<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/NCT04493060</url>
  </required_header>
  <id_info>
    <org_study_id>MC1841</org_study_id>
    <secondary_id>NCI-2020-05352</secondary_id>
    <secondary_id>MC1841</secondary_id>
    <nct_id>NCT04493060</nct_id>
  </id_info>
  <brief_title>Niraparib and Dostarlimab for the Treatment of Germline or Somatic BRCA1/2 and PALB2 Mutated Metastatic Pancreatic Cancer</brief_title>
  <official_title>Phase II Study of Niraparib and TSR-042 in Patients With Germline or Somatic BRCA1/2 and PALB2-Related Pancreatic Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Mayo Clinic</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Mayo Clinic</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 phase II trial studies how well niraparib and dostarlimab work in treating patients with&#xD;
      germline or somatic BRCA1/2 and PALB2 mutated pancreatic cancer that has spread to other&#xD;
      places in the body (metastatic). Niraparib may stop the growth of tumor cells by blocking&#xD;
      some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as&#xD;
      dostarlimab, may help the body's immune system attack the cancer, and may interfere with the&#xD;
      ability of tumor cells to grow and spread. Giving niraparib and dostarlimab may kill more&#xD;
      tumor cells.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVE:&#xD;
&#xD;
      I. To determine antitumor activity as measured by disease control rate at 12 weeks (DCR12) as&#xD;
      assessed using immune-modified Response Evaluation Criteria in Solid Tumors (iRECIST) in&#xD;
      select homologous recombination repair (HRR) deficient pancreatic cancer patients with HRR&#xD;
      deficiency (defined as mutations in BRCA 1/ 2, or PALB2).&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To assess adverse events according to the current National Cancer Institute (NCI) Common&#xD;
      Terminology Criteria for Adverse Events (CTCAE) and other safety parameters.&#xD;
&#xD;
      II. To assess the time to next treatment (TTNT), objective response rate (ORR), time to and&#xD;
      duration of response and duration of confirmed stable disease according to iRECIST.&#xD;
&#xD;
      III. To assess progression-free survival. IV. To assess overall survival.&#xD;
&#xD;
      CORRELATIVE RESEARCH OBJECTIVES:&#xD;
&#xD;
      I. To assess germline deoxyribonucleic acid (DNA) and serum markers of immune response.&#xD;
&#xD;
      II. To determine changes in circulating tumor DNA (ctDNA) profile after therapy with a PARP&#xD;
      inhibitor (i) and a PD-1 inhibitor.&#xD;
&#xD;
      III. To study mechanisms of resistance in ctDNA profile after therapy with a PARPi and a PD-1&#xD;
      inhibitor.&#xD;
&#xD;
      IV. To assess the tumor microenvironment for immune related changes (immune infiltration,&#xD;
      PD-L1 and PD-1 expression, tumor-infiltrating lymphocytes [TIL]).&#xD;
&#xD;
      V. To assess genetic profile of the tumor pre- and post-treatment. VI. To determine changes&#xD;
      in the cytokine profile pre- and post-treatment.&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      Patients receive niraparib orally (PO) once daily (QD) on days 1-21. Patients also receive&#xD;
      dostarlimab intravenously (IV) over 30 minutes on day 1 every 3 weeks (Q3W) for cycles 1-4&#xD;
      and every 6 weeks (Q6W) for subsequent cycles. Cycles repeat every 21 days for up to 2 years&#xD;
      in the absence of disease progression or unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up at 30 days, every 3 months&#xD;
      until progressive disease (PD), and then every 6 months for up to 5 years after registration.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">December 28, 2020</start_date>
  <completion_date type="Anticipated">September 1, 2024</completion_date>
  <primary_completion_date type="Anticipated">September 1, 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Disease control rate at 12 weeks (DCR12)</measure>
    <time_frame>At 12 weeks</time_frame>
    <description>Will be assessed using the standard immune-modified Response Evaluation Criteria in Solid Tumors (iRECIST) criteria.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Objective response rate (ORR)</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>The confirmed response rate (by iRECIST ) will be assessed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to next treatment (TTNT)</measure>
    <time_frame>From the end of study treatment to receiving the next treatment, assessed up to 5 years</time_frame>
    <description>TTNT will be estimated using the Kaplan-Meier method.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>From study entry to death from any cause, assessed up to 5 years</time_frame>
    <description>OS will be estimated using the Kaplan-Meier method.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to and duration of confirmed response</measure>
    <time_frame>From the first documented date of confirmed response (complete response [CR] or partial response [PR]) to the date at which progression is first documented, assessed up to 5 years</time_frame>
    <description>Will be assessed using the Kaplan-Meier method.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS)</measure>
    <time_frame>From study entry to the first of either disease progression or death from any cause, assessed up to 5 years</time_frame>
    <description>PFS will be estimated using the Kaplan-Meier method.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of adverse events (AEs)</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>The maximum grade for each type of adverse event will be summarized using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The frequency and percentage of grade 3+ adverse events will be estimated. Will also assess AEs at least possibly related to treatment as well.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Germline deoxyribonucleic acid (DNA) and serum markers of immune response</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>Due to the limited sample size, these analyses will be hypothesis generating and descriptive in nature. Descriptive statistics will be summarized and the blood and tissue marker data will be correlated with clinical endpoints (response, DCR12, duration of response, OS, PFS, adverse events, etc.). For time-to-event data, the Kaplan-Meier method will be used. For categorical data, will use the Fisher's exact test. For marker data used to predict binary outcomes (i.e. response versus [vs]. no response), will use logistic regression models.</description>
  </other_outcome>
  <other_outcome>
    <measure>Changes in circulating tumor DNA (ctDNA) profile after therapy with a PARP inhibitor (i) and a PD-1 inhibitor</measure>
    <time_frame>Baseline up to 5 years</time_frame>
    <description>Due to the limited sample size, these analyses will be hypothesis generating and descriptive in nature. Descriptive statistics will be summarized and the blood and tissue marker data will be correlated with clinical endpoints (response, DCR12, duration of response, OS, PFS, adverse events, etc.). For time-to-event data, the Kaplan-Meier method will be used. For categorical data, will use the Fisher's exact test. For marker data used to predict binary outcomes (i.e. response vs. no response), will use logistic regression models.</description>
  </other_outcome>
  <other_outcome>
    <measure>Mechanisms of resistance in ctDNA profile after therapy with a PARPi and a PD-1 inhibitor</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>Due to the limited sample size, these analyses will be hypothesis generating and descriptive in nature. Descriptive statistics will be summarized and the blood and tissue marker data will be correlated with clinical endpoints (response, DCR12, duration of response, OS, PFS, adverse events, etc.). For time-to-event data, the Kaplan-Meier method will be used. For categorical data, will use the Fisher's exact test. For marker data used to predict binary outcomes (i.e. response vs. no response), will use logistic regression models.</description>
  </other_outcome>
  <other_outcome>
    <measure>Tumor microenvironment for immune related changes (immune infiltration, PD-L1 and PD-1 expression, tumor-infiltrating lymphocytes)</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>Due to the limited sample size, these analyses will be hypothesis generating and descriptive in nature. Descriptive statistics will be summarized and the blood and tissue marker data will be correlated with clinical endpoints (response, DCR12, duration of response, OS, PFS, adverse events, etc.). For time-to-event data, the Kaplan-Meier method will be used. For categorical data, will use the Fisher's exact test. For marker data used to predict binary outcomes (i.e. response vs. no response), will use logistic regression models.</description>
  </other_outcome>
  <other_outcome>
    <measure>Genetic profile of the tumor pre- and post-treatment</measure>
    <time_frame>Baseline up to 5 years</time_frame>
    <description>Due to the limited sample size, these analyses will be hypothesis generating and descriptive in nature. Descriptive statistics will be summarized and the blood and tissue marker data will be correlated with clinical endpoints (response, DCR12, duration of response, OS, PFS, adverse events, etc.). For time-to-event data, the Kaplan-Meier method will be used. For categorical data, will use the Fisher's exact test. For marker data used to predict binary outcomes (i.e. response vs. no response), will use logistic regression models.</description>
  </other_outcome>
  <other_outcome>
    <measure>Changes in the cytokine profile pre- and post-treatment</measure>
    <time_frame>Baseline up to 5 years</time_frame>
    <description>Due to the limited sample size, these analyses will be hypothesis generating and descriptive in nature. Descriptive statistics will be summarized and the blood and tissue marker data will be correlated with clinical endpoints (response, DCR12, duration of response, OS, PFS, adverse events, etc.). For time-to-event data, the Kaplan-Meier method will be used. For categorical data, will use the Fisher's exact test. For marker data used to predict binary outcomes (i.e. response vs. no response), will use logistic regression models.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>Metastatic Pancreatic Ductal Adenocarcinoma</condition>
  <condition>Stage IV Pancreatic Cancer AJCC v8</condition>
  <arm_group>
    <arm_group_label>Treatment (niraparib, dostarlimab)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive niraparib PO QD on days 1-21. Patients also receive dostarlimab IV over 30 minutes on day 1 Q3W for cycles 1-4 and Q6W for subsequent cycles. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Dostarlimab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (niraparib, dostarlimab)</arm_group_label>
    <other_name>ANB011</other_name>
    <other_name>Immunoglobulin G4, Anti-programmed Cell Death Protein 1 (PDCD1) (Humanized Clone ABT1 Gamma4-chain), Disulfide with Humanized Clone ABT1 Kappa-chain, Dimer</other_name>
    <other_name>TSR 042</other_name>
    <other_name>TSR-042</other_name>
    <other_name>TSR042</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Niraparib</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (niraparib, dostarlimab)</arm_group_label>
    <other_name>MK-4827</other_name>
    <other_name>MK4827</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Presence of either a germline deleterious mutation or somatic deleterious mutation in&#xD;
             any one of the genes in our proposed gene-panel as determined by any of the&#xD;
             commercially available or institutional testing platforms. Note: The somatic mutation&#xD;
             could be either on a tissue-based test or the circulating tumor DNA (ctDNA)-based&#xD;
             assay. The 6 genes that would determine eligibility would be: BRCA1/2, PALB2, BARD1,&#xD;
             RAD51c, RAD51d&#xD;
&#xD;
          -  Provide written informed consent&#xD;
&#xD;
          -  Histological/cytological confirmation of diagnosis of metastatic pancreatic ductal&#xD;
             adenocarcinoma&#xD;
&#xD;
          -  At least one but no more than two prior lines of systemic therapy for metastatic&#xD;
             disease (maintenance therapy is not considered a line of treatment)&#xD;
&#xD;
               -  Note: Patients who have not had any prior chemotherapy can refuse chemotherapy&#xD;
                  and be considered eligible. This refusal and their reason for refusal would have&#xD;
                  to be documented&#xD;
&#xD;
          -  Received a platinum agent as part of first or second line treatment (unless&#xD;
             contraindicated)&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1&#xD;
&#xD;
          -  Serum creatinine =&lt; 1.5 x upper limit of normal (ULN) or estimated glomerular&#xD;
             filtration rate (eGFR) &gt;= 60 mL/min using the Cockcroft-Gault Equation (=&lt; 14 days&#xD;
             prior to registration)&#xD;
&#xD;
          -  Hemoglobin &gt;= 9.0 g/dL (=&lt; 14 days prior to registration)&#xD;
&#xD;
          -  Absolute neutrophil count &gt;= 1500/uL (=&lt; 14 days prior to registration:)&#xD;
&#xD;
          -  Platelets &gt;= 100 x 10^9/L (=&lt; 14 days prior to registration)&#xD;
&#xD;
          -  Total bilirubin =&lt; 1.5 x ULN, (2.0 x ULN for subjects with Gilbert's disease) (=&lt; 14&#xD;
             days prior to registration:)&#xD;
&#xD;
          -  Aspartate transaminase (AST) and alanine transaminase (ALT) =&lt; 2.5 x ULN (for subjects&#xD;
             with hepatic metastases =&lt; 5 x ULN) (=&lt; 14 days prior to registration). Note: One time&#xD;
             repeat testing to meet eligibility is allowed. If more testing is required, discuss&#xD;
             with principal investigator (PI)&#xD;
&#xD;
          -  International normalized ratio (INR) or prothrombin time (PT) =&lt; 1.5 x ULN unless&#xD;
             patient is receiving anticoagulant therapy as long as PT or partial thromboplastin&#xD;
             (PTT) is within therapeutic range of intended use of anticoagulants. Activated partial&#xD;
             thromboplastin time (aPTT) =&lt; 1.5 x ULN unless patient is receiving anticoagulant&#xD;
             therapy as long as PT or PTT is within therapeutic range of intended use of&#xD;
             anticoagulants (=&lt; 14 days prior to registration)&#xD;
&#xD;
          -  Evaluable or measurable disease per iRECIST&#xD;
&#xD;
          -  Life expectancy of &gt;= 3 months&#xD;
&#xD;
          -  Willingness to consent to translational studies&#xD;
&#xD;
          -  Willingness to undergo repeat biopsies of tumor lesions amenable to biopsy&#xD;
&#xD;
               -  Note: While biopsies are mandatory, subjects are allowed to participate if no&#xD;
                  lesions are amenable to biopsy, or if biopsy is not possible due to safety&#xD;
&#xD;
          -  Willingness to not donate blood during the study or for 90 days after the last dose of&#xD;
             study treatment&#xD;
&#xD;
          -  Willingness to not breastfeed during the study or for 90 days after the last dose of&#xD;
             study treatment&#xD;
&#xD;
          -  Negative pregnancy test done =&lt; 7 days prior to registration, for persons of&#xD;
             childbearing potential only&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Known hypersensitivity to any component of study treatments (either niraparib and/or&#xD;
             TSR-042 or similar medications)&#xD;
&#xD;
          -  Prior treatment with the combination of PARP inhibition and immunotherapy (either&#xD;
             CTLA-4 or anti-PD1/PD-L1 therapies). Prior treatment consisting of monotherapy with&#xD;
             either PARP inhibitors and/or with immunotherapy are allowed. Treatment with PARPi or&#xD;
             PD1 inhibitor as the most recent treatment prior to enrollment is not allowed&#xD;
&#xD;
          -  Patient experienced &gt;= grade 3 immune-related adverse events (AE) with prior&#xD;
             immunotherapy, with the exception of non-clinically significant lab abnormalities&#xD;
&#xD;
          -  Radiotherapy =&lt; 2 weeks prior to first study treatment or radionuclide treatment =&lt; 4&#xD;
             weeks of first study treatment&#xD;
&#xD;
          -  Live attenuated vaccine administration within 30 days prior to registration and/or&#xD;
             expected during study period&#xD;
&#xD;
          -  Known brain metastases, uncontrolled seizure disorder, or active neurologic disease&#xD;
             which in the opinion of the investigator would impede participation within the trial.&#xD;
             Subjects with treated brain metastases are allowed to enroll&#xD;
&#xD;
          -  Allogeneic bone marrow transplantation or high-dose chemotherapy requiring&#xD;
             hematopoietic stem cell rescue&#xD;
&#xD;
          -  Received a transfusion (platelets or red blood cells) =&lt; 4 weeks prior to registration&#xD;
&#xD;
               -  NOTE: patients are also deemed ineligible if they have received a transfusion =&lt;&#xD;
                  4 weeks prior to first dose of niraparib&#xD;
&#xD;
          -  Received colony-stimulating factors (e.g., granulocyte colony-stimulating factor,&#xD;
             granulocyte macrophage colony-stimulating factor, or recombinant erythropoietin) =&lt; 4&#xD;
             weeks prior to registration&#xD;
&#xD;
               -  NOTE: patients are also deemed ineligible if they have received&#xD;
                  colony-stimulating factors =&lt; 4 weeks prior to first dose of niraparib&#xD;
&#xD;
          -  Known grade 3 or 4 anemia, neutropenia or thrombocytopenia due to prior chemotherapy&#xD;
             that persisted &gt; 4 weeks and was related to the most recent treatment&#xD;
&#xD;
          -  Known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)&#xD;
&#xD;
          -  =&lt; 4 weeks since receiving treatment with another investigational drug, or anti-cancer&#xD;
             therapy, or within a time interval less than at least 5 half-lives of the&#xD;
             investigational agent (whichever is shorter), or insufficient recovery (to the&#xD;
             judgement of the investigator) from adverse events due to such a previously&#xD;
             administered agent, except for alopecia prior to initiating protocol therapy.&#xD;
             Bisphosphonate therapy and receptor activator of nuclear factor kappa-Β ligand (RANKL)&#xD;
             inhibitors are not considered anti-cancer therapy&#xD;
&#xD;
          -  Inadequate recovery from toxicity and/or complications from previous interventions,&#xD;
             including due to major surgery to the judgement of the investigator. Minor surgery&#xD;
             allowed up to 3 weeks from registration&#xD;
&#xD;
          -  Primary or secondary immunodeficiency, including immunosuppressive disease, and&#xD;
             immunosuppressive doses of corticosteroids (e.g., prednisone &gt; 20 mg per day during 2&#xD;
             weeks prior to first study treatment) or other immunosuppressive medications at dose&#xD;
             levels that to the judgement of the investigator would preclude participation within&#xD;
             the past 4 weeks prior to registration. Subjects with human immunodeficiency virus&#xD;
             (HIV) who are stable on highly active antiretroviral therapy (HAART) will not be&#xD;
             excluded&#xD;
&#xD;
          -  Participant has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg]&#xD;
             reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [qualitative]&#xD;
             is detected)&#xD;
&#xD;
          -  Pregnant or lactating&#xD;
&#xD;
          -  Clinically significant, active, bacterial infections that, to the judgement of the&#xD;
             investigator makes it undesirable for the subject to participate in the study&#xD;
&#xD;
          -  Persons of childbearing potential (POCBP) or those capable of causing pregnancy whose&#xD;
             sexual partners are POCBP who are unwilling or unable to use an effective method of&#xD;
             contraception for at least 1 month prior to study entry, for the duration of the&#xD;
             study, and for at least 180 days after the last dose of study drug. Nonchildbearing&#xD;
             potential is defined as follows (by other than medical reasons):&#xD;
&#xD;
               -  &gt;= 45 years of age and has not had menses for &gt; 1 year&#xD;
&#xD;
               -  Patients who have been amenorrhoeic for &lt; 2 years without history of a&#xD;
                  hysterectomy and oophorectomy must have a follicle stimulating hormone value in&#xD;
                  the postmenopausal range upon screening evaluation&#xD;
&#xD;
               -  Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation.&#xD;
                  Documented hysterectomy or oophorectomy must be confirmed with medical records of&#xD;
                  the actual procedure or confirmed by an ultrasound. Tubal ligation must be&#xD;
                  confirmed with medical records of the actual procedure, otherwise the patient&#xD;
                  must be willing to use an adequate barrier method throughout the study, starting&#xD;
                  with the screening visit through 180 days after the last dose of study treatment.&#xD;
                  Information must be captured appropriately within the site's source documents.&#xD;
                  Note: Abstinence is acceptable if this is the established and preferred&#xD;
                  contraception for the patient&#xD;
&#xD;
          -  History or active TB (Bacillus tuberculosis) that in the investigators opinion would&#xD;
             preclude participation within the study&#xD;
&#xD;
          -  Any gastro-intestinal conditions that to the judgement of the investigator would&#xD;
             interfere with the absorption of niraparib&#xD;
&#xD;
          -  Active, known or suspected unstable auto-immune disease, are excluded from this study.&#xD;
             Exceptions to this criterion are all auto-immune disease that have remained stable&#xD;
             within the past 3 months on corticosteroids (=&lt; prednisone 20 mg or equivalent) prior&#xD;
             to first study treatment are allowed to enroll. Patients with autoimmune diseases that&#xD;
             do not require active immunosuppression are also allowed to enroll&#xD;
&#xD;
               -  Note: Paraneoplastic disease as a cause of auto-immune phenomenon will not be&#xD;
                  considered as auto-immune disease and are allowed to enroll&#xD;
&#xD;
          -  Evidence of serious uncontrolled medical disorder, active infection or mental disorder&#xD;
             that, to the judgement of the investigator, makes it undesirable for the subject to&#xD;
             participate in the study or that would jeopardize compliance with the protocol.&#xD;
             Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent&#xD;
             (within 90 days) myocardial infarction, uncontrolled major seizure disorder, unstable&#xD;
             spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that&#xD;
             prohibits obtaining informed consent&#xD;
&#xD;
          -  Prior malignancy which required active systemic treatment within 2 years prior to&#xD;
             first study treatment. Exceptions are: successfully treated squamous cell carcinoma of&#xD;
             the skin, superficial bladder cancer, and in situ carcinoma of the cervix. Since&#xD;
             patients with BRCA 1/2 or PALB2 can have other tumors, as long as they have been&#xD;
             definitively treated, it would not be considered an exclusion&#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>Robert R McWilliams</last_name>
    <role>Principal Investigator</role>
    <affiliation>Mayo Clinic in Rochester</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Mayo Clinic in Arizona</name>
      <address>
        <city>Scottsdale</city>
        <state>Arizona</state>
        <zip>85259</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Clinical Trials Referral Office</last_name>
      <phone>855-776-0015</phone>
      <email>mayocliniccancerstudies@mayo.edu</email>
    </contact>
    <investigator>
      <last_name>Daniel H. Ahn, M.D.</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic in Florida</name>
      <address>
        <city>Jacksonville</city>
        <state>Florida</state>
        <zip>32224-9980</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Clinical Trials Referral Office</last_name>
      <phone>855-776-0015</phone>
      <email>mayocliniccancerstudies@mayo.edu</email>
    </contact>
    <investigator>
      <last_name>Hani M. Babiker, M.D.</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic in Rochester</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Clinical Trials Refeffal Office</last_name>
      <phone>855-776-0015</phone>
      <email>mayocliniccancerstudies@mayo.edu</email>
    </contact>
    <investigator>
      <last_name>Robert R. McWilliams, M.D.</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>July 27, 2020</study_first_submitted>
  <study_first_submitted_qc>July 27, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 30, 2020</study_first_posted>
  <last_update_submitted>July 20, 2023</last_update_submitted>
  <last_update_submitted_qc>July 20, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 24, 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>Pancreatic Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Niraparib</mesh_term>
    <mesh_term>Dostarlimab</mesh_term>
    <mesh_term>Immunoglobulins</mesh_term>
    <mesh_term>Immunoglobulin G</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/NCT04493060
org study id: MC1841
secondary id: NCI-2020-05352
secondary id: MC1841
nct id: NCT04493060
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This phase II trial studies how well niraparib and dostarlimab work in treating patients with
      germline or somatic BRCA1/2 and PALB2 mutated pancreatic cancer that has spread to other
      places in the body (metastatic). Niraparib may stop the growth of tumor cells by blocking
      some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as
      dostarlimab, may help the body's immune system attack the cancer, and may interfere with the
      ability of tumor cells to grow and spread. Giving niraparib and dostarlimab may kill more
      tumor cells.
PRIMARY OBJECTIVE:

      I. To determine antitumor activity as measured by disease control rate at 12 weeks (DCR12) as
      assessed using immune-modified Response Evaluation Criteria in Solid Tumors (iRECIST) in
      select homologous recombination repair (HRR) deficient pancreatic cancer patients with HRR
      deficiency (defined as mutations in BRCA 1/ 2, or PALB2).

      SECONDARY OBJECTIVES:

      I. To assess adverse events according to the current National Cancer Institute (NCI) Common
      Terminology Criteria for Adverse Events (CTCAE) and other safety parameters.

      II. To assess the time to next treatment (TTNT), objective response rate (ORR), time to and
      duration of response and duration of confirmed stable disease according to iRECIST.

      III. To assess progression-free survival. IV. To assess overall survival.

      CORRELATIVE RESEARCH OBJECTIVES:

      I. To assess germline deoxyribonucleic acid (DNA) and serum markers of immune response.

      II. To determine changes in circulating tumor DNA (ctDNA) profile after therapy with a PARP
      inhibitor (i) and a PD-1 inhibitor.

      III. To study mechanisms of resistance in ctDNA profile after therapy with a PARPi and a PD-1
      inhibitor.

      IV. To assess the tumor microenvironment for immune related changes (immune infiltration,
      PD-L1 and PD-1 expression, tumor-infiltrating lymphocytes [TIL]).

      V. To assess genetic profile of the tumor pre- and post-treatment. VI. To determine changes
      in the cytokine profile pre- and post-treatment.

      OUTLINE:

      Patients receive niraparib orally (PO) once daily (QD) on days 1-21. Patients also receive
      dostarlimab intravenously (IV) over 30 minutes on day 1 every 3 weeks (Q3W) for cycles 1-4
      and every 6 weeks (Q6W) for subsequent cycles. Cycles repeat every 21 days for up to 2 years
      in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days, every 3 months
      until progressive disease (PD), and then every 6 months for up to 5 years after registration.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Disease control rate at 12 weeks (DCR12)
time frame: At 12 weeks
description: Will be assessed using the standard immune-modified Response Evaluation Criteria in Solid Tumors (iRECIST) criteria.
measure: Objective response rate (ORR)
time frame: Up to 5 years
description: The confirmed response rate (by iRECIST ) will be assessed.
measure: Time to next treatment (TTNT)
time frame: From the end of study treatment to receiving the next treatment, assessed up to 5 years
description: TTNT will be estimated using the Kaplan-Meier method.
measure: Overall survival (OS)
time frame: From study entry to death from any cause, assessed up to 5 years
description: OS will be estimated using the Kaplan-Meier method.
measure: Time to and duration of confirmed response
time frame: From the first documented date of confirmed response (complete response [CR] or partial response [PR]) to the date at which progression is first documented, assessed up to 5 years
description: Will be assessed using the Kaplan-Meier method.
measure: Progression-free survival (PFS)
time frame: From study entry to the first of either disease progression or death from any cause, assessed up to 5 years
description: PFS will be estimated using the Kaplan-Meier method.
measure: Incidence of adverse events (AEs)
time frame: Up to 5 years
description: The maximum grade for each type of adverse event will be summarized using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The frequency and percentage of grade 3+ adverse events will be estimated. Will also assess AEs at least possibly related to treatment as well.
measure: Germline deoxyribonucleic acid (DNA) and serum markers of immune response
time frame: Up to 5 years
description: Due to the limited sample size, these analyses will be hypothesis generating and descriptive in nature. Descriptive statistics will be summarized and the blood and tissue marker data will be correlated with clinical endpoints (response, DCR12, duration of response, OS, PFS, adverse events, etc.). For time-to-event data, the Kaplan-Meier method will be used. For categorical data, will use the Fisher's exact test. For marker data used to predict binary outcomes (i.e. response versus [vs]. no response), will use logistic regression models.
measure: Changes in circulating tumor DNA (ctDNA) profile after therapy with a PARP inhibitor (i) and a PD-1 inhibitor
time frame: Baseline up to 5 years
description: Due to the limited sample size, these analyses will be hypothesis generating and descriptive in nature. Descriptive statistics will be summarized and the blood and tissue marker data will be correlated with clinical endpoints (response, DCR12, duration of response, OS, PFS, adverse events, etc.). For time-to-event data, the Kaplan-Meier method will be used. For categorical data, will use the Fisher's exact test. For marker data used to predict binary outcomes (i.e. response vs. no response), will use logistic regression models.
measure: Mechanisms of resistance in ctDNA profile after therapy with a PARPi and a PD-1 inhibitor
time frame: Up to 5 years
description: Due to the limited sample size, these analyses will be hypothesis generating and descriptive in nature. Descriptive statistics will be summarized and the blood and tissue marker data will be correlated with clinical endpoints (response, DCR12, duration of response, OS, PFS, adverse events, etc.). For time-to-event data, the Kaplan-Meier method will be used. For categorical data, will use the Fisher's exact test. For marker data used to predict binary outcomes (i.e. response vs. no response), will use logistic regression models.
measure: Tumor microenvironment for immune related changes (immune infiltration, PD-L1 and PD-1 expression, tumor-infiltrating lymphocytes)
time frame: Up to 5 years
description: Due to the limited sample size, these analyses will be hypothesis generating and descriptive in nature. Descriptive statistics will be summarized and the blood and tissue marker data will be correlated with clinical endpoints (response, DCR12, duration of response, OS, PFS, adverse events, etc.). For time-to-event data, the Kaplan-Meier method will be used. For categorical data, will use the Fisher's exact test. For marker data used to predict binary outcomes (i.e. response vs. no response), will use logistic regression models.
measure: Genetic profile of the tumor pre- and post-treatment
time frame: Baseline up to 5 years
description: Due to the limited sample size, these analyses will be hypothesis generating and descriptive in nature. Descriptive statistics will be summarized and the blood and tissue marker data will be correlated with clinical endpoints (response, DCR12, duration of response, OS, PFS, adverse events, etc.). For time-to-event data, the Kaplan-Meier method will be used. For categorical data, will use the Fisher's exact test. For marker data used to predict binary outcomes (i.e. response vs. no response), will use logistic regression models.
measure: Changes in the cytokine profile pre- and post-treatment
time frame: Baseline up to 5 years
description: Due to the limited sample size, these analyses will be hypothesis generating and descriptive in nature. Descriptive statistics will be summarized and the blood and tissue marker data will be correlated with clinical endpoints (response, DCR12, duration of response, OS, PFS, adverse events, etc.). For time-to-event data, the Kaplan-Meier method will be used. For categorical data, will use the Fisher's exact test. For marker data used to predict binary outcomes (i.e. response vs. no response), will use logistic regression models.
arm group label: Treatment (niraparib, dostarlimab)
arm group type: Experimental
description: Patients receive niraparib PO QD on days 1-21. Patients also receive dostarlimab IV over 30 minutes on day 1 Q3W for cycles 1-4 and Q6W for subsequent cycles. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
intervention type: Biological
intervention name: Dostarlimab
description: Given IV
arm group label: Treatment (niraparib, dostarlimab)
other name: ANB011
other name: Immunoglobulin G4, Anti-programmed Cell Death Protein 1 (PDCD1) (Humanized Clone ABT1 Gamma4-chain), Disulfide with Humanized Clone ABT1 Kappa-chain, Dimer
other name: TSR 042
other name: TSR-042
other name: TSR042
intervention type: Drug
intervention name: Niraparib
description: Given PO
arm group label: Treatment (niraparib, dostarlimab)
other name: MK-4827
other name: MK4827
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Robert R McWilliams
role: Principal Investigator
affiliation: Mayo Clinic in Rochester
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
responsible party type: Sponsor
mesh term: Pancreatic Neoplasms
mesh term: Niraparib
mesh term: Dostarlimab
mesh term: Immunoglobulins
mesh term: Immunoglobulin G