<clinical_study>
  <!-- This xml conforms to an XML Schema at:
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  <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/NCT03237780</url>
  </required_header>
  <id_info>
    <org_study_id>NCI-2017-01388</org_study_id>
    <secondary_id>NCI-2017-01388</secondary_id>
    <secondary_id>PHII-150</secondary_id>
    <secondary_id>10100</secondary_id>
    <secondary_id>10100</secondary_id>
    <secondary_id>UM1CA186717</secondary_id>
    <nct_id>NCT03237780</nct_id>
  </id_info>
  <brief_title>Atezolizumab With or Without Eribulin Mesylate in Treating Patients With Recurrent Locally Advanced or Metastatic Urothelial Cancer</brief_title>
  <official_title>A Randomized, Phase 2 Trial to Evaluate the Safety and Efficacy of Eribulin Mesylate in Combination With Atezolizumab Compared to Atezolizumab Alone in Subjects With Locally Advanced or Metastatic Transitional Cell Urothelial Cancer Where Cisplatin-Based Treatment is Not an Option</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Cancer Institute (NCI)</source>
  <oversight_info>
    <has_dmc>No</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>
      This phase II trial studies the side effects of atezolizumab with or without eribulin&#xD;
      mesylate and how well they work in treating patients with urothelial cancer that has come&#xD;
      back (recurrent), spread to nearby tissues or lymph nodes (locally advanced), or spread from&#xD;
      where it first started (primary site) to other places in the body (metastatic). Immunotherapy&#xD;
      with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack&#xD;
      the cancer, and may interfere with the ability of tumor cells to grow and spread.&#xD;
      Chemotherapy drugs, such as eribulin mesylate, work in different ways to stop the growth of&#xD;
      tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them&#xD;
      from spreading. Giving atezolizumab and eribulin mesylate may work better at treating&#xD;
      urothelial cancer compared to atezolizumab alone.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To confirm that eribulin mesylate (eribulin), at or close to the single agent recommended&#xD;
      phase 2 dose, and atezolizumab at the single agent recommended phase 2 dose, can be given&#xD;
      together with an acceptable toxicity profile. (Safety/Run-in) II. To estimate the objective&#xD;
      response rate (ORR) based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for&#xD;
      eribulin and atezolizumab in combination, and compare that to the ORR of atezolizumab alone.&#xD;
      (Phase 2)&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To summarize and characterize the toxicity associated with this 2-drug combination.&#xD;
&#xD;
      II. To estimate the best overall response rate (immune-related best overall response [irBOR]&#xD;
      rate) using the immune-related response criteria (irRC).&#xD;
&#xD;
      III. To estimate the disease control rate (DCR: complete response [CR] + partial response&#xD;
      [PR] + stable disease [SD]) based on RECIST 1.1.&#xD;
&#xD;
      IV. To estimate the duration of response and the duration of stable disease. V. To summarize&#xD;
      the progression-free survival (PFS). VI. To summarize the overall survival (OS). VII. To&#xD;
      evaluate efficacy in subsets of patients determined by PD-L1, CD3 and CD8 expression.&#xD;
&#xD;
      EXPLORATORY OBJECTIVES:&#xD;
&#xD;
      I. To assess the pharmacodynamic (PD) profile of eribulin when it is given in combination&#xD;
      with atezolizumab, specifically exploring the expression of putative tumor, circulating&#xD;
      microenvironment and computed tomography (CT) radiomic correlatives of epithelial-mesenchymal&#xD;
      transition (EMT)/ (mesenchymal-epithelial transition) MET phenotype at baseline and 6 weeks&#xD;
      on therapy.&#xD;
&#xD;
      II. To ascertain the role of expression of PD-L1 using the SP142 assay and potentially other&#xD;
      methods as a predictive biomarker for response to treatment with atezolizumab in combination&#xD;
      with eribulin.&#xD;
&#xD;
      III. To identify clinical biomarkers that may predict for efficacy and toxicity in this&#xD;
      population and with this treatment combination.&#xD;
&#xD;
      OUTLINE: Patients are randomized to 1 of 2 arms.&#xD;
&#xD;
      ARM I: Patients receive atezolizumab intravenously (IV) over 30-60 minutes on day 1. Cycles&#xD;
      repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients&#xD;
      also undergo collection of blood and CT with contrast throughout the trial. Patients may&#xD;
      undergo biopsy during screening and on study.&#xD;
&#xD;
      ARM II: Patients receive atezolizumab IV over 30-60 minutes on day 1 and eribulin mesylate IV&#xD;
      over 2-3 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease&#xD;
      progression or unacceptable toxicity. Patients also undergo collection of blood and CT with&#xD;
      contrast throughout the trial. Patients may undergo biopsy during screening and on study.&#xD;
&#xD;
      After completion of study treatment, patients are followed up every 3 or 6 months for 52&#xD;
      weeks.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">January 19, 2018</start_date>
  <completion_date type="Anticipated">January 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">January 31, 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of adverse events</measure>
    <time_frame>Up to 52 weeks</time_frame>
    <description>Will be graded according to the Common Terminology Criteria for Adverse Events version 5. Tables will be created to summarize the numbers of patients who experienced toxicities by arm, toxicity system, type, grade and attribution. If helpful, cumulative incidence curves will be constructed to summarize the onset of selected adverse events.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Objective tumor response</measure>
    <time_frame>Up to 52 weeks</time_frame>
    <description>Will be assessed by Response Evaluation Criteria in Solid Tumors version 1.1.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Overall response rate (probability of complete response [CR] or partial response [PR])</measure>
    <time_frame>Up to 52 weeks</time_frame>
    <description>Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The two arms will be compared using a one-sided, 0.10-level Mantel-Haenszel, stratifying by (a) cisplatin ineligible first line vs. having received prior platinum therapy, and PD-L1 status in archival tumor tissue (immunohistochemistry [IHC] 0-1 versus [vs] 2-3). Two-sided 80% confidence intervals will be constructed for the probability of response in each arm, as well as the difference between the two arms (unadjusted for the stratification variables). In addition, a logistic regression (exact, if required based on the numbers) will be used to estimate the odds ratio comparing the 2 arms adjusting for the stratification variables, and also by the Bellmunt risk group (1-2 versus [vs] 3-4).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Best overall response rate (immune-related best overall response [irBOR] rate) using the immune-related response criteria</measure>
    <time_frame>Up to 52 weeks</time_frame>
    <description>Analysis of the irBOR will be based on a modified intention-to-treat analysis which will include all eligible, randomized patients who receive any amount of either atezolizumab or eribulin. The proportion of patients in each of the 5 categories above will be calculated for each arm and two-sided 80% confidence intervals will be constructed. Two-sided 80% confidence intervals will be constructed for the probability of response in each arm, as well as the difference between the two arms (unadjusted for the stratification variables). In addition, a logistic regression (exact, if required based on the numbers) will be used to estimate the odds ratio comparing the 2 arms adjusting for the stratification variables, and also by the Bellmunt risk group (1-2 vs 3-4).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease control rate (DCR: CR + PR + stable disease)</measure>
    <time_frame>Up to 52 weeks</time_frame>
    <description>Will be assessed based on RECIST 1.1. The two arms will be compared in terms of the DCR using a one-sided, 0.10-level Mantel-Haenszel, stratifying by (a) cisplatin ineligible first line vs having received prior platinum therapy, and PD-L1 status in archival tumor tissue (IHC 0-1 vs 2-3). Two-sided 80% confidence intervals will be constructed for the probability of DCR in each arm, as well as the difference between the two arms (unadjusted for the stratification variables). In addition, a logistic regression (exact, if required based on the numbers) will be used to estimate the odds ratio comparing the 2 arms adjusting for the stratification variables, and also by the Bellmunt risk group (1-2 vs 3-4).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS)</measure>
    <time_frame>From randomization until progression or death, whichever occurs first, assessed up to 52 weeks</time_frame>
    <description>Will be displayed using Kaplan-Meier plots. Median PFS will be estimated and 80% confidence intervals constructed; PFS at 6 months and 12 months will be estimated and 80% confidence intervals constructed. The two arms will be compared using a one-sided, 0.10-level, stratified logrank test. If numbers permit, Kaplan-Meier plots will be drawn for patients grouped by the stratification variables. In addition, also, if numbers permit, a Cox proportional hazards regression be used to estimate the hazards ratio comparing the 2 arms adjusting for the stratification variables, and also by the Bellmunt risk group (1-2 vs 3-4).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>From randomization until death or date last known to be alive, assessed up to 52 weeks</time_frame>
    <description>OS will be displayed using Kaplan-Meier plots. Median OS will be estimated and 80% confidence intervals constructed; OS at 6 months and 12 months will be estimated and 80% confidence intervals constructed. The two arms will be compared using a one-sided, 0.10-level, stratified logrank test. If numbers permit, Kaplan-Meier plots will be drawn for patients grouped by the stratification variables. In addition, also, if numbers permit, a Cox proportional hazards regression be used to estimate the hazards ratio comparing the 2 arms adjusting for the stratification variables, and also by the Bellmunt risk group (1-2 vs 3-4).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response (DOR)</measure>
    <time_frame>From the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that progressive disease is objectively documented, assessed up to 52 weeks</time_frame>
    <description>Will be displayed using Kaplan-Meier plots. Median DOR will be estimated and 80% confidence intervals constructed; DOR at 6 months will be estimated and 80% confidence intervals constructed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Analysis based on PD-L1 expression</measure>
    <time_frame>Up to 52 weeks</time_frame>
    <description>The analyses described for ORR, DCR, irBOR, PFS, and OS will be repeated, examining patients whose tumors are PD-L1 &quot;positive&quot; (IHC = 2-3) and those whose tumors are PD-L1 &quot;negative (IHC = 0-1). Although numbers will be small, the odds ratio's and hazard ratio's will be compared (using the logistic or Cox regression models) to ascertain whether the impact of eribulin is different based on the PD-L1 status.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Analysis of baseline tumor</measure>
    <time_frame>Baseline</time_frame>
    <description>Standard descriptive methods will be used to summarize patterns.</description>
  </other_outcome>
  <other_outcome>
    <measure>Changes in tumor based on biopsies, radiomics and circulating tumor cells</measure>
    <time_frame>Baseline up to 6 weeks</time_frame>
    <description>Standard descriptive methods will be used to summarize patterns.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">72</enrollment>
  <condition>Locally Advanced Bladder Urothelial Carcinoma</condition>
  <condition>Locally Advanced Renal Pelvis Urothelial Carcinoma</condition>
  <condition>Locally Advanced Ureter Urothelial Carcinoma</condition>
  <condition>Locally Advanced Urethral Urothelial Carcinoma</condition>
  <condition>Metastatic Bladder Urothelial Carcinoma</condition>
  <condition>Metastatic Renal Pelvis Urothelial Carcinoma</condition>
  <condition>Metastatic Ureter Urothelial Carcinoma</condition>
  <condition>Metastatic Urethral Urothelial Carcinoma</condition>
  <condition>Recurrent Bladder Urothelial Carcinoma</condition>
  <condition>Recurrent Renal Pelvis Urothelial Carcinoma</condition>
  <condition>Recurrent Ureter Urothelial Carcinoma</condition>
  <condition>Recurrent Urethral Urothelial Carcinoma</condition>
  <condition>Stage III Bladder Cancer AJCC v8</condition>
  <condition>Stage III Renal Pelvis Cancer AJCC v8</condition>
  <condition>Stage III Ureter Cancer AJCC v8</condition>
  <condition>Stage III Urethral Cancer AJCC v8</condition>
  <condition>Stage IV Bladder Cancer AJCC v8</condition>
  <condition>Stage IV Renal Pelvis Cancer AJCC v8</condition>
  <condition>Stage IV Ureter Cancer AJCC v8</condition>
  <condition>Stage IV Urethral Cancer AJCC v8</condition>
  <condition>Unresectable Bladder Urothelial Carcinoma</condition>
  <condition>Unresectable Renal Pelvis Urothelial Carcinoma</condition>
  <condition>Unresectable Ureter Urothelial Carcinoma</condition>
  <condition>Unresectable Urethral Urothelial Carcinoma</condition>
  <arm_group>
    <arm_group_label>Arm I (atezolizumab)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive atezolizumab IV over 30-60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and CT with contrast throughout the trial. Patients may undergo biopsy during screening and on study.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm II (atezolizumab, eribulin mesylate)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive atezolizumab IV over 30-60 minutes on day 1 and eribulin mesylate IV over 2-3 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and CT with contrast throughout the trial. Patients may undergo biopsy during screening and on study.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Atezolizumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Arm I (atezolizumab)</arm_group_label>
    <arm_group_label>Arm II (atezolizumab, eribulin mesylate)</arm_group_label>
    <other_name>MPDL 3280A</other_name>
    <other_name>MPDL 328OA</other_name>
    <other_name>MPDL-3280A</other_name>
    <other_name>MPDL3280A</other_name>
    <other_name>MPDL328OA</other_name>
    <other_name>RG7446</other_name>
    <other_name>RO5541267</other_name>
    <other_name>Tecentriq</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Biopsy</intervention_name>
    <description>Undergo biopsy</description>
    <arm_group_label>Arm I (atezolizumab)</arm_group_label>
    <arm_group_label>Arm II (atezolizumab, eribulin mesylate)</arm_group_label>
    <other_name>BIOPSY_TYPE</other_name>
    <other_name>Bx</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Biospecimen Collection</intervention_name>
    <description>Undergo blood sample collection</description>
    <arm_group_label>Arm I (atezolizumab)</arm_group_label>
    <arm_group_label>Arm II (atezolizumab, eribulin mesylate)</arm_group_label>
    <other_name>Biological Sample Collection</other_name>
    <other_name>Biospecimen Collected</other_name>
    <other_name>Specimen Collection</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Computed Tomography with Contrast</intervention_name>
    <description>Undergo CT scan</description>
    <arm_group_label>Arm I (atezolizumab)</arm_group_label>
    <arm_group_label>Arm II (atezolizumab, eribulin mesylate)</arm_group_label>
    <other_name>Contrast Enhanced Computed Tomography</other_name>
    <other_name>CONTRAST ENHANCED CT SCAN</other_name>
    <other_name>Contrast-enhanced Computed Tomography</other_name>
    <other_name>CT Scan With Contrast</other_name>
    <other_name>CT with Contrast</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Eribulin Mesylate</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Arm II (atezolizumab, eribulin mesylate)</arm_group_label>
    <other_name>B1939 Mesylate</other_name>
    <other_name>E7389</other_name>
    <other_name>ER-086526 Mesylate</other_name>
    <other_name>Halaven</other_name>
    <other_name>Halichondrin B Analog</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Males or females age &gt; or = 18 years at the time of informed consent. Because no&#xD;
             dosing or adverse event data are currently available on the use of atezolizumab in&#xD;
             combination with eribulin in patients &lt; 18 years of age, children are excluded from&#xD;
             this study&#xD;
&#xD;
          -  Histologically- or cytologically-confirmed diagnosis of locally advanced/unresectable&#xD;
             (inoperable or not amenable to surgical treatment) and/or metastatic transitional cell&#xD;
             urothelial cancer of the renal pelvis, ureter, urinary bladder, or urethra&#xD;
&#xD;
          -  Presence of measurable disease meeting the following criteria:&#xD;
&#xD;
               -  At least one lesion of &gt;= 1.0 cm in long axis diameter for non-lymph nodes or &gt;=&#xD;
                  1.5 cm in short axis diameter for lymph nodes that is serially measurable&#xD;
                  according to RECIST 1.1 using either computerized tomography or magnetic&#xD;
                  resonance imaging or panoramic and close-up color photography with caliper&#xD;
                  measurement; if there is only one target lesion and it is a not a lymph node, it&#xD;
                  should have a long-axis diameter of at least 1.5 cm&#xD;
&#xD;
               -  Lesions that have had radiotherapy must show radiographic evidence of disease&#xD;
                  progression based on RECIST 1.1 may be deemed a target lesion&#xD;
&#xD;
          -  Archival paraffin-embedded invasive tumor tissue or newly obtained biopsy must be&#xD;
             available prior to the first dose of study drug for biomarker analysis; patients must&#xD;
             be offered sequential biopsies at baseline and 6 weeks unless in the opinion of the&#xD;
             trial principal investigator (PI) this would be hazardous; recent data suggest&#xD;
             discordance between primary tumor and tumor from recurrence or metastasis with high&#xD;
             percentages of PD-L1 SP142 positive immune cells after recurrence&#xD;
&#xD;
          -  PD-L1 status determined centrally by HistogeneX, which is funded by the study, must be&#xD;
             available before randomization of the patient to allow for stratification; COMMERCIAL&#xD;
             ASSESSMENT OF PD-L1 STATUS OBTAINED LOCALLY AT THE SITE WILL NOT SATISFY ELIGIBILITY&#xD;
             CRITERIA&#xD;
&#xD;
          -  New, progressive or recurrent disease occurring&#xD;
&#xD;
               -  During or within 12 months of treatment with a platinum containing regimen&#xD;
                  (cisplatin or carboplatin or novel platinum) in either in the metastatic or&#xD;
                  perioperative setting&#xD;
&#xD;
               -  In first-line patients defined as cisplatin-ineligible based on renal impairment&#xD;
                  (creatinine clearance calculated by Cockcroft-Gault method &lt; 60 ml/min), grade 2&#xD;
                  hearing loss and/or Eastern Cooperative Oncology Group (ECOG) status of 2; these&#xD;
                  patients will be chemotherapy naive or have received platinum based therapy in&#xD;
                  the adjuvant or neoadjuvant setting more than 12 months prior to study entry&#xD;
&#xD;
          -  May have received up to two prior lines of chemotherapy for advanced disease&#xD;
&#xD;
          -  Adequate recovery from any adverse events resulting from prior anti-neoplastic&#xD;
             treatment including chemotherapy, biological therapy, targeted small molecule therapy,&#xD;
             radiation therapy, and surgery as determined by the investigator (and in consultation&#xD;
             with the study PI); in most instances, adequate recovery is resolution to =&lt; grade 1&#xD;
             except for alopecia of any grade, grade 2 neuropathy and/ or any grade hearing loss&#xD;
&#xD;
          -  Subjects with known brain metastases will be eligible if they have completed the&#xD;
             primary brain therapy (such as whole brain radiotherapy, stereotactic radiosurgery, or&#xD;
             complete surgical resection) and if they have remained clinically stable,&#xD;
             asymptomatic, and off of steroids for at least 28 days&#xD;
&#xD;
          -  Life expectancy of &gt;= 12 weeks&#xD;
&#xD;
          -  Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of&#xD;
             0 to 2 (Karnofsky &gt;= 60%)&#xD;
&#xD;
          -  Leukocytes &gt;= 2,500/mcL&#xD;
&#xD;
          -  Absolute neutrophil count &gt;= 1,500/mcL&#xD;
&#xD;
          -  Platelets &gt;= 75,000/mcL&#xD;
&#xD;
          -  Hemoglobin &gt;= 8 g/dL&#xD;
&#xD;
          -  Total bilirubin =&lt; 1.5 x institutional upper limit of normal (ULN) (however, patients&#xD;
             with known Gilbert disease who have serum bilirubin level =&lt; 3 x ULN may be enrolled)&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase&#xD;
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])&#xD;
             =&lt; 3 x ULN (AST and/or ALT =&lt; 5 x ULN for patients with liver involvement)&#xD;
&#xD;
          -  Alkaline phosphatase =&lt; 2.5 x ULN (=&lt; 5 x ULN for patients with documented liver&#xD;
             involvement or bone metastases)&#xD;
&#xD;
          -  Creatinine clearance &gt;= 20 mL/min/1.73 m^2 by Cockcroft-Gault&#xD;
&#xD;
          -  International normalized ratio (INR) and activated partial thromboplastin time (aPTT)&#xD;
             =&lt; 1.5 x ULN (this applies only to patients who do not receive therapeutic&#xD;
             anticoagulation; patients receiving therapeutic anticoagulation, such as&#xD;
             low-molecular-weight heparin or warfarin, should be on a stable dose)&#xD;
&#xD;
          -  All females must have a negative serum or urine pregnancy test (minimum sensitivity 25&#xD;
             IU/L or equivalent units of beta-human chorionic gonadotropin [B-hCG]) at the&#xD;
             screening visit and the baseline visit; a pregnancy test needs to be performed within&#xD;
             72 hours of the first dose of study drug&#xD;
&#xD;
          -  Administration of atezolizumab and eribulin may have an adverse effect on pregnancy&#xD;
             and poses a risk to the human fetus, including embryo-lethality; women of&#xD;
             child-bearing potential and men must agree to use adequate contraception (hormonal or&#xD;
             barrier method of birth control; abstinence) prior to study entry, for the duration of&#xD;
             study participation, and for 5 months (150 days) after the last dose of study agent;&#xD;
             should a woman become pregnant or suspect she is pregnant while she or her partner is&#xD;
             participating in this study, she should inform her treating physician immediately&#xD;
&#xD;
          -  Male subjects who are partners of women of childbearing potential must use a condom&#xD;
             and spermicide and their female partners if of childbearing potential must use a&#xD;
             highly effective method of contraception beginning at least 1 menstrual cycle prior to&#xD;
             starting study drug(s), throughout the entire study period, and for 150 days after the&#xD;
             last dose of study drug, unless the male subjects are totally sexually abstinent or&#xD;
             have undergone a successful vasectomy with confirmed azoospermia or unless the female&#xD;
             partners have been sterilized surgically or are otherwise proven sterile&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document&#xD;
&#xD;
          -  Subject must be willing and able to comply with all aspects of the protocol&#xD;
&#xD;
          -  Patients positive for human immunodeficiency virus (HIV) are allowed on study, but&#xD;
             HIV-positive patients must have:&#xD;
&#xD;
               -  A stable regimen of highly active anti-retroviral therapy (HAART) using&#xD;
                  combination retroviral agents which are not CYP3A4 inducers or inhibitors&#xD;
&#xD;
               -  No requirement for concurrent antibiotics or antifungal agents for the prevention&#xD;
                  of opportunistic infections&#xD;
&#xD;
               -  A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard&#xD;
                  polymerase chain reaction (PCR)-based tests&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with prior allogeneic bone marrow transplantation or prior solid organ&#xD;
             transplantation&#xD;
&#xD;
          -  Patients who have had chemotherapy within 3 weeks or radiotherapy or targeted therapy&#xD;
             2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those&#xD;
             who have not recovered from adverse events (other than alopecia) due to agents&#xD;
             administered more than 4 weeks earlier; however, the following therapies are allowed:&#xD;
&#xD;
               -  Hormone-replacement therapy or oral contraceptives&#xD;
&#xD;
               -  Herbal therapy &gt; 1 week prior to cycle 1, day 1 (herbal therapy intended as&#xD;
                  anticancer therapy must be discontinued at least 1 week prior to cycle 1, day 1)&#xD;
&#xD;
               -  Palliative radiotherapy for bone metastases &gt; 2 weeks prior to cycle 1, day 1&#xD;
&#xD;
          -  Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or&#xD;
             pathway-targeting agents or eribulin&#xD;
&#xD;
               -  Patients who have received prior treatment with anti-CTLA-4 may be enrolled,&#xD;
                  provided the following requirements are met:&#xD;
&#xD;
                    -  Minimum of 12 weeks from the first dose of anti-CTLA-4 and &gt; 6 weeks from&#xD;
                       the last dose&#xD;
&#xD;
                    -  No history of severe immune-related adverse effects from anti-CTLA-4&#xD;
                       (National Cancer Institute [NCI] Common Terminology Criteria for Adverse&#xD;
                       Events [CTCAE] version 5.0)&#xD;
&#xD;
          -  Treatment with any other investigational agent within 4 weeks prior to cycle 1, day 1&#xD;
&#xD;
          -  Treatment with systemic immunostimulatory agents (including, but not limited to,&#xD;
             interferon [IFN]-alpha or interleukin [IL]-2) within 6 weeks prior to cycle 1, day 1&#xD;
&#xD;
          -  Treatment with systemic immunosuppressive medications (including, but not limited to,&#xD;
             prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor&#xD;
             necrosis factor [anti-TNF] agents) within 2 weeks prior to cycle 1, day 1&#xD;
&#xD;
               -  Patients who have received acute, low dose, systemic immunosuppressant&#xD;
                  medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled&#xD;
&#xD;
               -  The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone)&#xD;
                  for patients with orthostatic hypotension or adrenocortical insufficiency is&#xD;
                  allowed&#xD;
&#xD;
          -  Patients taking bisphosphonate therapy for symptomatic hypercalcemia; use of&#xD;
             bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) is&#xD;
             allowed&#xD;
&#xD;
          -  Patients requiring treatment with a receptor activator of nuclear factor kappa-B&#xD;
             ligand (RANKL) inhibitor (e.g. denosumab) who cannot discontinue it before treatment&#xD;
             with atezolizumab&#xD;
&#xD;
          -  Patients with known primary central nervous system (CNS) malignancy or symptomatic CNS&#xD;
             metastases are excluded, with the following exceptions:&#xD;
&#xD;
               -  Patients with asymptomatic untreated CNS disease may be enrolled, provided all of&#xD;
                  the following criteria are met:&#xD;
&#xD;
                    -  Evaluable or measurable disease outside the CNS&#xD;
&#xD;
                    -  No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within&#xD;
                       10 mm of the optic apparatus (optic nerves and chiasm)&#xD;
&#xD;
                    -  No history of intracranial hemorrhage or spinal cord hemorrhage&#xD;
&#xD;
                    -  No ongoing requirement for dexamethasone for CNS disease; patients on a&#xD;
                       stable dose of anticonvulsants are permitted&#xD;
&#xD;
                    -  No neurosurgical resection or brain biopsy within 28 days prior to cycle 1,&#xD;
                       day 1&#xD;
&#xD;
               -  Patients with asymptomatic treated CNS metastases may be enrolled, provided all&#xD;
                  the criteria listed above are met as well as the following:&#xD;
&#xD;
                    -  Radiographic demonstration of improvement upon the completion of CNS&#xD;
                       directed therapy and no evidence of interim progression between the&#xD;
                       completion of CNS directed therapy and the screening radiographic study&#xD;
&#xD;
                    -  No stereotactic radiation or whole-brain radiation within 28 days prior to&#xD;
                       cycle 1, day 1&#xD;
&#xD;
                    -  Screening CNS radiographic study &gt;= 4 weeks from completion of radiotherapy&#xD;
                       and &gt;= 2 weeks from discontinuation of corticosteroids&#xD;
&#xD;
          -  Known hypersensitivity to Chinese hamster ovary cell products or other recombinant&#xD;
             human antibodies&#xD;
&#xD;
          -  History of severe allergic, anaphylactic, or other hypersensitivity reactions to&#xD;
             chimeric or humanized antibodies or fusion proteins or eribulin&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to other agents used in study&#xD;
&#xD;
          -  Known additional malignancy that is progressing or requires active treatment excepting&#xD;
             basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has&#xD;
             undergone potentially curative therapy, or in situ cancer; patients with another known&#xD;
             malignancy are allowed as long that other cancer is in clinical remission for at least&#xD;
             2 years prior to cycle 1 (C1) day 1 (D1)&#xD;
&#xD;
          -  History of significant cardiovascular disease, defined as:&#xD;
&#xD;
               -  Congestive heart failure greater than New York Heart Association (NYHA) class III&#xD;
                  according to the NYHA functional classification&#xD;
&#xD;
               -  Unstable angina or myocardial infarction within 6 months of enrollment&#xD;
&#xD;
               -  Serious cardiac arrhythmia&#xD;
&#xD;
               -  A prolonged QT/corrected QT (QTc) interval calculated with Frederica's formula&#xD;
                  (QTcF &gt; 450 ms) demonstrated on electrocardiography (ECG) at screening or&#xD;
                  baseline; a history of risk factors for torsade de pointes (e.g., heart failure,&#xD;
                  hypokalemia, family history of long QT syndrome) or the use of concomitant&#xD;
                  medications that prolonged the QT/QTc interval&#xD;
&#xD;
          -  Autoimmune disease that has required systemic treatment in past 2 years&#xD;
&#xD;
          -  Clinically significant illness that requires medical treatment within 8 weeks or a&#xD;
             clinically significant infection that requires medical treatment within 4 weeks of&#xD;
             dosing&#xD;
&#xD;
          -  History of organ allograft&#xD;
&#xD;
          -  Active hepatitis b virus (positive hepatitis b surface antigen) or active hepatitis c&#xD;
             virus (measurable viral ribonucleic acid [RNA] load with polymerase chain reaction)&#xD;
             infection&#xD;
&#xD;
          -  Known intolerance to either of the study drugs (or any of the excipients)&#xD;
&#xD;
          -  Any medical or other condition which, in the opinion of the investigator, would&#xD;
             preclude participation in a clinical trial or the investigator's belief that the&#xD;
             subject is medically unfit to receive eribulin mesylate and atezolizumab or unsuitable&#xD;
             for any other reason&#xD;
&#xD;
          -  Known clinically significant liver disease, including active viral, alcoholic, or&#xD;
             other hepatitis; cirrhosis; fatty liver; and inherited liver disease&#xD;
&#xD;
               -  Patients with past or resolved hepatitis B infection (defined as having a&#xD;
                  negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc&#xD;
                  [antibody to hepatitis B core antigen] antibody test) are eligible&#xD;
&#xD;
               -  Patients positive for hepatitis C virus (HCV) antibody are eligible only if&#xD;
                  polymerase chain reaction (PCR) is negative for HCV RNA&#xD;
&#xD;
          -  History or risk of autoimmune disease, including, but not limited to, systemic lupus&#xD;
             erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis&#xD;
             associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's&#xD;
             syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune&#xD;
             thyroid disease, vasculitis, or glomerulonephritis&#xD;
&#xD;
               -  Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid&#xD;
                  replacement hormone may be eligible&#xD;
&#xD;
               -  Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may&#xD;
                  be eligible&#xD;
&#xD;
               -  Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with&#xD;
                  dermatologic manifestations only (e.g., patients with psoriatic arthritis would&#xD;
                  be excluded) are permitted provided that they meet the following conditions:&#xD;
&#xD;
                    -  Patients with psoriasis must have a baseline ophthalmologic exam to rule out&#xD;
                       ocular manifestations&#xD;
&#xD;
                    -  Rash must cover less than 10% of body surface area (BSA)&#xD;
&#xD;
                    -  Disease is well controlled at baseline and only requiring low potency&#xD;
                       topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%,&#xD;
                       fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)&#xD;
&#xD;
                    -  No acute exacerbations of underlying condition within the last 12 months&#xD;
                       (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate,&#xD;
                       retinoids, biologic agents, oral calcineurin inhibitors; high potency or&#xD;
                       oral steroids)&#xD;
&#xD;
          -  History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),&#xD;
             organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing&#xD;
             pneumonia, etc.), or evidence of active pneumonitis on screening chest computed&#xD;
             tomography (CT) scan; history of radiation pneumonitis in the radiation field&#xD;
             (fibrosis) is permitted&#xD;
&#xD;
          -  Patients with active tuberculosis (TB) are excluded&#xD;
&#xD;
          -  Severe infections within 4 weeks prior to cycle 1, day 1, including, but not limited&#xD;
             to, 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 oral or intravenous (IV) antibiotics within 2 weeks prior to cycle 1, day 1;&#xD;
             patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract&#xD;
             infection or chronic obstructive pulmonary disease) are eligible&#xD;
&#xD;
          -  Major surgical procedure within 28 days prior to cycle 1, day 1 or anticipation of&#xD;
             need for a major surgical procedure during the course of the study&#xD;
&#xD;
          -  Administration of a live, attenuated vaccine within 4 weeks before cycle 1, day 1 or&#xD;
             anticipation that such a live, attenuated vaccine will be required during the study&#xD;
             and up to 5 months after the last dose of atezolizumab&#xD;
&#xD;
               -  Influenza vaccination should be given during influenza season only (approximately&#xD;
                  October to March); patients must not receive live, attenuated influenza vaccine&#xD;
                  within 4 weeks prior to cycle 1, day 1 or at any time during the study&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac&#xD;
             arrhythmia, or psychiatric illness/social situations that would limit compliance with&#xD;
             study requirements&#xD;
&#xD;
          -  Pregnant women are excluded from this study because atezoluzumab and eribulin have not&#xD;
             been formally tested in pregnancy but have potential for teratogenic or abortifacient&#xD;
             effects; because there is an unknown but potential risk for adverse events in nursing&#xD;
             infants secondary to treatment of the mother with atezoluzumab and eribulin,&#xD;
             breastfeeding should be discontinued if the mother is treated with atezolizumab and&#xD;
             eribulin and for 2 weeks after last dose&#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>Anishka A D'Souza</last_name>
    <role>Principal Investigator</role>
    <affiliation>City of Hope Comprehensive Cancer Center LAO</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Alabama at Birmingham Cancer Center</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35233</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Keck Medicine of USC Buena Park</name>
      <address>
        <city>Buena Park</city>
        <state>California</state>
        <zip>90621</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>City of Hope Comprehensive Cancer Center</name>
      <address>
        <city>Duarte</city>
        <state>California</state>
        <zip>91010</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>City of Hope at Irvine Lennar</name>
      <address>
        <city>Irvine</city>
        <state>California</state>
        <zip>92618</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Keck Medicine of USC Koreatown</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90020</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Los Angeles County-USC Medical Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90033</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>USC / Norris Comprehensive Cancer Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90033</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>USC Norris Oncology/Hematology-Newport Beach</name>
      <address>
        <city>Newport Beach</city>
        <state>California</state>
        <zip>92663</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UC Irvine Health/Chao Family Comprehensive Cancer Center</name>
      <address>
        <city>Orange</city>
        <state>California</state>
        <zip>92868</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Keck Medical Center of USC Pasadena</name>
      <address>
        <city>Pasadena</city>
        <state>California</state>
        <zip>91105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of California Davis Comprehensive Cancer Center</name>
      <address>
        <city>Sacramento</city>
        <state>California</state>
        <zip>95817</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>City of Hope Upland</name>
      <address>
        <city>Upland</city>
        <state>California</state>
        <zip>91786</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Kansas Clinical Research Center</name>
      <address>
        <city>Fairway</city>
        <state>Kansas</state>
        <zip>66205</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Kansas Cancer Center</name>
      <address>
        <city>Kansas City</city>
        <state>Kansas</state>
        <zip>66160</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Kansas Cancer Center-Overland Park</name>
      <address>
        <city>Overland Park</city>
        <state>Kansas</state>
        <zip>66210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Kansas Hospital-Indian Creek Campus</name>
      <address>
        <city>Overland Park</city>
        <state>Kansas</state>
        <zip>66211</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Kansas Hospital-Westwood Cancer Center</name>
      <address>
        <city>Westwood</city>
        <state>Kansas</state>
        <zip>66205</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Kansas Cancer Center - North</name>
      <address>
        <city>Kansas City</city>
        <state>Missouri</state>
        <zip>64154</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Kansas Cancer Center - Lee's Summit</name>
      <address>
        <city>Lee's Summit</city>
        <state>Missouri</state>
        <zip>64064</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Kansas Cancer Center at North Kansas City Hospital</name>
      <address>
        <city>North Kansas City</city>
        <state>Missouri</state>
        <zip>64116</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Pittsburgh Cancer Institute (UPCI)</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>August 2, 2017</study_first_submitted>
  <study_first_submitted_qc>August 2, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 3, 2017</study_first_posted>
  <last_update_submitted>September 12, 2023</last_update_submitted>
  <last_update_submitted_qc>September 12, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 13, 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>Urinary Bladder Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Transitional Cell</mesh_term>
    <mesh_term>Urethral Neoplasms</mesh_term>
    <mesh_term>Ureteral Neoplasms</mesh_term>
    <mesh_term>Kidney Neoplasms</mesh_term>
    <mesh_term>Pelvic Neoplasms</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Atezolizumab</mesh_term>
    <mesh_term>Halichondrin B</mesh_term>
    <mesh_term>Antibodies, Monoclonal</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/NCT03237780
org study id: NCI-2017-01388
secondary id: NCI-2017-01388
secondary id: PHII-150
secondary id: 10100
secondary id: 10100
secondary id: UM1CA186717
nct id: NCT03237780
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This phase II trial studies the side effects of atezolizumab with or without eribulin
      mesylate and how well they work in treating patients with urothelial cancer that has come
      back (recurrent), spread to nearby tissues or lymph nodes (locally advanced), or spread from
      where it first started (primary site) to other places in the body (metastatic). Immunotherapy
      with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack
      the cancer, and may interfere with the ability of tumor cells to grow and spread.
      Chemotherapy drugs, such as eribulin mesylate, work in different ways to stop the growth of
      tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them
      from spreading. Giving atezolizumab and eribulin mesylate may work better at treating
      urothelial cancer compared to atezolizumab alone.
PRIMARY OBJECTIVES:

      I. To confirm that eribulin mesylate (eribulin), at or close to the single agent recommended
      phase 2 dose, and atezolizumab at the single agent recommended phase 2 dose, can be given
      together with an acceptable toxicity profile. (Safety/Run-in) II. To estimate the objective
      response rate (ORR) based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for
      eribulin and atezolizumab in combination, and compare that to the ORR of atezolizumab alone.
      (Phase 2)

      SECONDARY OBJECTIVES:

      I. To summarize and characterize the toxicity associated with this 2-drug combination.

      II. To estimate the best overall response rate (immune-related best overall response [irBOR]
      rate) using the immune-related response criteria (irRC).

      III. To estimate the disease control rate (DCR: complete response [CR] + partial response
      [PR] + stable disease [SD]) based on RECIST 1.1.

      IV. To estimate the duration of response and the duration of stable disease. V. To summarize
      the progression-free survival (PFS). VI. To summarize the overall survival (OS). VII. To
      evaluate efficacy in subsets of patients determined by PD-L1, CD3 and CD8 expression.

      EXPLORATORY OBJECTIVES:

      I. To assess the pharmacodynamic (PD) profile of eribulin when it is given in combination
      with atezolizumab, specifically exploring the expression of putative tumor, circulating
      microenvironment and computed tomography (CT) radiomic correlatives of epithelial-mesenchymal
      transition (EMT)/ (mesenchymal-epithelial transition) MET phenotype at baseline and 6 weeks
      on therapy.

      II. To ascertain the role of expression of PD-L1 using the SP142 assay and potentially other
      methods as a predictive biomarker for response to treatment with atezolizumab in combination
      with eribulin.

      III. To identify clinical biomarkers that may predict for efficacy and toxicity in this
      population and with this treatment combination.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM I: Patients receive atezolizumab intravenously (IV) over 30-60 minutes on day 1. Cycles
      repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients
      also undergo collection of blood and CT with contrast throughout the trial. Patients may
      undergo biopsy during screening and on study.

      ARM II: Patients receive atezolizumab IV over 30-60 minutes on day 1 and eribulin mesylate IV
      over 2-3 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease
      progression or unacceptable toxicity. Patients also undergo collection of blood and CT with
      contrast throughout the trial. Patients may undergo biopsy during screening and on study.

      After completion of study treatment, patients are followed up every 3 or 6 months for 52
      weeks.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Incidence of adverse events
time frame: Up to 52 weeks
description: Will be graded according to the Common Terminology Criteria for Adverse Events version 5. Tables will be created to summarize the numbers of patients who experienced toxicities by arm, toxicity system, type, grade and attribution. If helpful, cumulative incidence curves will be constructed to summarize the onset of selected adverse events.
measure: Objective tumor response
time frame: Up to 52 weeks
description: Will be assessed by Response Evaluation Criteria in Solid Tumors version 1.1.
measure: Overall response rate (probability of complete response [CR] or partial response [PR])
time frame: Up to 52 weeks
description: Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The two arms will be compared using a one-sided, 0.10-level Mantel-Haenszel, stratifying by (a) cisplatin ineligible first line vs. having received prior platinum therapy, and PD-L1 status in archival tumor tissue (immunohistochemistry [IHC] 0-1 versus [vs] 2-3). Two-sided 80% confidence intervals will be constructed for the probability of response in each arm, as well as the difference between the two arms (unadjusted for the stratification variables). In addition, a logistic regression (exact, if required based on the numbers) will be used to estimate the odds ratio comparing the 2 arms adjusting for the stratification variables, and also by the Bellmunt risk group (1-2 versus [vs] 3-4).
measure: Best overall response rate (immune-related best overall response [irBOR] rate) using the immune-related response criteria
time frame: Up to 52 weeks
description: Analysis of the irBOR will be based on a modified intention-to-treat analysis which will include all eligible, randomized patients who receive any amount of either atezolizumab or eribulin. The proportion of patients in each of the 5 categories above will be calculated for each arm and two-sided 80% confidence intervals will be constructed. Two-sided 80% confidence intervals will be constructed for the probability of response in each arm, as well as the difference between the two arms (unadjusted for the stratification variables). In addition, a logistic regression (exact, if required based on the numbers) will be used to estimate the odds ratio comparing the 2 arms adjusting for the stratification variables, and also by the Bellmunt risk group (1-2 vs 3-4).
measure: Disease control rate (DCR: CR + PR + stable disease)
time frame: Up to 52 weeks
description: Will be assessed based on RECIST 1.1. The two arms will be compared in terms of the DCR using a one-sided, 0.10-level Mantel-Haenszel, stratifying by (a) cisplatin ineligible first line vs having received prior platinum therapy, and PD-L1 status in archival tumor tissue (IHC 0-1 vs 2-3). Two-sided 80% confidence intervals will be constructed for the probability of DCR in each arm, as well as the difference between the two arms (unadjusted for the stratification variables). In addition, a logistic regression (exact, if required based on the numbers) will be used to estimate the odds ratio comparing the 2 arms adjusting for the stratification variables, and also by the Bellmunt risk group (1-2 vs 3-4).
measure: Progression-free survival (PFS)
time frame: From randomization until progression or death, whichever occurs first, assessed up to 52 weeks
description: Will be displayed using Kaplan-Meier plots. Median PFS will be estimated and 80% confidence intervals constructed; PFS at 6 months and 12 months will be estimated and 80% confidence intervals constructed. The two arms will be compared using a one-sided, 0.10-level, stratified logrank test. If numbers permit, Kaplan-Meier plots will be drawn for patients grouped by the stratification variables. In addition, also, if numbers permit, a Cox proportional hazards regression be used to estimate the hazards ratio comparing the 2 arms adjusting for the stratification variables, and also by the Bellmunt risk group (1-2 vs 3-4).
measure: Overall survival (OS)
time frame: From randomization until death or date last known to be alive, assessed up to 52 weeks
description: OS will be displayed using Kaplan-Meier plots. Median OS will be estimated and 80% confidence intervals constructed; OS at 6 months and 12 months will be estimated and 80% confidence intervals constructed. The two arms will be compared using a one-sided, 0.10-level, stratified logrank test. If numbers permit, Kaplan-Meier plots will be drawn for patients grouped by the stratification variables. In addition, also, if numbers permit, a Cox proportional hazards regression be used to estimate the hazards ratio comparing the 2 arms adjusting for the stratification variables, and also by the Bellmunt risk group (1-2 vs 3-4).
measure: Duration of response (DOR)
time frame: From the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that progressive disease is objectively documented, assessed up to 52 weeks
description: Will be displayed using Kaplan-Meier plots. Median DOR will be estimated and 80% confidence intervals constructed; DOR at 6 months will be estimated and 80% confidence intervals constructed.
measure: Analysis based on PD-L1 expression
time frame: Up to 52 weeks
description: The analyses described for ORR, DCR, irBOR, PFS, and OS will be repeated, examining patients whose tumors are PD-L1 "positive" (IHC = 2-3) and those whose tumors are PD-L1 "negative (IHC = 0-1). Although numbers will be small, the odds ratio's and hazard ratio's will be compared (using the logistic or Cox regression models) to ascertain whether the impact of eribulin is different based on the PD-L1 status.
measure: Analysis of baseline tumor
time frame: Baseline
description: Standard descriptive methods will be used to summarize patterns.
measure: Changes in tumor based on biopsies, radiomics and circulating tumor cells
time frame: Baseline up to 6 weeks
description: Standard descriptive methods will be used to summarize patterns.
arm group label: Arm I (atezolizumab)
arm group type: Experimental
description: Patients receive atezolizumab IV over 30-60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and CT with contrast throughout the trial. Patients may undergo biopsy during screening and on study.
arm group label: Arm II (atezolizumab, eribulin mesylate)
arm group type: Experimental
description: Patients receive atezolizumab IV over 30-60 minutes on day 1 and eribulin mesylate IV over 2-3 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and CT with contrast throughout the trial. Patients may undergo biopsy during screening and on study.
intervention type: Drug
intervention name: Atezolizumab
description: Given IV
arm group label: Arm I (atezolizumab)
arm group label: Arm II (atezolizumab, eribulin mesylate)
other name: MPDL 3280A
other name: MPDL 328OA
other name: MPDL-3280A
other name: MPDL3280A
other name: MPDL328OA
other name: RG7446
other name: RO5541267
other name: Tecentriq
intervention type: Procedure
intervention name: Biopsy
description: Undergo biopsy
arm group label: Arm I (atezolizumab)
arm group label: Arm II (atezolizumab, eribulin mesylate)
other name: BIOPSY_TYPE
other name: Bx
intervention type: Procedure
intervention name: Biospecimen Collection
description: Undergo blood sample collection
arm group label: Arm I (atezolizumab)
arm group label: Arm II (atezolizumab, eribulin mesylate)
other name: Biological Sample Collection
other name: Biospecimen Collected
other name: Specimen Collection
intervention type: Procedure
intervention name: Computed Tomography with Contrast
description: Undergo CT scan
arm group label: Arm I (atezolizumab)
arm group label: Arm II (atezolizumab, eribulin mesylate)
other name: Contrast Enhanced Computed Tomography
other name: CONTRAST ENHANCED CT SCAN
other name: Contrast-enhanced Computed Tomography
other name: CT Scan With Contrast
other name: CT with Contrast
intervention type: Drug
intervention name: Eribulin Mesylate
description: Given IV
arm group label: Arm II (atezolizumab, eribulin mesylate)
other name: B1939 Mesylate
other name: E7389
other name: ER-086526 Mesylate
other name: Halaven
other name: Halichondrin B Analog
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Anishka A D'Souza
role: Principal Investigator
affiliation: City of Hope Comprehensive Cancer Center LAO
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country: United States
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Urinary Bladder Neoplasms
mesh term: Carcinoma, Transitional Cell
mesh term: Urethral Neoplasms
mesh term: Ureteral Neoplasms
mesh term: Kidney Neoplasms
mesh term: Pelvic Neoplasms
mesh term: Recurrence
mesh term: Atezolizumab
mesh term: Halichondrin B
mesh term: Antibodies, Monoclonal