<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/NCT02251548</url>
  </required_header>
  <id_info>
    <org_study_id>14-296</org_study_id>
    <nct_id>NCT02251548</nct_id>
  </id_info>
  <brief_title>A Phase II Study of Ibrutinib Plus FCR in Previously Untreated, Younger Patients With Chronic Lymphocytic Leukemia</brief_title>
  <acronym>iFCR</acronym>
  <official_title>A Phase II Study of Ibrutinib in Combination With Fludarabine, Cyclophosphamide, and Rituximab (iFCR) in Previously Untreated, Younger Patients With Chronic Lymphocytic Leukemia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Dana-Farber Cancer Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Pharmacyclics LLC.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Leukemia and Lymphoma Society</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Blood Cancer Research Partnership</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Dana-Farber Cancer Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This research study is evaluating a new drug called ibrutinib in combination with the&#xD;
      standard drugs fludarabine, cyclophosphamide, and rituximab (FCR) as a possible treatment for&#xD;
      Chronic Lymphocytic Leukemia (CLL).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Ibrutinib is a type of drug called a kinase inhibitor. It is believed to block a protein&#xD;
      called Bruton's tyrosine kinase (BTK) that helps CLL cells live and grow. By blocking this,&#xD;
      it is possible that the study drug will kill cancer cells or stop them from growing.&#xD;
      Ibrutinib has been FDA approved for the treatment of CLL patients who have received at least&#xD;
      one prior treatment; however, the FDA has not yet approved ibrutinib as the first treatment&#xD;
      for previously untreated CLL. Therefore, ibrutinib is still considered to be study drug,&#xD;
      which means it is still being studied.&#xD;
&#xD;
      Fludarabine, cyclophosphamide, and rituximab (FCR) are intravenous chemotherapy and antibody&#xD;
      drugs that together are a standard chemotherapy regimen used for younger patients with CLL.&#xD;
      Although FCR is highly effective, it does not typically lead to cure.&#xD;
&#xD;
      In this research study, the investigators are combining a new treatment for CLL, ibrutinib,&#xD;
      with a standard chemotherapy regimen for CLL, FCR, to determine whether this combination&#xD;
      (iFCR) is safe and effective for patients with previously untreated CLL.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">October 2014</start_date>
  <completion_date type="Anticipated">January 2025</completion_date>
  <primary_completion_date type="Actual">January 2019</primary_completion_date>
  <phase>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>Part I: Participants Who Achieve a Minimal Residual Disease (MRD) Negative Complete Response (CR) in the Bone Marrow at 2 Months Post FCR</measure>
    <time_frame>2 months after completing combination therapy</time_frame>
    <description>To assess the number of participants who achieve an MRD negative complete response at the 2 months post last dose of FCR timepoint by 2008 IW-CLL criteria ( Hallek et. al). Participants will have a bone marrow biopsy procedure 2 months after completing combination therapy (Ibrutinib+ FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part II: Participants Who Achieve a Minimal Residual Disease (MRD) Negative Complete Response (CR) in the Bone Marrow at 2 Years Post Discontinuation of Ibrutinib After Having Achieved MRD Negative CR at the 2 Months Post FCR Timepoint</measure>
    <time_frame>2 years post discontinuation of ibrutinib after 24 months of ibrutinib maintenance</time_frame>
    <description>Participants will have bone marrow biopsies in tandem with a chest, neck, abdomen and pelvic PET CT scan as clinically indicated after discontinuation of treatment. A central read of the PET CT scan will confirm the radiographic response, and the bone marrow pathology and morphology assessments will confirm morphological response in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate</measure>
    <time_frame>Response assessed after Cycle 3, 2 months post FCR, at 1 year and 2 years post FCR, yearly thereafter for those not having achieved an MRD negative CR, and as clinically indicated</time_frame>
    <description>Participants will have bone marrow biopsies in tandem with a chest, neck, abdomen and pelvic PET CT scan at baseline, end of cycle 3, 2 months post FCR, 1 year post FCR for those not having reached a radiographic CR, 2 years post FCR, and as clinically indicated thereafter. A central read of the PET CT scan will confirm a radiographic response, and the bone marrow pathology and morphology assessments will confirm morphological response in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008). Overall response rate will include PR,CRi and CR</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of Complete Response</measure>
    <time_frame>Response assessed after Cycle 3, 2 months post FCR, at 1 year and 2 years post FCR, yearly thereafter for those not having achieved a radiographic CR, and as clinically indicated thereafter</time_frame>
    <description>Participants will have bone marrow biopsies in tandem with a chest, neck, abdomen and pelvic PET CT scan at baseline, end of cycle 3, 2 months post FCR, 1 year post FCR for those not having reached a radiographic CR, 2 years post FCR, and as clinically indicated thereafter. A central read of the PET CT scan will confirm a radiographic response, and the bone marrow pathology and morphology assessments will confirm morphological response in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of Partial Response</measure>
    <time_frame>Response assessed after Cycle 3, 2 months post FCR, at 1 year and 2 years post FCR, yearly thereafter for those not having achieved an MRD negative CR, and as clinically indicated</time_frame>
    <description>Participants will have bone marrow biopsies in tandem with a chest, neck, abdomen and pelvic PET CT scan at baseline, end of cycle 3, 2 months post FCR, 1 year post FCR for those not having reached a radiographic CR, 2 years post FCR, and as clinically indicated thereafter. A central read of the PET CT scan will confirm a radiographic response, and the bone marrow pathology and morphology assessments will confirm morphological response in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of Progression Free of Survival</measure>
    <time_frame>From date of study entry until the date of first documented progression or date of death from any cause, whichever came first</time_frame>
    <description>Progression free survival is defined as the time from study entry to the earliest documentation of disease progression as defined by 2008 IW-CLL criteria for CLL (Hallek et al., 2008). Participants will be followed for disease progression and/or survival after discontinuation of treatment every 3 months until subsequent therapy, withdrawal, lost to follow up, or death.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of Overall Survival</measure>
    <time_frame>From date of starting study treatment until the date of death from any cause</time_frame>
    <description>Overall survival is defined as the time from study entry to death or date last known alive. Participants will be followed for survival after discontinuation of treatment every 3 months until subsequent therapy, withdrawal, or death.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of MRD Negative CR After 3 Cycles of iFCR</measure>
    <time_frame>After 3 cycles of iFCR for each patient completing 3 cycles; on average, after 12 weeks of treatment during which 1 bone marrow biopsy is performed and MRD is tested</time_frame>
    <description>To determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow after 3 cycles of ibrutinib + FCR. Participants will have a bone marrow biopsy procedure after completing 3 cycles in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of MRD Negative CR After 1 Year of Ibrutinib+ FCR</measure>
    <time_frame>After 12 months (1 year) from the start of therapy</time_frame>
    <description>To determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow at 12 months from start of therapy, participants will have a bone marrow biopsy procedure at the 1 year timepoint after completing combination therapy (ibrutinib + FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of MRD Negative CR After 2 Years of Ibrutinib Maintenance</measure>
    <time_frame>2 years (24 months) from start of therapy</time_frame>
    <description>To determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow at 24 months post last cycle of FCR, participants will have a bone marrow biopsy procedure 24 months after completing combination therapy (ibrutinib + FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants Who Convert From Bone Marrow MRD Negative PR to Bone Marrow MRD Negative CR After 1 Year of Ibrutinib Maintenance</measure>
    <time_frame>12 months ( 1year) after starting therapy</time_frame>
    <description>To determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow at 12 months from start of therapy, participants will have a bone marrow biopsy procedure at the 1 year timepoint after completing combination therapy (ibrutinib + FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants Who Convert From Bone Marrow MRD Negative PR to Bone Marrow MRD Negative CR After 2 Years on Treatment</measure>
    <time_frame>2 years (24 months) from start of therapy</time_frame>
    <description>MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)- Bone marrow biopsies will be performed at baseline, after cycle 3, 2 months post FCR, at 1 year and 2 years of ibrutinib maintenance, and as clinically indicated thereafter- Participants will have a bone marrow biopsy procedure 24 months after completing combination therapy (Ibrutinib+ FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Bone Marrow MRD Negativity</measure>
    <time_frame>From date of starting study treatment until achievement of MRD negativity in the bone marrow</time_frame>
    <description>MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)- Bone marrow biopsies will be performed at baseline, after cycle 3, 2 months post FCR, at 1 year and 2 years of ibrutinib maintenance, and as clinically indicated thereafter</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Participants Who Convert From Bone Marrow MRD Negativity to MRD Positivity in Participants Who Discontinue Ibrutinib</measure>
    <time_frame>From date of starting study treatment until achievement of MRD negativity in the bone marrow to conversion to MRD positivity</time_frame>
    <description>.MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)- Bone marrow biopsies will be performed at baseline, after cycle 3, 2 months post FCR, at 1 year and 2 years of ibrutinib maintenance, and as clinically indicated thereafter</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">85</enrollment>
  <condition>Chronic Lymphocytic Leukemia</condition>
  <condition>Leukemia</condition>
  <arm_group>
    <arm_group_label>Ibrutinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>- Ibrutinib-&#xD;
Oral, daily during each cycle&#xD;
fludarabine-administered at standard dosing for up to 6 cycles&#xD;
cyclophosphamide-administered at standard dosing for up to 6 cycles&#xD;
rituximab-administered at standard dosing for up to 6 cycles</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ibrutinib</intervention_name>
    <description>Oral BTK inhibitor</description>
    <arm_group_label>Ibrutinib</arm_group_label>
    <other_name>Imbruvica™</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fludarabine</intervention_name>
    <description>IV purine analogue chemotherapy agent</description>
    <arm_group_label>Ibrutinib</arm_group_label>
    <other_name>Fludara</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclophosphamide</intervention_name>
    <description>IV alkylator chemotherapy agent</description>
    <arm_group_label>Ibrutinib</arm_group_label>
    <other_name>Cytoxan®</other_name>
    <other_name>Neosar®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rituximab</intervention_name>
    <description>IV anti-CD20 monoclonal antibody</description>
    <arm_group_label>Ibrutinib</arm_group_label>
    <other_name>Rituxan®</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Must have a confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic&#xD;
             lymphoma. as per IW-CLL 2008 criteria. Patients must also require therapy for that&#xD;
             diagnosis, based on meeting at least one of the following criteria:&#xD;
&#xD;
          -  evidence of progressive marrow failure as manifested by the development of, or&#xD;
             worsening of, anemia (hemoglobin &lt;11.0 g/L) and/or thrombocytopenia (platelets &lt;100 x&#xD;
             10^9/L)&#xD;
&#xD;
          -  massive (≥ 6 cm below the left costal margin), progressive, or symptomatic&#xD;
             splenomegaly&#xD;
&#xD;
          -  massive nodes (at least 10 cm longest diameter), progressive, or symptomatic&#xD;
             lymphadenopathy&#xD;
&#xD;
          -  progressive lymphocytosis with an increase of more than 50% over a 2-month period or&#xD;
             LDT of &lt;6 months. Lymphocyte doubling time may be obtained by linear regression&#xD;
             extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an&#xD;
             observation period of 2 to 3 months. In subjects with initial blood lymphocyte counts&#xD;
             of &lt;30 x 10^9/L, LDT should not be used as a single parameter to define indication for&#xD;
             treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other&#xD;
             than CLL (eg, infections) should be excluded&#xD;
&#xD;
          -  autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids&#xD;
             or other standard therapy&#xD;
&#xD;
          -  documented constitutional symptoms, defined as 1 or more of the following&#xD;
             disease-related symptoms or signs:&#xD;
&#xD;
               -  unintentional weight loss &gt;10% within 6 months prior to screening&#xD;
&#xD;
               -  significant fatigue (inability to work or perform usual activities)&#xD;
&#xD;
               -  fevers &gt;100.5° F or 38.0° C for 2 or more weeks prior to screening without&#xD;
                  evidence of infection&#xD;
&#xD;
               -  night sweats for more than 1 month prior to screening without evidence of&#xD;
                  infection&#xD;
&#xD;
                    -  No prior CLL-directed therapy that was instituted due to patient previously&#xD;
                       meeting IW-CLL 2008 criteria for treatment&#xD;
&#xD;
                    -  Age greater than or equal to 18 years and less than or equal to 65. Because&#xD;
                       CLL is extremely rare in persons &lt;18 years of age, children are excluded&#xD;
                       from this study. Because iFCR is an aggressive therapy that is likely to be&#xD;
                       less well-tolerated even in fit elderly subjects, persons &gt; 65 years of age&#xD;
                       are excluded&#xD;
&#xD;
                    -  ECOG performance status ≤ 1&#xD;
&#xD;
                    -  Adequate hematologic function independent of growth factor support for at&#xD;
                       least 7 days prior to screening and randomization, with the exception of&#xD;
                       pegylated G-CSF (pegfilgrastim) and darbepoetin which cannot be administered&#xD;
                       within 14 days of screening.&#xD;
&#xD;
          -  Patients must meet the following hematologic criteria at screening:&#xD;
&#xD;
               -  Absolute neutrophil count ≥ 750 cells/mm3 (0.75 x 109/L).&#xD;
&#xD;
               -  Platelet count ≥ 50,000 cells/mm3 (50 x 109/L).&#xD;
&#xD;
               -  Hemoglobin ≥ 8 g/L - Adequate hepatic and renal function defined as:&#xD;
&#xD;
          -  Serum aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x upper limit&#xD;
             of normal (ULN)&#xD;
&#xD;
               -  Bilirubin ≤ 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of&#xD;
                  non-hepatic origin)&#xD;
&#xD;
               -  Adequate renal function defined by serum creatinine &gt;1.5 x ULN&#xD;
&#xD;
               -  PT/INR &lt;1.5 x ULN and PTT (aPTT) &lt;1.5 x ULN.&#xD;
&#xD;
               -  The effects of ibrutinib on the developing human fetus are unknown. For this&#xD;
                  reason and because similar agents are known to be teratogenic, women of&#xD;
                  child-bearing potential and men must agree to use adequate contraception&#xD;
                  (hormonal or barrier method of birth control; abstinence) prior to study entry&#xD;
                  and for the duration of study participation.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Concurrent Conditions:&#xD;
&#xD;
          -  History of other malignancies, except:&#xD;
&#xD;
               -  Malignancy treated with curative intent and with no known active disease present&#xD;
                  for ≥ 3 years before the first dose of study drug and felt to be at low risk for&#xD;
                  recurrence by treating physician.&#xD;
&#xD;
               -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence&#xD;
                  of disease.&#xD;
&#xD;
               -  Adequately treated carcinoma in situ without evidence of disease.&#xD;
&#xD;
          -  Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc.,&#xD;
             or chronic administration of &gt;20 mg/day of prednisone) within 28 days of the first&#xD;
             dose of study drug.&#xD;
&#xD;
          -  Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.&#xD;
&#xD;
          -  Recent infection requiring systemic treatment that was completed ≤ 14 days before the&#xD;
             first dose of study drug.&#xD;
&#xD;
          -  Known bleeding disorders (eg, von Willebrand's disease) or hemophilia.&#xD;
&#xD;
          -  History of stroke or intracranial hemorrhage within 6 months prior to enrollment.&#xD;
&#xD;
          -  Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus&#xD;
             (HCV) or hepatitis B virus (HBV). Patients who are positive for hepatitis B core&#xD;
             antibody or hepatitis B surface antigen must have a negative polymerase chain reaction&#xD;
             (PCR) result before enrollment. Those who are PCR positive will be excluded.&#xD;
&#xD;
          -  Any uncontrolled active systemic infection.&#xD;
&#xD;
          -  Major surgery within 4 weeks of first dose of study drug.&#xD;
&#xD;
          -  Any life-threatening illness, medical condition, or organ system dysfunction that, in&#xD;
             the investigator's opinion, could compromise the subject's safety or put the study&#xD;
             outcomes at undue risk.&#xD;
&#xD;
          -  Currently active, clinically significant cardiovascular disease, such as uncontrolled&#xD;
             arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart&#xD;
             Association Functional Classification; or a history of myocardial infarction, unstable&#xD;
             angina, or acute coronary syndrome within 6 months prior to randomization.&#xD;
&#xD;
          -  Unable to swallow capsules or malabsorption syndrome, disease significantly affecting&#xD;
             gastrointestinal function, or resection of the stomach or small bowel, symptomatic&#xD;
             inflammatory bowel disease or ulcerative colitis, or partial or complete bowel&#xD;
             obstruction.&#xD;
&#xD;
          -  Lactating or pregnant.&#xD;
&#xD;
          -  Patients receiving any other study agents&#xD;
&#xD;
          -  Patients with known CNS involvement&#xD;
&#xD;
          -  Baseline QTcF &gt;480 ms. NOTE: This criterion does not apply to patients with a left&#xD;
             bundle branch block.&#xD;
&#xD;
          -  Patients who require warfarin or other vitamin K antagonists for anticoagulation&#xD;
             (other anticoagulants are allowed after consultation with the Principal Investigator).&#xD;
&#xD;
          -  Concurrent administration of medications or foods that are strong inhibitors or&#xD;
             inducers of CYP3A&#xD;
&#xD;
          -  Patients with ongoing use of prophylactic antibiotics are eligible as long as there is&#xD;
             no evidence of active infection and the antibiotic is not included on the list of&#xD;
             prohibited medications&#xD;
&#xD;
          -  Significant co-morbid condition or disease which in the judgment of the Principal&#xD;
             Investigator would place the patient at undue risk or interfere with the study&#xD;
&#xD;
          -  Unable to receive prophylactic treatment for pneumocystis&#xD;
&#xD;
          -  Patients with del(17p) confirmed by FISH in ≥20% of cells or on stimulated&#xD;
             karyotype3.2.24 Patients with del(17p) confirmed by FISH in ≥20% of cells or on&#xD;
             stimulated karyotype&#xD;
&#xD;
          -  Patients with unmutated IGHV who also have a complex karyotype on a stimulated&#xD;
             karyotype&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Matthew Davids, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Dana-Farber Cancer Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Miami Sylvester Comprehensive Cancer Center</name>
      <address>
        <city>Coral Gables</city>
        <state>Florida</state>
        <zip>33146</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Miami Sylvester Comprehensive Cancer Center</name>
      <address>
        <city>Deerfield Beach</city>
        <state>Florida</state>
        <zip>33442</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Unversity of Miami Sylvester Comprehensve Cancer Center</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33136</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Kansas Cancer Center</name>
      <address>
        <city>Westwood</city>
        <state>Kansas</state>
        <zip>66205</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Beth Israel Deaconess Medical Center</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dana Farber Cancer Institute</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>West Michigan Cancer Center</name>
      <address>
        <city>Kalamazoo</city>
        <state>Michigan</state>
        <zip>49007</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Duke University Medical Center</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27710</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>September 23, 2014</study_first_submitted>
  <study_first_submitted_qc>September 25, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 29, 2014</study_first_posted>
  <results_first_submitted>March 11, 2020</results_first_submitted>
  <results_first_submitted_qc>May 13, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">May 15, 2020</results_first_posted>
  <last_update_submitted>March 8, 2023</last_update_submitted>
  <last_update_submitted_qc>March 8, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 10, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Dana-Farber Cancer Institute</investigator_affiliation>
    <investigator_full_name>Matthew S. Davids, MD</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Chronic lymphocytic leukemia</keyword>
  <keyword>Leukemia</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Leukemia, Lymphoid</mesh_term>
    <mesh_term>Leukemia, Lymphocytic, Chronic, B-Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cyclophosphamide</mesh_term>
    <mesh_term>Rituximab</mesh_term>
    <mesh_term>Fludarabine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>July 11, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/48/NCT02251548/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>The study opened to enrollment on 10/3/2014 and closed to enrollment on 4/24/2018. 58 participants were enrolled at Dana-Farber, 9 at Massachusetts General Hospital, 3 at Beth Israel Deaconess Medical Center, 9 at Duke University, 1 at University of Kansas, 3 at West Michigan Cancer Center, and 2 at University of Miami for a total of 85 enrolled.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>FCR +420mg Ibrutinib Daily</title>
          <description>Patients received oral agent ibrutinib daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ibrutinib run in, then will continue daily dosing.Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="85"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="85"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Age greater than or equal to 18 years and less than or equal to 65 with no prior CLL directed therapy that was instituted due to patient previously meeting IWCLL 2008 criteria for treatment</population>
      <group_list>
        <group group_id="B1">
          <title>FCR+ 420 mg Ibrutinib Daily</title>
          <description>Patients received oral agent ibrutinib daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ibrutinib run in, then will continue daily dosing.Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="85"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <description>Participants were eligible if their age was greater than or equal to 18 years and less than or equal to 65</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="85"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="55" lower_limit="38" upper_limit="65"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="30"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="55"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="81"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="82"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <description>Enrolled in the United States of America</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="85"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Part I: Participants Who Achieve a Minimal Residual Disease (MRD) Negative Complete Response (CR) in the Bone Marrow at 2 Months Post FCR</title>
        <description>To assess the number of participants who achieve an MRD negative complete response at the 2 months post last dose of FCR timepoint by 2008 IW-CLL criteria ( Hallek et. al). Participants will have a bone marrow biopsy procedure 2 months after completing combination therapy (Ibrutinib+ FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4.</description>
        <time_frame>2 months after completing combination therapy</time_frame>
        <population>No prior CLL-directed therapy that was instituted due to patient previously meeting IWCLL 2008 criteria for treatment- Age greater than or equal to 18 years and less than or equal to 65 and must require therapy by standard IW-CLL 2008 criteria with adequate renal, hepatic, and hematologic function</population>
        <group_list>
          <group group_id="O1">
            <title>FCR+ 420mg Ibrutinib Daily</title>
            <description>Patients received oral agent ibrutinib daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ibrutinib run in, then will continue daily dosing.Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities</description>
          </group>
        </group_list>
        <measure>
          <title>Part I: Participants Who Achieve a Minimal Residual Disease (MRD) Negative Complete Response (CR) in the Bone Marrow at 2 Months Post FCR</title>
          <description>To assess the number of participants who achieve an MRD negative complete response at the 2 months post last dose of FCR timepoint by 2008 IW-CLL criteria ( Hallek et. al). Participants will have a bone marrow biopsy procedure 2 months after completing combination therapy (Ibrutinib+ FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4.</description>
          <population>No prior CLL-directed therapy that was instituted due to patient previously meeting IWCLL 2008 criteria for treatment- Age greater than or equal to 18 years and less than or equal to 65 and must require therapy by standard IW-CLL 2008 criteria with adequate renal, hepatic, and hematologic function</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="85"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="28"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Part II: Participants Who Achieve a Minimal Residual Disease (MRD) Negative Complete Response (CR) in the Bone Marrow at 2 Years Post Discontinuation of Ibrutinib After Having Achieved MRD Negative CR at the 2 Months Post FCR Timepoint</title>
        <description>Participants will have bone marrow biopsies in tandem with a chest, neck, abdomen and pelvic PET CT scan as clinically indicated after discontinuation of treatment. A central read of the PET CT scan will confirm the radiographic response, and the bone marrow pathology and morphology assessments will confirm morphological response in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008).</description>
        <time_frame>2 years post discontinuation of ibrutinib after 24 months of ibrutinib maintenance</time_frame>
        <population>All participants have not yet reached this timepoint therefore we have not analyzed or published this endpoint a the time of this submission</population>
        <group_list>
          <group group_id="O1">
            <title>FCR+ 420mg Ibrutinib Daily</title>
            <description>Patients received oral agent ibrutinib daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ibrutinib run in, then will continue daily dosing.Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities</description>
          </group>
        </group_list>
        <measure>
          <title>Part II: Participants Who Achieve a Minimal Residual Disease (MRD) Negative Complete Response (CR) in the Bone Marrow at 2 Years Post Discontinuation of Ibrutinib After Having Achieved MRD Negative CR at the 2 Months Post FCR Timepoint</title>
          <description>Participants will have bone marrow biopsies in tandem with a chest, neck, abdomen and pelvic PET CT scan as clinically indicated after discontinuation of treatment. A central read of the PET CT scan will confirm the radiographic response, and the bone marrow pathology and morphology assessments will confirm morphological response in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008).</description>
          <population>All participants have not yet reached this timepoint therefore we have not analyzed or published this endpoint a the time of this submission</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Response Rate</title>
        <description>Participants will have bone marrow biopsies in tandem with a chest, neck, abdomen and pelvic PET CT scan at baseline, end of cycle 3, 2 months post FCR, 1 year post FCR for those not having reached a radiographic CR, 2 years post FCR, and as clinically indicated thereafter. A central read of the PET CT scan will confirm a radiographic response, and the bone marrow pathology and morphology assessments will confirm morphological response in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008). Overall response rate will include PR,CRi and CR</description>
        <time_frame>Response assessed after Cycle 3, 2 months post FCR, at 1 year and 2 years post FCR, yearly thereafter for those not having achieved an MRD negative CR, and as clinically indicated</time_frame>
        <posting_date>01/2023</posting_date>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Rate of Complete Response</title>
        <description>Participants will have bone marrow biopsies in tandem with a chest, neck, abdomen and pelvic PET CT scan at baseline, end of cycle 3, 2 months post FCR, 1 year post FCR for those not having reached a radiographic CR, 2 years post FCR, and as clinically indicated thereafter. A central read of the PET CT scan will confirm a radiographic response, and the bone marrow pathology and morphology assessments will confirm morphological response in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008).</description>
        <time_frame>Response assessed after Cycle 3, 2 months post FCR, at 1 year and 2 years post FCR, yearly thereafter for those not having achieved a radiographic CR, and as clinically indicated thereafter</time_frame>
        <posting_date>01/2023</posting_date>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Rate of Partial Response</title>
        <description>Participants will have bone marrow biopsies in tandem with a chest, neck, abdomen and pelvic PET CT scan at baseline, end of cycle 3, 2 months post FCR, 1 year post FCR for those not having reached a radiographic CR, 2 years post FCR, and as clinically indicated thereafter. A central read of the PET CT scan will confirm a radiographic response, and the bone marrow pathology and morphology assessments will confirm morphological response in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008).</description>
        <time_frame>Response assessed after Cycle 3, 2 months post FCR, at 1 year and 2 years post FCR, yearly thereafter for those not having achieved an MRD negative CR, and as clinically indicated</time_frame>
        <posting_date>01/2023</posting_date>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Rate of Progression Free of Survival</title>
        <description>Progression free survival is defined as the time from study entry to the earliest documentation of disease progression as defined by 2008 IW-CLL criteria for CLL (Hallek et al., 2008). Participants will be followed for disease progression and/or survival after discontinuation of treatment every 3 months until subsequent therapy, withdrawal, lost to follow up, or death.</description>
        <time_frame>From date of study entry until the date of first documented progression or date of death from any cause, whichever came first</time_frame>
        <posting_date>01/2023</posting_date>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Rate of Overall Survival</title>
        <description>Overall survival is defined as the time from study entry to death or date last known alive. Participants will be followed for survival after discontinuation of treatment every 3 months until subsequent therapy, withdrawal, or death.</description>
        <time_frame>From date of starting study treatment until the date of death from any cause</time_frame>
        <posting_date>01/2023</posting_date>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Rate of MRD Negative CR After 3 Cycles of iFCR</title>
        <description>To determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow after 3 cycles of ibrutinib + FCR. Participants will have a bone marrow biopsy procedure after completing 3 cycles in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)</description>
        <time_frame>After 3 cycles of iFCR for each patient completing 3 cycles; on average, after 12 weeks of treatment during which 1 bone marrow biopsy is performed and MRD is tested</time_frame>
        <group_list>
          <group group_id="O1">
            <title>FCR +420mg Ibrutinib Daily</title>
            <description>Patients received oral agent ipilimumab daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ipilimumab run in, then will continue daily dosing.Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities</description>
          </group>
        </group_list>
        <measure>
          <title>Rate of MRD Negative CR After 3 Cycles of iFCR</title>
          <description>To determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow after 3 cycles of ibrutinib + FCR. Participants will have a bone marrow biopsy procedure after completing 3 cycles in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="85"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Rate of MRD Negative CR After 1 Year of Ibrutinib+ FCR</title>
        <description>To determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow at 12 months from start of therapy, participants will have a bone marrow biopsy procedure at the 1 year timepoint after completing combination therapy (ibrutinib + FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)</description>
        <time_frame>After 12 months (1 year) from the start of therapy</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Rate of MRD Negative CR After 2 Years of Ibrutinib Maintenance</title>
        <description>To determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow at 24 months post last cycle of FCR, participants will have a bone marrow biopsy procedure 24 months after completing combination therapy (ibrutinib + FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)</description>
        <time_frame>2 years (24 months) from start of therapy</time_frame>
        <posting_date>01/2023</posting_date>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants Who Convert From Bone Marrow MRD Negative PR to Bone Marrow MRD Negative CR After 1 Year of Ibrutinib Maintenance</title>
        <description>To determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow at 12 months from start of therapy, participants will have a bone marrow biopsy procedure at the 1 year timepoint after completing combination therapy (ibrutinib + FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)</description>
        <time_frame>12 months ( 1year) after starting therapy</time_frame>
        <posting_date>01/2023</posting_date>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants Who Convert From Bone Marrow MRD Negative PR to Bone Marrow MRD Negative CR After 2 Years on Treatment</title>
        <description>MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)- Bone marrow biopsies will be performed at baseline, after cycle 3, 2 months post FCR, at 1 year and 2 years of ibrutinib maintenance, and as clinically indicated thereafter- Participants will have a bone marrow biopsy procedure 24 months after completing combination therapy (Ibrutinib+ FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4.</description>
        <time_frame>2 years (24 months) from start of therapy</time_frame>
        <posting_date>01/2023</posting_date>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time to Bone Marrow MRD Negativity</title>
        <description>MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)- Bone marrow biopsies will be performed at baseline, after cycle 3, 2 months post FCR, at 1 year and 2 years of ibrutinib maintenance, and as clinically indicated thereafter</description>
        <time_frame>From date of starting study treatment until achievement of MRD negativity in the bone marrow</time_frame>
        <posting_date>01/2023</posting_date>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Participants Who Convert From Bone Marrow MRD Negativity to MRD Positivity in Participants Who Discontinue Ibrutinib</title>
        <description>.MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)- Bone marrow biopsies will be performed at baseline, after cycle 3, 2 months post FCR, at 1 year and 2 years of ibrutinib maintenance, and as clinically indicated thereafter</description>
        <time_frame>From date of starting study treatment until achievement of MRD negativity in the bone marrow to conversion to MRD positivity</time_frame>
        <posting_date>01/2023</posting_date>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events are assessed from the time the participants sign informed consent, and then are assessed by the study team at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, then every three cycles thereafter while in maintenance for the duration of their time on active treatment through study completion, an average of 3 years. Intra-cycle communication occurs throughout the treatment phase of the trial by electronic medical record secure email.</time_frame>
      <desc>Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2, 3, or 4 unexpected and treatment related event, and all and 5 events regardless of attribution to study treatment , and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review.</desc>
      <group_list>
        <group group_id="E1">
          <title>FCR+Ibrutinib 420mg Daily</title>
          <description>Patients received oral agent ipilimumab daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day ipilimumab run in, then will continue daily dosing. Fludarabine, cyclophosphamide, rituximab (FCR) will be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients will receive ibrutinib monotherapy indefinitely unless they are found to be minimal residual disease(MRD) negative in the bone marrow at the 24 months of ibrutinib maintenance timepoint, at which point they will discontinue ibrutinib to undergo active disease monitoring. If during active monitoring they develop MRD positivity in the blood, they may resume ibrutinib monotherapy. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="24" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Non-Cardiac Chest Pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Atrial Fibrillation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Pneumatosis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Sudden Death</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Cholecystitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Hemophagocytic lymphohistiocytosis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Appendicitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Anaplasmosis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Pneumocystis Jivrocii Pneumonia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Respiratory Syncytial Virus</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Appendiceal Mucocele</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <description>MRSA; Septic Shock</description>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Febrile Neutropenia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Aspartate Aminotransferase Increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Lipase Increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Alanine Amintransferase Increased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hypoglycemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Spondylosis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Secondary Malignancy- Myelodysplastic Syndrome</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>CTCAE 4.0</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="85" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Leukocytosis</sub_title>
                <counts group_id="E1" subjects_affected="18" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Palpitations</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="18" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Gastroesophageal reflux disease</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Gastrointestinal disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" subjects_affected="17" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Infusion related reaction</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Localized edema</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Upper respiratory infection</sub_title>
                <counts group_id="E1" subjects_affected="18" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="25" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Lymphocyte count increased</sub_title>
                <counts group_id="E1" subjects_affected="20" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="17" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Investigations - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" subjects_affected="23" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" subjects_affected="17" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" subjects_affected="14" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Hypoglycemia</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Hypernatremia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Metabolism and nutrition disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="23" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="20" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Musculoskeletal and connective tissue disorder - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Flank pain</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="21" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="17" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Sore throat</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Allergic rhinitis</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash acneiform</sub_title>
                <counts group_id="E1" subjects_affected="26" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Skin/subcutaneous tissue disorders; Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="21" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Hyperhidrosis</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hot flashes</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Matthew Davids, MD</name_or_title>
      <organization>Dana-Farber Cancer Institute</organization>
      <phone>617-632-6331</phone>
      <email>matthew_davids@dfci.harvard.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT02251548
org study id: 14-296
nct id: NCT02251548
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
This research study is evaluating a new drug called ibrutinib in combination with the
      standard drugs fludarabine, cyclophosphamide, and rituximab (FCR) as a possible treatment for
      Chronic Lymphocytic Leukemia (CLL).
Ibrutinib is a type of drug called a kinase inhibitor. It is believed to block a protein
      called Bruton's tyrosine kinase (BTK) that helps CLL cells live and grow. By blocking this,
      it is possible that the study drug will kill cancer cells or stop them from growing.
      Ibrutinib has been FDA approved for the treatment of CLL patients who have received at least
      one prior treatment; however, the FDA has not yet approved ibrutinib as the first treatment
      for previously untreated CLL. Therefore, ibrutinib is still considered to be study drug,
      which means it is still being studied.

      Fludarabine, cyclophosphamide, and rituximab (FCR) are intravenous chemotherapy and antibody
      drugs that together are a standard chemotherapy regimen used for younger patients with CLL.
      Although FCR is highly effective, it does not typically lead to cure.

      In this research study, the investigators are combining a new treatment for CLL, ibrutinib,
      with a standard chemotherapy regimen for CLL, FCR, to determine whether this combination
      (iFCR) is safe and effective for patients with previously untreated CLL.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Part I: Participants Who Achieve a Minimal Residual Disease (MRD) Negative Complete Response (CR) in the Bone Marrow at 2 Months Post FCR
time frame: 2 months after completing combination therapy
description: To assess the number of participants who achieve an MRD negative complete response at the 2 months post last dose of FCR timepoint by 2008 IW-CLL criteria ( Hallek et. al). Participants will have a bone marrow biopsy procedure 2 months after completing combination therapy (Ibrutinib+ FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4.
measure: Part II: Participants Who Achieve a Minimal Residual Disease (MRD) Negative Complete Response (CR) in the Bone Marrow at 2 Years Post Discontinuation of Ibrutinib After Having Achieved MRD Negative CR at the 2 Months Post FCR Timepoint
time frame: 2 years post discontinuation of ibrutinib after 24 months of ibrutinib maintenance
description: Participants will have bone marrow biopsies in tandem with a chest, neck, abdomen and pelvic PET CT scan as clinically indicated after discontinuation of treatment. A central read of the PET CT scan will confirm the radiographic response, and the bone marrow pathology and morphology assessments will confirm morphological response in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008).
measure: Overall Response Rate
time frame: Response assessed after Cycle 3, 2 months post FCR, at 1 year and 2 years post FCR, yearly thereafter for those not having achieved an MRD negative CR, and as clinically indicated
description: Participants will have bone marrow biopsies in tandem with a chest, neck, abdomen and pelvic PET CT scan at baseline, end of cycle 3, 2 months post FCR, 1 year post FCR for those not having reached a radiographic CR, 2 years post FCR, and as clinically indicated thereafter. A central read of the PET CT scan will confirm a radiographic response, and the bone marrow pathology and morphology assessments will confirm morphological response in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008). Overall response rate will include PR,CRi and CR
measure: Rate of Complete Response
time frame: Response assessed after Cycle 3, 2 months post FCR, at 1 year and 2 years post FCR, yearly thereafter for those not having achieved a radiographic CR, and as clinically indicated thereafter
description: Participants will have bone marrow biopsies in tandem with a chest, neck, abdomen and pelvic PET CT scan at baseline, end of cycle 3, 2 months post FCR, 1 year post FCR for those not having reached a radiographic CR, 2 years post FCR, and as clinically indicated thereafter. A central read of the PET CT scan will confirm a radiographic response, and the bone marrow pathology and morphology assessments will confirm morphological response in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008).
measure: Rate of Partial Response
time frame: Response assessed after Cycle 3, 2 months post FCR, at 1 year and 2 years post FCR, yearly thereafter for those not having achieved an MRD negative CR, and as clinically indicated
description: Participants will have bone marrow biopsies in tandem with a chest, neck, abdomen and pelvic PET CT scan at baseline, end of cycle 3, 2 months post FCR, 1 year post FCR for those not having reached a radiographic CR, 2 years post FCR, and as clinically indicated thereafter. A central read of the PET CT scan will confirm a radiographic response, and the bone marrow pathology and morphology assessments will confirm morphological response in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008).
measure: Rate of Progression Free of Survival
time frame: From date of study entry until the date of first documented progression or date of death from any cause, whichever came first
description: Progression free survival is defined as the time from study entry to the earliest documentation of disease progression as defined by 2008 IW-CLL criteria for CLL (Hallek et al., 2008). Participants will be followed for disease progression and/or survival after discontinuation of treatment every 3 months until subsequent therapy, withdrawal, lost to follow up, or death.
measure: Rate of Overall Survival
time frame: From date of starting study treatment until the date of death from any cause
description: Overall survival is defined as the time from study entry to death or date last known alive. Participants will be followed for survival after discontinuation of treatment every 3 months until subsequent therapy, withdrawal, or death.
measure: Rate of MRD Negative CR After 3 Cycles of iFCR
time frame: After 3 cycles of iFCR for each patient completing 3 cycles; on average, after 12 weeks of treatment during which 1 bone marrow biopsy is performed and MRD is tested
description: To determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow after 3 cycles of ibrutinib + FCR. Participants will have a bone marrow biopsy procedure after completing 3 cycles in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)
measure: Rate of MRD Negative CR After 1 Year of Ibrutinib+ FCR
time frame: After 12 months (1 year) from the start of therapy
description: To determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow at 12 months from start of therapy, participants will have a bone marrow biopsy procedure at the 1 year timepoint after completing combination therapy (ibrutinib + FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)
measure: Rate of MRD Negative CR After 2 Years of Ibrutinib Maintenance
time frame: 2 years (24 months) from start of therapy
description: To determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow at 24 months post last cycle of FCR, participants will have a bone marrow biopsy procedure 24 months after completing combination therapy (ibrutinib + FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)
measure: Number of Participants Who Convert From Bone Marrow MRD Negative PR to Bone Marrow MRD Negative CR After 1 Year of Ibrutinib Maintenance
time frame: 12 months ( 1year) after starting therapy
description: To determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow at 12 months from start of therapy, participants will have a bone marrow biopsy procedure at the 1 year timepoint after completing combination therapy (ibrutinib + FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)
measure: Number of Participants Who Convert From Bone Marrow MRD Negative PR to Bone Marrow MRD Negative CR After 2 Years on Treatment
time frame: 2 years (24 months) from start of therapy
description: MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)- Bone marrow biopsies will be performed at baseline, after cycle 3, 2 months post FCR, at 1 year and 2 years of ibrutinib maintenance, and as clinically indicated thereafter- Participants will have a bone marrow biopsy procedure 24 months after completing combination therapy (Ibrutinib+ FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4.
measure: Time to Bone Marrow MRD Negativity
time frame: From date of starting study treatment until achievement of MRD negativity in the bone marrow
description: MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)- Bone marrow biopsies will be performed at baseline, after cycle 3, 2 months post FCR, at 1 year and 2 years of ibrutinib maintenance, and as clinically indicated thereafter
measure: Participants Who Convert From Bone Marrow MRD Negativity to MRD Positivity in Participants Who Discontinue Ibrutinib
time frame: From date of starting study treatment until achievement of MRD negativity in the bone marrow to conversion to MRD positivity
description: .MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)- Bone marrow biopsies will be performed at baseline, after cycle 3, 2 months post FCR, at 1 year and 2 years of ibrutinib maintenance, and as clinically indicated thereafter
arm group label: Ibrutinib
arm group type: Experimental
description: - Ibrutinib-
Oral, daily during each cycle
fludarabine-administered at standard dosing for up to 6 cycles
cyclophosphamide-administered at standard dosing for up to 6 cycles
rituximab-administered at standard dosing for up to 6 cycles
intervention type: Drug
intervention name: Ibrutinib
description: Oral BTK inhibitor
arm group label: Ibrutinib
other name: Imbruvica™
intervention type: Drug
intervention name: Fludarabine
description: IV purine analogue chemotherapy agent
arm group label: Ibrutinib
other name: Fludara
intervention type: Drug
intervention name: Cyclophosphamide
description: IV alkylator chemotherapy agent
arm group label: Ibrutinib
other name: Cytoxan®
other name: Neosar®
intervention type: Drug
intervention name: Rituximab
description: IV anti-CD20 monoclonal antibody
arm group label: Ibrutinib
other name: Rituxan®
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Matthew Davids, MD
role: Principal Investigator
affiliation: Dana-Farber Cancer Institute
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country: United States
responsible party type: Principal Investigator
investigator affiliation: Dana-Farber Cancer Institute
investigator full name: Matthew S. Davids, MD
investigator title: Principal Investigator
mesh term: Leukemia
mesh term: Leukemia, Lymphoid
mesh term: Leukemia, Lymphocytic, Chronic, B-Cell
mesh term: Cyclophosphamide
mesh term: Rituximab
mesh term: Fludarabine
sharing ipd: No
provided document: 
participant flow: 
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outcome list: 
reported events: 
certain agreements: 
point of contact: 