<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/NCT02203526</url>
  </required_header>
  <id_info>
    <org_study_id>140157</org_study_id>
    <secondary_id>14-C-0157</secondary_id>
    <nct_id>NCT02203526</nct_id>
  </id_info>
  <brief_title>Phase 1 Study of Ibrutinib and Immuno-Chemotherapy Using Temozolomide, Etoposide, Doxil, Dexamethasone, Ibrutinib,Rituximab (TEDDI-R) in Primary CNS Lymphoma</brief_title>
  <official_title>Phase 1 Study of Ibrutinib and Immuno-Chemotherapy Using Temozolomide, Etoposide, Doxil, Dexamethasone, Ibrutinib, Rituximab (TEDDI-R) in Primary CNS Lymphoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      BACKGROUND:&#xD;
&#xD;
        -  Primary CNS lymphoma (PCNSL) is a rare subtype of diffuse large B-cell lymphoma.&#xD;
&#xD;
        -  The outcome for patients with this diagnosis is significantly worse than for that of&#xD;
           systemic DLBCL. Most treatment approaches in the past have included high dose&#xD;
           methotrexate and radiation treatment.&#xD;
&#xD;
        -  Most PCNSLs appear to be of activated B-cell (ABC) origin.&#xD;
&#xD;
        -  Ibrutinib is an inhibitor of Bruton s tyrosine kinase (BTK) and effective for systemic&#xD;
           DLBCL of ABC origin.&#xD;
&#xD;
        -  We propose doing a study in which ibrutinib is combined with a novel chemotherapy&#xD;
           platform called dose adjusted temozolomide, etoposide, doxil, dexamethasone, ibrutinib,&#xD;
           rituximab (TEDDI-R).&#xD;
&#xD;
      OBJECTIVE:&#xD;
&#xD;
      - Identify the maximum tolerated dose (MTD) of ibrutinib or the dose that achieves adequate&#xD;
      CSF concentrations, whichever comes first, when ibrutinib is given with TEDDI-R.&#xD;
&#xD;
      ELIGIBILITY:&#xD;
&#xD;
        -  Relapsed/refractory PCNSL.&#xD;
&#xD;
        -  Age greater than or equal to 18 years.&#xD;
&#xD;
        -  No pregnant or breast-feeding women.&#xD;
&#xD;
        -  Adequate organ function (defined in protocol).&#xD;
&#xD;
      STUDY DESIGN:&#xD;
&#xD;
        -  This is a phase 1 study of 40 patients.&#xD;
&#xD;
        -  The study will have two components.&#xD;
&#xD;
             1. Phase 1: MTD of ibrutinib will be identified or the dose at which ibrutinib&#xD;
                achieves a concentration of less than or equal to 100 nM in the CSF, when given in&#xD;
                combination with TEDDI-R immuno-chemotherapy, whichever comes first.&#xD;
&#xD;
             2. Expansion cohort: Safety and tolerability of the regimen in relapsed/refractory or&#xD;
                previously untreated PCNSL (DLBCL type) will be assessed at the final ibrutinib&#xD;
                dose with TEDDI-R in 10 patients. Secondary objectives will be PFS and OS....&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
        -  Primary CNS lymphoma (PCNSL) is a rare subtype of diffuse large B-cell lymphoma&#xD;
&#xD;
        -  The outcome for patients with this diagnosis is significantly worse than for that of&#xD;
           systemic DLBCL.&#xD;
&#xD;
      Most treatment approaches in the past have included high dose methotrexate and radiation&#xD;
      treatment.&#xD;
&#xD;
        -  Most PCNSLs appear to be of activated B-cell (ABC) origin&#xD;
&#xD;
        -  Ibrutinib is an inhibitor of Bruton s tyrosine kinase (BTK) and effective for systemic&#xD;
           DLBCL of ABC origin.&#xD;
&#xD;
        -  We propose doing a study in which ibrutinib is combined with a novel chemotherapy&#xD;
           platform called temozolomide, etoposide, doxil, dexamethasone, ibrutinib, rituximab&#xD;
           (TEDDI-R).&#xD;
&#xD;
      Objective:&#xD;
&#xD;
        -  To identify the dose of ibrutinib with anti-fungal prophylaxis that can be safely&#xD;
           administered to achieve an ibrutinib median CSF CMAX of 1.98 nM (Range 0.69 to 11.1)&#xD;
&#xD;
        -  Revised in Amendment M (version date: 11/03/2020): To assess the safety, feasibility,&#xD;
           and complete response (CR) rate of the TEDDI-R in untreated PCNSL (DLBCL type) patients.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
        -  Relapsed/refractory or untreated PCNSL&#xD;
&#xD;
        -  Age &gt;= 18 years.&#xD;
&#xD;
        -  No pregnant or breast-feeding women.&#xD;
&#xD;
        -  Adequate organ function (defined in protocol).&#xD;
&#xD;
      Study Design:&#xD;
&#xD;
        -  This is a phase 1 study of 93 patients.&#xD;
&#xD;
        -  The study will have three components.&#xD;
&#xD;
             -  Phase 1: MTD of ibrutinib will be identified or the dose at which ibrutinib&#xD;
                achieves a concentration of &gt;= 100 nM in the CSF, when given in combination with&#xD;
                TEDDI-R immuno-chemotherapy, whichever comes first.&#xD;
&#xD;
             -  Expansion cohort: Safety and tolerability of the regimen in relapsed/refractory&#xD;
                PCNSL (DLBCL type) will be assessed at the final ibrutinib dose with TEDDI-R in 10&#xD;
                patients. Secondary objectives will be PFS and OS.&#xD;
&#xD;
             -  Revised Study Design: Effective with Amendment G (version date: 7/31/2017), new&#xD;
                ibrutinib dose levels are being added together with anti-fungal prophylaxis to&#xD;
                determine the dose of ibrutinib that may be safely given with the chemotherapy&#xD;
                platform.&#xD;
&#xD;
             -  Effective with Amendment M (version date: 11/03/2020), a second expansion cohort of&#xD;
                untreated PCNSL (DLBCL type) will be added: Safety, feasibility, and complete&#xD;
                response rate of the regimen in untreated PCNSL (DLBCL type) will be assessed at&#xD;
                the final ibrutinib dose with TEDDI-R in 15 patients. Secondary objectives will be&#xD;
                PFS and OS.&#xD;
&#xD;
             -  Effective with Amendment 06/04/2021, a new dosing schedule will be tested in up to&#xD;
                10 relapsed or refractory patients and 15 patients with untreated PCNSL. Secondary&#xD;
                objectives will be PFS and OS.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">August 14, 2014</start_date>
  <completion_date type="Anticipated">June 15, 2024</completion_date>
  <primary_completion_date type="Anticipated">June 15, 2024</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>safety and feasibility in untreated PCNSL patients</measure>
    <time_frame>Initiation of ibrutinib until 30 days after treatment</time_frame>
    <description>Incidence of adverse events (i.e., grade and frequency)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>MTD of ibrutinib with anti-fungal prophylaxis when given with TEDD-R</measure>
    <time_frame>after one cycle</time_frame>
    <description>AEs will be tabulated and reported</description>
  </primary_outcome>
  <primary_outcome>
    <measure>MTD of ibrutinib when given with TEDD-R</measure>
    <time_frame>after one cycle</time_frame>
    <description>AEs will be tabulated and reported</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Complete Response rate in untreated PCNSL patients</measure>
    <time_frame>every 3 months for 1 year, every 4 months year 2, every 6 months year 3 then yearly</time_frame>
    <description>The response rate will be determined and reported along with a 95% confidence interval</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Safety and Tolerability</measure>
    <time_frame>Initiation of ibrutinib until 30 days after treatment</time_frame>
    <description>Incidence of adverse events (i.e., grade and frequency)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival</measure>
    <time_frame>every 3 months for 1 year, every 4 months year 2, every 6 months year 3 then yearly</time_frame>
    <description>The response rate will be determined and reported along with a 95% confidence interval</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>every 3 months for 1 year, every 4 months year 2, every 6 months year 3 then yearly</time_frame>
    <description>The response rate will be determined and reported along with a 95% confidence interval</description>
  </secondary_outcome>
  <number_of_arms>5</number_of_arms>
  <enrollment type="Anticipated">93</enrollment>
  <condition>Primary Central Nervous System Lymphoma</condition>
  <arm_group>
    <arm_group_label>Arm 1-A (original study design - prior to Amendment G)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>TEDD-R (cycle 1) with ibrutinib; TEDDI-R with cytarabine (cycles 2-6)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm 1-B (original study design-prior to Amendment G)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>TEDDI-R with cytarabine</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm 2 (Dose Escalation; prior to Amendment 06/04/2021)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>TEDDI-R with cytarabine, and isavuconazole</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm 3 (Dose Expansion; prior to Amendment 06/04/2021)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>TEDDI-R with cytarabine and isavuconazole</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm 4 (Dose Expansion; Amendment 06/04/21)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>TEDDI-R, cytarabine or methotrexate, isavuconazole, ibrutinib for 10 days</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Isavuconazole</intervention_name>
    <description>Isavuconazole to begin at least 3 days prior to ibrutinib and continue throughout chemotherapy (cycles 1-6)</description>
    <arm_group_label>Arm 2 (Dose Escalation; prior to Amendment 06/04/2021)</arm_group_label>
    <arm_group_label>Arm 3 (Dose Expansion; prior to Amendment 06/04/2021)</arm_group_label>
    <arm_group_label>Arm 4 (Dose Expansion; Amendment 06/04/21)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>TEDDI</intervention_name>
    <description>Temozolomide, etoposide, doxil, dexamthasone, ibrutinib (TEDDI) given every 21 days for cycles 2-6 (Arm 1-A); given every 21 days for cycles 1-6 (Arms 1-B, 2, 3 and 4)</description>
    <arm_group_label>Arm 1-A (original study design - prior to Amendment G)</arm_group_label>
    <arm_group_label>Arm 1-B (original study design-prior to Amendment G)</arm_group_label>
    <arm_group_label>Arm 2 (Dose Escalation; prior to Amendment 06/04/2021)</arm_group_label>
    <arm_group_label>Arm 3 (Dose Expansion; prior to Amendment 06/04/2021)</arm_group_label>
    <arm_group_label>Arm 4 (Dose Expansion; Amendment 06/04/21)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Rituximab</intervention_name>
    <description>Rituximab (R) given with TEDD and TEDDI every 3 weeks for cycles 1-6 (all arms)</description>
    <arm_group_label>Arm 1-A (original study design - prior to Amendment G)</arm_group_label>
    <arm_group_label>Arm 1-B (original study design-prior to Amendment G)</arm_group_label>
    <arm_group_label>Arm 2 (Dose Escalation; prior to Amendment 06/04/2021)</arm_group_label>
    <arm_group_label>Arm 3 (Dose Expansion; prior to Amendment 06/04/2021)</arm_group_label>
    <arm_group_label>Arm 4 (Dose Expansion; Amendment 06/04/21)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cytarabine</intervention_name>
    <description>Cytarabine given via Ommaya reservoir (IT therapy) on days 1 and day 5 of cycles 2-6 (all arms)</description>
    <arm_group_label>Arm 1-A (original study design - prior to Amendment G)</arm_group_label>
    <arm_group_label>Arm 1-B (original study design-prior to Amendment G)</arm_group_label>
    <arm_group_label>Arm 2 (Dose Escalation; prior to Amendment 06/04/2021)</arm_group_label>
    <arm_group_label>Arm 3 (Dose Expansion; prior to Amendment 06/04/2021)</arm_group_label>
    <arm_group_label>Arm 4 (Dose Expansion; Amendment 06/04/21)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>TEDD</intervention_name>
    <description>Temozolomide, etoposide, doxil, dexamthasone, (TEDD) given on first cycle (Arm 1-A)</description>
    <arm_group_label>Arm 1-A (original study design - prior to Amendment G)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ibrutinib (Arms 2, 3 and 4)</intervention_name>
    <description>Ibrutinib given on day -3 to day -1 on cycle 1 (Arms 2, 3 and 4)</description>
    <arm_group_label>Arm 1-A (original study design - prior to Amendment G)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Methotrexate</intervention_name>
    <description>Methotrexate on days 1 and day 5 of cycles 2-6 (Arm 4)</description>
    <arm_group_label>Arm 4 (Dose Expansion; Amendment 06/04/21)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ibrutinib (Arm 1 - Closed with Amendment G)</intervention_name>
    <description>Ibrutinib given on day -14 to day -1 on cycle 1 (Arm 1)</description>
    <arm_group_label>Arm 1-A (original study design - prior to Amendment G)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ibrutinib (Arm 4)</intervention_name>
    <description>Ibrutinib given on days 1-10 for cycles 1-6 (Arm 4)</description>
    <arm_group_label>Arm 1-A (original study design - prior to Amendment G)</arm_group_label>
    <arm_group_label>Arm 4 (Dose Expansion; Amendment 06/04/21)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  ELIGIBILITY CRITERIA:&#xD;
&#xD;
          -  Patients must have histologically or cytologically confirmed primary central nervous&#xD;
             system diffuse large B-cell lymphoma. Patients with PCNSL that is only extracranial&#xD;
             will not be eligible. Patients with relapsed or refractory disease, as well as&#xD;
             untreated patients,&#xD;
&#xD;
        are eligible. Untreated patients must not have high dose chemotherapy and autologous stem&#xD;
        cell transplantation (ASCT) planned as part of frontline therapy to be eligible for the&#xD;
        trial.&#xD;
&#xD;
          -  At least 2 weeks have passed since prior chemotherapy, biological therapy, radiation&#xD;
             therapy,other investigational or anti-cancer therapy that is considered&#xD;
             disease-directed.&#xD;
&#xD;
          -  Ibrutinib must be discontinued 7 days before (when possible) until 7 days after major&#xD;
             surgery, and 3 days before (when possible) until 3 days after minor surgery. Thus,&#xD;
             patients to be enrolled on an ibrutinib trial must have completed major surgery&#xD;
             greater than or equal to 7 days before initiating treatment, and/or must have&#xD;
             completed minor surgery greater than or equal to 3 days before initiating treatment.&#xD;
&#xD;
          -  Recovered from prior toxicities to Grade 0-1 at least 2 weeks prior to investigational&#xD;
             therapy.&#xD;
&#xD;
          -  Men and women age &gt;=18 years. Because no dosing or adverse event data are currently&#xD;
             available on the use of ibrutinib and TEDDI-R in patients &lt;18 years of age, children&#xD;
             are excluded from this study, but may be eligible for future pediatric trials.&#xD;
&#xD;
          -  ECOG performance status less than or equal to 2 (Karnofsky greater than or equal to&#xD;
             60%) unless due to neurologic deficits caused by CNS lymphoma with the following&#xD;
             exceptions: patients with ECOG PS = 4 where neurologic deficits are unlikely to&#xD;
             resolve with tumor resolution and may cause clinical management problems are excluded.&#xD;
&#xD;
          -  Patients must have normal organ and marrow function as defined below, independent of&#xD;
             growth factor or transfusion support. Patients should not receive growth factors or&#xD;
             transfusions for at least 7 days prior to first dose of study drug with the exception&#xD;
             of pegylated G-CSF (pegfilgrastim) and darbepoeitin which require at least 14 days&#xD;
             prior to screening and randomization.&#xD;
&#xD;
               -  absolute neutrophil count greater than or equal to 750 cells/mcL (0.75 x 10(9)/L)&#xD;
&#xD;
               -  platelet count greater than or equal to 50,000 cells/mcL (50 X 10(9)/L)&#xD;
&#xD;
               -  hemoglobin greater than 8.0 g/dL&#xD;
&#xD;
               -  total bilirubin less than or equal to1.5 times ULN (unless Gilbert s syndrome or&#xD;
                  disease infiltration of the liver is present)&#xD;
&#xD;
               -  AST(SGOT)/ALT(SGPT) less than or equal to 3.0 times institutional ULN&#xD;
&#xD;
               -  Serum Creatinine less than or equal to 1.5 mg/dL OR creatinine clearance greater&#xD;
                  than or equal to 40 ml/min/1.73m(2) unless lymphoma related.&#xD;
&#xD;
          -  Prothrombin time/INR (PT) and activated partial thromboplastin time (aPTT) must be&#xD;
             less than or equal to 1.5 times the upper limit of the normal range (ULN); except if,&#xD;
             in the opinion of the Investigator, the aPTT is elevated because of a positive Lupus&#xD;
             Anticoagulant.&#xD;
&#xD;
          -  Left ventricular ejection fraction (LVEF) &gt; 40% as assessed by echocardiogram&#xD;
&#xD;
          -  The effects of ibrutinib on the developing human fetus are unknown. For this reason&#xD;
             and because tyrosine kinase inhibitors as well as other therapeutic agents used in&#xD;
             this trial may be teratogenic, women of reproductive potential and men must agree to&#xD;
             use adequate contraception (hormonal or barrier method of birth control; abstinence)&#xD;
             prior to study entry.&#xD;
&#xD;
          -  Female patients who are of non-reproductive potential (i.e., post-menopausal by&#xD;
             history - no menses for greater than or equal to 1 year; OR history of hysterectomy;&#xD;
             OR history of bilateral tubal ligation; OR history of bilateral oophorectomy). Female&#xD;
             patients of childbearing potential must have a negative serum pregnancy test upon&#xD;
             study entry.&#xD;
&#xD;
          -  Male and female patients must agree to use highly effective methods of birth control.&#xD;
             A highly effective method of birth control is defined as a method that has a low&#xD;
             failure rate (i.e., less than 1% per year) when used consistently and correctly and&#xD;
             includes implants, injectables, birth control pills with two hormones, some&#xD;
             intrauterine devices (IUDs). Male subject cannot use highly effective methods and are&#xD;
             required to use barrier. The specific guidelines are as follows:&#xD;
&#xD;
               -  Women: If you can have children, you must use a highly effective method of birth&#xD;
                  control and a barrier method, or sexual abstinence (which is defined as&#xD;
                  refraining from all aspects of sexual activity), while taking study treatment, as&#xD;
                  well as for 12 months after the last dose of rituximab.&#xD;
&#xD;
               -  Men: You must use a barrier method while on treatment with ibrutinib and for 3&#xD;
                  months after the last dose of treatment to prevent pregnancy of your partner. You&#xD;
                  should not donate sperm while you are taking the study drug and for 12 months&#xD;
                  after you stop taking the last dose of rituximab.&#xD;
&#xD;
          -  Patient or appointed surrogate decision-maker or legally authorized representative&#xD;
             must have ability to understand the purpose and risks of the study and willingness to&#xD;
             provide a signed and dated informed consent form (ICF) and authorization to use&#xD;
             protected health information (in accordance with national and local subject privacy&#xD;
             regulations).&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          -  Prior exposure to a BTK inhibitor&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to ibrutinib or other agents used in study.&#xD;
&#xD;
          -  Patients who are allergic to isavuconazole or any of its ingredients.&#xD;
&#xD;
          -  Patients who received a strong cytochrome P450 (CYP) 3A inhibitor or inducer within 7&#xD;
             days prior to the first dose of protocol anti-fungal prophylaxis, or patients who&#xD;
             require continuous treatment with a strong CYP3A inhibitor/inducer (i.e., with the&#xD;
             exception of any medication to be specifically studied in this protocol).&#xD;
&#xD;
          -  Because the lists of these agents are constantly changing, it is important to&#xD;
             regularly consult a frequently-updated list; medical reference texts such as the&#xD;
             Physicians Desk Reference may also provide this information. As part of the&#xD;
             enrollment/informed consent procedures, the patient will be counseled on the risk of&#xD;
             interactions with other agents, and what to do if new medications need to be&#xD;
             prescribed or if the patient is considering a new over-the-counter medicine or herbal&#xD;
             product.&#xD;
&#xD;
          -  HIV positive patients will be excluded because of their increased susceptibility to&#xD;
             fungal infections which outweighs the potential benefit of participation.&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection or an infection requiring systemic antibiotics, symptomatic congestive heart&#xD;
             failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social&#xD;
             situations that would limit compliance with study requirements. Recent infections&#xD;
             requiring systemic treatment need to have completed therapy greater than 14 days&#xD;
             before the first dose of study drug.&#xD;
&#xD;
          -  Pregnant and breastfeeding women are excluded from this study. Pregnant women are&#xD;
             excluded in this study because ibrutinib is a tyrosine kinase inhibitor with the&#xD;
             potential for teratogenic or abortifacient effects. Because there is an unknown but&#xD;
             potential risk for adverse events in nursing infants secondary to treatment of the&#xD;
             mother with ibrutinib, breastfeeding should be discontinued if the mother is treated&#xD;
             with ibrutinib.&#xD;
&#xD;
          -  Uncontrolled Autoimmune Hemolytic Anemia or ITP resulting in (or as evidenced by)&#xD;
             declining platelet or Hgb levels within the 4 weeks prior to first dose of study drug.&#xD;
&#xD;
          -  Presence of transfusion-dependent thrombocytopenia.&#xD;
&#xD;
          -  History of prior malignancy, with the exception of the following:&#xD;
&#xD;
               -  Malignancy treated with curative intent and with no evidence of active disease&#xD;
                  present for more than 3 years prior to Screening and felt to be at low risk for&#xD;
                  recurrence by treating physician&#xD;
&#xD;
               -  Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma&#xD;
                  without current evidence of disease&#xD;
&#xD;
               -  Adequately treated carcinoma in situ without current evidence of disease.&#xD;
&#xD;
          -  Currently active clinically significant cardiovascular disease such as uncontrolled&#xD;
             arrhythmia, congestive heart failure, or Class 3 or 4 congestive heart failure as&#xD;
             defined by the New York Heart Association Functional Classification, or history of&#xD;
             myocardial infarction unstable angina, or acute coronary syndrome within 6 months&#xD;
             prior to enrollment in the study.&#xD;
&#xD;
          -  Unable to swallow capsules, or disease significantly affecting gastrointestinal&#xD;
             function or resection of the stomach or small bowel, or symptomatic inflammatory bowel&#xD;
             disease or ulcerative colitis, or partial or complete bowel obstruction.&#xD;
&#xD;
          -  Serologic status reflecting active hepatitis B or C infection. Patients that are&#xD;
             positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or&#xD;
             hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to&#xD;
             enrollment. Those who are PCR positive will be excluded. Those with a negative PCR for&#xD;
             hepatitis B will be treated with antivirals designed to prevent hepatitis B&#xD;
             reactivation (e.g., entecavir) and have monitoring for hepatitis B reactivation with&#xD;
             PCR.&#xD;
&#xD;
          -  History of stroke or intracranial hemorrhage within 6 months prior to enrollment.&#xD;
&#xD;
          -  Any life-threatening illness, medical condition, or organ system dysfunction that, in&#xD;
             the Investigator s opinion, could compromise the patient s safety, or put the study at&#xD;
             undue risk. Patients with suspicious radiologic evidence of aspergillosis infection&#xD;
             (i.e., Chest CT and/or Brain MRI) will not be eligible unless confirmatory laboratory&#xD;
             testing of Beta-D glucan and aspergillus antigen are negative.&#xD;
&#xD;
          -  Concomitant use of warfarin or other vitamin K antagonists within the last 7 days.&#xD;
&#xD;
          -  Concurrent systemic immunosuppressant therapy other than corticosteroids (e.g.,&#xD;
             cyclosporine A, tacrolimus, etc.) within 28 days of the first dose of study drug.&#xD;
&#xD;
          -  Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.&#xD;
&#xD;
          -  Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved&#xD;
             to grade less than or equal to1, or to the levels dictated in the inclusion/exclusion&#xD;
             criteria with the exception of alopecia.&#xD;
&#xD;
          -  Known bleeding disorders (e.g., von Willebrand s disease) or hemophilia.&#xD;
&#xD;
          -  Major surgery within 7 days of first dose of study drug.&#xD;
&#xD;
          -  Unwilling or unable to participate in all required study evaluations and procedures.&#xD;
&#xD;
          -  Currently active, clinically significant hepatic impairment (greater than or equal to&#xD;
             moderate hepatic impairment according to the NCI/Child Pugh classification.&#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>Mark J Roschewski, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Cancer Institute (NCI)</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Kimberly A Johnson, R.N.</last_name>
    <phone>(240) 271-8477</phone>
    <email>kim.johnson@nih.gov</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Mark J Roschewski, M.D.</last_name>
    <phone>(240) 760-6183</phone>
    <email>mark.roschewski@nih.gov</email>
  </overall_contact_backup>
  <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>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2014-C-0157.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <verification_date>June 28, 2023</verification_date>
  <study_first_submitted>July 29, 2014</study_first_submitted>
  <study_first_submitted_qc>July 29, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 30, 2014</study_first_posted>
  <last_update_submitted>September 8, 2023</last_update_submitted>
  <last_update_submitted_qc>September 8, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 11, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Tyrosine Kinase Inhibitor</keyword>
  <keyword>ABC DLCBL</keyword>
  <keyword>Lymphoma in Brain and CNS</keyword>
  <keyword>Diffuse Large B-Cell Lymphomas in CNS</keyword>
  <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>Cytarabine</mesh_term>
    <mesh_term>Isavuconazole</mesh_term>
    <mesh_term>Rituximab</mesh_term>
    <mesh_term>Methotrexate</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>.All IPD recorded in the medical record will be shared with intramural investigators upon request. @@@@@@In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP. @@@@@@All collected IPD will be shared with collaborators under the terms of collaborative agreements.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_time_frame>Clinical data will be available during the study and indefinitely.@@@@@@Genomic data will be available once genomic data are uploaded per protocol GDS plan for as long as database is active.</ipd_time_frame>
    <ipd_access_criteria>Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. @@@@@@Genomic data will be made available via dbGaP through requests to the data custodians.</ipd_access_criteria>
  </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/NCT02203526
org study id: 140157
secondary id: 14-C-0157
nct id: NCT02203526
lead sponsor: 
is fda regulated drug: Yes
is fda regulated device: No
BACKGROUND:

        -  Primary CNS lymphoma (PCNSL) is a rare subtype of diffuse large B-cell lymphoma.

        -  The outcome for patients with this diagnosis is significantly worse than for that of
           systemic DLBCL. Most treatment approaches in the past have included high dose
           methotrexate and radiation treatment.

        -  Most PCNSLs appear to be of activated B-cell (ABC) origin.

        -  Ibrutinib is an inhibitor of Bruton s tyrosine kinase (BTK) and effective for systemic
           DLBCL of ABC origin.

        -  We propose doing a study in which ibrutinib is combined with a novel chemotherapy
           platform called dose adjusted temozolomide, etoposide, doxil, dexamethasone, ibrutinib,
           rituximab (TEDDI-R).

      OBJECTIVE:

      - Identify the maximum tolerated dose (MTD) of ibrutinib or the dose that achieves adequate
      CSF concentrations, whichever comes first, when ibrutinib is given with TEDDI-R.

      ELIGIBILITY:

        -  Relapsed/refractory PCNSL.

        -  Age greater than or equal to 18 years.

        -  No pregnant or breast-feeding women.

        -  Adequate organ function (defined in protocol).

      STUDY DESIGN:

        -  This is a phase 1 study of 40 patients.

        -  The study will have two components.

             1. Phase 1: MTD of ibrutinib will be identified or the dose at which ibrutinib
                achieves a concentration of less than or equal to 100 nM in the CSF, when given in
                combination with TEDDI-R immuno-chemotherapy, whichever comes first.

             2. Expansion cohort: Safety and tolerability of the regimen in relapsed/refractory or
                previously untreated PCNSL (DLBCL type) will be assessed at the final ibrutinib
                dose with TEDDI-R in 10 patients. Secondary objectives will be PFS and OS....
Background:

        -  Primary CNS lymphoma (PCNSL) is a rare subtype of diffuse large B-cell lymphoma

        -  The outcome for patients with this diagnosis is significantly worse than for that of
           systemic DLBCL.

      Most treatment approaches in the past have included high dose methotrexate and radiation
      treatment.

        -  Most PCNSLs appear to be of activated B-cell (ABC) origin

        -  Ibrutinib is an inhibitor of Bruton s tyrosine kinase (BTK) and effective for systemic
           DLBCL of ABC origin.

        -  We propose doing a study in which ibrutinib is combined with a novel chemotherapy
           platform called temozolomide, etoposide, doxil, dexamethasone, ibrutinib, rituximab
           (TEDDI-R).

      Objective:

        -  To identify the dose of ibrutinib with anti-fungal prophylaxis that can be safely
           administered to achieve an ibrutinib median CSF CMAX of 1.98 nM (Range 0.69 to 11.1)

        -  Revised in Amendment M (version date: 11/03/2020): To assess the safety, feasibility,
           and complete response (CR) rate of the TEDDI-R in untreated PCNSL (DLBCL type) patients.

      Eligibility:

        -  Relapsed/refractory or untreated PCNSL

        -  Age >= 18 years.

        -  No pregnant or breast-feeding women.

        -  Adequate organ function (defined in protocol).

      Study Design:

        -  This is a phase 1 study of 93 patients.

        -  The study will have three components.

             -  Phase 1: MTD of ibrutinib will be identified or the dose at which ibrutinib
                achieves a concentration of >= 100 nM in the CSF, when given in combination with
                TEDDI-R immuno-chemotherapy, whichever comes first.

             -  Expansion cohort: Safety and tolerability of the regimen in relapsed/refractory
                PCNSL (DLBCL type) will be assessed at the final ibrutinib dose with TEDDI-R in 10
                patients. Secondary objectives will be PFS and OS.

             -  Revised Study Design: Effective with Amendment G (version date: 7/31/2017), new
                ibrutinib dose levels are being added together with anti-fungal prophylaxis to
                determine the dose of ibrutinib that may be safely given with the chemotherapy
                platform.

             -  Effective with Amendment M (version date: 11/03/2020), a second expansion cohort of
                untreated PCNSL (DLBCL type) will be added: Safety, feasibility, and complete
                response rate of the regimen in untreated PCNSL (DLBCL type) will be assessed at
                the final ibrutinib dose with TEDDI-R in 15 patients. Secondary objectives will be
                PFS and OS.

             -  Effective with Amendment 06/04/2021, a new dosing schedule will be tested in up to
                10 relapsed or refractory patients and 15 patients with untreated PCNSL. Secondary
                objectives will be PFS and OS.
allocation: N/A
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: safety and feasibility in untreated PCNSL patients
time frame: Initiation of ibrutinib until 30 days after treatment
description: Incidence of adverse events (i.e., grade and frequency)
measure: MTD of ibrutinib with anti-fungal prophylaxis when given with TEDD-R
time frame: after one cycle
description: AEs will be tabulated and reported
measure: MTD of ibrutinib when given with TEDD-R
time frame: after one cycle
description: AEs will be tabulated and reported
measure: Complete Response rate in untreated PCNSL patients
time frame: every 3 months for 1 year, every 4 months year 2, every 6 months year 3 then yearly
description: The response rate will be determined and reported along with a 95% confidence interval
measure: Safety and Tolerability
time frame: Initiation of ibrutinib until 30 days after treatment
description: Incidence of adverse events (i.e., grade and frequency)
measure: Progression-free survival
time frame: every 3 months for 1 year, every 4 months year 2, every 6 months year 3 then yearly
description: The response rate will be determined and reported along with a 95% confidence interval
measure: Overall survival
time frame: every 3 months for 1 year, every 4 months year 2, every 6 months year 3 then yearly
description: The response rate will be determined and reported along with a 95% confidence interval
arm group label: Arm 1-A (original study design - prior to Amendment G)
arm group type: Experimental
description: TEDD-R (cycle 1) with ibrutinib; TEDDI-R with cytarabine (cycles 2-6)
arm group label: Arm 1-B (original study design-prior to Amendment G)
arm group type: Experimental
description: TEDDI-R with cytarabine
arm group label: Arm 2 (Dose Escalation; prior to Amendment 06/04/2021)
arm group type: Experimental
description: TEDDI-R with cytarabine, and isavuconazole
arm group label: Arm 3 (Dose Expansion; prior to Amendment 06/04/2021)
arm group type: Experimental
description: TEDDI-R with cytarabine and isavuconazole
arm group label: Arm 4 (Dose Expansion; Amendment 06/04/21)
arm group type: Experimental
description: TEDDI-R, cytarabine or methotrexate, isavuconazole, ibrutinib for 10 days
intervention type: Drug
intervention name: Isavuconazole
description: Isavuconazole to begin at least 3 days prior to ibrutinib and continue throughout chemotherapy (cycles 1-6)
arm group label: Arm 2 (Dose Escalation; prior to Amendment 06/04/2021)
arm group label: Arm 3 (Dose Expansion; prior to Amendment 06/04/2021)
arm group label: Arm 4 (Dose Expansion; Amendment 06/04/21)
intervention type: Drug
intervention name: TEDDI
description: Temozolomide, etoposide, doxil, dexamthasone, ibrutinib (TEDDI) given every 21 days for cycles 2-6 (Arm 1-A); given every 21 days for cycles 1-6 (Arms 1-B, 2, 3 and 4)
arm group label: Arm 1-A (original study design - prior to Amendment G)
arm group label: Arm 1-B (original study design-prior to Amendment G)
arm group label: Arm 2 (Dose Escalation; prior to Amendment 06/04/2021)
arm group label: Arm 3 (Dose Expansion; prior to Amendment 06/04/2021)
arm group label: Arm 4 (Dose Expansion; Amendment 06/04/21)
intervention type: Biological
intervention name: Rituximab
description: Rituximab (R) given with TEDD and TEDDI every 3 weeks for cycles 1-6 (all arms)
arm group label: Arm 1-A (original study design - prior to Amendment G)
arm group label: Arm 1-B (original study design-prior to Amendment G)
arm group label: Arm 2 (Dose Escalation; prior to Amendment 06/04/2021)
arm group label: Arm 3 (Dose Expansion; prior to Amendment 06/04/2021)
arm group label: Arm 4 (Dose Expansion; Amendment 06/04/21)
intervention type: Drug
intervention name: Cytarabine
description: Cytarabine given via Ommaya reservoir (IT therapy) on days 1 and day 5 of cycles 2-6 (all arms)
arm group label: Arm 1-A (original study design - prior to Amendment G)
arm group label: Arm 1-B (original study design-prior to Amendment G)
arm group label: Arm 2 (Dose Escalation; prior to Amendment 06/04/2021)
arm group label: Arm 3 (Dose Expansion; prior to Amendment 06/04/2021)
arm group label: Arm 4 (Dose Expansion; Amendment 06/04/21)
intervention type: Drug
intervention name: TEDD
description: Temozolomide, etoposide, doxil, dexamthasone, (TEDD) given on first cycle (Arm 1-A)
arm group label: Arm 1-A (original study design - prior to Amendment G)
intervention type: Drug
intervention name: Ibrutinib (Arms 2, 3 and 4)
description: Ibrutinib given on day -3 to day -1 on cycle 1 (Arms 2, 3 and 4)
arm group label: Arm 1-A (original study design - prior to Amendment G)
intervention type: Drug
intervention name: Methotrexate
description: Methotrexate on days 1 and day 5 of cycles 2-6 (Arm 4)
arm group label: Arm 4 (Dose Expansion; Amendment 06/04/21)
intervention type: Drug
intervention name: Ibrutinib (Arm 1 - Closed with Amendment G)
description: Ibrutinib given on day -14 to day -1 on cycle 1 (Arm 1)
arm group label: Arm 1-A (original study design - prior to Amendment G)
intervention type: Drug
intervention name: Ibrutinib (Arm 4)
description: Ibrutinib given on days 1-10 for cycles 1-6 (Arm 4)
arm group label: Arm 1-A (original study design - prior to Amendment G)
arm group label: Arm 4 (Dose Expansion; Amendment 06/04/21)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Mark J Roschewski, M.D.
role: Principal Investigator
affiliation: National Cancer Institute (NCI)
last name: Kimberly A Johnson, R.N.
phone: (240) 271-8477
email: kim.johnson@nih.gov
last name: Mark J Roschewski, M.D.
phone: (240) 760-6183
email: mark.roschewski@nih.gov
facility: 
status: Recruiting
country: United States
url: https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2014-C-0157.html
description: NIH Clinical Center Detailed Web Page
responsible party type: Sponsor
mesh term: Lymphoma
mesh term: Cytarabine
mesh term: Isavuconazole
mesh term: Rituximab
mesh term: Methotrexate
sharing ipd: Yes
ipd description: .All IPD recorded in the medical record will be shared with intramural investigators upon request. @@@@@@In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP. @@@@@@All collected IPD will be shared with collaborators under the terms of collaborative agreements.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd time frame: Clinical data will be available during the study and indefinitely.@@@@@@Genomic data will be available once genomic data are uploaded per protocol GDS plan for as long as database is active.
ipd access criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. @@@@@@Genomic data will be made available via dbGaP through requests to the data custodians.