<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/NCT03015792</url>
  </required_header>
  <id_info>
    <org_study_id>MC148A</org_study_id>
    <secondary_id>NCI-2017-00006</secondary_id>
    <nct_id>NCT03015792</nct_id>
  </id_info>
  <brief_title>Ibrutinib, Lenalidomide, and Dexamethasone in Treating Patients With Multiple Myeloma Ineligible for Transplant</brief_title>
  <official_title>Phase I/II Trial of Ibrutinib, Dexamethasone, and Lenalidomide as Initial Therapy for Transplant Ineligible Multiple Myeloma Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Mayo Clinic</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Mayo Clinic</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase I/II trial studies the best dose and side effects of ibrutinib when given together&#xD;
      with lenalidomide and dexamethasone and how well they work in treating patients with multiple&#xD;
      myeloma that are not eligible for transplant. Ibrutinib may stop the growth of tumor cells by&#xD;
      blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as&#xD;
      lenalidomide and dexamethasone, work in different ways to stop the growth of tumor cells,&#xD;
      either by killing the cells, by stopping them from dividing, or by stopping them from&#xD;
      spreading. Giving ibrutinib, lenalidomide, and dexamethasone may work better in treating&#xD;
      patients with multiple myeloma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To determine the maximum tolerated dose (MTD) of ibrutinib that can be combined with&#xD;
      lenalidomide and dexamethasone in relapsed multiple myeloma (MM) patients. (Phase I) II. To&#xD;
      estimate the overall response rate (ORR) including partial response (PR) or better of the&#xD;
      combination of ibrutinib, lenalidomide, and dexamethasone in subjects with newly diagnosed MM&#xD;
      who are not candidates for high dose chemotherapy and autologous stem cell transplantation&#xD;
      (ASCT). (Phase II)&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To evaluate the safety profile of this regimen in relapsed MM patients. (Phase I) II. To&#xD;
      evaluate the progression free survival (PFS) of the combination of ibrutinib, lenalidomide,&#xD;
      and dexamethasone in MM patients. (Phase II) III. To evaluate the safety profile of this&#xD;
      regimen in untreated MM patients. (Phase II) IV. To evaluate the duration of response for&#xD;
      patients treated with this 3-drug regimen. (Phase II) V. To evaluate overall survival (OS)&#xD;
      for patients treated with this 3-drug regimen. (Phase II)&#xD;
&#xD;
      EXPLORATORY OBJECTIVES:&#xD;
&#xD;
      I. To explore compliance to treatment. II. To assess effects of treatment on patient-reported&#xD;
      quality of life (QoL) measures.&#xD;
&#xD;
      CORRELATIVE RESEARCH OBJECTIVES:&#xD;
&#xD;
      I. To determine the role of members of the BTK signalosome in achievement or lack thereof of&#xD;
      response to ibrutinib.&#xD;
&#xD;
      II. To explore biologic effects of ibrutinib on microenvironment in MM and correlate with&#xD;
      response to treatment.&#xD;
&#xD;
      III. To evaluate pharmacodynamic measures including receptor occupancy for BTK prior to&#xD;
      introducing lenalidomide in patients treated with ibrutinib and dexamethasone.&#xD;
&#xD;
      IV. To evaluate the impact of ibrutinib on platelet aggregation.&#xD;
&#xD;
      OUTLINE: This is a phase I, dose-escalation study of ibrutinib followed by a phase II study.&#xD;
&#xD;
      PHASE I: Patients receive ibrutinib orally (PO) on days 1-28, lenalidomide PO on days 1-21,&#xD;
      and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 24&#xD;
      courses in the absence of disease progression or unacceptable toxicity. Beginning course 25,&#xD;
      patients receive lenalidomide PO on days 1-21 and dexamethasone PO on days 1, 8, 15, and 22.&#xD;
      Courses repeat every 84 days in the absence of disease progression or unacceptable toxicity.&#xD;
&#xD;
      PHASE II: Patients receive ibrutinib and dexamethasone as in phase I and lenalidomide PO on&#xD;
      days 1-21 beginning course 2. Beginning course 25, patients receive lenalidomide and&#xD;
      dexamethasone as in phase I.&#xD;
&#xD;
      After completion of study treatment, patients are followed up every 3 months, then every 6&#xD;
      months for up to 3 years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Per CS0139535 -submitter stated we can update status to Admin complete- low accrual reasoning&#xD;
  </why_stopped>
  <start_date type="Actual">March 10, 2017</start_date>
  <completion_date type="Actual">October 18, 2022</completion_date>
  <primary_completion_date type="Actual">October 18, 2022</primary_completion_date>
  <phase>Phase 1/Phase 2</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 (MTD) defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.0 (Phase I)</measure>
    <time_frame>Up to 28 days</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Rate of confirmed response defined as patient who has achieved a stringent (s) complete response (CR), CR, very good partial response (VGPR), or partial response (PR) on two consecutive evaluations at any time during treatment (Phase II)</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Response will be evaluated using all cycles of treatment. Responses will be summarized by simple descriptive summary statistics delineating depth of response as well as stable and progressive disease in this patient population. Ninety-five percent confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (Phase II)</measure>
    <time_frame>From registration to the time of progression or death due to any cause, assessed up to 3 years</time_frame>
    <description>The distribution of progression-free survival will be estimated using the method of Kaplan-Meier.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (Phase II)</measure>
    <time_frame>From registration to death due to any cause, assessed up to 3 years</time_frame>
    <description>The distribution of survival time will be estimated using the method of Kaplan-Meier.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response (Phase II)</measure>
    <time_frame>The date at which the patient's objective status is first noted to be a sCR, CR, VGPR, or PR to the earliest date progression is documented, assessed up to 3 years</time_frame>
    <description>The distribution of duration of response will be estimated using the method of Kaplan-Meier.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of adverse events assessed by CTCAE v 4.0 (Phase II)</measure>
    <time_frame>Up to 30 days after last dose of study treatment</time_frame>
    <description>The number and severity of all adverse events (overall and by dose-level) will be tabulated and summarized in this patient population. The grade 3+ adverse events will also be described and summarized in a similar fashion. Overall toxicity incidence as well as toxicity profiles by dose level and patient will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Compliance to treatment (Phase II)</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Patient compliance to ibrutinib, dexamethasone, and lenalidomide will be assessed by means of self-reported and healthcare staff assessed pill count/diary. Correlation between medication adherence and disease response will be assessed.</description>
  </other_outcome>
  <other_outcome>
    <measure>QoL measured by the MD Anderson Symptom Inventory - Multiple Myeloma (Phase II)</measure>
    <time_frame>Up to 3 years</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>BTK signalosome members (Phase II)</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Will be profiled by MSD-based mesoscale assay (or phospho-flow) at baseline before treatment, after cycle 1 (phase II patients only), and at the time of response assessment or disease progression. BTK signalosome component expression levels will be determined from BM and/or peripheral blood. Each measure will be summarized descriptively at each time point and changes across time will be evaluated. Correlation with response to overall therapy will be assessed using Wilcoxon's rank sum tests.</description>
  </other_outcome>
  <other_outcome>
    <measure>T-cells populations modulation (Phase II)</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Will conduct flow cytometry/fluorescence activated cell sorting (FACS) analysis to identify percentages of the immune cell populations (T-cells, natural killer cells, macrophages) in the bone marrow and peripheral blood at baseline before treatment, after cycle 1 (phase II patients only) and at the time of response assessment or disease progression. Each measure will be summarized descriptively at each time point and changes across time will be evaluated. Correlation with response to overall therapy will be assessed using Wilcoxon's rank sum tests.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">18</enrollment>
  <condition>Recurrent Plasma Cell Myeloma</condition>
  <condition>Refractory Plasma Cell Myeloma</condition>
  <arm_group>
    <arm_group_label>Treatment (ibrutinib, lenalidomide, dexamethasone)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>PHASE I: Patients receive ibrutinib PO on days 1-28, lenalidomide PO on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Beginning course 25, patients receive lenalidomide PO on days 1-21 and dexamethasone PO on days 1, 8, 15, and 22. Courses repeat every 84 days in the absence of disease progression or unacceptable toxicity.&#xD;
PHASE II: Patients receive ibrutinib and dexamethasone as in phase I and lenalidomide PO on days 1-21 beginning course 2. Beginning course 25, patients receive lenalidomide and dexamethasone as in phase I.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dexamethasone</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (ibrutinib, lenalidomide, dexamethasone)</arm_group_label>
    <other_name>Aacidexam</other_name>
    <other_name>Adexone</other_name>
    <other_name>Aknichthol Dexa</other_name>
    <other_name>Alba-Dex</other_name>
    <other_name>Alin</other_name>
    <other_name>Alin Depot</other_name>
    <other_name>Alin Oftalmico</other_name>
    <other_name>Amplidermis</other_name>
    <other_name>Anemul mono</other_name>
    <other_name>Auricularum</other_name>
    <other_name>Auxiloson</other_name>
    <other_name>Baycadron</other_name>
    <other_name>Baycuten</other_name>
    <other_name>Baycuten N</other_name>
    <other_name>Cortidexason</other_name>
    <other_name>Cortisumman</other_name>
    <other_name>Decacort</other_name>
    <other_name>Decadrol</other_name>
    <other_name>Decadron</other_name>
    <other_name>Decadron DP</other_name>
    <other_name>Decalix</other_name>
    <other_name>Decameth</other_name>
    <other_name>Decasone R.p.</other_name>
    <other_name>Dectancyl</other_name>
    <other_name>Dekacort</other_name>
    <other_name>Deltafluorene</other_name>
    <other_name>Deronil</other_name>
    <other_name>Desamethasone</other_name>
    <other_name>Desameton</other_name>
    <other_name>Dexa-Mamallet</other_name>
    <other_name>Dexa-Rhinosan</other_name>
    <other_name>Dexa-Scheroson</other_name>
    <other_name>Dexa-sine</other_name>
    <other_name>Dexacortal</other_name>
    <other_name>Dexacortin</other_name>
    <other_name>Dexafarma</other_name>
    <other_name>Dexafluorene</other_name>
    <other_name>Dexalocal</other_name>
    <other_name>Dexamecortin</other_name>
    <other_name>Dexameth</other_name>
    <other_name>Dexamethasone Intensol</other_name>
    <other_name>Dexamethasonum</other_name>
    <other_name>Dexamonozon</other_name>
    <other_name>Dexapos</other_name>
    <other_name>Dexinoral</other_name>
    <other_name>Dexone</other_name>
    <other_name>Dinormon</other_name>
    <other_name>Dxevo</other_name>
    <other_name>Fluorodelta</other_name>
    <other_name>Fortecortin</other_name>
    <other_name>Gammacorten</other_name>
    <other_name>Hemady</other_name>
    <other_name>Hexadecadrol</other_name>
    <other_name>Hexadrol</other_name>
    <other_name>Lokalison-F</other_name>
    <other_name>Loverine</other_name>
    <other_name>Methylfluorprednisolone</other_name>
    <other_name>Millicorten</other_name>
    <other_name>Mymethasone</other_name>
    <other_name>Orgadrone</other_name>
    <other_name>Spersadex</other_name>
    <other_name>TaperDex</other_name>
    <other_name>Visumetazone</other_name>
    <other_name>ZoDex</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ibrutinib</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (ibrutinib, lenalidomide, dexamethasone)</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>Other</intervention_type>
    <intervention_name>Laboratory Biomarker Analysis</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Treatment (ibrutinib, lenalidomide, dexamethasone)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lenalidomide</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (ibrutinib, lenalidomide, dexamethasone)</arm_group_label>
    <other_name>CC-5013</other_name>
    <other_name>CC5013</other_name>
    <other_name>CDC 501</other_name>
    <other_name>Revlimid</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Pharmacological Study</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Treatment (ibrutinib, lenalidomide, dexamethasone)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Quality-of-Life Assessment</intervention_name>
    <description>Ancillary studies</description>
    <arm_group_label>Treatment (ibrutinib, lenalidomide, dexamethasone)</arm_group_label>
    <other_name>Quality of Life Assessment</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age &gt;= 18 years&#xD;
&#xD;
          -  Diagnosis&#xD;
&#xD;
               -  Phase I: confirmed diagnosis of relapsed or refractory multiple myeloma&#xD;
&#xD;
               -  Phase II: confirmed diagnosis of active multiple myeloma and must be newly&#xD;
                  diagnosed&#xD;
&#xD;
               -  NOTE: all tests for establishing disease status must be completed =&lt; 28 days&#xD;
                  prior to registration&#xD;
&#xD;
          -  Measurable disease =&lt; 28 days prior to registration, defined by at least one of the&#xD;
             following:&#xD;
&#xD;
               -  Serum monoclonal protein &gt;= 1.0 g/dL&#xD;
&#xD;
               -  &gt; 200 mg of monoclonal protein in the urine on 24-hour electrophoresis&#xD;
&#xD;
               -  Serum immunoglobulin free light chain &gt; 10 mg/dL AND abnormal serum&#xD;
                  immunoglobulin kappa to lambda free light chain ratio&#xD;
&#xD;
               -  Monoclonal bone marrow plasmacytosis &gt; 30% (evaluable disease)&#xD;
&#xD;
          -  Prior treatment&#xD;
&#xD;
               -  Phase I: exposure to 2-3 prior lines of therapy or no therapeutic options&#xD;
&#xD;
               -  Phase II: previously untreated for symptomatic MM&#xD;
&#xD;
               -  EXCEPTION: =&lt; 7 days with pulse steroids or localized radiation therapy, without&#xD;
                  curative intent, for a myeloma-related complication prior to registration is&#xD;
                  allowed, as considered necessary by the treating physician&#xD;
&#xD;
          -  Myeloma Frailty Score:&#xD;
&#xD;
               -  NOTE: this will include calculating a frailty score (based on age, activities of&#xD;
                  daily living, instrumental activities of daily living and Charlson comorbidity&#xD;
                  index)&#xD;
&#xD;
                    -  Phase I: &quot;intermediate fitness&quot; or &quot;frail&quot;; NOTE: no &quot;fit&quot; patients will be&#xD;
                       included in the phase 1 portion of the trial which is being done to&#xD;
                       determine the MTD of the 3-drug combination&#xD;
&#xD;
                    -  Phase II: transplant-ineligible as per their treating physician; NOTE: all&#xD;
                       the patients with &quot;intermediate fitness&quot; or &quot;frail&quot; status will be&#xD;
                       considered transplant-ineligible; other reasons to consider transplant&#xD;
                       ineligibility may include, but are not limited to: financial constraints or&#xD;
                       patient preference; in case such patients have a frailty score of &quot;fit&quot;, it&#xD;
                       should be duly noted by the treating physician&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) &gt;= 1,000 cell/mm^3 without growth factor support&#xD;
             (obtained =&lt; 14 days prior to registration)&#xD;
&#xD;
          -  Platelets &gt;= 50,000 cells/mm^3 for patients who have bone marrow (obtained =&lt; 14 days&#xD;
             prior to registration)&#xD;
&#xD;
          -  Plasmacytosis &lt; 50% or &gt;= 30,000 cells/mm^3 for patients who have bone marrow&#xD;
             plasmacytosis of &gt;= 50% (obtained =&lt; 14 days prior to registration)&#xD;
&#xD;
          -  Calculated or measured creatinine clearance &gt;= 30 ml/min (obtained =&lt; 14 days prior to&#xD;
             registration)&#xD;
&#xD;
          -  Total bilirubin =&lt; 1.5 x upper limit of normal (ULN) unless due to Gilbert's syndrome&#xD;
             (obtained =&lt; 14 days prior to registration)&#xD;
&#xD;
          -  Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) and&#xD;
             alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) =&lt; 3 x ULN&#xD;
             (obtained =&lt; 14 days prior to registration)&#xD;
&#xD;
          -  Prothrombin time (PT)/international normalized ratio (INR) =&lt; 1.5 X ULN (obtained =&lt;&#xD;
             14 days prior to registration)&#xD;
&#xD;
          -  Provide informed written consent&#xD;
&#xD;
          -  Willing to return to enrolling institution for follow-up (during the active monitoring&#xD;
             phase of the study)&#xD;
&#xD;
          -  Persons able to become pregnant must be willing to adhere to the scheduled pregnancy&#xD;
             testing as required in the REVLIMID Risk Evaluation and Mitigation Strategy (REMS)&#xD;
             program&#xD;
&#xD;
          -  Willing to be registered into the mandatory REVLIMID REMS program, and willing and&#xD;
             able to comply with the requirements of the REVLIMID REMS program&#xD;
&#xD;
          -  Ability to complete study-related (QoL, pill diary) questionnaire(s) by themselves or&#xD;
             with assistance&#xD;
&#xD;
          -  Willing to provide bone marrow aspirate and core, and blood samples for correlative&#xD;
             research purposes&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Non-secretory MM or known amyloid light-chain (AL) amyloidosis&#xD;
&#xD;
          -  Clinically significant active infection requiring intravenous antibiotics =&lt; 14 days&#xD;
             prior to registration&#xD;
&#xD;
          -  &gt;= grade 3 neuropathy and/or POEMS syndrome (plasma cell dyscrasia with&#xD;
             polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)&#xD;
&#xD;
          -  Other prior malignancy; EXCEPTIONS:&#xD;
&#xD;
               -  Adequately treated basal cell or squamous cell skin cancer&#xD;
&#xD;
               -  Any in situ cancer&#xD;
&#xD;
               -  Adequately treated stage I or II cancer from which the patient is currently in&#xD;
                  complete remission, or&#xD;
&#xD;
               -  Any other cancer from which the patient has been disease-free for &gt;= at least&#xD;
                  three years prior to registration&#xD;
&#xD;
          -  Concurrent therapy considered to be investigational; NOTE: patients must not be&#xD;
             planning to receive any radiation therapy (except localized radiation for palliative&#xD;
             care that must be completed prior to starting cycle 1, day 1)&#xD;
&#xD;
          -  Any of the following:&#xD;
&#xD;
               -  Pregnant women&#xD;
&#xD;
               -  Nursing women (lactating females are eligible provided that they agree not to&#xD;
                  breast feed while taking lenalidomide)&#xD;
&#xD;
               -  Men or women of childbearing potential who are unwilling to employ adequate&#xD;
                  contraception&#xD;
&#xD;
          -  Requires treatment with a strong cytochrome (CYP) 3A4/5 inhibitor&#xD;
&#xD;
          -  Major surgery =&lt; 4 weeks prior to registration&#xD;
&#xD;
          -  History of stroke/intracranial hemorrhage =&lt; 6 months prior to registration&#xD;
&#xD;
          -  Requires use of therapeutic anticoagulation prior to registration&#xD;
&#xD;
               -  NOTE: thromboprophylaxis with any agent is permitted&#xD;
&#xD;
          -  History of clinically significant bleeding or known platelet or coagulation disorder&#xD;
&#xD;
          -  Clinically significant cardiac illness including New York Heart Association (NYHA)&#xD;
             class III or class IV heart failure, unstable angina pectoris, myocardial infarction&#xD;
             within the past 6 months, or &gt;= grade 3 cardiac arrhythmias noted =&lt; 14 days prior to&#xD;
             registration&#xD;
&#xD;
          -  Hepatic impairment:&#xD;
&#xD;
               -  Phase I: any currently active, clinically significant hepatic impairment&#xD;
                  (Child-Pugh class A, B, or C according to the Child Pugh classification)&#xD;
&#xD;
               -  Phase II: currently active, clinically significant hepatic impairment Child-Pugh&#xD;
                  class B or C according to the Child Pugh classification&#xD;
&#xD;
          -  Known human immunodeficiency virus (HIV) positive (+) patients; EXCEPTION: if they&#xD;
             meet the following additional criteria =&lt; 28 days prior to registration:&#xD;
&#xD;
               -  CD4 cells &gt;= 500/mm^3&#xD;
&#xD;
               -  Viral load of &lt; 50 copies HIV messenger (m) ribonucleic acid (RNA)/mm^3 if on&#xD;
                  combination antiretroviral therapy (cART) or &lt; 10,000 copies HIV mRNA if not on&#xD;
                  cART • No zidovudine or stavudine as part of cART&#xD;
&#xD;
          -  Known hepatitis B or hepatitis C infection; EXCEPTION: if viral load &lt; 800,000 IU/L&#xD;
&#xD;
          -  Phase I: active dermatologic disease &gt;= grade 3&#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>Sikander Ailawadhi</last_name>
    <role>Principal Investigator</role>
    <affiliation>Mayo Clinic</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Mayo Clinic in Florida</name>
      <address>
        <city>Jacksonville</city>
        <state>Florida</state>
        <zip>32224-9980</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>January 4, 2017</study_first_submitted>
  <study_first_submitted_qc>January 6, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 10, 2017</study_first_posted>
  <last_update_submitted>March 3, 2023</last_update_submitted>
  <last_update_submitted_qc>March 3, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 7, 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>Multiple Myeloma</mesh_term>
    <mesh_term>Neoplasms, Plasma Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dexamethasone</mesh_term>
    <mesh_term>Dexamethasone acetate</mesh_term>
    <mesh_term>Lenalidomide</mesh_term>
    <mesh_term>Ichthammol</mesh_term>
    <mesh_term>BB 1101</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/NCT03015792
org study id: MC148A
secondary id: NCI-2017-00006
nct id: NCT03015792
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This phase I/II trial studies the best dose and side effects of ibrutinib when given together
      with lenalidomide and dexamethasone and how well they work in treating patients with multiple
      myeloma that are not eligible for transplant. Ibrutinib may stop the growth of tumor cells by
      blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as
      lenalidomide and dexamethasone, work in different ways to stop the growth of tumor cells,
      either by killing the cells, by stopping them from dividing, or by stopping them from
      spreading. Giving ibrutinib, lenalidomide, and dexamethasone may work better in treating
      patients with multiple myeloma.
PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated dose (MTD) of ibrutinib that can be combined with
      lenalidomide and dexamethasone in relapsed multiple myeloma (MM) patients. (Phase I) II. To
      estimate the overall response rate (ORR) including partial response (PR) or better of the
      combination of ibrutinib, lenalidomide, and dexamethasone in subjects with newly diagnosed MM
      who are not candidates for high dose chemotherapy and autologous stem cell transplantation
      (ASCT). (Phase II)

      SECONDARY OBJECTIVES:

      I. To evaluate the safety profile of this regimen in relapsed MM patients. (Phase I) II. To
      evaluate the progression free survival (PFS) of the combination of ibrutinib, lenalidomide,
      and dexamethasone in MM patients. (Phase II) III. To evaluate the safety profile of this
      regimen in untreated MM patients. (Phase II) IV. To evaluate the duration of response for
      patients treated with this 3-drug regimen. (Phase II) V. To evaluate overall survival (OS)
      for patients treated with this 3-drug regimen. (Phase II)

      EXPLORATORY OBJECTIVES:

      I. To explore compliance to treatment. II. To assess effects of treatment on patient-reported
      quality of life (QoL) measures.

      CORRELATIVE RESEARCH OBJECTIVES:

      I. To determine the role of members of the BTK signalosome in achievement or lack thereof of
      response to ibrutinib.

      II. To explore biologic effects of ibrutinib on microenvironment in MM and correlate with
      response to treatment.

      III. To evaluate pharmacodynamic measures including receptor occupancy for BTK prior to
      introducing lenalidomide in patients treated with ibrutinib and dexamethasone.

      IV. To evaluate the impact of ibrutinib on platelet aggregation.

      OUTLINE: This is a phase I, dose-escalation study of ibrutinib followed by a phase II study.

      PHASE I: Patients receive ibrutinib orally (PO) on days 1-28, lenalidomide PO on days 1-21,
      and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 24
      courses in the absence of disease progression or unacceptable toxicity. Beginning course 25,
      patients receive lenalidomide PO on days 1-21 and dexamethasone PO on days 1, 8, 15, and 22.
      Courses repeat every 84 days in the absence of disease progression or unacceptable toxicity.

      PHASE II: Patients receive ibrutinib and dexamethasone as in phase I and lenalidomide PO on
      days 1-21 beginning course 2. Beginning course 25, patients receive lenalidomide and
      dexamethasone as in phase I.

      After completion of study treatment, patients are followed up every 3 months, then every 6
      months for up to 3 years.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum tolerated dose (MTD) defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.0 (Phase I)
time frame: Up to 28 days
measure: Rate of confirmed response defined as patient who has achieved a stringent (s) complete response (CR), CR, very good partial response (VGPR), or partial response (PR) on two consecutive evaluations at any time during treatment (Phase II)
time frame: Up to 3 years
description: Response will be evaluated using all cycles of treatment. Responses will be summarized by simple descriptive summary statistics delineating depth of response as well as stable and progressive disease in this patient population. Ninety-five percent confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner.
measure: Progression-free survival (Phase II)
time frame: From registration to the time of progression or death due to any cause, assessed up to 3 years
description: The distribution of progression-free survival will be estimated using the method of Kaplan-Meier.
measure: Overall survival (Phase II)
time frame: From registration to death due to any cause, assessed up to 3 years
description: The distribution of survival time will be estimated using the method of Kaplan-Meier.
measure: Duration of response (Phase II)
time frame: The date at which the patient's objective status is first noted to be a sCR, CR, VGPR, or PR to the earliest date progression is documented, assessed up to 3 years
description: The distribution of duration of response will be estimated using the method of Kaplan-Meier.
measure: Incidence of adverse events assessed by CTCAE v 4.0 (Phase II)
time frame: Up to 30 days after last dose of study treatment
description: The number and severity of all adverse events (overall and by dose-level) will be tabulated and summarized in this patient population. The grade 3+ adverse events will also be described and summarized in a similar fashion. Overall toxicity incidence as well as toxicity profiles by dose level and patient will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses.
measure: Compliance to treatment (Phase II)
time frame: Up to 3 years
description: Patient compliance to ibrutinib, dexamethasone, and lenalidomide will be assessed by means of self-reported and healthcare staff assessed pill count/diary. Correlation between medication adherence and disease response will be assessed.
measure: QoL measured by the MD Anderson Symptom Inventory - Multiple Myeloma (Phase II)
time frame: Up to 3 years
measure: BTK signalosome members (Phase II)
time frame: Up to 3 years
description: Will be profiled by MSD-based mesoscale assay (or phospho-flow) at baseline before treatment, after cycle 1 (phase II patients only), and at the time of response assessment or disease progression. BTK signalosome component expression levels will be determined from BM and/or peripheral blood. Each measure will be summarized descriptively at each time point and changes across time will be evaluated. Correlation with response to overall therapy will be assessed using Wilcoxon's rank sum tests.
measure: T-cells populations modulation (Phase II)
time frame: Up to 3 years
description: Will conduct flow cytometry/fluorescence activated cell sorting (FACS) analysis to identify percentages of the immune cell populations (T-cells, natural killer cells, macrophages) in the bone marrow and peripheral blood at baseline before treatment, after cycle 1 (phase II patients only) and at the time of response assessment or disease progression. Each measure will be summarized descriptively at each time point and changes across time will be evaluated. Correlation with response to overall therapy will be assessed using Wilcoxon's rank sum tests.
arm group label: Treatment (ibrutinib, lenalidomide, dexamethasone)
arm group type: Experimental
description: PHASE I: Patients receive ibrutinib PO on days 1-28, lenalidomide PO on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Beginning course 25, patients receive lenalidomide PO on days 1-21 and dexamethasone PO on days 1, 8, 15, and 22. Courses repeat every 84 days in the absence of disease progression or unacceptable toxicity.
PHASE II: Patients receive ibrutinib and dexamethasone as in phase I and lenalidomide PO on days 1-21 beginning course 2. Beginning course 25, patients receive lenalidomide and dexamethasone as in phase I.
intervention type: Drug
intervention name: Dexamethasone
description: Given PO
arm group label: Treatment (ibrutinib, lenalidomide, dexamethasone)
other name: Aacidexam
other name: Adexone
other name: Aknichthol Dexa
other name: Alba-Dex
other name: Alin
other name: Alin Depot
other name: Alin Oftalmico
other name: Amplidermis
other name: Anemul mono
other name: Auricularum
other name: Auxiloson
other name: Baycadron
other name: Baycuten
other name: Baycuten N
other name: Cortidexason
other name: Cortisumman
other name: Decacort
other name: Decadrol
other name: Decadron
other name: Decadron DP
other name: Decalix
other name: Decameth
other name: Decasone R.p.
other name: Dectancyl
other name: Dekacort
other name: Deltafluorene
other name: Deronil
other name: Desamethasone
other name: Desameton
other name: Dexa-Mamallet
other name: Dexa-Rhinosan
other name: Dexa-Scheroson
other name: Dexa-sine
other name: Dexacortal
other name: Dexacortin
other name: Dexafarma
other name: Dexafluorene
other name: Dexalocal
other name: Dexamecortin
other name: Dexameth
other name: Dexamethasone Intensol
other name: Dexamethasonum
other name: Dexamonozon
other name: Dexapos
other name: Dexinoral
other name: Dexone
other name: Dinormon
other name: Dxevo
other name: Fluorodelta
other name: Fortecortin
other name: Gammacorten
other name: Hemady
other name: Hexadecadrol
other name: Hexadrol
other name: Lokalison-F
other name: Loverine
other name: Methylfluorprednisolone
other name: Millicorten
other name: Mymethasone
other name: Orgadrone
other name: Spersadex
other name: TaperDex
other name: Visumetazone
other name: ZoDex
intervention type: Drug
intervention name: Ibrutinib
description: Given PO
arm group label: Treatment (ibrutinib, lenalidomide, dexamethasone)
other name: BTK Inhibitor PCI-32765
other name: CRA-032765
other name: Imbruvica
other name: PCI-32765
intervention type: Other
intervention name: Laboratory Biomarker Analysis
description: Correlative studies
arm group label: Treatment (ibrutinib, lenalidomide, dexamethasone)
intervention type: Drug
intervention name: Lenalidomide
description: Given PO
arm group label: Treatment (ibrutinib, lenalidomide, dexamethasone)
other name: CC-5013
other name: CC5013
other name: CDC 501
other name: Revlimid
intervention type: Other
intervention name: Pharmacological Study
description: Correlative studies
arm group label: Treatment (ibrutinib, lenalidomide, dexamethasone)
intervention type: Other
intervention name: Quality-of-Life Assessment
description: Ancillary studies
arm group label: Treatment (ibrutinib, lenalidomide, dexamethasone)
other name: Quality of Life Assessment
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Sikander Ailawadhi
role: Principal Investigator
affiliation: Mayo Clinic
facility: 
country: United States
responsible party type: Sponsor
mesh term: Multiple Myeloma
mesh term: Neoplasms, Plasma Cell
mesh term: Dexamethasone
mesh term: Dexamethasone acetate
mesh term: Lenalidomide
mesh term: Ichthammol
mesh term: BB 1101