<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/NCT04491942</url>
  </required_header>
  <id_info>
    <org_study_id>NCI-2020-05428</org_study_id>
    <secondary_id>NCI-2020-05428</secondary_id>
    <secondary_id>PHI-117</secondary_id>
    <secondary_id>10404</secondary_id>
    <secondary_id>10404</secondary_id>
    <secondary_id>UM1CA186717</secondary_id>
    <nct_id>NCT04491942</nct_id>
  </id_info>
  <brief_title>Testing the Addition of an Anti-cancer Drug, BAY 1895344, to the Usual Chemotherapy Treatment (Cisplatin, or Cisplatin and Gemcitabine) for Advanced Solid Tumors With Emphasis on Urothelial Cancer</brief_title>
  <official_title>A Phase 1 Trial of the ATR Inhibitor BAY 1895344 in Combination With Cisplatin and With Cisplatin Plus Gemcitabine in Advanced Solid Tumors With an Emphasis on Urothelial Carcinoma</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 I trial identifies the best dose, possible benefits and/or side effects of BAY&#xD;
      1895344 in combination with chemotherapy in treating patients with solid tumors or urothelial&#xD;
      cancer that has spread to other places in the body (advanced). BAY 1895344 may stop the&#xD;
      growth of tumor cells by blocking some of the enzymes needed for cell growth. Cisplatin and&#xD;
      gemcitabine are chemotherapy drugs that stop the growth of tumor cells by killing the cells.&#xD;
      Combining BAY 1895344 with chemotherapy treatment (cisplatin, or cisplatin and gemcitabine)&#xD;
      may be effective for the treatment of advanced solid tumors, including urothelial cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To establish the safety and tolerability of the combination of cisplatin + elimusertib&#xD;
      (BAY 1895344) in patients with advanced solid tumors.&#xD;
&#xD;
      II. To establish the safety and tolerability of the combination of cisplatin + gemcitabine +&#xD;
      BAY 1895344 in patients with advanced solid tumors with an emphasis on urothelial carcinoma&#xD;
      (UC).&#xD;
&#xD;
      III. To establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of&#xD;
      cisplatin + BAY 1895344 and cisplatin + gemcitabine + BAY 1895344.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To evaluate the pharmacokinetic profile of BAY 1895344 (in the doublet and triplet&#xD;
      combinations) and gemcitabine (in the triplet) in combination with cisplatin.&#xD;
&#xD;
      II. To further evaluate the toxicity of the combination of cisplatin + gemcitabine + BAY&#xD;
      1895344 in patients with UC.&#xD;
&#xD;
      III. To evaluate preliminary efficacy observed with cisplatin + BAY 1895344 and cisplatin +&#xD;
      gemcitabine + BAY 1895344 in patients with advanced solid tumors, including UC.&#xD;
&#xD;
      IV. To monitor for tumor response and symptom relief in addition to safety and tolerability.&#xD;
&#xD;
      V. To evaluate the association between ATM expression by immunohistochemical staining and&#xD;
      responses to therapy.&#xD;
&#xD;
      EXPLORATORY OBJECTIVES:&#xD;
&#xD;
      I. To evaluate the correlation of biomarkers, including deleterious deoxyribonucleic acid&#xD;
      (DNA) damage response (DDR) gene alterations and circulating tumor (ct)DNA with responses to&#xD;
      therapy using whole exome sequencing (WES) and messenger ribonucleic acid sequencing (RNA&#xD;
      seq) analysis of archival formalin fixed paraffin embedded (FFPE) tissue, as well as blood.&#xD;
&#xD;
      II. To correlate drug exposure with response and/or toxicity.&#xD;
&#xD;
      OUTLINE: This is a dose-escalation study of elimusertib. Patients are assigned to 1 of 2&#xD;
      arms.&#xD;
&#xD;
      ARM I (DOUBLET COMBINATION): Patients receive cisplatin intravenously (IV) over 1-2 hours on&#xD;
      day 1 and 8, and elimusertib orally (PO) once daily (QD) on days 2 and 9. Treatment repeats&#xD;
      every 21 days for up to 6 cycles in the absence of disease progression or unacceptable&#xD;
      toxicity.&#xD;
&#xD;
      ARM II (TRIPLET COMBINATION): Patients receive cisplatin IV over 1-2 hours on day 1 and 8,&#xD;
      gemcitabine IV over 30 minutes on days 1 and 8, and elimusertib PO QD on days 2 and 9.&#xD;
      Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or&#xD;
      unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up at 30 days, then every 3 months&#xD;
      thereafter.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 1, 2021</start_date>
  <completion_date type="Anticipated">December 31, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2023</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-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 28 days after completion of study treatment</time_frame>
    <description>Toxicities will be tabulated and reported according to dose level, grade, type, cycle, and attribution. Tables will be created to summarize these toxicities and side effects, overall and by cohort. Proportions and associated 95% confidence intervals will be calculated for each cohort separately. Cumulative incidence curves will be used to estimate the proportion of patients who will discontinue therapy for reasons of toxicity or general inability to tolerate the regimen.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Recommended phase 2 dose (RP2D) of BAY 1895344</measure>
    <time_frame>Up to 21 days from treatment start date</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic (PK) parameter - maximum concentration (Cmax)</measure>
    <time_frame>Day 2 and day 9 after treatment start date</time_frame>
    <description>Estimated using non-compartmental methods. The PK variables will be tabulated and descriptive statistics (e.g., geometric means and coefficients of variation) calculated for each dose level. PK parameters will be reported descriptively for exploratory comparison with historical data (gemcitabine).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PK parameter - area under the concentration-time curve (AUC)</measure>
    <time_frame>Day 2 and day 9 after treatment start date</time_frame>
    <description>Estimated using non-compartmental methods. The PK variables will be tabulated and descriptive statistics (e.g., geometric means and coefficients of variation) calculated for each dose level. PK parameters will be reported descriptively for exploratory comparison with historical data (gemcitabine). The impact of cisplatin on BAY 1895344 exposure will be evaluated by calculation of the AUC ratio of (day 9 / day 2) and testing non-parametrically with a null hypothesis of a ratio = 1.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Deoxyribonucleic acid (DNA) damage repair (DDR) mutations</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>The association between DDR mutations and responses will be described, with a table outlining patients who achieved by progressive disease, stable disease, partial or complete responses and DDR mutation status.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ATM expression</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>The association between ATM and responses will be described, with a table outlining patients who achieved progressive disease, stable disease, partial or complete responses and whether they exhibited ATM expression by immunohistochemistry (IHC) or not.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Response rate</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>The percent of responders will be calculated and associated exact 95% confidence intervals will be constructed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS)</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Kaplan-Meier plots will be used to summarize PFS.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">74</enrollment>
  <condition>Advanced Bile Duct Carcinoma</condition>
  <condition>Advanced Breast Carcinoma</condition>
  <condition>Advanced Cervical Carcinoma</condition>
  <condition>Advanced Endometrial Carcinoma</condition>
  <condition>Advanced Esophageal Carcinoma</condition>
  <condition>Advanced Gastric Carcinoma</condition>
  <condition>Advanced Head and Neck Carcinoma</condition>
  <condition>Advanced Lung Non-Small Cell Carcinoma</condition>
  <condition>Advanced Lung Small Cell Carcinoma</condition>
  <condition>Advanced Malignant Solid Neoplasm</condition>
  <condition>Advanced Ovarian Carcinoma</condition>
  <condition>Advanced Penile Carcinoma</condition>
  <condition>Advanced Pleural Malignant Mesothelioma</condition>
  <condition>Advanced Urothelial Carcinoma</condition>
  <condition>Anatomic Stage III Breast Cancer AJCC v8</condition>
  <condition>Anatomic Stage IV Breast Cancer AJCC v8</condition>
  <condition>Clinical Stage III Gastric Cancer AJCC v8</condition>
  <condition>Clinical Stage IV Gastric Cancer AJCC v8</condition>
  <condition>Stage III Cervical Cancer AJCC v8</condition>
  <condition>Stage III Distal Bile Duct Cancer AJCC v8</condition>
  <condition>Stage III Intrahepatic Bile Duct Cancer AJCC v8</condition>
  <condition>Stage III Lung Cancer AJCC v8</condition>
  <condition>Stage III Ovarian Cancer AJCC v8</condition>
  <condition>Stage III Penile Cancer AJCC v8</condition>
  <condition>Stage III Pleural Malignant Mesothelioma AJCC v8</condition>
  <condition>Stage IV Cervical Cancer AJCC v8</condition>
  <condition>Stage IV Distal Bile Duct Cancer AJCC v8</condition>
  <condition>Stage IV Intrahepatic Bile Duct Cancer AJCC v8</condition>
  <condition>Stage IV Lung Cancer AJCC v8</condition>
  <condition>Stage IV Ovarian Cancer AJCC v8</condition>
  <condition>Stage IV Penile Cancer AJCC v8</condition>
  <condition>Stage IV Pleural Malignant Mesothelioma AJCC v8</condition>
  <condition>Triple-Negative Breast Carcinoma</condition>
  <condition>Unresectable Urothelial Carcinoma</condition>
  <arm_group>
    <arm_group_label>Arm I (cisplatin, elimusertib)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive cisplatin IV over 1-2 hours on day 1 and 8, and elimusertib PO QD on days 2 and 9. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm II (cisplatin, gemcitabine, elimusertib)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive cisplatin IV over 1-2 hours on day 1 and 8, gemcitabine IV over 30 minutes on days 1 and 8, and elimusertib PO QD on days 2 and 9. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cisplatin</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Arm I (cisplatin, elimusertib)</arm_group_label>
    <arm_group_label>Arm II (cisplatin, gemcitabine, elimusertib)</arm_group_label>
    <other_name>Abiplatin</other_name>
    <other_name>Blastolem</other_name>
    <other_name>Briplatin</other_name>
    <other_name>CDDP</other_name>
    <other_name>Cis-diammine-dichloroplatinum</other_name>
    <other_name>Cis-diamminedichloridoplatinum</other_name>
    <other_name>Cis-diamminedichloro Platinum (II)</other_name>
    <other_name>Cis-diamminedichloroplatinum</other_name>
    <other_name>Cis-dichloroammine Platinum (II)</other_name>
    <other_name>Cis-platinous Diamine Dichloride</other_name>
    <other_name>Cis-platinum</other_name>
    <other_name>Cis-platinum II</other_name>
    <other_name>Cis-platinum II Diamine Dichloride</other_name>
    <other_name>Cismaplat</other_name>
    <other_name>Cisplatina</other_name>
    <other_name>Cisplatinum</other_name>
    <other_name>Cisplatyl</other_name>
    <other_name>Citoplatino</other_name>
    <other_name>Citosin</other_name>
    <other_name>Cysplatyna</other_name>
    <other_name>DDP</other_name>
    <other_name>Lederplatin</other_name>
    <other_name>Metaplatin</other_name>
    <other_name>Neoplatin</other_name>
    <other_name>Peyrone's Chloride</other_name>
    <other_name>Peyrone's Salt</other_name>
    <other_name>Placis</other_name>
    <other_name>Plastistil</other_name>
    <other_name>Platamine</other_name>
    <other_name>Platiblastin</other_name>
    <other_name>Platiblastin-S</other_name>
    <other_name>Platinex</other_name>
    <other_name>Platinol</other_name>
    <other_name>Platinol- AQ</other_name>
    <other_name>Platinol-AQ</other_name>
    <other_name>Platinol-AQ VHA Plus</other_name>
    <other_name>Platinoxan</other_name>
    <other_name>Platinum</other_name>
    <other_name>Platinum Diamminodichloride</other_name>
    <other_name>Platiran</other_name>
    <other_name>Platistin</other_name>
    <other_name>Platosin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Elimusertib</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Arm I (cisplatin, elimusertib)</arm_group_label>
    <arm_group_label>Arm II (cisplatin, gemcitabine, elimusertib)</arm_group_label>
    <other_name>ATR Inhibitor BAY1895344</other_name>
    <other_name>ATR Kinase Inhibitor BAY1895344</other_name>
    <other_name>BAY 1895344</other_name>
    <other_name>BAY-1895344</other_name>
    <other_name>BAY1895344</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Gemcitabine Hydrochloride</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Arm II (cisplatin, gemcitabine, elimusertib)</arm_group_label>
    <other_name>dFdCyd</other_name>
    <other_name>Difluorodeoxycytidine Hydrochloride</other_name>
    <other_name>Gemcitabine HCI</other_name>
    <other_name>Gemzar</other_name>
    <other_name>LY-188011</other_name>
    <other_name>LY188011</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically-confirmed advanced solid tumor with measurable disease by Response&#xD;
             Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 criteria, for which&#xD;
             cisplatin-based therapy would be considered appropriate, including:&#xD;
&#xD;
               -  Non-small cell lung cancer (NSCLC)&#xD;
&#xD;
               -  UC&#xD;
&#xD;
               -  Penile cancer&#xD;
&#xD;
               -  Malignant pleural mesothelioma&#xD;
&#xD;
               -  Small cell lung cancer&#xD;
&#xD;
               -  Biliary tract cancer&#xD;
&#xD;
               -  Esophageal and gastric cancers&#xD;
&#xD;
               -  Ovarian cancer&#xD;
&#xD;
               -  Endometrial cancer&#xD;
&#xD;
               -  Cervical cancer&#xD;
&#xD;
               -  Head and neck cancer&#xD;
&#xD;
               -  Triple-negative breast cancer (Her2/neu-negative, estrogen receptor&#xD;
                  [ER]/progesterone receptor [PR]-negative breast cancer)&#xD;
&#xD;
          -  For the expansion cohort of the triplet combination at MTD/RP2D only:&#xD;
&#xD;
               -  Patients with histologically confirmed advanced or unresectable urothelial&#xD;
                  carcinoma are eligible&#xD;
&#xD;
               -  The histology should be predominantly urothelial (&gt;= 50% of sample evaluated&#xD;
                  contains urothelial histology)&#xD;
&#xD;
          -  Age &gt;= 18 years. Because no dosing or adverse event data are currently available on&#xD;
             the use of BAY 1895344 in combination with gemcitabine and cisplatin in patients &lt; 18&#xD;
             years of age, children are excluded from this study&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status =&lt; 2 (Karnofsky &gt;= 60%)&#xD;
&#xD;
          -  Availability of archival FFPE tissue&#xD;
&#xD;
          -  Prior cisplatin exposure of &lt; 300 mg/m^2. Patients with prior cisplatin treatment must&#xD;
             have received last cisplatin treatment &gt; 6 months prior to enrollment&#xD;
&#xD;
          -  Prior treatment with PARP inhibitors is permitted (such as olaparib, rucaparib, or&#xD;
             other experimental inhibitors of PARP administered in a clinical trial)&#xD;
&#xD;
          -  Prior immune checkpoint inhibitor therapy is permitted (including anti-programmed cell&#xD;
             death protein 1 [PD-1], anti-PD-ligand [L]1 therapy, such as pembrolizumab, nivolumab,&#xD;
             avelumab, durvalumab, atezolizumab, or anti-cytotoxic t-lymphocyte protein 4 [CTLA4]&#xD;
             therapy such as ipilimumab, or other experimental immune checkpoint pathway inhibitors&#xD;
             administered in a clinical trial)&#xD;
&#xD;
          -  Leukocytes &gt;= 3,000/mcL&#xD;
&#xD;
          -  Hemoglobin &gt;= 9 g/dL&#xD;
&#xD;
          -  Neutrophil count &gt;= 1,500/mcL&#xD;
&#xD;
          -  Platelets &gt;= 100,000/mcL&#xD;
&#xD;
          -  Total bilirubin =&lt; 2 mg/dL&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase&#xD;
             [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =&lt;&#xD;
             3 x institutional upper limit of normal (ULN)&#xD;
&#xD;
          -  Creatinine clearance &gt;= 40 mL/min OR glomerular filtration rate (GFR) &gt;= 40&#xD;
             mL/min/1.73 m^2 unless data exists supporting safe use at lower kidney function&#xD;
             values, no lower than 30 mL/min/1.73 m^2&#xD;
&#xD;
          -  Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral&#xD;
             therapy with undetectable viral load within 6 months are eligible for this trial&#xD;
&#xD;
          -  For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral&#xD;
             load must be undetectable on suppressive therapy, if indicated&#xD;
&#xD;
          -  Patients with a history of hepatitis C virus (HCV) infection must have been treated&#xD;
             and cured. For patients with HCV infection who are currently on treatment, they are&#xD;
             eligible if they have an undetectable HCV viral load.&#xD;
&#xD;
          -  Patients with treated brain metastases are eligible if follow-up brain imaging after&#xD;
             central nervous system (CNS)-directed therapy shows no evidence of progression&#xD;
&#xD;
          -  Patients with new or progressive brain metastases (active brain metastases) or&#xD;
             leptomeningeal disease are eligible if the treating physician determines that&#xD;
             immediate CNS specific treatment is not required and is unlikely to be required during&#xD;
             the first cycle of therapy; patients with stable brain metastases that are&#xD;
             asymptomatic and on a stable dose of steroids are also considered eligible&#xD;
&#xD;
          -  Patients with known history or current symptoms of cardiac disease, or history of&#xD;
             treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac&#xD;
             function using the New York Heart Association Functional classification. To be&#xD;
             eligible for this trial, patients should be class 2B or better&#xD;
&#xD;
          -  The effects of BAY 1895344, cisplatin, and gemcitabine on the developing human fetus&#xD;
             are unknown. For this reason and because deoxyribonucleic acid (DNA)-damage response&#xD;
             inhibitors agents as well as other therapeutic agents used in this trial are known to&#xD;
             be teratogenic, women of child-bearing potential and men must agree to use adequate&#xD;
             contraception (hormonal or barrier method of birth control; abstinence) prior to study&#xD;
             entry and for the duration of study participation and for 6 months after completion of&#xD;
             BAY 1895344 administration. Should a woman become pregnant or suspect she is pregnant&#xD;
             while she or her partner is participating in this study, she should inform her&#xD;
             treating physician immediately. Men treated or enrolled on this protocol must also&#xD;
             agree to use adequate contraception prior to the study, for the duration of study&#xD;
             participation, and 6 months after completion of BAY 1895344 administration&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Life expectancy &lt; 6 weeks by investigator assessment&#xD;
&#xD;
          -  Other active malignancy requiring treatment, except for cutaneous malignancies that&#xD;
             require resection such as squamous cell carcinoma, basal cell carcinoma, or cutaneous&#xD;
             melanoma, and except for prostate cancer if only on androgen deprivation therapy&#xD;
&#xD;
          -  Significant peripheral neuropathy (grade 2 or higher by Common Terminology Criteria&#xD;
             for Adverse Events [CTCAE])&#xD;
&#xD;
          -  Sensorineural hearing loss (grade 2 or higher by CTCAE)&#xD;
&#xD;
          -  Must NOT have had prior treatment with ATR inhibitor (prior BAY1895344 or other&#xD;
             investigational ATR inhibitors), or current treatment with any other investigational&#xD;
             agents&#xD;
&#xD;
          -  Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for&#xD;
             nitrosoureas or mitomycin C) prior to entering the study. Patients who have targeted&#xD;
             therapies (such as PARP inhibitors) within 2 weeks prior to entering the study&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to BAY 1895344 or other agents used in study&#xD;
&#xD;
          -  Patients receiving any medications that are substrates of CYP3A4 with a narrow&#xD;
             therapeutic window, or strong inhibitors/inducers of CYP3A4 are ineligible, if they&#xD;
             cannot be transferred to alternative medication. Because the lists of these agents are&#xD;
             constantly changing, it is important to regularly consult a frequently-updated medical&#xD;
             reference. As part of the enrollment/informed consent procedures, the patient will be&#xD;
             counseled on the risk of interactions with other agents, and what to do if new&#xD;
             medications need to be prescribed or if the patient is considering a new&#xD;
             over-the-counter medicine or herbal product&#xD;
&#xD;
          -  Patients with uncontrolled intercurrent illness&#xD;
&#xD;
          -  Patients with psychiatric illness/social situations that would limit compliance with&#xD;
             study requirements&#xD;
&#xD;
          -  Pregnant women are excluded from this study because BAY 1895344 as a DNA-damage&#xD;
             response inhibitor, cisplatin, and gemcitabine may have the potential for teratogenic&#xD;
             or abortifacient effects. Because there is an unknown but potential risk for adverse&#xD;
             events in nursing infants secondary to treatment of the mother with BAY 1895344&#xD;
             breastfeeding should be discontinued if the mother is treated with BAY 1895344 and for&#xD;
             4 months after end of treatment. These potential risks may also apply to other agents&#xD;
             used in this study&#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>Mamta Parikh</last_name>
    <role>Principal Investigator</role>
    <affiliation>City of Hope Comprehensive Cancer Center LAO</affiliation>
  </overall_official>
  <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>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>916-734-3089</phone>
    </contact>
    <investigator>
      <last_name>Mamta Parikh</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>National Cancer Institute Developmental Therapeutics Clinic</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>800-411-1222</phone>
    </contact>
    <investigator>
      <last_name>Naoko Takebe</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>National Institutes of Health Clinical Center</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>800-411-1222</phone>
    </contact>
    <investigator>
      <last_name>Naoko Takebe</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Suspended</status>
  </location>
  <location>
    <facility>
      <name>Ohio State University Comprehensive Cancer Center</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>800-293-5066</phone>
      <email>Jamesline@osumc.edu</email>
    </contact>
    <investigator>
      <last_name>J. P. Monk</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </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>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>412-647-8073</phone>
    </contact>
    <investigator>
      <last_name>Leonard J. Appleman</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Wisconsin Carbone Cancer Center</name>
      <address>
        <city>Madison</city>
        <state>Wisconsin</state>
        <zip>53792</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>800-622-8922</phone>
    </contact>
    <investigator>
      <last_name>Hamid Emamekhoo</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University Health Network-Princess Margaret Hospital</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 2M9</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>416-946-4501</phone>
      <email>clinical.trials@uhn.on.ca</email>
    </contact>
    <investigator>
      <last_name>Philippe L. Bedard</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Canada</country>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>July 29, 2020</study_first_submitted>
  <study_first_submitted_qc>July 29, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 30, 2020</study_first_posted>
  <last_update_submitted>August 8, 2023</last_update_submitted>
  <last_update_submitted_qc>August 8, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 9, 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>Breast Neoplasms</mesh_term>
    <mesh_term>Lung Neoplasms</mesh_term>
    <mesh_term>Ovarian Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Ovarian Epithelial</mesh_term>
    <mesh_term>Stomach Neoplasms</mesh_term>
    <mesh_term>Uterine Cervical Neoplasms</mesh_term>
    <mesh_term>Mesothelioma</mesh_term>
    <mesh_term>Mesothelioma, Malignant</mesh_term>
    <mesh_term>Carcinoma, Transitional Cell</mesh_term>
    <mesh_term>Endometrial Neoplasms</mesh_term>
    <mesh_term>Bile Duct Neoplasms</mesh_term>
    <mesh_term>Cholangiocarcinoma</mesh_term>
    <mesh_term>Esophageal Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Non-Small-Cell Lung</mesh_term>
    <mesh_term>Carcinoma, Small Cell</mesh_term>
    <mesh_term>Small Cell Lung Carcinoma</mesh_term>
    <mesh_term>Penile 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>Yes</sharing_ipd>
    <ipd_description>NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.</ipd_description>
    <ipd_url>https://grants.nih.gov/policy/sharing.htm</ipd_url>
  </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/NCT04491942
org study id: NCI-2020-05428
secondary id: NCI-2020-05428
secondary id: PHI-117
secondary id: 10404
secondary id: 10404
secondary id: UM1CA186717
nct id: NCT04491942
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This phase I trial identifies the best dose, possible benefits and/or side effects of BAY
      1895344 in combination with chemotherapy in treating patients with solid tumors or urothelial
      cancer that has spread to other places in the body (advanced). BAY 1895344 may stop the
      growth of tumor cells by blocking some of the enzymes needed for cell growth. Cisplatin and
      gemcitabine are chemotherapy drugs that stop the growth of tumor cells by killing the cells.
      Combining BAY 1895344 with chemotherapy treatment (cisplatin, or cisplatin and gemcitabine)
      may be effective for the treatment of advanced solid tumors, including urothelial cancer.
PRIMARY OBJECTIVES:

      I. To establish the safety and tolerability of the combination of cisplatin + elimusertib
      (BAY 1895344) in patients with advanced solid tumors.

      II. To establish the safety and tolerability of the combination of cisplatin + gemcitabine +
      BAY 1895344 in patients with advanced solid tumors with an emphasis on urothelial carcinoma
      (UC).

      III. To establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of
      cisplatin + BAY 1895344 and cisplatin + gemcitabine + BAY 1895344.

      SECONDARY OBJECTIVES:

      I. To evaluate the pharmacokinetic profile of BAY 1895344 (in the doublet and triplet
      combinations) and gemcitabine (in the triplet) in combination with cisplatin.

      II. To further evaluate the toxicity of the combination of cisplatin + gemcitabine + BAY
      1895344 in patients with UC.

      III. To evaluate preliminary efficacy observed with cisplatin + BAY 1895344 and cisplatin +
      gemcitabine + BAY 1895344 in patients with advanced solid tumors, including UC.

      IV. To monitor for tumor response and symptom relief in addition to safety and tolerability.

      V. To evaluate the association between ATM expression by immunohistochemical staining and
      responses to therapy.

      EXPLORATORY OBJECTIVES:

      I. To evaluate the correlation of biomarkers, including deleterious deoxyribonucleic acid
      (DNA) damage response (DDR) gene alterations and circulating tumor (ct)DNA with responses to
      therapy using whole exome sequencing (WES) and messenger ribonucleic acid sequencing (RNA
      seq) analysis of archival formalin fixed paraffin embedded (FFPE) tissue, as well as blood.

      II. To correlate drug exposure with response and/or toxicity.

      OUTLINE: This is a dose-escalation study of elimusertib. Patients are assigned to 1 of 2
      arms.

      ARM I (DOUBLET COMBINATION): Patients receive cisplatin intravenously (IV) over 1-2 hours on
      day 1 and 8, and elimusertib orally (PO) once daily (QD) on days 2 and 9. Treatment repeats
      every 21 days for up to 6 cycles in the absence of disease progression or unacceptable
      toxicity.

      ARM II (TRIPLET COMBINATION): Patients receive cisplatin IV over 1-2 hours on day 1 and 8,
      gemcitabine IV over 30 minutes on days 1 and 8, and elimusertib PO QD on days 2 and 9.
      Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days, then every 3 months
      thereafter.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Incidence of adverse events
time frame: Up to 28 days after completion of study treatment
description: Toxicities will be tabulated and reported according to dose level, grade, type, cycle, and attribution. Tables will be created to summarize these toxicities and side effects, overall and by cohort. Proportions and associated 95% confidence intervals will be calculated for each cohort separately. Cumulative incidence curves will be used to estimate the proportion of patients who will discontinue therapy for reasons of toxicity or general inability to tolerate the regimen.
measure: Recommended phase 2 dose (RP2D) of BAY 1895344
time frame: Up to 21 days from treatment start date
measure: Pharmacokinetic (PK) parameter - maximum concentration (Cmax)
time frame: Day 2 and day 9 after treatment start date
description: Estimated using non-compartmental methods. The PK variables will be tabulated and descriptive statistics (e.g., geometric means and coefficients of variation) calculated for each dose level. PK parameters will be reported descriptively for exploratory comparison with historical data (gemcitabine).
measure: PK parameter - area under the concentration-time curve (AUC)
time frame: Day 2 and day 9 after treatment start date
description: Estimated using non-compartmental methods. The PK variables will be tabulated and descriptive statistics (e.g., geometric means and coefficients of variation) calculated for each dose level. PK parameters will be reported descriptively for exploratory comparison with historical data (gemcitabine). The impact of cisplatin on BAY 1895344 exposure will be evaluated by calculation of the AUC ratio of (day 9 / day 2) and testing non-parametrically with a null hypothesis of a ratio = 1.
measure: Deoxyribonucleic acid (DNA) damage repair (DDR) mutations
time frame: Up to 2 years
description: The association between DDR mutations and responses will be described, with a table outlining patients who achieved by progressive disease, stable disease, partial or complete responses and DDR mutation status.
measure: ATM expression
time frame: Up to 2 years
description: The association between ATM and responses will be described, with a table outlining patients who achieved progressive disease, stable disease, partial or complete responses and whether they exhibited ATM expression by immunohistochemistry (IHC) or not.
measure: Response rate
time frame: Up to 2 years
description: The percent of responders will be calculated and associated exact 95% confidence intervals will be constructed.
measure: Progression-free survival (PFS)
time frame: Up to 2 years
description: Kaplan-Meier plots will be used to summarize PFS.
arm group label: Arm I (cisplatin, elimusertib)
arm group type: Experimental
description: Patients receive cisplatin IV over 1-2 hours on day 1 and 8, and elimusertib PO QD on days 2 and 9. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
arm group label: Arm II (cisplatin, gemcitabine, elimusertib)
arm group type: Experimental
description: Patients receive cisplatin IV over 1-2 hours on day 1 and 8, gemcitabine IV over 30 minutes on days 1 and 8, and elimusertib PO QD on days 2 and 9. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
intervention type: Drug
intervention name: Cisplatin
description: Given IV
arm group label: Arm I (cisplatin, elimusertib)
arm group label: Arm II (cisplatin, gemcitabine, elimusertib)
other name: Abiplatin
other name: Blastolem
other name: Briplatin
other name: CDDP
other name: Cis-diammine-dichloroplatinum
other name: Cis-diamminedichloridoplatinum
other name: Cis-diamminedichloro Platinum (II)
other name: Cis-diamminedichloroplatinum
other name: Cis-dichloroammine Platinum (II)
other name: Cis-platinous Diamine Dichloride
other name: Cis-platinum
other name: Cis-platinum II
other name: Cis-platinum II Diamine Dichloride
other name: Cismaplat
other name: Cisplatina
other name: Cisplatinum
other name: Cisplatyl
other name: Citoplatino
other name: Citosin
other name: Cysplatyna
other name: DDP
other name: Lederplatin
other name: Metaplatin
other name: Neoplatin
other name: Peyrone's Chloride
other name: Peyrone's Salt
other name: Placis
other name: Plastistil
other name: Platamine
other name: Platiblastin
other name: Platiblastin-S
other name: Platinex
other name: Platinol
other name: Platinol- AQ
other name: Platinol-AQ
other name: Platinol-AQ VHA Plus
other name: Platinoxan
other name: Platinum
other name: Platinum Diamminodichloride
other name: Platiran
other name: Platistin
other name: Platosin
intervention type: Drug
intervention name: Elimusertib
description: Given PO
arm group label: Arm I (cisplatin, elimusertib)
arm group label: Arm II (cisplatin, gemcitabine, elimusertib)
other name: ATR Inhibitor BAY1895344
other name: ATR Kinase Inhibitor BAY1895344
other name: BAY 1895344
other name: BAY-1895344
other name: BAY1895344
intervention type: Drug
intervention name: Gemcitabine Hydrochloride
description: Given IV
arm group label: Arm II (cisplatin, gemcitabine, elimusertib)
other name: dFdCyd
other name: Difluorodeoxycytidine Hydrochloride
other name: Gemcitabine HCI
other name: Gemzar
other name: LY-188011
other name: LY188011
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Mamta Parikh
role: Principal Investigator
affiliation: City of Hope Comprehensive Cancer Center LAO
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Suspended
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
country: Canada
country: United States
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Breast Neoplasms
mesh term: Lung Neoplasms
mesh term: Ovarian Neoplasms
mesh term: Carcinoma, Ovarian Epithelial
mesh term: Stomach Neoplasms
mesh term: Uterine Cervical Neoplasms
mesh term: Mesothelioma
mesh term: Mesothelioma, Malignant
mesh term: Carcinoma, Transitional Cell
mesh term: Endometrial Neoplasms
mesh term: Bile Duct Neoplasms
mesh term: Cholangiocarcinoma
mesh term: Esophageal Neoplasms
mesh term: Carcinoma, Non-Small-Cell Lung
mesh term: Carcinoma, Small Cell
mesh term: Small Cell Lung Carcinoma
mesh term: Penile Neoplasms
mesh term: Cisplatin
mesh term: Gemcitabine
sharing ipd: Yes
ipd description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
ipd url: https://grants.nih.gov/policy/sharing.htm