<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/NCT04462328</url>
  </required_header>
  <id_info>
    <org_study_id>202009139</org_study_id>
    <nct_id>NCT04462328</nct_id>
  </id_info>
  <brief_title>Acalabrutinib and Durvalumab in Primary and Secondary Central Nervous System Lymphoma</brief_title>
  <official_title>Phase I Study With Dose Expansion of Acalabrutinib and Durvalumab (MEDI 4736) in Primary and Secondary Central Nervous System Lymphoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Washington University School of Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>AstraZeneca</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Washington University School of Medicine</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      BTK inhibition and checkpoint blockade are promising classes of therapy for central nervous&#xD;
      system (CNS) lymphoma and have demonstrated efficacy with acceptable toxicity. A multidrug&#xD;
      approach may carry a higher chance of durable efficacy in this aggressive disease that&#xD;
      carries significant morbidity and mortality. Given the poor outcomes and limited options for&#xD;
      patients who are not candidates for high-dose methotrexate, the investigators seek to&#xD;
      evaluate the combination in this patient population.&#xD;
&#xD;
      08/30/2022: The study was originally designed for those with primary and secondary central&#xD;
      nervous system (CNS) lymphoma. However, the first three patients who were enrolled all had&#xD;
      secondary CNS lymphoma and most had germinal center phenotype disease with double hit&#xD;
      phenotypes. In these three patients, two dose limiting toxicities were seen including 1&#xD;
      patient with grade 4 neutropenia at the time of disease progression and one with pneumonia in&#xD;
      the setting of disease progression and worsening of existing heart disease. The third patient&#xD;
      came off for clinical progression within cycle 1. Given the lack of response in patients with&#xD;
      secondary CNS lymphomas, who do not exhibit the same biology as primary CNS lymphoma&#xD;
      patients, Amendment 3 updates the study to only include patients with primary CNS lymphomas.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">April 29, 2021</start_date>
  <completion_date type="Anticipated">August 31, 2028</completion_date>
  <primary_completion_date type="Anticipated">September 30, 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>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safe and tolerable dose of regimen</measure>
    <time_frame>Completion of first 12 weeks of treatment within phase I portion of study (estimated to be 14 months)</time_frame>
    <description>Defined as Dose Level 2 if 0 or 1 dose limiting toxicities (DLTs) are seen in patients at that dose level, or Dose Level 1 if 2+ DLTs are seen in Dose Level 2 but only 0 or 1 DLTs are seen in patients at Dose Level 1.&#xD;
A DLT is defined as the occurrence of an adverse event (AE) that is at least possibly related to the investigational product (IP) or investigational regimen (IR)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall response rate (complete response (CR) + partial response (PR))</measure>
    <time_frame>Through completion of treatment (estimated to be 6 months)</time_frame>
    <description>CR is defined as disappearance of all contrast-enhancing CNS (brain and spine if latter abnormal at baseline) disease, absence of any systemic corticosteroids prescribed to treat lymphoma (prophylactic steroid eye drops, topical steroids, corticosteroid antiemetics and steroids prescribed for non-disease reasons [e.g. asthma exacerbation, dermatologic or rheumatologic conditions] are allowed and not considered in the definition of CR), resolution of abnormal ocular findings on ophthalmological examination, negative CSF cytology/flow cytometry.&#xD;
PR is defined as &gt;50% reduction in contrast-enhancing CNS (brain and spine if latter abnormal at baseline) disease either with minor abnormalities on ophthalmological examination or normal ophthalmological examination OR disappearance of all contrast-enhancing CNS (brain and spine if latter abnormal at baseline) but only reduction of vitreous cells or retinal infiltrates or residual suspicious or positive CSF cytology.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response</measure>
    <time_frame>Through 2 years post treatment (estimated to be 2 years and 6 months)</time_frame>
    <description>-The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to response</measure>
    <time_frame>Through completion of treatment (estimated to be 6 months)</time_frame>
    <description>-Time to response is measured from the start of treatment until the time measurement criteria are met for first objective tumor response (CR or PR, whichever is first recorded).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS)</measure>
    <time_frame>Through 2 years post treatment (estimated to be 2 years and 6 months)</time_frame>
    <description>PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.&#xD;
Progressive disease is defined as &gt; 25% increase in contrast-enhancing CNS (brain and spine if latter abnormal at baseline) disease, appearance of any new, measurable (&gt;/= 10mm) contrast-enhancing disease or recurrent or new ocular or CSF disease.&#xD;
Progression free survival will include all patients with at least one response assessment. Patients will be censored for progression free survival and duration of response if alive and without disease progression at completion of follow-up period.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>Until death (estimated to be 5 years and 6 months)</time_frame>
    <description>OS is defined as the duration of time from start of treatment to time of death.&#xD;
All patients who receive treatment on study will be included in overall survival. Patients will be censored for overall survival is alive at last study data collection point (completion of follow-up).</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">21</enrollment>
  <condition>Primary Central Nervous System Lymphoma</condition>
  <arm_group>
    <arm_group_label>Phase I Dose Level 1: Durvalumab + Acalabruitinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Acalabrutinib 100 mg twice per day by mouth on days 1-28&#xD;
Durvalumab 1500 mg intravenous on day 1 of a 28 day cycle</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase I Dose Level 2: Durvalumab + Acalabruitinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Acalabrutinib 200 mg twice per day by mouth on days 1-28&#xD;
Durvalumab 1500 mg intravenous on day 1 of a 28 day cycle</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Expansion Cohort: Durvalumab + Acalabrutinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Acalabrutinib 100 mg or 200 mg (depends on tolerable dose found in Phase I portion of study) twice per day by mouth on days 1-28&#xD;
Durvalumab 1500 mg intravenous on day 1 of a 28 day cycle</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Durvalumab</intervention_name>
    <description>Durvalumab will be administered over 60 minutes</description>
    <arm_group_label>Expansion Cohort: Durvalumab + Acalabrutinib</arm_group_label>
    <arm_group_label>Phase I Dose Level 1: Durvalumab + Acalabruitinib</arm_group_label>
    <arm_group_label>Phase I Dose Level 2: Durvalumab + Acalabruitinib</arm_group_label>
    <other_name>Imfinzi</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Acalabrutinib</intervention_name>
    <description>Patients will take acalabrutinib orally every 12 hours (+/- 3 hours) daily.</description>
    <arm_group_label>Expansion Cohort: Durvalumab + Acalabrutinib</arm_group_label>
    <arm_group_label>Phase I Dose Level 1: Durvalumab + Acalabruitinib</arm_group_label>
    <arm_group_label>Phase I Dose Level 2: Durvalumab + Acalabruitinib</arm_group_label>
    <other_name>Calquence</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically documented primary CNS lymphoma with either:&#xD;
&#xD;
               -  Relapsed or refractory disease with at least 1 prior therapy OR&#xD;
&#xD;
               -  Ineligible for high dose methotrexate based therapy as determined by the treating&#xD;
                  physician, including previously untreated patients. Examples of medical&#xD;
                  conditions that for which a patient could be considered ineligible for high dose&#xD;
                  methotrexate include renal impairment, liver disease, heart failure or having&#xD;
                  ascites or effusions.&#xD;
&#xD;
               -  Patients with leptomeningeal disease only must have been previously treated with&#xD;
                  intrathecal therapy Note: Patients with secondary CNS lymphoma are excluded even&#xD;
                  if the disease is isolated to the CNS.&#xD;
&#xD;
          -  Patients must have evaluable disease. This includes radiographic evidence of&#xD;
             parenchymal disease or leptomeningeal enhancement or thickening, or disease detected&#xD;
             in the CSF.&#xD;
&#xD;
             *Patients with vitreous involvement alone are not eligible.&#xD;
&#xD;
          -  ECOG performance status of 0, 1, or 2. Patients with ECOG performance status of 3 are&#xD;
             permitted if their performance status limitations are due to lymphoma in the opinion&#xD;
             of the treating physician.&#xD;
&#xD;
          -  Participants must have adequate bone marrow and organ function shown by:&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) ≥ 1.0 x 109/L&#xD;
&#xD;
               -  Platelets ≥ 75 x 10^9/L and no platelet transfusion within the past 7 days prior&#xD;
                  to initiation of protocol treatment&#xD;
&#xD;
               -  Prothrombin time (PT), partial thromboplastin time (PTT), and international&#xD;
                  normalized ratio (INR) &lt; 2 times the upper limit of normal&#xD;
&#xD;
               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times&#xD;
                  the upper limit of normal&#xD;
&#xD;
               -  Serum bilirubin ≤ 1.5 times the upper limit of normal&#xD;
&#xD;
               -  Creatinine clearance &gt; 30 mL/min calculated by the Cockcroft-Gault formula using&#xD;
                  actual body weight&#xD;
&#xD;
          -  Age ≥ 18 years of age&#xD;
&#xD;
          -  Body weight &gt;30 kg&#xD;
&#xD;
          -  Participants must have a documented negative antibody to HIV&#xD;
&#xD;
          -  Evidence of post-menopausal status or negative urinary or serum pregnancy test for&#xD;
             female pre-menopausal patients. Women will be considered post-menopausal if they have&#xD;
             been amenorrheic for 12 months without an alternative medical cause. The following&#xD;
             age-specific requirements apply:&#xD;
&#xD;
               -  Women &lt;50 years of age would be considered post-menopausal if they have been&#xD;
                  amenorrheic for 12 months or more following cessation of exogenous hormonal&#xD;
                  treatments and if they have luteinizing hormone and follicle-stimulating hormone&#xD;
                  levels in the post-menopausal range for the institution or underwent surgical&#xD;
                  sterilization (bilateral oophorectomy or hysterectomy).&#xD;
&#xD;
               -  Women ≥50 years of age would be considered post-menopausal if they have been&#xD;
                  amenorrheic for 12 months or more following cessation of all exogenous hormonal&#xD;
                  treatments, had radiation-induced menopause with last menses &gt;1 year ago, had&#xD;
                  chemotherapy-induced menopause with last menses &gt;1 year ago, or underwent&#xD;
                  surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or&#xD;
                  hysterectomy).&#xD;
&#xD;
          -  Female subjects of childbearing potential must have a negative pregnancy test no more&#xD;
             than 3 days prior to the start of study treatment.&#xD;
&#xD;
          -  Able to understand and willing to sign an IRB approved written informed consent&#xD;
             document. A legally authorized representative can consent on behalf of a patient who&#xD;
             is able to understand the purpose and risk of the study but not able to provide a&#xD;
             signature on the ICF and authorization to use PHI due to neurologic deficits (e.g.&#xD;
             motor or language deficits)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Concurrent use of other approved or investigational antineoplastic agents (with the&#xD;
             exception of corticosteroids)&#xD;
&#xD;
          -  Participation in another clinical study with an investigational product during the 4&#xD;
             weeks prior to the first day of study treatment.&#xD;
&#xD;
          -  Prior chemotherapy or targeted small molecule therapy (or other therapy for CNS&#xD;
             lymphoma) within 3 weeks prior to the first day of study treatment (or 5 half-lives&#xD;
             (whichever is shorter)), or 2 weeks prior to the first day of study treatment for&#xD;
             monoclonal antibodies&#xD;
&#xD;
             *The patient must have recovered to baseline or ≤ grade 1 from prior toxicities of&#xD;
             therapy with the exception of alopecia. Recovery to ≤ grade 2 neuropathy is permitted&#xD;
&#xD;
          -  External beam radiation therapy to the CNS within 14 days of the first day of study&#xD;
             treatment.&#xD;
&#xD;
          -  Patient requires more than 8 mg of dexamethasone daily or the equivalent for control&#xD;
             of CNS symptoms at the time of initiation of study therapy. Patients must taper off&#xD;
             high dose corticosteroids for the control of CNS symptoms within 14 days after&#xD;
             starting on study therapy.&#xD;
&#xD;
          -  History of intracranial hemorrhage or clinically significant stroke within 6 months&#xD;
             prior to first day of study treatment&#xD;
&#xD;
          -  Inability to swallow oral medications.&#xD;
&#xD;
          -  History of significant gastrointestinal disease that would limit absorption of oral&#xD;
             medications. This could include refractory nausea, vomiting, chronic gastrointestinal&#xD;
             disease, bariatric surgery such as gastric bypass, partial or complete bowel&#xD;
             obstruction, or previous significant bowel resection that would preclude adequate&#xD;
             absorption, distribution, metabolism, or excretion of study treatment.&#xD;
&#xD;
          -  Active concurrent malignancy requiring active therapy.&#xD;
&#xD;
          -  Prior therapy with a checkpoint inhibitor, including durvalumab.&#xD;
&#xD;
          -  Prior therapy with BTK inhibitor.&#xD;
&#xD;
          -  Warfarin or any other Coumadin-derivative anticoagulant or vitamin K antagonists.&#xD;
             Patients must be off warfarin-derivative anticoagulants for at least seven days prior&#xD;
             to starting the study drug. Use of low molecular weight heparin and novel oral&#xD;
             anticoagulants (eg. rivaroxaban, apixaban) is permitted if required.&#xD;
&#xD;
          -  Concurrent use of a moderate or strong inhibitor or inducer of the P450 isoenzyme&#xD;
             CYP3A. Participants must be off P450/CYP3A inhibitors and inducers prior to starting&#xD;
             the study drug.&#xD;
&#xD;
             *Study therapy may be started after 5-half-lives or 7 days (whichever is shorter) have&#xD;
             surpassed since last administration of a strong or moderate CYP3A4 inducer/inhibitors.&#xD;
&#xD;
          -  Requires treatment with proton pump inhibitors (e.g., omeprazole, esomeprazole,&#xD;
             lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving&#xD;
             proton pump inhibitors who switch to H2-receptor antagonists or antacids any time&#xD;
             prior to initiating study therapy are eligible for enrollment to this study.&#xD;
&#xD;
          -  Use of systemic immunosuppressant therapy, including cyclosporine A, tacrolimus,&#xD;
             sirolimus, and other such medications, or chronic administration of &gt; 10 mg/day of&#xD;
             prednisone or the equivalent. This does not refer to patients on corticosteroids for&#xD;
             CNS lymphoma symptoms. Participants must be off of immunosuppressant therapy (with the&#xD;
             exception of steroids) for at least 14 days prior to the first day of study treatment.&#xD;
             The items listed below are exceptions to this criterion:&#xD;
&#xD;
               -  Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra&#xD;
                  articular injection)&#xD;
&#xD;
               -  Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of&#xD;
                  prednisone or its equivalent&#xD;
&#xD;
               -  Steroids as premedication for hypersensitivity reactions (e.g., CT scan&#xD;
                  premedication)&#xD;
&#xD;
          -  Receipt of live attenuated vaccine within 30 days prior to the first day of study&#xD;
             treatment. Note: Patients, if enrolled, should not receive live vaccine while&#xD;
             receiving IP and up to 30 days after the last day of study treatment.&#xD;
&#xD;
          -  Suspicion of or confirmed progressive multifocal leukoencephalopathy&#xD;
&#xD;
          -  Active autoimmune disease (including autoimmune hemolytic anemia and immune&#xD;
             thrombocytopenia purpura) requiring systemic treatment within the past two years (i.e.&#xD;
             with the use of disease modifying agents, corticosteroids, or immunosuppressive&#xD;
             drugs). The following are exceptions to this criterion:&#xD;
&#xD;
               -  Patients with vitiligo or alopecia&#xD;
&#xD;
               -  Patients with hypothyroidism (e.g., due to Hashimoto syndrome) stable on hormone&#xD;
                  replacement&#xD;
&#xD;
               -  Any chronic skin condition that does not require systemic therapy&#xD;
&#xD;
               -  Patients without active disease in the last 5 years may be included but only&#xD;
                  after consultation with the study physician&#xD;
&#xD;
               -  Patients with celiac disease controlled by diet alone&#xD;
&#xD;
               -  Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroids&#xD;
                  replacement therapy for adrenal or pituitary insufficiency, etc.)&#xD;
&#xD;
          -  Significant medical diseases or conditions, as assessed by the investigator, that&#xD;
             would substantially increase the risk to benefit ratio of participating in the study.&#xD;
             This includes, but is not limited to, acute myocardial infarction in the past 6&#xD;
             months, unstable angina, uncontrolled diabetes mellitus, significant active&#xD;
             infections,, severely immunocompromised state, and congestive heart failure, New York&#xD;
             Heart Association Class III-IV.&#xD;
&#xD;
          -  Known bleeding diathesis (e.g. von Willebrand's disease), hemophilia, or active&#xD;
             bleeding.&#xD;
&#xD;
          -  Known Human immunodeficiency virus (HIV) infection.&#xD;
&#xD;
          -  Known active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) as&#xD;
             determined by serologic tests and/or PCR.&#xD;
&#xD;
          -  History of invasive fungal infection, including invasive aspergillosis, or known&#xD;
             active tuberculosis.&#xD;
&#xD;
          -  Major surgery ≤ 28 days prior to starting the trial treatment (or has not recovered&#xD;
             from the side effects of such surgery) or plans to have surgery within 2 weeks of the&#xD;
             first dose of the study drug.&#xD;
&#xD;
          -  Prior allogenic stem cell transplant (autologous stem cell transplant is NOT an&#xD;
             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>Neha Mehta-Shah, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Washington University School of Medicine</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Neha Mehta-Shah, M.D.</last_name>
    <phone>314-747-7510</phone>
    <email>mehta-n@wustl.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>Washington University School of Medicine</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Neha Mehta-shah, M.D.</last_name>
      <phone>314-747-7510</phone>
      <email>mehta-n@wustl.edu</email>
    </contact>
    <investigator>
      <last_name>Neha Mehta-Shah, M.D.</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Nancy Bartlett, M.D.</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Mary-Kate Malecek, M.D.</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Fei Wan, Ph.D.</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Maria Rosana Ponisio, M.D.</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>The Ohio State University Hospital</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Narendranath Epperla, M.D.</last_name>
      <phone>800-293-5066</phone>
    </contact>
    <investigator>
      <last_name>Narendranath Epperla, M.D.</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.siteman.wustl.edu</url>
    <description>Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine</description>
  </link>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>July 2, 2020</study_first_submitted>
  <study_first_submitted_qc>July 2, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 8, 2020</study_first_posted>
  <last_update_submitted>July 11, 2023</last_update_submitted>
  <last_update_submitted_qc>July 11, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 13, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Durvalumab</mesh_term>
    <mesh_term>Acalabrutinib</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/NCT04462328
org study id: 202009139
nct id: NCT04462328
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
BTK inhibition and checkpoint blockade are promising classes of therapy for central nervous
      system (CNS) lymphoma and have demonstrated efficacy with acceptable toxicity. A multidrug
      approach may carry a higher chance of durable efficacy in this aggressive disease that
      carries significant morbidity and mortality. Given the poor outcomes and limited options for
      patients who are not candidates for high-dose methotrexate, the investigators seek to
      evaluate the combination in this patient population.

      08/30/2022: The study was originally designed for those with primary and secondary central
      nervous system (CNS) lymphoma. However, the first three patients who were enrolled all had
      secondary CNS lymphoma and most had germinal center phenotype disease with double hit
      phenotypes. In these three patients, two dose limiting toxicities were seen including 1
      patient with grade 4 neutropenia at the time of disease progression and one with pneumonia in
      the setting of disease progression and worsening of existing heart disease. The third patient
      came off for clinical progression within cycle 1. Given the lack of response in patients with
      secondary CNS lymphomas, who do not exhibit the same biology as primary CNS lymphoma
      patients, Amendment 3 updates the study to only include patients with primary CNS lymphomas.
allocation: Non-Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Safe and tolerable dose of regimen
time frame: Completion of first 12 weeks of treatment within phase I portion of study (estimated to be 14 months)
description: Defined as Dose Level 2 if 0 or 1 dose limiting toxicities (DLTs) are seen in patients at that dose level, or Dose Level 1 if 2+ DLTs are seen in Dose Level 2 but only 0 or 1 DLTs are seen in patients at Dose Level 1.
A DLT is defined as the occurrence of an adverse event (AE) that is at least possibly related to the investigational product (IP) or investigational regimen (IR)
measure: Overall response rate (complete response (CR) + partial response (PR))
time frame: Through completion of treatment (estimated to be 6 months)
description: CR is defined as disappearance of all contrast-enhancing CNS (brain and spine if latter abnormal at baseline) disease, absence of any systemic corticosteroids prescribed to treat lymphoma (prophylactic steroid eye drops, topical steroids, corticosteroid antiemetics and steroids prescribed for non-disease reasons [e.g. asthma exacerbation, dermatologic or rheumatologic conditions] are allowed and not considered in the definition of CR), resolution of abnormal ocular findings on ophthalmological examination, negative CSF cytology/flow cytometry.
PR is defined as >50% reduction in contrast-enhancing CNS (brain and spine if latter abnormal at baseline) disease either with minor abnormalities on ophthalmological examination or normal ophthalmological examination OR disappearance of all contrast-enhancing CNS (brain and spine if latter abnormal at baseline) but only reduction of vitreous cells or retinal infiltrates or residual suspicious or positive CSF cytology.
measure: Duration of response
time frame: Through 2 years post treatment (estimated to be 2 years and 6 months)
description: -The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).
measure: Time to response
time frame: Through completion of treatment (estimated to be 6 months)
description: -Time to response is measured from the start of treatment until the time measurement criteria are met for first objective tumor response (CR or PR, whichever is first recorded).
measure: Progression-free survival (PFS)
time frame: Through 2 years post treatment (estimated to be 2 years and 6 months)
description: PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.
Progressive disease is defined as > 25% increase in contrast-enhancing CNS (brain and spine if latter abnormal at baseline) disease, appearance of any new, measurable (>/= 10mm) contrast-enhancing disease or recurrent or new ocular or CSF disease.
Progression free survival will include all patients with at least one response assessment. Patients will be censored for progression free survival and duration of response if alive and without disease progression at completion of follow-up period.
measure: Overall survival (OS)
time frame: Until death (estimated to be 5 years and 6 months)
description: OS is defined as the duration of time from start of treatment to time of death.
All patients who receive treatment on study will be included in overall survival. Patients will be censored for overall survival is alive at last study data collection point (completion of follow-up).
arm group label: Phase I Dose Level 1: Durvalumab + Acalabruitinib
arm group type: Experimental
description: Acalabrutinib 100 mg twice per day by mouth on days 1-28
Durvalumab 1500 mg intravenous on day 1 of a 28 day cycle
arm group label: Phase I Dose Level 2: Durvalumab + Acalabruitinib
arm group type: Experimental
description: Acalabrutinib 200 mg twice per day by mouth on days 1-28
Durvalumab 1500 mg intravenous on day 1 of a 28 day cycle
arm group label: Expansion Cohort: Durvalumab + Acalabrutinib
arm group type: Experimental
description: Acalabrutinib 100 mg or 200 mg (depends on tolerable dose found in Phase I portion of study) twice per day by mouth on days 1-28
Durvalumab 1500 mg intravenous on day 1 of a 28 day cycle
intervention type: Drug
intervention name: Durvalumab
description: Durvalumab will be administered over 60 minutes
arm group label: Expansion Cohort: Durvalumab + Acalabrutinib
arm group label: Phase I Dose Level 1: Durvalumab + Acalabruitinib
arm group label: Phase I Dose Level 2: Durvalumab + Acalabruitinib
other name: Imfinzi
intervention type: Drug
intervention name: Acalabrutinib
description: Patients will take acalabrutinib orally every 12 hours (+/- 3 hours) daily.
arm group label: Expansion Cohort: Durvalumab + Acalabrutinib
arm group label: Phase I Dose Level 1: Durvalumab + Acalabruitinib
arm group label: Phase I Dose Level 2: Durvalumab + Acalabruitinib
other name: Calquence
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Neha Mehta-Shah, M.D.
role: Principal Investigator
affiliation: Washington University School of Medicine
last name: Neha Mehta-Shah, M.D.
phone: 314-747-7510
email: mehta-n@wustl.edu
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
url: http://www.siteman.wustl.edu
description: Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
responsible party type: Sponsor
mesh term: Lymphoma
mesh term: Durvalumab
mesh term: Acalabrutinib
sharing ipd: No