<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/NCT02219737</url>
  </required_header>
  <id_info>
    <org_study_id>NCI-2014-00571</org_study_id>
    <secondary_id>NCI-2014-00571</secondary_id>
    <secondary_id>14-145</secondary_id>
    <secondary_id>9588</secondary_id>
    <secondary_id>9588</secondary_id>
    <secondary_id>P30CA008748</secondary_id>
    <nct_id>NCT02219737</nct_id>
  </id_info>
  <brief_title>Ibrutinib and Combination Chemotherapy in Treating Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma</brief_title>
  <official_title>A Phase I Study Combining Ibrutinib With Rituximab, Ifosfamide, Carboplatin, and Etoposide (R-ICE) in Patients With Relapsed or Primary Refractory Diffuse Large B-Cell Lymphoma (DLBCL)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Cancer Institute (NCI)</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase I trial studies the side effects and best dose of ibrutinib when given together&#xD;
      with rituximab, ifosfamide, carboplatin, and etoposide (combination chemotherapy) in treating&#xD;
      patients with diffuse large B-cell lymphoma (DLBCL) that has returned after a period of&#xD;
      improvement (relapsed) or has not responded to treatment (refractory). Ibrutinib may stop the&#xD;
      growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in&#xD;
      chemotherapy, such as, rituximab, ifosfamide, carboplatin, and etoposide, work in different&#xD;
      ways to stop the growth of cancer cells, either by killing the cells, by stopping them from&#xD;
      dividing, or by stopping them from spreading. Giving ibrutinib together with combination&#xD;
      chemotherapy may be a better treatment for patients with relapsed or refractory DLBCL.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. Safety of ibrutinib in combination with rituximab-ifosfamide, carboplatin, and etoposide&#xD;
      (R-ICE).&#xD;
&#xD;
      II. Establishment of maximum tolerated dose of ibrutinib with R-ICE.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. Pharmacokinetic (PK) studies of ibrutinib in combination with R-ICE. II. Clinical response&#xD;
      rate of ibrutinib+R-ICE.&#xD;
&#xD;
      OUTLINE: This is a dose-escalation study of ibrutinib.&#xD;
&#xD;
      Patients receive ibrutinib orally (PO) once daily (QD) on days 1-21, rituximab intravenously&#xD;
      (IV) on day 1, ifosfamide IV on day 3, carboplatin intravenously piggy back (IVPB) on day 3,&#xD;
      and etoposide IVPB on days 2-4. Treatment repeats every 21 days for up to 3 courses in the&#xD;
      absence of disease progression or unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up for 52 weeks.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 12, 2014</start_date>
  <completion_date type="Actual">May 11, 2017</completion_date>
  <primary_completion_date type="Actual">May 11, 2017</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>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Maximum tolerated dose of the combination of ibrutinib with standard dosing R-ICE, graded using the Common Terminology Criteria for Adverse Events 4.0</measure>
    <time_frame>Day 21</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Toxicity of the combination of ibrutinib with standard dosing R-ICE, graded using the CTCAE 4.0</measure>
    <time_frame>Up to week 52</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall response rate, defined as the sum of partial and complete responses as determined by revised International Working Group Criteria for Malignant Lymphoma</measure>
    <time_frame>Up to week 52</time_frame>
    <description>The proportion of patients who achieve a clinical response (partial response or better) will be estimated in this patient population. This will be calculated among patients who receive any study drug, and additionally among patients who complete three cycles of therapy.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PK parameters of ibrutinib in the presence of R-ICE as a measure of potential drug-drug interaction</measure>
    <time_frame>Predose, 30 minutes, 1, 2, 3, 4, 6, 8, 10 (optional), and 24 hours on day 15 (course 1) and day 1 (course 2)</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">26</enrollment>
  <condition>CD20 Positive</condition>
  <condition>Recurrent Diffuse Large B-Cell Lymphoma</condition>
  <condition>Refractory Diffuse Large B-Cell Lymphoma</condition>
  <arm_group>
    <arm_group_label>Treatment (ibrutinib, R-ICE)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive ibrutinib PO QD on days 1-21, rituximab IV on day 1, ifosfamide IV on day 3, carboplatin IVPB on day 3, and etoposide IVPB on days 2-4. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carboplatin</intervention_name>
    <description>Given IVPB</description>
    <arm_group_label>Treatment (ibrutinib, R-ICE)</arm_group_label>
    <other_name>Blastocarb</other_name>
    <other_name>Carboplat</other_name>
    <other_name>Carboplatin Hexal</other_name>
    <other_name>Carboplatino</other_name>
    <other_name>Carbosin</other_name>
    <other_name>Carbosol</other_name>
    <other_name>Carbotec</other_name>
    <other_name>CBDCA</other_name>
    <other_name>Displata</other_name>
    <other_name>Ercar</other_name>
    <other_name>JM-8</other_name>
    <other_name>Nealorin</other_name>
    <other_name>Novoplatinum</other_name>
    <other_name>Paraplatin</other_name>
    <other_name>Paraplatin AQ</other_name>
    <other_name>Paraplatine</other_name>
    <other_name>Platinwas</other_name>
    <other_name>Ribocarbo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Etoposide</intervention_name>
    <description>Given IVPB</description>
    <arm_group_label>Treatment (ibrutinib, R-ICE)</arm_group_label>
    <other_name>Demethyl Epipodophyllotoxin Ethylidine Glucoside</other_name>
    <other_name>EPEG</other_name>
    <other_name>Lastet</other_name>
    <other_name>Toposar</other_name>
    <other_name>Vepesid</other_name>
    <other_name>VP 16-213</other_name>
    <other_name>VP-16</other_name>
    <other_name>VP-16-213</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ibrutinib</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (ibrutinib, R-ICE)</arm_group_label>
    <other_name>BTK Inhibitor PCI-32765</other_name>
    <other_name>CRA-032765</other_name>
    <other_name>Imbruvica</other_name>
    <other_name>PCI-32765</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ifosfamide</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (ibrutinib, R-ICE)</arm_group_label>
    <other_name>Asta Z 4942</other_name>
    <other_name>Asta Z-4942</other_name>
    <other_name>Cyfos</other_name>
    <other_name>Holoxan</other_name>
    <other_name>Holoxane</other_name>
    <other_name>Ifex</other_name>
    <other_name>IFO</other_name>
    <other_name>IFO-Cell</other_name>
    <other_name>Ifolem</other_name>
    <other_name>Ifomida</other_name>
    <other_name>Ifomide</other_name>
    <other_name>Ifosfamidum</other_name>
    <other_name>Ifoxan</other_name>
    <other_name>IFX</other_name>
    <other_name>Iphosphamid</other_name>
    <other_name>Iphosphamide</other_name>
    <other_name>Iso-Endoxan</other_name>
    <other_name>Isoendoxan</other_name>
    <other_name>Isophosphamide</other_name>
    <other_name>Mitoxana</other_name>
    <other_name>MJF 9325</other_name>
    <other_name>MJF-9325</other_name>
    <other_name>Naxamide</other_name>
    <other_name>Seromida</other_name>
    <other_name>Tronoxal</other_name>
    <other_name>Z 4942</other_name>
    <other_name>Z-4942</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Laboratory Biomarker Analysis</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Treatment (ibrutinib, R-ICE)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Pharmacological Study</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Treatment (ibrutinib, R-ICE)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Rituximab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (ibrutinib, R-ICE)</arm_group_label>
    <other_name>ABP 798</other_name>
    <other_name>BI 695500</other_name>
    <other_name>C2B8 Monoclonal Antibody</other_name>
    <other_name>Chimeric Anti-CD20 Antibody</other_name>
    <other_name>CT-P10</other_name>
    <other_name>IDEC-102</other_name>
    <other_name>IDEC-C2B8</other_name>
    <other_name>IDEC-C2B8 Monoclonal Antibody</other_name>
    <other_name>MabThera</other_name>
    <other_name>Monoclonal Antibody IDEC-C2B8</other_name>
    <other_name>PF-05280586</other_name>
    <other_name>Rituxan</other_name>
    <other_name>Rituximab Biosimilar ABP 798</other_name>
    <other_name>Rituximab Biosimilar BI 695500</other_name>
    <other_name>Rituximab Biosimilar CT-P10</other_name>
    <other_name>Rituximab Biosimilar GB241</other_name>
    <other_name>Rituximab Biosimilar IBI301</other_name>
    <other_name>Rituximab Biosimilar PF-05280586</other_name>
    <other_name>Rituximab Biosimilar RTXM83</other_name>
    <other_name>Rituximab Biosimilar SAIT101</other_name>
    <other_name>RTXM83</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Autologous transplant eligible patients must have histologically or cytologically&#xD;
             confirmed cluster of differentiation (CD)20 positive relapsed or refractory DLBCL by&#xD;
             biopsy within 45 days prior to subject enrollment and must have been previously&#xD;
             treated with an anthracycline and rituximab-containing regimen&#xD;
&#xD;
          -  Baseline fludeoxyglucose F 18 (FDG)-positron emission tomography (PET) scans must&#xD;
             demonstrate positive lesions compatible with computed tomography (CT) defined&#xD;
             anatomical tumor sites&#xD;
&#xD;
               -  CT scan showing at least:&#xD;
&#xD;
                    -  2 or more clearly demarcated lesions/nodes with a long axis &gt; 1.5 cm and&#xD;
                       short axis &gt;= 1.0 cm OR&#xD;
&#xD;
                    -  1 clearly demarcated lesion/node with a long axis &gt; 2.0 cm and short axis &gt;=&#xD;
                       1.0 cm&#xD;
&#xD;
          -  Patient must have been previously treated for B cell non-Hodgkin lymphoma with any of&#xD;
             the allowable below:&#xD;
&#xD;
               -  First-line treatment with rituximab and an anthracycline-based chemotherapy&#xD;
&#xD;
               -  Monotherapy rituximab, dosed prior to first-line rituximab combined with&#xD;
                  anthracycline containing chemotherapy, or as maintenance therapy&#xD;
&#xD;
               -  Radiotherapy as part of the first-line treatment plan including anthracycline and&#xD;
                  rituximab&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status =&lt; 2 (Karnofsky &gt;= 60%)&#xD;
&#xD;
          -  Life expectancy of greater than 6 weeks&#xD;
&#xD;
          -  Absolute neutrophil count &gt;= 1,000/mcL (unless due to lymphoma involvement of the bone&#xD;
             marrow)&#xD;
&#xD;
          -  Platelets &gt;= 75,000/mcL (unless due to lymphoma involvement of the bone marrow)&#xD;
&#xD;
          -  Total bilirubin &lt; 1.5 x within normal institutional limits (unless due to lymphoma&#xD;
             involvement of liver or a known history of Gilbert's disease)&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase&#xD;
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])&#xD;
             =&lt; 2.5 × institutional upper limit of normal (unless due to lymphoma involvement of&#xD;
             liver)&#xD;
&#xD;
          -  Creatinine within normal institutional limits OR creatinine clearance &gt;= 40&#xD;
             mL/min/1.73 m^2 for patients with creatinine levels above institutional normal (unless&#xD;
             due to lymphoma)&#xD;
&#xD;
          -  Women of child-bearing potential and men must agree to use adequate contraception&#xD;
             (hormonal or barrier method of birth control; abstinence) prior to study entry and for&#xD;
             90 days after the last dose of study drug; should a woman become pregnant or suspect&#xD;
             she is pregnant while she or her partner is participating in this study, she should&#xD;
             inform her treating physician immediately&#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 within&#xD;
             4 weeks before initiating treatment, and/or must have completed minor surgery &gt; 3 days&#xD;
             before initiating treatment&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document&#xD;
&#xD;
          -  Must be able to swallow whole capsules&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients who have had chemotherapy or radiotherapy =&lt; 21 days (=&lt; 6 weeks for&#xD;
             monoclonal antibodies) prior to first administration of study treatment or those who&#xD;
             have not recovered from adverse events due to agents administered more than 4 weeks&#xD;
             earlier&#xD;
&#xD;
          -  Patients who are receiving any other investigational agents&#xD;
&#xD;
          -  Patients with known brain metastases should be excluded from this clinical trial&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to ibrutinib or R-ICE&#xD;
&#xD;
          -  Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor; strong inhibitors&#xD;
             or inducers of CYP3A4/5 should be avoided and moderate inhibitors or inducers should&#xD;
             be used with caution; it is important to regularly consult a frequently-updated list;&#xD;
             medical reference texts such as the Physicians' Desk Reference may also provide this&#xD;
             information; as part of the enrollment/informed consent procedures, the patient will&#xD;
             be counseled on the risk of interactions with other agents, and what to do if new&#xD;
             medications need to be prescribed or if the patient is considering a new&#xD;
             over-the-counter medicine or herbal product&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac&#xD;
             arrhythmia, or psychiatric illness/social situations that would limit compliance with&#xD;
             study requirements; recent infections requiring systemic treatment need to have&#xD;
             completed therapy &gt; 14 days before the first dose of study drug&#xD;
&#xD;
          -  Pregnant women are excluded from this study; breastfeeding should be discontinued if&#xD;
             the mother is treated with ibrutinib R-ICE&#xD;
&#xD;
          -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral&#xD;
             therapy are eligible, unless the patient's CD4 count is below the institutional lower&#xD;
             limit of normal, or the patient is taking prohibited CYP3A4/5 strong inhibitors or&#xD;
             inducers&#xD;
&#xD;
          -  Patients may not have received any anti-cancer therapy for their primary relapsed&#xD;
             (rel)/refractory (ref) DLBCL with the exception of palliative radiation therapy (RT)&#xD;
&#xD;
          -  Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura (ITP)&#xD;
             resulting in (or as evidenced by) declining platelet or hemoglobin (Hgb) levels within&#xD;
             the 4 weeks prior to first dose of study drug&#xD;
&#xD;
          -  Presence of transfusion-dependent thrombocytopenia&#xD;
&#xD;
          -  Prior exposure to bruton tyrosine kinase (BTK) inhibitor&#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 cervical 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 first dose with study drug&#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 will need a negative polymerase chain reaction (PCR) prior to&#xD;
             enrollment (PCR positive patients will be excluded); hepatitis C antibody positive&#xD;
             patients are eligible if PCR is negative&#xD;
&#xD;
          -  History of stroke or intracranial hemorrhage within 6 months prior to enrollment&#xD;
&#xD;
          -  Current life-threatening illness, medical condition, or organ system dysfunction&#xD;
             which, in the Investigator's opinion, could compromise the patient's safety, or put&#xD;
             the study at risk&#xD;
&#xD;
          -  Received anticoagulation therapy with Coumadin or equivalent vitamin K antagonists&#xD;
             within the last 28 days&#xD;
&#xD;
          -  Vaccinated with live, attenuated vaccines with 4 weeks of first does of study drug&#xD;
&#xD;
          -  Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved&#xD;
             to Common Terminology Criteria for Adverse Event (CTCAE, version 4), grade =&lt; 1, or to&#xD;
             the levels dictated in the inclusion/exclusion criteria with the exception of alopecia&#xD;
&#xD;
          -  Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia&#xD;
&#xD;
          -  Unwilling or unable to participate in all required study evaluations and procedures&#xD;
&#xD;
          -  Currently active, clinically significant hepatic impairment &gt;= moderate hepatic&#xD;
             impairment according to the National Cancer Institute (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>Craig Sauter</last_name>
    <role>Principal Investigator</role>
    <affiliation>Memorial Sloan Kettering Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Memorial Sloan-Kettering Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2018</verification_date>
  <study_first_submitted>July 16, 2014</study_first_submitted>
  <study_first_submitted_qc>August 15, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 19, 2014</study_first_posted>
  <last_update_submitted>January 25, 2018</last_update_submitted>
  <last_update_submitted_qc>January 25, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">January 26, 2018</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>
    <mesh_term>Lymphoma, B-Cell</mesh_term>
    <mesh_term>Lymphoma, Large B-Cell, Diffuse</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rituximab</mesh_term>
    <mesh_term>Antineoplastic Agents, Immunological</mesh_term>
    <mesh_term>Carboplatin</mesh_term>
    <mesh_term>Etoposide</mesh_term>
    <mesh_term>Etoposide phosphate</mesh_term>
    <mesh_term>Ifosfamide</mesh_term>
    <mesh_term>Isophosphamide mustard</mesh_term>
    <mesh_term>Podophyllotoxin</mesh_term>
    <mesh_term>Antibodies</mesh_term>
    <mesh_term>Immunoglobulins</mesh_term>
    <mesh_term>Antibodies, Monoclonal</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/NCT02219737
org study id: NCI-2014-00571
secondary id: NCI-2014-00571
secondary id: 14-145
secondary id: 9588
secondary id: 9588
secondary id: P30CA008748
nct id: NCT02219737
lead sponsor: 
has dmc: No
This phase I trial studies the side effects and best dose of ibrutinib when given together
      with rituximab, ifosfamide, carboplatin, and etoposide (combination chemotherapy) in treating
      patients with diffuse large B-cell lymphoma (DLBCL) that has returned after a period of
      improvement (relapsed) or has not responded to treatment (refractory). Ibrutinib may stop the
      growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in
      chemotherapy, such as, rituximab, ifosfamide, carboplatin, and etoposide, work in different
      ways to stop the growth of cancer cells, either by killing the cells, by stopping them from
      dividing, or by stopping them from spreading. Giving ibrutinib together with combination
      chemotherapy may be a better treatment for patients with relapsed or refractory DLBCL.
PRIMARY OBJECTIVES:

      I. Safety of ibrutinib in combination with rituximab-ifosfamide, carboplatin, and etoposide
      (R-ICE).

      II. Establishment of maximum tolerated dose of ibrutinib with R-ICE.

      SECONDARY OBJECTIVES:

      I. Pharmacokinetic (PK) studies of ibrutinib in combination with R-ICE. II. Clinical response
      rate of ibrutinib+R-ICE.

      OUTLINE: This is a dose-escalation study of ibrutinib.

      Patients receive ibrutinib orally (PO) once daily (QD) on days 1-21, rituximab intravenously
      (IV) on day 1, ifosfamide IV on day 3, carboplatin intravenously piggy back (IVPB) on day 3,
      and etoposide IVPB on days 2-4. Treatment repeats every 21 days for up to 3 courses in the
      absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for 52 weeks.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum tolerated dose of the combination of ibrutinib with standard dosing R-ICE, graded using the Common Terminology Criteria for Adverse Events 4.0
time frame: Day 21
measure: Toxicity of the combination of ibrutinib with standard dosing R-ICE, graded using the CTCAE 4.0
time frame: Up to week 52
measure: Overall response rate, defined as the sum of partial and complete responses as determined by revised International Working Group Criteria for Malignant Lymphoma
time frame: Up to week 52
description: The proportion of patients who achieve a clinical response (partial response or better) will be estimated in this patient population. This will be calculated among patients who receive any study drug, and additionally among patients who complete three cycles of therapy.
measure: PK parameters of ibrutinib in the presence of R-ICE as a measure of potential drug-drug interaction
time frame: Predose, 30 minutes, 1, 2, 3, 4, 6, 8, 10 (optional), and 24 hours on day 15 (course 1) and day 1 (course 2)
arm group label: Treatment (ibrutinib, R-ICE)
arm group type: Experimental
description: Patients receive ibrutinib PO QD on days 1-21, rituximab IV on day 1, ifosfamide IV on day 3, carboplatin IVPB on day 3, and etoposide IVPB on days 2-4. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.
intervention type: Drug
intervention name: Carboplatin
description: Given IVPB
arm group label: Treatment (ibrutinib, R-ICE)
other name: Blastocarb
other name: Carboplat
other name: Carboplatin Hexal
other name: Carboplatino
other name: Carbosin
other name: Carbosol
other name: Carbotec
other name: CBDCA
other name: Displata
other name: Ercar
other name: JM-8
other name: Nealorin
other name: Novoplatinum
other name: Paraplatin
other name: Paraplatin AQ
other name: Paraplatine
other name: Platinwas
other name: Ribocarbo
intervention type: Drug
intervention name: Etoposide
description: Given IVPB
arm group label: Treatment (ibrutinib, R-ICE)
other name: Demethyl Epipodophyllotoxin Ethylidine Glucoside
other name: EPEG
other name: Lastet
other name: Toposar
other name: Vepesid
other name: VP 16-213
other name: VP-16
other name: VP-16-213
intervention type: Drug
intervention name: Ibrutinib
description: Given PO
arm group label: Treatment (ibrutinib, R-ICE)
other name: BTK Inhibitor PCI-32765
other name: CRA-032765
other name: Imbruvica
other name: PCI-32765
intervention type: Drug
intervention name: Ifosfamide
description: Given IV
arm group label: Treatment (ibrutinib, R-ICE)
other name: Asta Z 4942
other name: Asta Z-4942
other name: Cyfos
other name: Holoxan
other name: Holoxane
other name: Ifex
other name: IFO
other name: IFO-Cell
other name: Ifolem
other name: Ifomida
other name: Ifomide
other name: Ifosfamidum
other name: Ifoxan
other name: IFX
other name: Iphosphamid
other name: Iphosphamide
other name: Iso-Endoxan
other name: Isoendoxan
other name: Isophosphamide
other name: Mitoxana
other name: MJF 9325
other name: MJF-9325
other name: Naxamide
other name: Seromida
other name: Tronoxal
other name: Z 4942
other name: Z-4942
intervention type: Other
intervention name: Laboratory Biomarker Analysis
description: Correlative studies
arm group label: Treatment (ibrutinib, R-ICE)
intervention type: Other
intervention name: Pharmacological Study
description: Correlative studies
arm group label: Treatment (ibrutinib, R-ICE)
intervention type: Biological
intervention name: Rituximab
description: Given IV
arm group label: Treatment (ibrutinib, R-ICE)
other name: ABP 798
other name: BI 695500
other name: C2B8 Monoclonal Antibody
other name: Chimeric Anti-CD20 Antibody
other name: CT-P10
other name: IDEC-102
other name: IDEC-C2B8
other name: IDEC-C2B8 Monoclonal Antibody
other name: MabThera
other name: Monoclonal Antibody IDEC-C2B8
other name: PF-05280586
other name: Rituxan
other name: Rituximab Biosimilar ABP 798
other name: Rituximab Biosimilar BI 695500
other name: Rituximab Biosimilar CT-P10
other name: Rituximab Biosimilar GB241
other name: Rituximab Biosimilar IBI301
other name: Rituximab Biosimilar PF-05280586
other name: Rituximab Biosimilar RTXM83
other name: Rituximab Biosimilar SAIT101
other name: RTXM83
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Craig Sauter
role: Principal Investigator
affiliation: Memorial Sloan Kettering Cancer Center
facility: 
country: United States
responsible party type: Sponsor
mesh term: Lymphoma
mesh term: Lymphoma, B-Cell
mesh term: Lymphoma, Large B-Cell, Diffuse
mesh term: Rituximab
mesh term: Antineoplastic Agents, Immunological
mesh term: Carboplatin
mesh term: Etoposide
mesh term: Etoposide phosphate
mesh term: Ifosfamide
mesh term: Isophosphamide mustard
mesh term: Podophyllotoxin
mesh term: Antibodies
mesh term: Immunoglobulins
mesh term: Antibodies, Monoclonal