become pregnant or suspect she is&#xD;
          pregnant while she or her partner is participating in this study, she should inform her&#xD;
          treating physician immediately. NOTE: Azoospermic males and WOCBP who are continuously not&#xD;
          heterosexually active are exempt from contraceptive requirements. However, WOCBP must still&#xD;
          undergo pregnancy testing as described in these sections.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
          Any of the following criteria will disqualify the patient from participation:&#xD;
  &#xD;
            1. Any other malignancy from which the patient has been disease-free for less than 2&#xD;
               years (exceptions: non-melanoma skin cancer or in situ carcinoma of any site are&#xD;
               allowed)&#xD;
  &#xD;
            2. Fibrolamellar HCC, sarcomatoid HCC, or hepatocellular cholangiocarcinoma&#xD;
  &#xD;
            3. Prior systemic therapy, anti-PD-1/PD-L1 or VEGF inhibitor or ADI-PEG 20 therapy.&#xD;
  &#xD;
               Note: Prior surgery, radiation therapy, or local-regional therapy (ablation or&#xD;
               arterial directed therapies) are allowed.&#xD;
  &#xD;
            4. Receipt of organ allograft(s)&#xD;
  &#xD;
            5. Major surgical procedure, open biopsy, or significant traumatic injury with poorly&#xD;
               healed wound within 6 weeks prior to first dose of study drug; or anticipates needing&#xD;
               for a major surgical procedure during the course of the study (other than defined by&#xD;
               protocol such as the pre-treatment fine needle aspirations or core biopsies) within 7&#xD;
               days prior to first dose of study drug.&#xD;
  &#xD;
            6. History of inflammatory bowel disease (including Crohn's disease and ulcerative&#xD;
               colitis) or a history of autoimmune disease (e.g., rheumatoid arthritis, systemic&#xD;
               progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune&#xD;
               vasculitis [e.g., Wegener's granulomatosis]).&#xD;
  &#xD;
            7. History of testing positive for human immunodeficiency virus or has acquired&#xD;
               immunodeficiency syndrome (AIDS).&#xD;
  &#xD;
            8. Underlying medical condition, which in the opinion of the Investigator, will make the&#xD;
               administration of study drug hazardous or will obscure the interpretation of adverse&#xD;
               events, such as a condition associated with frequent diarrhea.&#xD;
  &#xD;
            9. Has a known risk factor for bowel perforation including a history of acute&#xD;
               diverticulitis, abdominal fistula, gastrointestinal perforation, intra-abdominal&#xD;
               abscess, or gastrointestinal obstruction.&#xD;
  &#xD;
           10. History of primary brain tumor (excluding meningiomas and other benign lesions), any&#xD;
               brain metastases, leptomeningeal disease, seizure disorders not controlled with&#xD;
               standard medical therapy, or (within the past year) a history of stroke.&#xD;
  &#xD;
           11. History of serious systemic disease, including myocardial infarction or unstable&#xD;
               angina within the last 12 months; a history of hypertensive crisis or hypertensive&#xD;
               encephalopathy, uncontrolled hypertension (systolic ≥ 150 mmHg and/or diastolic ≥ 100&#xD;
               mmHg at the time of enrollment); New York Heart Association (NYHA) Grade II or greater&#xD;
               congestive heart failure, unstable symptomatic arrhythmia requiring medication&#xD;
               (patients with chronic atrial arrhythmia, i.e., atrial fibrillation or paroxysmal&#xD;
               supraventricular tachycardia are eligible); significant vascular disease or&#xD;
               symptomatic peripheral vascular disease.&#xD;
  &#xD;
           12. History of other diseases, metabolic dysfunction, physical examination finding, or&#xD;
               clinical laboratory finding giving reasonable suspicion of a disease or condition that&#xD;
               contraindicates the use of an investigational drug or that might affect the&#xD;
               interpretation of the results of the study or render the subject at high risk from&#xD;
               treatment complications.&#xD;
  &#xD;
           13. History of seizure disorder not related to underlying cancer.&#xD;
  &#xD;
           14. Known allergy to pegylated compounds.&#xD;
  &#xD;
           15. Known allergy to E. coli drug products (such as granulocyte-macrophage colony&#xD;
               stimulating factor).&#xD;
  &#xD;
           16. Has had influenza-, hepatitis-, or other vaccines within a month prior to initiation&#xD;
               of study drugs.&#xD;
  &#xD;
           17. Has had a clinical history of coagulopathy, bleeding diathesis or thrombosis within&#xD;
               the past year.&#xD;
  &#xD;
           18. Significant pulmonary disease including tuberculosis, pneumonia, pneumonitis, etc.&#xD;
  &#xD;
           19. Requires recurrent drainage procedures including pleural effusion, ascites, etc.&#xD;
  &#xD;
           20. Surgical procedure within 6 weeks of initiation of study treatment.&#xD;
  &#xD;
           21. History of severe allergic/anaphylactic reactions to chimeric or humanized antibodies&#xD;
               or fusion proteins.&#xD;
  &#xD;
           22. Known hypersensitivity to Chinese hamster ovary cell products or to any component of&#xD;
               the atezolizumab formulation.&#xD;
  &#xD;
           23. Known hypersensitivity to bevacizumab.&#xD;
  &#xD;
           24. Receipt of investigational agents within 28 days prior to initiation of study&#xD;
               treatment.&#xD;
  &#xD;
           25. History of severe infection within 4 weeks of initiation of treatment.&#xD;
  &#xD;
           26. Receipt of stem cell transplantation, liver transplantation, or solid organ&#xD;
               transplantation&#xD;
  &#xD;
           27. Serious, non-healing wound, ulcer, or bone fracture.&#xD;
  &#xD;
           28. Patient is pregnant (positive pregnancy test) or lactating.&#xD;
  &#xD;
           29. Prior orthotropic liver transplantation.&#xD;
  &#xD;
           30. Prohibited therapies and/or medications:&#xD;
  &#xD;
                 -  Prior anticancer therapy with ADI-PEG 20 or anti-VEGF or anti-PD-1/PD-L1 for HCC.&#xD;
                    Must not be receiving any concomitant systemic therapy for HCC&#xD;
  &#xD;
                 -  Complementary medications (e.g., herbal supplements or traditional Chinese&#xD;
                    medicines) intended to treat the disease under study unless patients agree to&#xD;
                    stop the complementary medicines at least 14 days before the first study dose.&#xD;
                    Such medications are permitted if they are used as supportive care.&#xD;
  &#xD;
                 -  Live / attenuated vaccine (e.g., varicella; zoster; yellow fever; rotavirus; oral&#xD;
                    polio; or and measles, mumps, rubella) within a month prior to initiation of&#xD;
                    study drug or during treatment.&#xD;
  &#xD;
                 -  Any other experimental drug while on this study.&#xD;
  &#xD;
                 -  Ongoing anticoagulation therapy (although aspirin is permitted).&#xD;
  &#xD;
                 -  total parenteral nutrition.&#xD;
  &#xD;
                 -  high dose steroid (e.g., &gt; 10 mg prednisone daily or equivalent) or other more&#xD;
                    potent immune suppression medications (e.g., infliximab).&#xD;
  &#xD;
           31. Inability to comply with the appointments required in this protocol.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Zishuo (Ian) Hu, MD</last_name>
      <role>Principal Investigator</role>
      <affiliation>M.D. Anderson Cancer Center</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Zishuo ( (Ian) Hu, MD</last_name>
      <phone>(713) 792-9112</phone>
      <email>zhu8@mdanderson.org</email>
    </overall_contact>
    <location>
      <facility>
        <name>M D Anderson Cancer Center</name>
        <address>
          <city>Houston</city>
          <state>Texas</state>
          <zip>77030</zip>
          <country>United States</country>
        </address>
      </facility>
      <contact>
        <last_name>Zishuo (Ian) Hu, MD</last_name>
        <phone>713-792-9112</phone>
        <email>zhu8@mdanderson.org</email>
      </contact>
      <investigator>
        <last_name>Zishuo (Ian) Hu, MD</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>United States</country>
    </location_countries>
    <link>
      <url>http://www.mdanderson.org</url>
      <description>M D Anderson Cancer Center</description>
    </link>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 17, 2023</study_first_submitted>
    <study_first_submitted_qc>August 17, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 23, 2023</study_first_posted>
    <last_update_submitted>August 24, 2023</last_update_submitted>
    <last_update_submitted_qc>August 24, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 25, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Carcinoma</mesh_term>
      <mesh_term>Carcinoma, Hepatocellular</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Bevacizumab</mesh_term>
      <mesh_term>Atezolizumab</mesh_term>
    </intervention_browse>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT06006286
  org study id: 2023-0208
  secondary id: NCI-2023-06581
  nct id: NCT06006286
  lead sponsor: 
  has dmc: Yes
  is fda regulated drug: Yes
  is fda regulated device: No
  To learn about the safety and tolerability of atezolizumab, bevacizumab, and ADI-PEG 20 when
        given in combination to patients with locally advanced or metastatic liver cancer
  Primary Objectives:
  
        --To evaluate the safety and tolerability of treatment with atezolizumab and bevacizumab +
        ADI-PEG 20 in Patients with Locally Advanced/ Metastatic Hepatocellular Carcinoma.
  
        Secondary Objectives:
  
        --To assess the pathologic response rate including pathologic complete response (pCR) per
        RECIST and degree of necrosis (>50% in tumor volume) with atezolizumab and bevacizumab +
        ADI-PEG 20 in treatment-naïve locally advanced or metastatic HCC.
  
        Exploratory Objectives:
  
        --To assess the immunological/biomarker changes (pre- vs. post-treatment) in tumor tissues
        and peripheral blood in response to atezolizumab and bevacizumab + ADI-PEG 20 in HCC therapy
        and explore any potential association between these biomarker measures and antitumor
        response.
  allocation: N/A
  intervention model: Single Group Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0
  time frame: through study completion; an average of 1 year
  arm group label: ADI-PEG20/ATEZO/BEV
  arm group type: Experimental
  description: Participants will first receive the study drug combination for up to 12 weeks. If participants have stable disease or a partial response to the study drug after 12 weeks, participants may continue to receive ADI-PEG 20 for up to 2 years of total dosing, and participants may continue to receive atezolizumab and bevacizumab indefinitely (no limit)
  intervention type: Drug
  intervention name: Atezolizumab
  description: Given by IV (vein)
  arm group label: ADI-PEG20/ATEZO/BEV
  intervention type: Drug
  intervention name: Bevacizumab
  description: Given by IV (vein)
  arm group label: ADI-PEG20/ATEZO/BEV
  intervention type: Drug
  intervention name: ADI-PEG 20
  description: Given by Injection (inj)
  arm group label: ADI-PEG20/ATEZO/BEV
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Zishuo (Ian) Hu, MD
  role: Principal Investigator
  affiliation: M.D. Anderson Cancer Center
  last name: Zishuo ( (Ian) Hu, MD
  phone: (713) 792-9112
  email: zhu8@mdanderson.org
  facility: 
  contact: 
  investigator: 
  country: United States
  url: http://www.mdanderson.org
  description: M D Anderson Cancer Center
  responsible party type: Sponsor
  mesh term: Carcinoma
  mesh term: Carcinoma, Hepatocellular
  mesh term: Bevacizumab
  mesh term: Atezolizumab