<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/NCT04430036</url>
  </required_header>
  <id_info>
    <org_study_id>CTMS 19-0193</org_study_id>
    <secondary_id>HSC20200027H</secondary_id>
    <nct_id>NCT04430036</nct_id>
  </id_info>
  <brief_title>AGEN1884 Plus AGEN2034 Combined With Cisplatin-Gemcitabine for Muscle-Invasive Bladder Cancer</brief_title>
  <official_title>A Phase II Trial of Neoadjuvant AGEN1884 Plus AGEN2034 in Combination With Cisplatin-Gemcitabine for Muscle-Invasive Bladder Cancer Prior to Radical Cystectomy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The University of Texas Health Science Center at San Antonio</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>The University of Texas Health Science Center at San Antonio</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>
      This is a phase II trial to evaluate the tolerability, efficacy, and immune outcomes of&#xD;
      AGEN1884 plus AGEN2034 concurrent with cisplatin and gemcitabine in the neoadjuvant treatment&#xD;
      of muscle-invasive, non-metastatic bladder cancer prior to radical cystectomy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      We will begin with an initial safety run-in to establish the safety of the combination prior&#xD;
      to expansion to the full planned phase II. The overall phase II will be an open-label, single&#xD;
      arm study in two stages to evaluate the efficacy of the combination in pathologic downstaging&#xD;
      of MIBC. Patients will receive four 21-day cycles of neoadjuvant therapy consisting of&#xD;
      cisplatin and gemcitabine plus AGEN2034 in all 4 cycles and AGEN1884 in cycles 1 and 3.&#xD;
      Patients will proceed to radical cystectomy within 10 weeks after the final dose of this&#xD;
      therapy. The primary endpoint of pathologic tumor downstaging will be assessed at the time of&#xD;
      cystectomy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">October 14, 2020</start_date>
  <completion_date type="Anticipated">October 2022</completion_date>
  <primary_completion_date type="Actual">October 18, 2021</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Pathologic tumor downstaging of &gt;T2 to pT0</measure>
    <time_frame>Completion of four 21 day cycles (approximately 10 weeks)</time_frame>
    <description>pT0 or pCR (defined as no residual tumor in bladder and lymph nodes on resected specimen). Surgery should be performed within 6 weeks after completing up to 4 cycles (last dose) of neoadjuvant therapy, but can be done up to 10 weeks after treatment ends to be evaluable. Otherwise this patient must be replaced for response evaluation.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Evaluation of safety and tolerability of AGEN1884 plus AGEN2034 plus cisplatin and gemcitabine</measure>
    <time_frame>Baseline to 90 days</time_frame>
    <description>Evaluation of safety and tolerability of using Agen1884 plus AGEN2034 plus cisplating and gemcitabine chemotherapy in the neoadjuvant treatment of muscle-invasive bladder cancer prior to radial cystectomy. Number of adverse events assessed between 3-5 using the National Cancer Institution Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE v5.0)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pathologic downstaging to &lt;T2 rate</measure>
    <time_frame>Completion of four 21 day cycles (approximately 10 weeks)</time_frame>
    <description>Number of subjects who achieved downstaging of the tumor at completion of the possible 4 chemotherapy cycles.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Completion of surgery</measure>
    <time_frame>90 days</time_frame>
    <description>Number of subjects that progressed from therapy to surgery</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival at 1 year</measure>
    <time_frame>1 year</time_frame>
    <description>Number of subjects that survived to 1 year from study start without disease progression</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Correlate Immune Outcomes</measure>
    <time_frame>2 years</time_frame>
    <description>To correlate clinical outcomes with immune and biologic endpoints and identify patient and tumor characteristics that can predict treatment responses</description>
  </other_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">4</enrollment>
  <condition>Urinary Bladder Neoplasms</condition>
  <arm_group>
    <arm_group_label>Safety Run-In</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The safety run-in of the study will first enroll three patients who will begin treatment with cisplatin and gemcitabine plus AGEN2034 and AGEN1884 as outlined in the treatment plan. These first 3 patients will be assessed for DLTs and there will be a pause in enrollment until all three complete the DLT period. If there are no DLTs in the first 3 patients, we will proceed to further accrual to stage I of phase II. If there is 1 DLT in the initial 3 patients, we will enroll 3 additional patients to the safety run-in. If &gt; 2 DLTs are experienced in the initial 3 patients, the study will be terminated.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase II, Stage 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>In the first stage of phase II of this study, 17 patients will be enrolled. Patients will begin treatment with cisplatin and gemcitabine plus AGEN2034 and AGEN1884 as outlined in the treatment plan. They will be evaluated with each cycle of therapy, with radiographic restaging assessment after 2 cycles of therapy and prior to the third cycle of treatment. If no disease progression is identified, patients will receive a third and fourth cycle of therapy. Following this neoadjuvant regimen, they will proceed to planned surgery following preoperative clearance within 10 weeks of the last dose of neoadjuvant therapy.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase II, Stage 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>If criteria are met to continue to the second stage of the Phase II portion of the study, 19 more patients will be enrolled for a total of 36 evaluable patients. Patients will be treated and endpoints evaluated.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AGEN1884</intervention_name>
    <description>A fully human monoclonal Anti-PD-1 Antibody</description>
    <arm_group_label>Phase II, Stage 1</arm_group_label>
    <arm_group_label>Phase II, Stage 2</arm_group_label>
    <arm_group_label>Safety Run-In</arm_group_label>
    <other_name>anti-CTLA-4 antibody</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AGEN2034</intervention_name>
    <description>A fully human monoclonal Anti-PD-1 Antibody</description>
    <arm_group_label>Phase II, Stage 1</arm_group_label>
    <arm_group_label>Phase II, Stage 2</arm_group_label>
    <arm_group_label>Safety Run-In</arm_group_label>
    <other_name>Anti-PD-1</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cisplatin</intervention_name>
    <description>Alkylating antineoplastic agent</description>
    <arm_group_label>Phase II, Stage 1</arm_group_label>
    <arm_group_label>Phase II, Stage 2</arm_group_label>
    <arm_group_label>Safety Run-In</arm_group_label>
    <other_name>Gemzar, Platinol® and Platinol®-AQ</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Gemcitabine</intervention_name>
    <description>Antimetabolite antineoplastic agent</description>
    <arm_group_label>Phase II, Stage 1</arm_group_label>
    <arm_group_label>Phase II, Stage 2</arm_group_label>
    <arm_group_label>Safety Run-In</arm_group_label>
    <other_name>Gebina, Gemalata, Gembin, Gembine, Gembio, Gemcel, Gemcetin</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria&#xD;
&#xD;
          1. Diagnosis of muscle-invasive, non-metastatic urothelial carcinoma of the bladder,&#xD;
             cT2-4, N0-1, M0&#xD;
&#xD;
          2. Eligible to receive cisplatin-based chemotherapy, with eligibility defined as meeting&#xD;
             all of the following criteria:&#xD;
&#xD;
               1. Eastern Cooperative Oncology Group performance status of ¬0-1&#xD;
&#xD;
               2. Creatinine clearance (CrCl) of &gt;50 mL/min, as measured by 24-hour urine&#xD;
                  collection or estimated by the CKD-EPI equation. Patients with CrCl between 50 -&#xD;
                  60 mL/min are eligible for the study but will receive split dose cisplatin&#xD;
&#xD;
               3. Grade &lt; 2 hearing loss&#xD;
&#xD;
               4. Grade &lt; 2 peripheral neuropathy&#xD;
&#xD;
               5. New York Heart Association Class &lt; III heart failure&#xD;
&#xD;
          3. Eligible to receive gemcitabine as dosed here&#xD;
&#xD;
          4. Patients must have organ and marrow function meeting the criteria below:&#xD;
&#xD;
             Absolute neutrophil count &gt; 2,000/mcL Hemoglobin &gt; 9.0 mg/mL Platelets &gt; 100,000/mcL&#xD;
             Total bilirubin within normal limits or known to be elevated due to a benign&#xD;
             conjugation defect such as Gilbert's syndrome, as evidenced by normal conjugated&#xD;
             bilirubin level AST/ALT &lt; 3X institutional normal limits Creatinine clearance (CrCl) &gt;&#xD;
             50 mL/min/1.73m2, as measured with 24 hr urine collection or estimated by CKD-EPI,&#xD;
             whichever is greater&#xD;
&#xD;
          5. Signed, written informed consents to allow transfer of tumor tissue and production of&#xD;
             peptides and to receive experimental treatment and monitoring if agreeable, or&#xD;
             monitoring without experimental treatment otherwise&#xD;
&#xD;
          6. Age ≥18 years&#xD;
&#xD;
          7. Available fresh tissue from surgical excision. If fresh tissue is not available,&#xD;
             archival tissue may be used.&#xD;
&#xD;
          8. Female subjects of childbearing potential must have a negative serum pregnancy test at&#xD;
             screening (within 72 hours of first dose of study medication). Non-childbearing&#xD;
             potential (other than by medical reasons) is defined as 1 of the following:&#xD;
&#xD;
               1. ≥ 45 years of age and amenorrheic for &gt;1 year by self-report.&#xD;
&#xD;
               2. Amenorrheic for &gt;2 years without a hysterectomy and oophorectomy, and&#xD;
                  follicle-stimulating hormone value in the postmenopausal range upon pretrial&#xD;
                  (screening) evaluation.&#xD;
&#xD;
               3. Status post-hysterectomy, -oophorectomy, or -tubal ligation. If of childbearing&#xD;
                  potential, female subjects must be willing to use adequate birth control during&#xD;
                  the study, starting with the screening visit through 120 days after the last dose&#xD;
                  of study therapy.&#xD;
&#xD;
        Male subjects with a female partner(s) of childbearing potential must agree to use a condom&#xD;
        throughout the trial, starting with the screening visit through 120 days after the last&#xD;
        dose of study therapy. Males with pregnant partners must agree to use a condom; no&#xD;
        additional method of contraception is required for the pregnant partner.&#xD;
&#xD;
        Note: Abstinence is acceptable for both female and male subjects if this is the subject's&#xD;
        established and preferred contraception method.&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          1. Subjects must not have previously received a checkpoint inhibitor ie, anti-PD-1,&#xD;
             anti-PD L1, or anti CTLA-4 antibody.&#xD;
&#xD;
          2. Subjects must not have previously received anticancer medications or investigational&#xD;
             drugs for the disease under study within the following windows:&#xD;
&#xD;
             a. ≤ 28 days for prior monoclonal antibody used for anticancer therapy, with the&#xD;
             exception of denosumab b. ≤ 7 days for immunosuppressive treatment for any reason,&#xD;
             with the following exceptions: i. Physiologic steroid replacement for adrenal&#xD;
             insufficiency (e.g., &lt;10 mg prednisone per day) is permitted.&#xD;
&#xD;
             ii. Use of inhaled or topical corticosteroid for radiographic procedures is permitted.&#xD;
&#xD;
             c. Systemic corticosteroids &lt; 7 days are not allowed except as defined above. d. ≤ 28&#xD;
             days before first dose of study drug for all other investigational study drugs or&#xD;
             devices&#xD;
&#xD;
          3. Has persisting toxicity related to prior therapy of National Cancer Institute Common&#xD;
             Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE) Grade &gt;1 severity.&#xD;
&#xD;
             Note: Sensory neuropathy or alopecia of Grade ≤2 is acceptable.&#xD;
&#xD;
          4. Has known severe hypersensitivity reactions to fully human monoclonal antibodies&#xD;
             (NCI-CTCAE Version 5.0 Grade ≥3), any history of anaphylaxis, or uncontrolled asthma.&#xD;
&#xD;
          5. Active or history of any autoimmune disease (subjects with diabetes type 1, vitiligo,&#xD;
             psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are&#xD;
             eligible). Patients with a history of inflammatory bowel disease (including Crohn's&#xD;
             disease and ulcerative colitis) and autoimmune disorders such as rheumatoid arthritis,&#xD;
             systemic progressive sclerosis [scleroderma], Systemic Lupus Erythematosus or&#xD;
             autoimmune vasculitis [e.g., Wegener's Granulomatosis] are excluded from this study.&#xD;
&#xD;
          6. Any condition requiring systemic treatment with corticosteroids (&gt;10mg daily&#xD;
             prednisone equivalents) or other immunosuppressive medications within 14 days prior to&#xD;
             first dose of study drug. Inhaled steroids and adrenal replacement steroids doses&#xD;
             &gt;10mg daily prednisone equivalents are permitted in the absence of active autoimmune&#xD;
             disease.&#xD;
&#xD;
          7. Uncontrolled intercurrent illness, including but not limited to uncontrolled&#xD;
             infection, interstitial lung disease or active, non-infectious pneumonitis,&#xD;
             symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac&#xD;
             arrhythmia, or social situations that would limit compliance with study requirements&#xD;
             in the opinion of the treating investigator or medical monitor.&#xD;
&#xD;
          8. History of intolerance or allergic reactions attributed to compounds of similar&#xD;
             chemical or biologic composition to AGEN1884 or AGEN2034.&#xD;
&#xD;
          9. Women who are pregnant or breastfeeding.&#xD;
&#xD;
         10. Receipt of a live vaccine within 30 days prior to the first dose of study drug.&#xD;
&#xD;
         11. Inability to adhere to the 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>Chethan Ramamurthy, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Texas Health Science Center San Antonio</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Mays Cancer Center</name>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <zip>78229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2022</verification_date>
  <study_first_submitted>May 8, 2020</study_first_submitted>
  <study_first_submitted_qc>June 10, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 12, 2020</study_first_posted>
  <last_update_submitted>March 11, 2022</last_update_submitted>
  <last_update_submitted_qc>March 11, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">March 28, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>muscle-invasive, non-metastatic</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Urinary Bladder Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cisplatin</mesh_term>
    <mesh_term>Gemcitabine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT04430036
org study id: CTMS 19-0193
secondary id: HSC20200027H
nct id: NCT04430036
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This is a phase II trial to evaluate the tolerability, efficacy, and immune outcomes of
      AGEN1884 plus AGEN2034 concurrent with cisplatin and gemcitabine in the neoadjuvant treatment
      of muscle-invasive, non-metastatic bladder cancer prior to radical cystectomy.
We will begin with an initial safety run-in to establish the safety of the combination prior
      to expansion to the full planned phase II. The overall phase II will be an open-label, single
      arm study in two stages to evaluate the efficacy of the combination in pathologic downstaging
      of MIBC. Patients will receive four 21-day cycles of neoadjuvant therapy consisting of
      cisplatin and gemcitabine plus AGEN2034 in all 4 cycles and AGEN1884 in cycles 1 and 3.
      Patients will proceed to radical cystectomy within 10 weeks after the final dose of this
      therapy. The primary endpoint of pathologic tumor downstaging will be assessed at the time of
      cystectomy.
allocation: Non-Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Pathologic tumor downstaging of >T2 to pT0
time frame: Completion of four 21 day cycles (approximately 10 weeks)
description: pT0 or pCR (defined as no residual tumor in bladder and lymph nodes on resected specimen). Surgery should be performed within 6 weeks after completing up to 4 cycles (last dose) of neoadjuvant therapy, but can be done up to 10 weeks after treatment ends to be evaluable. Otherwise this patient must be replaced for response evaluation.
measure: Evaluation of safety and tolerability of AGEN1884 plus AGEN2034 plus cisplatin and gemcitabine
time frame: Baseline to 90 days
description: Evaluation of safety and tolerability of using Agen1884 plus AGEN2034 plus cisplating and gemcitabine chemotherapy in the neoadjuvant treatment of muscle-invasive bladder cancer prior to radial cystectomy. Number of adverse events assessed between 3-5 using the National Cancer Institution Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE v5.0)
measure: Pathologic downstaging to <T2 rate
time frame: Completion of four 21 day cycles (approximately 10 weeks)
description: Number of subjects who achieved downstaging of the tumor at completion of the possible 4 chemotherapy cycles.
measure: Completion of surgery
time frame: 90 days
description: Number of subjects that progressed from therapy to surgery
measure: Progression-free survival at 1 year
time frame: 1 year
description: Number of subjects that survived to 1 year from study start without disease progression
measure: Correlate Immune Outcomes
time frame: 2 years
description: To correlate clinical outcomes with immune and biologic endpoints and identify patient and tumor characteristics that can predict treatment responses
arm group label: Safety Run-In
arm group type: Experimental
description: The safety run-in of the study will first enroll three patients who will begin treatment with cisplatin and gemcitabine plus AGEN2034 and AGEN1884 as outlined in the treatment plan. These first 3 patients will be assessed for DLTs and there will be a pause in enrollment until all three complete the DLT period. If there are no DLTs in the first 3 patients, we will proceed to further accrual to stage I of phase II. If there is 1 DLT in the initial 3 patients, we will enroll 3 additional patients to the safety run-in. If > 2 DLTs are experienced in the initial 3 patients, the study will be terminated.
arm group label: Phase II, Stage 1
arm group type: Experimental
description: In the first stage of phase II of this study, 17 patients will be enrolled. Patients will begin treatment with cisplatin and gemcitabine plus AGEN2034 and AGEN1884 as outlined in the treatment plan. They will be evaluated with each cycle of therapy, with radiographic restaging assessment after 2 cycles of therapy and prior to the third cycle of treatment. If no disease progression is identified, patients will receive a third and fourth cycle of therapy. Following this neoadjuvant regimen, they will proceed to planned surgery following preoperative clearance within 10 weeks of the last dose of neoadjuvant therapy.
arm group label: Phase II, Stage 2
arm group type: Experimental
description: If criteria are met to continue to the second stage of the Phase II portion of the study, 19 more patients will be enrolled for a total of 36 evaluable patients. Patients will be treated and endpoints evaluated.
intervention type: Drug
intervention name: AGEN1884
description: A fully human monoclonal Anti-PD-1 Antibody
arm group label: Phase II, Stage 1
arm group label: Phase II, Stage 2
arm group label: Safety Run-In
other name: anti-CTLA-4 antibody
intervention type: Drug
intervention name: AGEN2034
description: A fully human monoclonal Anti-PD-1 Antibody
arm group label: Phase II, Stage 1
arm group label: Phase II, Stage 2
arm group label: Safety Run-In
other name: Anti-PD-1
intervention type: Drug
intervention name: Cisplatin
description: Alkylating antineoplastic agent
arm group label: Phase II, Stage 1
arm group label: Phase II, Stage 2
arm group label: Safety Run-In
other name: Gemzar, Platinol® and Platinol®-AQ
intervention type: Drug
intervention name: Gemcitabine
description: Antimetabolite antineoplastic agent
arm group label: Phase II, Stage 1
arm group label: Phase II, Stage 2
arm group label: Safety Run-In
other name: Gebina, Gemalata, Gembin, Gembine, Gembio, Gemcel, Gemcetin
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Chethan Ramamurthy, MD
role: Principal Investigator
affiliation: University of Texas Health Science Center San Antonio
facility: 
country: United States
responsible party type: Sponsor
mesh term: Urinary Bladder Neoplasms
mesh term: Cisplatin
mesh term: Gemcitabine
sharing ipd: No