<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/NCT02982694</url>
  </required_header>
  <id_info>
    <org_study_id>VHIO16001 - EORTC 1604</org_study_id>
    <secondary_id>2016-002001-19</secondary_id>
    <nct_id>NCT02982694</nct_id>
  </id_info>
  <brief_title>Study With Atezolizumab Plus Bevacizumab in Patients With Chemotherapy Resistant, MSI-like, Colorectal Cancer</brief_title>
  <official_title>A Phase II Open-label Study With the Anti-PD-L1 Atezolizumab Monoclonal Antibody in Combination With Bevacizumab in Patients With Advanced Chemotherapy Resistant Colorectal Cancer and MSI-like Molecular Signature</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vall d'Hebron Institute of Oncology</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>European Organisation for Research and Treatment of Cancer - EORTC</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Vall d'Hebron Institute of Oncology</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The primary objective of this study is to determine the anti-tumor activity, as measured by&#xD;
      overall response rate (ORR) of atezolizumab in combination with bevacizumab in patients with&#xD;
      chemotherapy resistant CRC and positivity for MSI-like molecular signature. This is an&#xD;
      international, open-label single arm (non-randomized), one-stage phase II trial.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    The results of the interim analysis showed that the efficacy in the MSS subgroup (MSI like) is&#xD;
    inferior to the expected, and this situation is very unlikely to be reversed if the trial is&#xD;
    fully completed.&#xD;
  </why_stopped>
  <start_date type="Actual">November 24, 2017</start_date>
  <completion_date type="Actual">November 27, 2020</completion_date>
  <primary_completion_date type="Actual">November 27, 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <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>Overall Response Rate</measure>
    <time_frame>36 months from first patient in</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Immune-related tumor response</measure>
    <time_frame>36 months from first patient in</time_frame>
    <description>the measurement that will be used is ir-RECIST (Immune-Related Response Criteria).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival</measure>
    <time_frame>36 months from first patient in</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>36 months from first patient in</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety and tolerability (adverse event assessment according to CTCAE v 4.0)</measure>
    <time_frame>36 months from first patient in</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">46</enrollment>
  <condition>MSI</condition>
  <condition>ColoRectal Cancer</condition>
  <condition>Chemotherapy</condition>
  <condition>Resistance, APC</condition>
  <arm_group>
    <arm_group_label>Atezolizumab and Bevacizumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Atezolizumab will be administered intravenously at 1200 mg on Day 1 every 3 weeks. The dose of bevacizumab in this study is 7.5 mg/kg administered by IV infusion every 3 weeks on Day 1 of each 21 days cycle. Atezolizumab will be administered first, followed by Bevacizumab, with a minimum of 5 minutes between dosing. The interval between cycle infusions must not be &lt; 10 days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Atezolizumab</intervention_name>
    <description>Atezolizumab will be administered 1200 mg in 250 ml 0.9% NaCl IV infusion bag, on day 1 of each cycle of 21 days.</description>
    <arm_group_label>Atezolizumab and Bevacizumab</arm_group_label>
    <other_name>TECENTRIQ</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bevacizumab</intervention_name>
    <description>Bevacizumab will be administered 7.5 ml/kg (diluted in 0.9% sodium chloride solution) on day 1 of each 21 days cycle.</description>
    <arm_group_label>Atezolizumab and Bevacizumab</arm_group_label>
    <other_name>Avastin</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Written informed consent must be given according to ICH/GCP and national/local&#xD;
             regulations.&#xD;
&#xD;
          -  Histological or cytological proof of metastatic CRC.&#xD;
&#xD;
          -  Disease progression or relapse after at least one line of treatment for advanced CRC&#xD;
             with a fluoropyrimidine containing chemotherapy as single agent or in combination&#xD;
             (combinations with oxaliplatin, irinotecan, bevacizumab, and cetuximab or panitumumab&#xD;
             are allowed).&#xD;
&#xD;
          -  Written documentation of positivity for MSI-like gene signature as determined by&#xD;
             Agendia test.&#xD;
&#xD;
          -  Unresectable disease, with at least one measurable lesion according to RECIST 1.1.&#xD;
&#xD;
          -  Age ≥ 18 years.&#xD;
&#xD;
          -  WHO performance status of 0-1.&#xD;
&#xD;
          -  Ability and capacity to comply with study and follow-up procedures.&#xD;
&#xD;
          -  Adequate hematologic and end-organ function, defined by the following laboratory&#xD;
             results obtained within 28 calendar days prior to the first study treatment:&#xD;
&#xD;
          -  ANC &gt; 1.5 x 109/L (without granulocyte colony-stimulating factor support within 2&#xD;
             weeks prior to Cycle 1, Day 1)&#xD;
&#xD;
          -  WBC counts &gt; 2500/μL&#xD;
&#xD;
          -  Platelet count &gt; 100,000/ μL (without transfusion within 2 weeks prior to Cycle 1, Day&#xD;
             1)&#xD;
&#xD;
          -  Hemoglobin &gt; 9.0 g/dL&#xD;
&#xD;
          -  AST, ALT, and alkaline phosphatase &lt; 2.5 x ULN, with the following exceptions:&#xD;
&#xD;
               -  Patients with documented liver metastases: AST and ALT &lt; 5 x ULN&#xD;
&#xD;
               -  Patients with documented liver or bone metastases: alkaline phosphatase &lt; 5 x ULN&#xD;
                  Bilirubin &lt;1.5 x ULN. Patients with known Gilbert disease who have serum&#xD;
                  bilirubin level &lt; 3 x ULN may be enrolled.&#xD;
&#xD;
          -  PT and PTT &lt;1.5 x ULN, unless on a stable dose of warfarin&#xD;
&#xD;
          -  Serum albumin &gt; 2.5 g/dL&#xD;
&#xD;
          -  Creatinine clearance &gt; 30 mL/min (Cockcroft-Gault formula or based on 24-hour urine&#xD;
             collection)&#xD;
&#xD;
          -  Protein &lt; 2+ on dipstick urinalysis or ≤ 1.0 g in a 24-hour urine collection. All&#xD;
             patients with ≥2+ protein on dipstick urinalysis at baseline must undergo a 24-hour&#xD;
             urine collection for protein.&#xD;
&#xD;
          -  Women of child bearing potential (WOCBP) must have a negative serum pregnancy test&#xD;
             before registration.&#xD;
&#xD;
          -  Patients of childbearing / reproductive potential should use adequate birth control&#xD;
             measures, as defined by the investigator, during the study treatment period and for at&#xD;
             least 6 months after the last bevacizumab treatment (for women and men) and 5 months&#xD;
             after the last atezolizumab treatment (for women). A highly effective method of birth&#xD;
             control is defined as those which result in low failure rate (i.e. less than 1% per&#xD;
             year) when used consistently and correctly.&#xD;
&#xD;
          -  Female subjects who are breast feeding should discontinue nursing before trial&#xD;
             registration and until 6 months after the last bevacizumab treatment and 5 months&#xD;
             after the last atezolizumab treatment.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any treatment with investigational drugs (bevacizumab is not considered&#xD;
             investigational drug in CRC) within 28 days prior to Cycle 1, Day 1.&#xD;
&#xD;
          -  Previous cytotoxic agent within 14 days of planed treatment initiation.&#xD;
&#xD;
          -  Active or untreated CNS metastases as determined by computed tomography (CT) or&#xD;
             magnetic resonance imaging (MRI)&#xD;
&#xD;
               -  Note: Patients with treated asymptomatic CNS metastases are eligible, provided&#xD;
                  they meet all of the following criteria:&#xD;
&#xD;
                    -  Evaluable or measurable disease outside the CNS&#xD;
&#xD;
                    -  No metastases to midbrain, pons, medulla, cerebellum, or within 10 mm of the&#xD;
                       optic apparatus (optic nerves and chiasm)&#xD;
&#xD;
                    -  No history of intracranial or spinal cord haemorrhage&#xD;
&#xD;
                    -  No ongoing requirement for dexamethasone as therapy for CNS disease;&#xD;
                       anticonvulsants at a stable dose are allowed.&#xD;
&#xD;
                    -  No evidence of significant vasogenic edema.&#xD;
&#xD;
                    -  No stereotactic radiation, whole-brain radiation or neurosurgical resection&#xD;
                       within 4 weeks prior to Cycle 1, Day 1.&#xD;
&#xD;
                    -  Radiographic demonstration of interim stability (i.e., no progression)&#xD;
                       between the completion of CNS-directed therapy and the screening&#xD;
                       radiographic study.&#xD;
&#xD;
                    -  Screening CNS radiographic study &gt; 4 weeks since completion of radiotherapy&#xD;
                       or surgical resection and &gt; 2 weeks since discontinuation of&#xD;
                       corticosteroids.&#xD;
&#xD;
          -  Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or&#xD;
             metastases causing nerve impingement) should be treated at least 14 days prior to&#xD;
             Cycle 1, Day 1.&#xD;
&#xD;
          -  Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent&#xD;
             drainage procedures (once monthly or more frequently).&#xD;
&#xD;
          -  Previous (within the last 5 years) or concurrent malignancies, with the exception of&#xD;
             those treated with expected curative outcome as cone-biopsied in situ carcinoma of the&#xD;
             cervix, basal cell carcinoma of the skin, localized prostate cancer or ductal&#xD;
             carcinoma in situ of the breast.&#xD;
&#xD;
          -  Life expectancy of &lt; 12 weeks.&#xD;
&#xD;
          -  History of severe allergic, anaphylactic, or other hypersensitivity reactions to&#xD;
             chimeric or humanized antibodies or fusion proteins.&#xD;
&#xD;
          -  Positive test for human immunodeficiency virus (HIV).&#xD;
&#xD;
          -  Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg]&#xD;
             test prior to randomization) or hepatitis C.&#xD;
&#xD;
               -  Note: Patients with past hepatitis B virus (HBV) infection or resolved HBV&#xD;
                  infection (defined as having a negative HBsAg test and a positive antibody to&#xD;
                  hepatitis B core antigen [anti-HBc] antibody test) are eligible.&#xD;
&#xD;
          -  Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase&#xD;
             chain reaction (PCR) is negative for HCV RNA.&#xD;
&#xD;
          -  Active tuberculosis.&#xD;
&#xD;
          -  Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to&#xD;
             hospitalization for complications of infection, bacteremia, or severe pneumonia.&#xD;
&#xD;
          -  Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1.&#xD;
&#xD;
          -  Received therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1.&#xD;
&#xD;
               -  Note: Patients receiving routine antibiotic prophylaxis (e.g., to prevent chronic&#xD;
                  obstructive pulmonary disease exacerbation or for dental extraction) are&#xD;
                  eligible.&#xD;
&#xD;
          -  Significant cardiovascular or cerebrovascular disease, such as New York Heart&#xD;
             Association cardiac disease (Class II or greater), unstable angina, history of stroke,&#xD;
             transient ischemic attack, myocardial infarction or cerebrovascular events within the&#xD;
             previous 6 months or unstable arrhythmias within the previous 3 months:&#xD;
&#xD;
          -  Patients with known coronary artery disease, arrhythmias, congestive heart failure not&#xD;
             meeting the above criteria must be on a stable medical regimen that is optimized in&#xD;
             the opinion of the treating physician, in consultation with a cardiologist if&#xD;
             appropriate. Baseline evaluation of left ventricular ejection fraction should be&#xD;
             considered for all patients, especially in those with cardiac risk factors and/or&#xD;
             history of coronary artery disease.&#xD;
&#xD;
          -  Patients with known left ventricular ejection fraction &lt;50%.&#xD;
&#xD;
          -  Major surgical procedure within 28 days prior to cycle 1, day 1 (or until the surgical&#xD;
             wound is fully healed), or planned procedure or surgery during the study.&#xD;
&#xD;
          -  Prior allogeneic stem cell or solid organ transplant.&#xD;
&#xD;
          -  Any other diseases, metabolic dysfunction, physical examination finding, or clinical&#xD;
             laboratory finding giving reasonable suspicion of a disease or condition that&#xD;
             contraindicates the use of an investigational drug or that may affect the&#xD;
             interpretation of the results or render the patient at high risk from treatment&#xD;
             complications.&#xD;
&#xD;
          -  Prior treatment with CD137 agonists, anti-CTLA-4, anti-PD-1, or anti-PD-L1 therapeutic&#xD;
             antibody or immune-related pathway-targeting agents.&#xD;
&#xD;
          -  Current or recent (within 10 calendar days prior to Cycle 1, Day 1) use of&#xD;
             dipyridamole, ticlopidine, clopidogrel, or cilostazol.&#xD;
&#xD;
          -  Prophylactic or therapeutic use of low molecular-weight heparin (e.g., enoxaparin),&#xD;
             direct thrombin inhibitors, or warfarin are permitted, provided, where appropriate&#xD;
             anticoagulation indices are stable. Patients should have been on a stable dose (for&#xD;
             therapeutic use) for at least two weeks (or until reaching steady state level of the&#xD;
             drug) prior to the first study treatment.&#xD;
&#xD;
          -  Inadequately controlled hypertension (defined as systolic blood pressure &gt;150 mmHg&#xD;
             and/or diastolic blood pressure &gt;100 mmHg) (Anti-hypertensive therapy to achieve these&#xD;
             parameters is allowable).&#xD;
&#xD;
          -  Prior history of hypertensive crisis or hypertensive encephalopathy.&#xD;
&#xD;
          -  Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or&#xD;
             recent peripheral arterial thrombosis) within 6 months prior to Cycle 1, Day 1.&#xD;
&#xD;
          -  Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster&#xD;
             ovary cells or any component of the bevacizumab or atezolizumab formulation.&#xD;
&#xD;
          -  Evidence of bleeding diathesis or clinically significant coagulopathy (in the absence&#xD;
             of therapeutic anticoagulation).&#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>Josep Tabernero Caturla, Prof</last_name>
    <role>Principal Investigator</role>
    <affiliation>Vall d'Hebron Institute of Oncology</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>KU Leuven</name>
      <address>
        <city>Leuven</city>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ospedale Niguarda CA Granda</name>
      <address>
        <city>Milano</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Second University of Naples</name>
      <address>
        <city>Naples</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Netherlands Cancer Institute</name>
      <address>
        <city>Amsterdam</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Català d'Oncologia</name>
      <address>
        <city>Barcelona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vall d'Hebron Institute of Oncology</name>
      <address>
        <city>Barcelona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fundación Investigación Clínico de Valencia</name>
      <address>
        <city>Valencia</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Belgium</country>
    <country>Italy</country>
    <country>Netherlands</country>
    <country>Spain</country>
  </location_countries>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>December 1, 2016</study_first_submitted>
  <study_first_submitted_qc>December 2, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 5, 2016</study_first_posted>
  <last_update_submitted>October 4, 2021</last_update_submitted>
  <last_update_submitted_qc>October 4, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">October 12, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>MSI</keyword>
  <keyword>colorectal</keyword>
  <keyword>chemotherapy</keyword>
  <keyword>Bevacizumab</keyword>
  <keyword>Atezolizumab</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Colorectal Neoplasms</mesh_term>
    <mesh_term>Activated Protein C Resistance</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>


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/NCT02982694
org study id: VHIO16001 - EORTC 1604
secondary id: 2016-002001-19
nct id: NCT02982694
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The primary objective of this study is to determine the anti-tumor activity, as measured by
      overall response rate (ORR) of atezolizumab in combination with bevacizumab in patients with
      chemotherapy resistant CRC and positivity for MSI-like molecular signature. This is an
      international, open-label single arm (non-randomized), one-stage phase II trial.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall Response Rate
time frame: 36 months from first patient in
measure: Immune-related tumor response
time frame: 36 months from first patient in
description: the measurement that will be used is ir-RECIST (Immune-Related Response Criteria).
measure: Progression Free Survival
time frame: 36 months from first patient in
measure: Overall Survival
time frame: 36 months from first patient in
measure: Safety and tolerability (adverse event assessment according to CTCAE v 4.0)
time frame: 36 months from first patient in
arm group label: Atezolizumab and Bevacizumab
arm group type: Experimental
description: Atezolizumab will be administered intravenously at 1200 mg on Day 1 every 3 weeks. The dose of bevacizumab in this study is 7.5 mg/kg administered by IV infusion every 3 weeks on Day 1 of each 21 days cycle. Atezolizumab will be administered first, followed by Bevacizumab, with a minimum of 5 minutes between dosing. The interval between cycle infusions must not be < 10 days.
intervention type: Drug
intervention name: Atezolizumab
description: Atezolizumab will be administered 1200 mg in 250 ml 0.9% NaCl IV infusion bag, on day 1 of each cycle of 21 days.
arm group label: Atezolizumab and Bevacizumab
other name: TECENTRIQ
intervention type: Drug
intervention name: Bevacizumab
description: Bevacizumab will be administered 7.5 ml/kg (diluted in 0.9% sodium chloride solution) on day 1 of each 21 days cycle.
arm group label: Atezolizumab and Bevacizumab
other name: Avastin
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Josep Tabernero Caturla, Prof
role: Principal Investigator
affiliation: Vall d'Hebron Institute of Oncology
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Belgium
country: Italy
country: Netherlands
country: Spain
responsible party type: Sponsor
mesh term: Colorectal Neoplasms
mesh term: Activated Protein C Resistance
mesh term: Bevacizumab
mesh term: Atezolizumab