<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/NCT01723839</url>
  </required_header>
  <id_info>
    <org_study_id>Pro00002262 RV-CLL-PI-0530</org_study_id>
    <nct_id>NCT01723839</nct_id>
  </id_info>
  <brief_title>Phase II Protocol for CLL With Fludarabine and Cyclophosphamide With Rituximab (FCR) Plus Lenalidomide</brief_title>
  <acronym>FCR</acronym>
  <official_title>Phase II Clinical Protocol for the Treatment of Patients With Previously Untreated CLL With Four or Six Cycles of Fludarabine and Cyclophosphamide With Rituximab (FCR) Plus Lenalidomide Followed by Lenalidomide Consolidation/ Maintenance</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hackensack Meridian Health</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Celgene Corporation</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Hackensack Meridian Health</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      In previously-untreated subjects with CLL, fludarabine and rituximab with or without&#xD;
      cyclophosphamide (FR or FCR) produces complete responses (CR) of 40-80%. The major&#xD;
      complication of FCR has been grade 3/4 neutropenia which was reduced using a lower dose of&#xD;
      fludarabine and cyclophosphamide (FCR-Lite) The objective of this study is to evaluate the&#xD;
      minimal residual disease (MRD) complete response rate (using the 2008 IWCLL guidelines) after&#xD;
      4 cycles of FCR-Lite plus lenalidomide in subjects with previously untreated CLL.&#xD;
      Lenalidomide is active in frontline treatment of CLL as well as in patients with refractory&#xD;
      disease. MRD has been demonstrated to be a sensitive surrogate marker for progression-free&#xD;
      survival. If patients are MRD negative complete responders (CR) they will stop at 4 cycles of&#xD;
      FCR-Lite followed by the lenalidomide consolidation/maintenance arm of the study. If they&#xD;
      have a MRD positive CR or partial response (PR) they will continue with 2 additional cycles&#xD;
      of FCR-Lite plus lenalidomide followed by lenalidomide consolidation/maintenance. They will&#xD;
      be re-tested for MRD after the 6th cycle of FCR-Lite and after 6 and 12 months of&#xD;
      lenalidomide monotherapy If they have no response (NR) or progressive disease (PD) following&#xD;
      4 cycles of FCR-Lite plus lenalidomide they will be removed from the study.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      STUDY OBJECTIVES:&#xD;
&#xD;
      Primary:&#xD;
&#xD;
      The primary objective is to evaluate the complete response rate following 4 cycles of&#xD;
      FCR-Lite plus lenalidomide in previously untreated patients with CLL.&#xD;
&#xD;
      Secondary:&#xD;
&#xD;
      The first secondary objective is to evaluate the toxicity of patients with previously&#xD;
      untreated CLL treated with FCR-Lite plus lenalidomide, followed by lenalidomide. The second&#xD;
      is to evaluate the overall response rate and overall survival of patients with previously&#xD;
      untreated CLL treated with FCR-Lite plus lenalidomide followed by lenalidomide. The third is&#xD;
      to determine whether adding lenalidomide as a consolidation/maintenance therapy will&#xD;
      eliminate bone marrow minimal residual disease in CR patients and whether patients who have a&#xD;
      PR after 6 cycles of FCR-Lite plus lenalidomide will respond to 12 months of lenalidomide.&#xD;
      The final secondary objective is to determine whether the expression of ZAP-70, CD38, and&#xD;
      chromosomes correlate with response rate, duration of response, and survival for previously&#xD;
      untreated patients with CLL.&#xD;
&#xD;
      STUDY DESIGN:&#xD;
&#xD;
      2-stage phase 2 study-design. 19 subjects are treated in stage-1 with FCR-Lite plus 5mg&#xD;
      lenalidomide increasing to 10mg and 15mg in subsequent cycles depending on toxicity. If there&#xD;
      are at least 5 CRs the study will accrue an additional 35 subjects (see statistical section).&#xD;
      A secondary objective of this study will be to determine if MRD positive patients will become&#xD;
      MRD negative with lenalidomide consolidation/maintenance and whether PR patients will convert&#xD;
      to CRs Lenalidomide will begin 2 months after the last dose of FCR-Lite in all subjects with&#xD;
      CR. It may begin as soon as 1 month after FCR-Lite plus lenalidomide in subjects with PR.&#xD;
      Lenalidomide is given in 28 d cycles increasing the dose from 5 mg/d to 10 mg/d in cycle 2&#xD;
      and to 15mg in cycles 3-6 if well- tolerated (no grade-3 or -4 toxicity). Patients with&#xD;
      creatinine clearance ≥30ml/min and &lt;60ml/min will start at 2.5mg daily increasing to 5 and&#xD;
      10mg in subsequent cycles . Reduction to the prior dose is allowed for grade-3/-4 toxicity.&#xD;
      MRD will be studied by flow cytometry from bone marrow and peripheral blood samples following&#xD;
      4 and 6 cycles of FCR-Lite and after 6 and 12 months of lenalidomide in CR patients.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 22, 2012</start_date>
  <completion_date type="Actual">June 8, 2021</completion_date>
  <primary_completion_date type="Actual">June 8, 2021</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>Complete Response</measure>
    <time_frame>28 day cycle, up to 4 cycles</time_frame>
    <description>Analysis of the Primary Endpoint: The complete responses will be estimated by the number of patients with CR divided by the total number of evaluable patients.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate</measure>
    <time_frame>28 day cycle, up to 6 cycles</time_frame>
    <description>Analysis of the other Secondary Endpoints: The overall response rate will be estimated by the number of patients with complete and partial responses divided by the total number of evaluable patients.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">21</enrollment>
  <condition>Chronic Lymphocytic Leukemia (CLL)</condition>
  <arm_group>
    <arm_group_label>FCR with Lenalidomide</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Fludarabine, Cyclophosphamide, Rituximab, Lenalidomide - 19 subjects are treated in stage-1 with FCR plus 5mg lenalidomide increasing to 10mg and 15mg in subsequent cycles depending on toxicity. If there are at least 5 CRs after 4 cycles of FCR plus lenalidomide the study will accrue an additional 35 subjects.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fludarabine, Cyclophosphamide, Rituximab, Lenalidomide</intervention_name>
    <description>19 subjects are treated in stage-1 with FCR plus 5mg lenalidomide increasing to 10mg and 15mg in subsequent cycles depending on toxicity.</description>
    <arm_group_label>FCR with Lenalidomide</arm_group_label>
    <other_name>FCR + Lenalidomide</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have diagnosis of CLL (as defined by the NCI Criteria below:&#xD;
&#xD;
               -  Patients must have peripheral blood absolute lymphocyte count of &gt;5,000/mm3&#xD;
                  obtained within 2 weeks prior to start of study.&#xD;
&#xD;
               -  The lymphocytosis must consist of small, mature lymphocytes, with ≤55% (not&#xD;
                  greater than 55%) prolymphocytes.&#xD;
&#xD;
          -  Patients must have phenotypically characterized CLL as defined as:&#xD;
&#xD;
               1. The predominant population of cells share B-cell antigens with CD5 in the absence&#xD;
                  of other pan-T-cell markers (CD3, CD2, etc.);&#xD;
&#xD;
               2. Surface immunoglobulin (slg) and CD20 with low-cell surface density expression.&#xD;
&#xD;
               3. If surface immunoglobulin can be demonstrated, the leukemic cells are restricted&#xD;
                  to expression of either kappa or lambda.&#xD;
&#xD;
          -  Splenomegaly, hepatomegaly or lymphadenopathy are not required for the diagnosis of&#xD;
             CLL&#xD;
&#xD;
          -  Patients must require chemotherapy&#xD;
&#xD;
          -  Patients must not have received prior treatment cytotoxic, immunotherapy or&#xD;
             investigational therapy.&#xD;
&#xD;
          -  Patients must not have history of corticosteroid treatment for CLL, Autoimmune&#xD;
             thrombocytopenia, or autoimmune hemolytic anemia.&#xD;
&#xD;
          -  Calculated creatinine clearance ≥30ml/min by Cockcroft-Gault formula&#xD;
&#xD;
          -  Bilirubin must be ≤1.5mg/dl, unless secondary to tumor, obtained within 2 weeks prior&#xD;
             to registration&#xD;
&#xD;
          -  Platelets ≥75x109/L, unless due to CLL involvement of bone marrow&#xD;
&#xD;
          -  Neutrophils ≥1.5x109/L, unless due to CLL involvement of bone marrow&#xD;
&#xD;
          -  AST or ALT &lt; 2x upper limit of normal, unless related to CLL&#xD;
&#xD;
          -  Age ≥18 years&#xD;
&#xD;
          -  ECOG performance status 0-2&#xD;
&#xD;
          -  Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy&#xD;
             test&#xD;
&#xD;
          -  Men must agree to use a latex condom during sexual contact with a FCBP even if they&#xD;
             have had a successful vasectomy&#xD;
&#xD;
          -  Able to take aspirin (81mg or 325mg) daily as prophylactic anticoagulation&#xD;
&#xD;
          -  Subject must provide written informed consent&#xD;
&#xD;
          -  All study participants must be registered into the mandatory RevAssist® program, and&#xD;
             be willing and able to comply with the requirements of RevAssist®&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with autoimmune hemolytic anemia or autoimmune thrombocytopenia are not&#xD;
             eligible&#xD;
&#xD;
          -  No prior immunotherapy, investigational or cytotoxic chemotherapy&#xD;
&#xD;
          -  Patients with a history of steroid treatment for CLL/SLL autoimmune hemolytic anemia,&#xD;
             or autoimmune thrombocytopenia are not eligible&#xD;
&#xD;
          -  Patients with active infections requiring oral or intravenous (IV) antibiotics until&#xD;
             resolution of the infection and completion of therapeutic antibiotics&#xD;
&#xD;
          -  Women of childbearing potential and sexually active males who both refuse to use an&#xD;
             accepted and effective method of contraception or women who are breastfeeding&#xD;
&#xD;
          -  Patients with a second malignancy other than basal cell carcinoma or squamous cell&#xD;
             carcinoma of the skin or in situ carcinoma of the cervix are not eligible unless the&#xD;
             tumor was treated with curative intent at least two years previously&#xD;
&#xD;
          -  History of known HIV&#xD;
&#xD;
          -  History or presence CNS disease&#xD;
&#xD;
          -  Evidence of laboratory TLS by Cairo-Bishop definition of Tumor Lysis Syndrome&#xD;
&#xD;
          -  History of corticosteroid treatment for CLL, Autoimmune thrombocytopenia, or&#xD;
             autoimmune hemolytic anemia.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Andre Goy, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>John Theurer Cancer Center at HackensackUMC</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>John Theurer Cancer Center at HackensackUMC</name>
      <address>
        <city>Hackensack</city>
        <state>New Jersey</state>
        <zip>07601</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Rai KR, Patel DV. Chronic Lymphocytic Leukemia, in Hoffman R, Benz E, Shattil 5, Furie B, Cohen H, Silberstein L (eds): Hematology: Basic Principles and Practice, New York, Churchill Livingstone, 1995, p. 1308.</citation>
  </reference>
  <reference>
    <citation>Linet MS, Cartwright RA. Chronic lymphocytic leukemia: epidemiology and etiologic findings. Nouv Rev Fr Hematol (1978). 1988;30(5-6):353-7.</citation>
    <PMID>3222144</PMID>
  </reference>
  <reference>
    <citation>Jaksic B, Vitale B, Hauptmann E, Planinc-Peraica A, Ostojic S, Kusec R. The roles of age and sex in the prognosis of chronic leukaemias. A study of 373 cases. Br J Cancer. 1991 Aug;64(2):345-8. doi: 10.1038/bjc.1991.303.</citation>
    <PMID>1892761</PMID>
  </reference>
  <reference>
    <citation>Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ; International Workshop on Chronic Lymphocytic Leukemia. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008 Jun 15;111(12):5446-56. doi: 10.1182/blood-2007-06-093906. Epub 2008 Jan 23. Erratum In: Blood. 2008 Dec 15;112(13):5259.</citation>
    <PMID>18216293</PMID>
  </reference>
  <reference>
    <citation>Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood. 1975 Aug;46(2):219-34.</citation>
    <PMID>1139039</PMID>
  </reference>
  <reference>
    <citation>Rai KR, Sawitsky A. A review of the prognostic role of cytogenetic, phenotypic, morphologic, and immune function characteristics in chronic lymphocytic leukemia. Blood Cells. 1987;12(2):327-38.</citation>
    <PMID>3304471</PMID>
  </reference>
  <reference>
    <citation>Montserrat E, Rozman C. Bone marrow biopsy in chronic lymphocytic leukemia: a review of its prognostic importance. Blood Cells. 1987;12(2):315-26.</citation>
    <PMID>3304470</PMID>
  </reference>
  <reference>
    <citation>Montserrat E, Rozman C. Chronic lymphocytic leukaemia: prognostic factors and natural history. Baillieres Clin Haematol. 1993 Dec;6(4):849-66. doi: 10.1016/s0950-3536(05)80179-9.</citation>
    <PMID>8038493</PMID>
  </reference>
  <reference>
    <citation>Han T, Bhargava A, Henderson ES, et al. Prognostic significance of beta-2-microglobulin (-2m) in chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL). Proc Amer Soc Clin Oncol 1989; 8:270 (abstr 270).</citation>
  </reference>
  <reference>
    <citation>Montserrat E, Alcala A, Parody R, Domingo A, Garcia-Conde J, Bueno J, Ferran C, Sanz MA, Giralt M, Rubio D, et al. Treatment of chronic lymphocytic leukemia in advanced stages. A randomized trial comparing chlorambucil plus prednisone versus cyclophosphamide, vincristine, and prednisone. Cancer. 1985 Nov 15;56(10):2369-75. doi: 10.1002/1097-0142(19851115)56:103.0.co;2-n.</citation>
    <PMID>3899346</PMID>
  </reference>
  <reference>
    <citation>Fais F, Ghiotto F, Hashimoto S, Sellars B, Valetto A, Allen SL, Schulman P, Vinciguerra VP, Rai K, Rassenti LZ, Kipps TJ, Dighiero G, Schroeder HW Jr, Ferrarini M, Chiorazzi N. Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors. J Clin Invest. 1998 Oct 15;102(8):1515-25. doi: 10.1172/JCI3009.</citation>
    <PMID>9788964</PMID>
  </reference>
  <reference>
    <citation>Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL, Buchbinder A, Budman D, Dittmar K, Kolitz J, Lichtman SM, Schulman P, Vinciguerra VP, Rai KR, Ferrarini M, Chiorazzi N. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999 Sep 15;94(6):1840-7.</citation>
    <PMID>10477712</PMID>
  </reference>
  <reference>
    <citation>Oscier DG, Thompsett A, Zhu D, Stevenson FK. Differential rates of somatic hypermutation in V(H) genes among subsets of chronic lymphocytic leukemia defined by chromosomal abnormalities. Blood. 1997 Jun 1;89(11):4153-60.</citation>
    <PMID>9166858</PMID>
  </reference>
  <reference>
    <citation>Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999 Sep 15;94(6):1848-54.</citation>
    <PMID>10477713</PMID>
  </reference>
  <reference>
    <citation>Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, Rozman M, Marce S, Lopez-Guillermo A, Campo E, Montserrat E. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med. 2003 May 1;348(18):1764-75. doi: 10.1056/NEJMoa023143.</citation>
    <PMID>12724482</PMID>
  </reference>
  <reference>
    <citation>Lin K, Sherrington PD, Dennis M, Matrai Z, Cawley JC, Pettitt AR. Relationship between p53 dysfunction, CD38 expression, and IgV(H) mutation in chronic lymphocytic leukemia. Blood. 2002 Aug 15;100(4):1404-9. doi: 10.1182/blood-2001-11-0066. Erratum In: Blood 2002 Oct 1;100(7):2291.</citation>
    <PMID>12149224</PMID>
  </reference>
  <reference>
    <citation>Gahrton G, Juliusson G. Clinical implication of chromosomal aberrations in chronic B-lymphocytic leukaemia cells. Nouv Rev Fr Hematol (1978). 1988;30(5-6):389-92.</citation>
    <PMID>3265508</PMID>
  </reference>
  <reference>
    <citation>Bird ML, Ueshima Y, Rowley JD, Haren JM, Vardiman JW. Chromosome abnormalities in B cell chronic lymphocytic leukemia and their clinical correlations. Leukemia. 1989 Mar;3(3):182-91.</citation>
    <PMID>2918755</PMID>
  </reference>
  <reference>
    <citation>Krober A, Seiler T, Benner A, Bullinger L, Bruckle E, Lichter P, Dohner H, Stilgenbauer S. V(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood. 2002 Aug 15;100(4):1410-6.</citation>
    <PMID>12149225</PMID>
  </reference>
  <reference>
    <citation>Rozman C, Montserrat E. Bone marrow biopsy in chronic lymphocytic leukemia. Nouv Rev Fr Hematol (1978). 1988;30(5-6):369-71.</citation>
    <PMID>3065734</PMID>
  </reference>
  <reference>
    <citation>Pangalis GA, Boussiotis VA, Kittas C. B-chronic lymphocytic leukemia. Disease progression in 150 untreated stage A and B patients as predicted by bone marrow pattern. Nouv Rev Fr Hematol (1978). 1988;30(5-6):373-5.</citation>
    <PMID>3222147</PMID>
  </reference>
  <reference>
    <citation>Montserrat E, Vinolas N, Reverter JC, Rozman C. Natural history of chronic lymphocytic leukemia: on the progression and progression and prognosis of early clinical stages. Nouv Rev Fr Hematol (1978). 1988;30(5-6):359-61.</citation>
    <PMID>3222145</PMID>
  </reference>
  <reference>
    <citation>Shustik C, Mick R, Silver R, Sawitsky A, Rai K, Shapiro L. Treatment of early chronic lymphocytic leukemia: intermittent chlorambucil versus observation. Hematol Oncol. 1988 Jan-Mar;6(1):7-12. doi: 10.1002/hon.2900060103.</citation>
    <PMID>3277904</PMID>
  </reference>
  <reference>
    <citation>Liepman M, Votaw ML. The treatment of chronic lymphocytic leukemia with COP chemotherapy. Cancer. 1978 May;41(5):1664-9. doi: 10.1002/1097-0142(197805)41:53.0.co;2-q.</citation>
    <PMID>647620</PMID>
  </reference>
  <reference>
    <citation>Oken MM, Kaplan ME. Combination chemotherapy with cyclophosphamide, vincristine, and prednisone in the treatment of refractory chronic lymphocytic leukemia. Cancer Treat Rep. 1979 Mar;63(3):441-7. No abstract available.</citation>
    <PMID>371799</PMID>
  </reference>
  <reference>
    <citation>Hansen MM, Andersen E, Christensen BE, Christiansen I, Geisler C, Kristensen D, Jensen KB, Junker P. CHOP versus prednisolone + chlorambucil in chronic lymphocytic leukemia (CLL): preliminary results of a randomized multicenter study. Nouv Rev Fr Hematol (1978). 1988;30(5-6):433-6.</citation>
    <PMID>3065739</PMID>
  </reference>
  <reference>
    <citation>Raphael B, Andersen JW, Silber R, Oken M, Moore D, Bennett J, Bonner H, Hahn R, Knospe WH, Mazza J, et al. Comparison of chlorambucil and prednisone versus cyclophosphamide, vincristine, and prednisone as initial treatment for chronic lymphocytic leukemia: long-term follow-up of an Eastern Cooperative Oncology Group randomized clinical trial. J Clin Oncol. 1991 May;9(5):770-6. doi: 10.1200/JCO.1991.9.5.770.</citation>
    <PMID>2016618</PMID>
  </reference>
  <reference>
    <citation>Grever MR, Kopecky KJ, Coltman CA, Files JC, Greenberg BR, Hutton JJ, Talley R, Von Hoff DD, Balcerzak SP. Fludarabine monophosphate: a potentially useful agent in chronic lymphocytic leukemia. Nouv Rev Fr Hematol (1978). 1988;30(5-6):457-9.</citation>
    <PMID>2464793</PMID>
  </reference>
  <reference>
    <citation>Keating MJ, Kantarjian H, O'Brien S, Koller C, Talpaz M, Schachner J, Childs CC, Freireich EJ, McCredie KB. Fludarabine: a new agent with marked cytoreductive activity in untreated chronic lymphocytic leukemia. J Clin Oncol. 1991 Jan;9(1):44-9. doi: 10.1200/JCO.1991.9.1.44.</citation>
    <PMID>1702145</PMID>
  </reference>
  <reference>
    <citation>Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L, Hines J, Threatte GA, Larson RA, Cheson BD, Schiffer CA. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000 Dec 14;343(24):1750-7. doi: 10.1056/NEJM200012143432402.</citation>
    <PMID>11114313</PMID>
  </reference>
  <reference>
    <citation>O'Brien S, Kantarjian H, Beran M, Smith T, Koller C, Estey E, Robertson LE, Lerner S, Keating M. Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment. Blood. 1993 Sep 15;82(6):1695-700.</citation>
    <PMID>8400226</PMID>
  </reference>
  <reference>
    <citation>Anaissie E, Kontoyiannis DP, Kantarjian H, Elting L, Robertson LE, Keating M. Listeriosis in patients with chronic lymphocytic leukemia who were treated with fludarabine and prednisone. Ann Intern Med. 1992 Sep 15;117(6):466-9. doi: 10.7326/0003-4819-117-6-466.</citation>
    <PMID>1354425</PMID>
  </reference>
  <reference>
    <citation>Johnston JB, Verburg L, Shore T, Williams M, Israels LG, Begleiter A. Combination therapy with nucleoside analogs and alkylating agents. Leukemia. 1994 Apr;8 Suppl 1:S140-3.</citation>
    <PMID>8152282</PMID>
  </reference>
  <reference>
    <citation>Begleiter A, Pugh L, Israels LG, Johnston JB. Enhanced cytotoxicity and inhibition of DNA damage repair in irradiated murine L5178Y lymphoblasts and human chronic lymphocytic leukemia cells treated with 2'-deoxycoformycin and deoxyadenosine in vitro. Cancer Res. 1988 Jul 15;48(14):3981-6.</citation>
    <PMID>3260129</PMID>
  </reference>
  <reference>
    <citation>O'Brien SM, Kantarjian HM, Cortes J, Beran M, Koller CA, Giles FJ, Lerner S, Keating M. Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia. J Clin Oncol. 2001 Mar 1;19(5):1414-20. doi: 10.1200/JCO.2001.19.5.1414.</citation>
    <PMID>11230486</PMID>
  </reference>
  <reference>
    <citation>Flinn IW, Byrd JC, Morrison C, Jamison J, Diehl LF, Murphy T, Piantadosi S, Seifter E, Ambinder RF, Vogelsang G, Grever MR. Fludarabine and cyclophosphamide with filgrastim support in patients with previously untreated indolent lymphoid malignancies. Blood. 2000 Jul 1;96(1):71-5.</citation>
    <PMID>10891432</PMID>
  </reference>
  <reference>
    <citation>Hainsworth JD, Litchy S, Barton JH, Houston GA, Hermann RC, Bradof JE, Greco FA; Minnie Pearl Cancer Research Network. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2003 May 1;21(9):1746-51. doi: 10.1200/JCO.2003.09.027.</citation>
    <PMID>12721250</PMID>
  </reference>
  <reference>
    <citation>O'Brien SM, Kantarjian H, Thomas DA, Giles FJ, Freireich EJ, Cortes J, Lerner S, Keating MJ. Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol. 2001 Apr 15;19(8):2165-70. doi: 10.1200/JCO.2001.19.8.2165.</citation>
    <PMID>11304768</PMID>
  </reference>
  <reference>
    <citation>Byrd JC, Murphy T, Howard RS, Lucas MS, Goodrich A, Park K, Pearson M, Waselenko JK, Ling G, Grever MR, Grillo-Lopez AJ, Rosenberg J, Kunkel L, Flinn IW. Rituximab using a thrice weekly dosing schedule in B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity. J Clin Oncol. 2001 Apr 15;19(8):2153-64. doi: 10.1200/JCO.2001.19.8.2153.</citation>
    <PMID>11304767</PMID>
  </reference>
  <reference>
    <citation>Ladetto M, Bergui L, Ricca I, Campana S, Pileri A, Tarella C. Rituximab anti-CD20 monoclonal antibody induces marked but transient reductions of peripheral blood lymphocytes in chronic lymphocytic leukaemia patients. Med Oncol. 2000 Aug;17(3):203-10. doi: 10.1007/BF02780529.</citation>
    <PMID>10962531</PMID>
  </reference>
  <reference>
    <citation>Huhn D, von Schilling C, Wilhelm M, Ho AD, Hallek M, Kuse R, Knauf W, Riedel U, Hinke A, Srock S, Serke S, Peschel C, Emmerich B; German Chronic Lymphocytic Leukemia Study Group. Rituximab therapy of patients with B-cell chronic lymphocytic leukemia. Blood. 2001 Sep 1;98(5):1326-31. doi: 10.1182/blood.v98.5.1326.</citation>
    <PMID>11520778</PMID>
  </reference>
  <reference>
    <citation>List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D, Rimsza L, Heaton R, Knight R, Zeldis JB. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005 Feb 10;352(6):549-57. doi: 10.1056/NEJMoa041668.</citation>
    <PMID>15703420</PMID>
  </reference>
  <reference>
    <citation>List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, Powell B, Greenberg P, Thomas D, Stone R, Reeder C, Wride K, Patin J, Schmidt M, Zeldis J, Knight R; Myelodysplastic Syndrome-003 Study Investigators. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006 Oct 5;355(14):1456-65. doi: 10.1056/NEJMoa061292.</citation>
    <PMID>17021321</PMID>
  </reference>
  <reference>
    <citation>Richardson PG, Schlossman RL, Weller E, Hideshima T, Mitsiades C, Davies F, LeBlanc R, Catley LP, Doss D, Kelly K, McKenney M, Mechlowicz J, Freeman A, Deocampo R, Rich R, Ryoo JJ, Chauhan D, Balinski K, Zeldis J, Anderson KC. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood. 2002 Nov 1;100(9):3063-7. doi: 10.1182/blood-2002-03-0996.</citation>
    <PMID>12384400</PMID>
  </reference>
  <reference>
    <citation>Richardson PG, Blood E, Mitsiades CS, Jagannath S, Zeldenrust SR, Alsina M, Schlossman RL, Rajkumar SV, Desikan KR, Hideshima T, Munshi NC, Kelly-Colson K, Doss D, McKenney ML, Gorelik S, Warren D, Freeman A, Rich R, Wu A, Olesnyckyj M, Wride K, Dalton WS, Zeldis J, Knight R, Weller E, Anderson KC. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006 Nov 15;108(10):3458-64. doi: 10.1182/blood-2006-04-015909. Epub 2006 Jul 13.</citation>
    <PMID>16840727</PMID>
  </reference>
  <reference>
    <citation>Rajkumar SV, Hayman SR, Lacy MQ, Dispenzieri A, Geyer SM, Kabat B, Zeldenrust SR, Kumar S, Greipp PR, Fonseca R, Lust JA, Russell SJ, Kyle RA, Witzig TE, Gertz MA. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood. 2005 Dec 15;106(13):4050-3. doi: 10.1182/blood-2005-07-2817. Epub 2005 Aug 23.</citation>
    <PMID>16118317</PMID>
  </reference>
  <reference>
    <citation>Marriott JB, Clarke IA, Dredge K, Muller G, Stirling D, Dalgleish AG. Thalidomide and its analogues have distinct and opposing effects on TNF-alpha and TNFR2 during co-stimulation of both CD4(+) and CD8(+) T cells. Clin Exp Immunol. 2002 Oct;130(1):75-84. doi: 10.1046/j.1365-2249.2002.01954.x.</citation>
    <PMID>12296856</PMID>
  </reference>
  <reference>
    <citation>Mangiameli DP, Blansfield JA, Kachala S, Lorang D, Schafer PH, Muller GW, Stirling DI, Libutti SK. Combination therapy targeting the tumor microenvironment is effective in a model of human ocular melanoma. J Transl Med. 2007 Jul 18;5:38. doi: 10.1186/1479-5876-5-38.</citation>
    <PMID>17640369</PMID>
  </reference>
  <reference>
    <citation>Tai YT, Li XF, Catley L, Coffey R, Breitkreutz I, Bae J, Song W, Podar K, Hideshima T, Chauhan D, Schlossman R, Richardson P, Treon SP, Grewal IS, Munshi NC, Anderson KC. Immunomodulatory drug lenalidomide (CC-5013, IMiD3) augments anti-CD40 SGN-40-induced cytotoxicity in human multiple myeloma: clinical implications. Cancer Res. 2005 Dec 15;65(24):11712-20. doi: 10.1158/0008-5472.CAN-05-1657.</citation>
    <PMID>16357183</PMID>
  </reference>
  <reference>
    <citation>LeBlanc R, Hideshima T, Catley LP, Shringarpure R, Burger R, Mitsiades N, Mitsiades C, Cheema P, Chauhan D, Richardson PG, Anderson KC, Munshi NC. Immunomodulatory drug costimulates T cells via the B7-CD28 pathway. Blood. 2004 Mar 1;103(5):1787-90. doi: 10.1182/blood-2003-02-0361. Epub 2003 Sep 25.</citation>
    <PMID>14512311</PMID>
  </reference>
  <reference>
    <citation>Hernandez-Ilizaliturri FJ, Reddy N, Holkova B, Ottman E, Czuczman MS. Immunomodulatory drug CC-5013 or CC-4047 and rituximab enhance antitumor activity in a severe combined immunodeficient mouse lymphoma model. Clin Cancer Res. 2005 Aug 15;11(16):5984-92. doi: 10.1158/1078-0432.CCR-05-0577.</citation>
    <PMID>16115943</PMID>
  </reference>
  <reference>
    <citation>Pellagatti A, Jadersten M, Forsblom AM, Cattan H, Christensson B, Emanuelsson EK, Merup M, Nilsson L, Samuelsson J, Sander B, Wainscoat JS, Boultwood J, Hellstrom-Lindberg E. Lenalidomide inhibits the malignant clone and up-regulates the SPARC gene mapping to the commonly deleted region in 5q- syndrome patients. Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11406-11. doi: 10.1073/pnas.0610477104. Epub 2007 Jun 18.</citation>
    <PMID>17576924</PMID>
  </reference>
  <reference>
    <citation>Chanan-Khan A, Miller KC, Musial L, Lawrence D, Padmanabhan S, Takeshita K, Porter CW, Goodrich DW, Bernstein ZP, Wallace P, Spaner D, Mohr A, Byrne C, Hernandez-Ilizaliturri F, Chrystal C, Starostik P, Czuczman MS. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol. 2006 Dec 1;24(34):5343-9. doi: 10.1200/JCO.2005.05.0401. Epub 2006 Nov 6.</citation>
    <PMID>17088571</PMID>
  </reference>
  <reference>
    <citation>Ferrajoli A, Lee BN, Schlette EJ, O'Brien SM, Gao H, Wen S, Wierda WG, Estrov Z, Faderl S, Cohen EN, Li C, Reuben JM, Keating MJ. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood. 2008 Jun 1;111(11):5291-7. doi: 10.1182/blood-2007-12-130120. Epub 2008 Mar 11.</citation>
    <PMID>18334676</PMID>
  </reference>
  <reference>
    <citation>Andritsos LA, Johnson AJ, Lozanski G, Blum W, Kefauver C, Awan F, Smith LL, Lapalombella R, May SE, Raymond CA, Wang DS, Knight RD, Ruppert AS, Lehman A, Jarjoura D, Chen CS, Byrd JC. Higher doses of lenalidomide are associated with unacceptable toxicity including life-threatening tumor flare in patients with chronic lymphocytic leukemia. J Clin Oncol. 2008 May 20;26(15):2519-25. doi: 10.1200/JCO.2007.13.9709. Epub 2008 Apr 21.</citation>
    <PMID>18427150</PMID>
  </reference>
  <reference>
    <citation>Chen C, Paul H, Xu W, et al: A phase II study of lenalidomide in previously untreated, symptomatic chronic lymphocytic leukemia (CLL). Blood 112:23, 2008 (abstr 44).</citation>
  </reference>
  <reference>
    <citation>Byrd JC, Peterson BL, Morrison VA, Park K, Jacobson R, Hoke E, Vardiman JW, Rai K, Schiffer CA, Larson RA. Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood. 2003 Jan 1;101(1):6-14. doi: 10.1182/blood-2002-04-1258. Epub 2002 Jul 5.</citation>
    <PMID>12393429</PMID>
  </reference>
  <reference>
    <citation>Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, Hensel M, Hopfinger G, Hess G, von Grunhagen U, Bergmann M, Catalano J, Zinzani PL, Caligaris-Cappio F, Seymour JF, Berrebi A, Jager U, Cazin B, Trneny M, Westermann A, Wendtner CM, Eichhorst BF, Staib P, Buhler A, Winkler D, Zenz T, Bottcher S, Ritgen M, Mendila M, Kneba M, Dohner H, Stilgenbauer S; International Group of Investigators; German Chronic Lymphocytic Leukaemia Study Group. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010 Oct 2;376(9747):1164-74. doi: 10.1016/S0140-6736(10)61381-5.</citation>
    <PMID>20888994</PMID>
  </reference>
  <reference>
    <citation>Keating MJ, O'Brien S, Albitar M, Lerner S, Plunkett W, Giles F, Andreeff M, Cortes J, Faderl S, Thomas D, Koller C, Wierda W, Detry MA, Lynn A, Kantarjian H. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 20;23(18):4079-88. doi: 10.1200/JCO.2005.12.051. Epub 2005 Mar 14.</citation>
    <PMID>15767648</PMID>
  </reference>
  <reference>
    <citation>Brown JR, Abramson J, Hochberg E, Mikler E, Dalton V, Werner L, Reynolds H, Thompson C, McDonough SM, Kuang Y, Ritz J, Neuberg D, Freedman AS. A phase I study of lenalidomide in combination with fludarabine and rituximab in previously untreated CLL/SLL. Leukemia. 2010 Nov;24(11):1972-5. doi: 10.1038/leu.2010.199. Epub 2010 Sep 16. No abstract available.</citation>
    <PMID>20844565</PMID>
  </reference>
  <reference>
    <citation>Provan D, Bartlett-Pandite L, Zwicky C, Neuberg D, Maddocks A, Corradini P, Soiffer R, Ritz J, Nadler LM, Gribben JG. Eradication of polymerase chain reaction-detectable chronic lymphocytic leukemia cells is associated with improved outcome after bone marrow transplantation. Blood. 1996 Sep 15;88(6):2228-35.</citation>
    <PMID>8822943</PMID>
  </reference>
  <reference>
    <citation>Moreton P, Kennedy B, Lucas G, Leach M, Rassam SM, Haynes A, Tighe J, Oscier D, Fegan C, Rawstron A, Hillmen P. Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. J Clin Oncol. 2005 May 1;23(13):2971-9. doi: 10.1200/JCO.2005.04.021. Epub 2005 Feb 28.</citation>
    <PMID>15738539</PMID>
  </reference>
  <reference>
    <citation>Bosch F, Ferrer A, Lopez-Guillermo A, Gine E, Bellosillo B, Villamor N, Colomer D, Cobo F, Perales M, Esteve J, Altes A, Besalduch J, Ribera JM, Montserrat E; GELCAB (Grup per l'Estudi dels Limfomes a Catalunya i Balears). Fludarabine, cyclophosphamide and mitoxantrone in the treatment of resistant or relapsed chronic lymphocytic leukaemia. Br J Haematol. 2002 Dec;119(4):976-84. doi: 10.1046/j.1365-2141.2002.03959.x.</citation>
    <PMID>12472576</PMID>
  </reference>
  <reference>
    <citation>Boettcher S, Fischer K, Stilgenbauer S, Busch R, Fingerle-Rowson G, Fink AM et al. Quantitative MRD assessments predict progression-free survival in CLL patients treated with fludarabine and cyclophosphamide with or without rituximab - a prospective analysis in 471 patients from the randomized GCLLSG CLL8 trial. Blood 2008; 112: 11, abstract 326)</citation>
  </reference>
  <reference>
    <citation>Kay NE, Geyer SM, Call TG, Shanafelt TD, Zent CS, Jelinek DF, Tschumper R, Bone ND, Dewald GW, Lin TS, Heerema NA, Smith L, Grever MR, Byrd JC. Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia. Blood. 2007 Jan 15;109(2):405-11. doi: 10.1182/blood-2006-07-033274. Epub 2006 Sep 28.</citation>
    <PMID>17008537</PMID>
  </reference>
  <reference>
    <citation>Foon KA, Boyiadzis M, Land SR, Marks S, Raptis A, Pietragallo L, Meisner D, Laman A, Sulecki M, Butchko A, Schaefer P, Lenzer D, Tarhini A. Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009 Feb 1;27(4):498-503. doi: 10.1200/JCO.2008.17.2619. Epub 2008 Dec 15.</citation>
    <PMID>19075274</PMID>
  </reference>
  <reference>
    <citation>Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989 Mar;10(1):1-10. doi: 10.1016/0197-2456(89)90015-9.</citation>
    <PMID>2702835</PMID>
  </reference>
  <reference>
    <citation>Dufy DE, Santner TJ, Confidence intervals for binomial parameter based on multistage tests. Biometrics 43:81-93, 1987.</citation>
  </reference>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>November 6, 2012</study_first_submitted>
  <study_first_submitted_qc>November 7, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 8, 2012</study_first_posted>
  <results_first_submitted>July 8, 2022</results_first_submitted>
  <results_first_submitted_qc>October 7, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">October 10, 2022</results_first_posted>
  <last_update_submitted>October 7, 2022</last_update_submitted>
  <last_update_submitted_qc>October 7, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 10, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>CLL</keyword>
  <keyword>FCR</keyword>
  <keyword>Rituximab</keyword>
  <keyword>Lenalidomide</keyword>
  <keyword>Cyclophosphamide</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <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>
    <mesh_term>Lenalidomide</mesh_term>
  </intervention_browse>
  <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>March 14, 2014</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/39/NCT01723839/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>FCR With Lenalidomide</title>
          <description>Fludarabine, Cyclophosphamide, Rituximab, Lenalidomide - 19 subjects are treated in stage-1 with FCR plus 5mg lenalidomide increasing to 10mg and 15mg in subsequent cycles depending on toxicity. If there are at least 5 CRs after 4 cycles of FCR plus lenalidomide the study will accrue an additional 35 subjects.&#xD;
Fludarabine, Cyclophosphamide, Rituximab, Lenalidomide: 19 subjects are treated in stage-1 with FCR plus 5mg lenalidomide increasing to 10mg and 15mg in subsequent cycles depending on toxicity.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="21"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>FCR With Lenalidomide</title>
          <description>Fludarabine, Cyclophosphamide, Rituximab, Lenalidomide - 19 subjects are treated in stage-1 with FCR plus 5mg lenalidomide increasing to 10mg and 15mg in subsequent cycles depending on toxicity. If there are at least 5 CRs after 4 cycles of FCR plus lenalidomide the study will accrue an additional 35 subjects.&#xD;
Fludarabine, Cyclophosphamide, Rituximab, Lenalidomide: 19 subjects are treated in stage-1 with FCR plus 5mg lenalidomide increasing to 10mg and 15mg in subsequent cycles depending on toxicity.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="21"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <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="62.5" lower_limit="42" upper_limit="75"/>
                  </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="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                  </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="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="21"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </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="18"/>
                  </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>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="21"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Complete Response</title>
        <description>Analysis of the Primary Endpoint: The complete responses will be estimated by the number of patients with CR divided by the total number of evaluable patients.</description>
        <time_frame>28 day cycle, up to 4 cycles</time_frame>
        <population>Of the 21 were enrolled, 20 were eligible for response evaluation.</population>
        <group_list>
          <group group_id="O1">
            <title>FCR With Lenalidomide</title>
            <description>Fludarabine, Cyclophosphamide, Rituximab, Lenalidomide - 19 subjects are treated in stage-1 with FCR plus 5mg lenalidomide increasing to 10mg and 15mg in subsequent cycles depending on toxicity. If there are at least 5 CRs after 4 cycles of FCR plus lenalidomide the study will accrue an additional 35 subjects.&#xD;
Fludarabine, Cyclophosphamide, Rituximab, Lenalidomide: 19 subjects are treated in stage-1 with FCR plus 5mg lenalidomide increasing to 10mg and 15mg in subsequent cycles depending on toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Complete Response</title>
          <description>Analysis of the Primary Endpoint: The complete responses will be estimated by the number of patients with CR divided by the total number of evaluable patients.</description>
          <population>Of the 21 were enrolled, 20 were eligible for response evaluation.</population>
          <units>Percentage of Participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="45"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Response Rate</title>
        <description>Analysis of the other Secondary Endpoints: The overall response rate will be estimated by the number of patients with complete and partial responses divided by the total number of evaluable patients.</description>
        <time_frame>28 day cycle, up to 6 cycles</time_frame>
        <population>Of the 21 were enrolled, 20 were eligible for response evaluation.</population>
        <group_list>
          <group group_id="O1">
            <title>FCR With Lenalidomide</title>
            <description>Fludarabine, Cyclophosphamide, Rituximab, Lenalidomide - 19 subjects are treated in stage-1 with FCR plus 5mg lenalidomide increasing to 10mg and 15mg in subsequent cycles depending on toxicity. If there are at least 5 CRs after 4 cycles of FCR plus lenalidomide the study will accrue an additional 35 subjects.&#xD;
Fludarabine, Cyclophosphamide, Rituximab, Lenalidomide: 19 subjects are treated in stage-1 with FCR plus 5mg lenalidomide increasing to 10mg and 15mg in subsequent cycles depending on toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Response Rate</title>
          <description>Analysis of the other Secondary Endpoints: The overall response rate will be estimated by the number of patients with complete and partial responses divided by the total number of evaluable patients.</description>
          <population>Of the 21 were enrolled, 20 were eligible for response evaluation.</population>
          <units>Percentage of Participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="95"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From study enrollment to end of treatment, up to 18 months</time_frame>
      <group_list>
        <group group_id="E1">
          <title>FCR With Lenalidomide</title>
          <description>Fludarabine, Cyclophosphamide, Rituximab, Lenalidomide - 19 subjects are treated in stage-1 with FCR plus 5mg lenalidomide increasing to 10mg and 15mg in subsequent cycles depending on toxicity. If there are at least 5 CRs after 4 cycles of FCR plus lenalidomide the study will accrue an additional 35 subjects.&#xD;
Fludarabine, Cyclophosphamide, Rituximab, Lenalidomide: 19 subjects are treated in stage-1 with FCR plus 5mg lenalidomide increasing to 10mg and 15mg in subsequent cycles depending on toxicity.</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Non-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="21"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Neutropenic Fever</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Bilateral Leg Weakness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Seizure</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Upper Respiratory Infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Maculopapular Rash</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Non-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="19" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Leukopenia</sub_title>
                <counts group_id="E1" events="13" subjects_affected="13" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" events="33" subjects_affected="19" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Thrombocytopenia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Infusion Reaction</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Bacteremia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Pustular Rash</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
              </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>Joshua Zenreich</name_or_title>
      <organization>John Theurer Cancer Center at Hackensack Meridian Health</organization>
      <phone>551-996-4248</phone>
      <email>joshua.zenreich@hmhn.org</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/NCT01723839
org study id: Pro00002262 RV-CLL-PI-0530
nct id: NCT01723839
lead sponsor: 
collaborator: 
has dmc: Yes
In previously-untreated subjects with CLL, fludarabine and rituximab with or without
      cyclophosphamide (FR or FCR) produces complete responses (CR) of 40-80%. The major
      complication of FCR has been grade 3/4 neutropenia which was reduced using a lower dose of
      fludarabine and cyclophosphamide (FCR-Lite) The objective of this study is to evaluate the
      minimal residual disease (MRD) complete response rate (using the 2008 IWCLL guidelines) after
      4 cycles of FCR-Lite plus lenalidomide in subjects with previously untreated CLL.
      Lenalidomide is active in frontline treatment of CLL as well as in patients with refractory
      disease. MRD has been demonstrated to be a sensitive surrogate marker for progression-free
      survival. If patients are MRD negative complete responders (CR) they will stop at 4 cycles of
      FCR-Lite followed by the lenalidomide consolidation/maintenance arm of the study. If they
      have a MRD positive CR or partial response (PR) they will continue with 2 additional cycles
      of FCR-Lite plus lenalidomide followed by lenalidomide consolidation/maintenance. They will
      be re-tested for MRD after the 6th cycle of FCR-Lite and after 6 and 12 months of
      lenalidomide monotherapy If they have no response (NR) or progressive disease (PD) following
      4 cycles of FCR-Lite plus lenalidomide they will be removed from the study.
STUDY OBJECTIVES:

      Primary:

      The primary objective is to evaluate the complete response rate following 4 cycles of
      FCR-Lite plus lenalidomide in previously untreated patients with CLL.

      Secondary:

      The first secondary objective is to evaluate the toxicity of patients with previously
      untreated CLL treated with FCR-Lite plus lenalidomide, followed by lenalidomide. The second
      is to evaluate the overall response rate and overall survival of patients with previously
      untreated CLL treated with FCR-Lite plus lenalidomide followed by lenalidomide. The third is
      to determine whether adding lenalidomide as a consolidation/maintenance therapy will
      eliminate bone marrow minimal residual disease in CR patients and whether patients who have a
      PR after 6 cycles of FCR-Lite plus lenalidomide will respond to 12 months of lenalidomide.
      The final secondary objective is to determine whether the expression of ZAP-70, CD38, and
      chromosomes correlate with response rate, duration of response, and survival for previously
      untreated patients with CLL.

      STUDY DESIGN:

      2-stage phase 2 study-design. 19 subjects are treated in stage-1 with FCR-Lite plus 5mg
      lenalidomide increasing to 10mg and 15mg in subsequent cycles depending on toxicity. If there
      are at least 5 CRs the study will accrue an additional 35 subjects (see statistical section).
      A secondary objective of this study will be to determine if MRD positive patients will become
      MRD negative with lenalidomide consolidation/maintenance and whether PR patients will convert
      to CRs Lenalidomide will begin 2 months after the last dose of FCR-Lite in all subjects with
      CR. It may begin as soon as 1 month after FCR-Lite plus lenalidomide in subjects with PR.
      Lenalidomide is given in 28 d cycles increasing the dose from 5 mg/d to 10 mg/d in cycle 2
      and to 15mg in cycles 3-6 if well- tolerated (no grade-3 or -4 toxicity). Patients with
      creatinine clearance ≥30ml/min and <60ml/min will start at 2.5mg daily increasing to 5 and
      10mg in subsequent cycles . Reduction to the prior dose is allowed for grade-3/-4 toxicity.
      MRD will be studied by flow cytometry from bone marrow and peripheral blood samples following
      4 and 6 cycles of FCR-Lite and after 6 and 12 months of lenalidomide in CR patients.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Complete Response
time frame: 28 day cycle, up to 4 cycles
description: Analysis of the Primary Endpoint: The complete responses will be estimated by the number of patients with CR divided by the total number of evaluable patients.
measure: Overall Response Rate
time frame: 28 day cycle, up to 6 cycles
description: Analysis of the other Secondary Endpoints: The overall response rate will be estimated by the number of patients with complete and partial responses divided by the total number of evaluable patients.
arm group label: FCR with Lenalidomide
arm group type: Other
description: Fludarabine, Cyclophosphamide, Rituximab, Lenalidomide - 19 subjects are treated in stage-1 with FCR plus 5mg lenalidomide increasing to 10mg and 15mg in subsequent cycles depending on toxicity. If there are at least 5 CRs after 4 cycles of FCR plus lenalidomide the study will accrue an additional 35 subjects.
intervention type: Drug
intervention name: Fludarabine, Cyclophosphamide, Rituximab, Lenalidomide
description: 19 subjects are treated in stage-1 with FCR plus 5mg lenalidomide increasing to 10mg and 15mg in subsequent cycles depending on toxicity.
arm group label: FCR with Lenalidomide
other name: FCR + Lenalidomide
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Andre Goy, MD
role: Principal Investigator
affiliation: John Theurer Cancer Center at HackensackUMC
facility: 
country: United States
citation: Rai KR, Patel DV. Chronic Lymphocytic Leukemia, in Hoffman R, Benz E, Shattil 5, Furie B, Cohen H, Silberstein L (eds): Hematology: Basic Principles and Practice, New York, Churchill Livingstone, 1995, p. 1308.
citation: Linet MS, Cartwright RA. Chronic lymphocytic leukemia: epidemiology and etiologic findings. Nouv Rev Fr Hematol (1978). 1988;30(5-6):353-7.
PMID: 3222144
citation: Jaksic B, Vitale B, Hauptmann E, Planinc-Peraica A, Ostojic S, Kusec R. The roles of age and sex in the prognosis of chronic leukaemias. A study of 373 cases. Br J Cancer. 1991 Aug;64(2):345-8. doi: 10.1038/bjc.1991.303.
PMID: 1892761
citation: Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ; International Workshop on Chronic Lymphocytic Leukemia. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008 Jun 15;111(12):5446-56. doi: 10.1182/blood-2007-06-093906. Epub 2008 Jan 23. Erratum In: Blood. 2008 Dec 15;112(13):5259.
PMID: 18216293
citation: Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood. 1975 Aug;46(2):219-34.
PMID: 1139039
citation: Rai KR, Sawitsky A. A review of the prognostic role of cytogenetic, phenotypic, morphologic, and immune function characteristics in chronic lymphocytic leukemia. Blood Cells. 1987;12(2):327-38.
PMID: 3304471
citation: Montserrat E, Rozman C. Bone marrow biopsy in chronic lymphocytic leukemia: a review of its prognostic importance. Blood Cells. 1987;12(2):315-26.
PMID: 3304470
citation: Montserrat E, Rozman C. Chronic lymphocytic leukaemia: prognostic factors and natural history. Baillieres Clin Haematol. 1993 Dec;6(4):849-66. doi: 10.1016/s0950-3536(05)80179-9.
PMID: 8038493
citation: Han T, Bhargava A, Henderson ES, et al. Prognostic significance of beta-2-microglobulin (-2m) in chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL). Proc Amer Soc Clin Oncol 1989; 8:270 (abstr 270).
citation: Montserrat E, Alcala A, Parody R, Domingo A, Garcia-Conde J, Bueno J, Ferran C, Sanz MA, Giralt M, Rubio D, et al. Treatment of chronic lymphocytic leukemia in advanced stages. A randomized trial comparing chlorambucil plus prednisone versus cyclophosphamide, vincristine, and prednisone. Cancer. 1985 Nov 15;56(10):2369-75. doi: 10.1002/1097-0142(19851115)56:103.0.co;2-n.
PMID: 3899346
citation: Fais F, Ghiotto F, Hashimoto S, Sellars B, Valetto A, Allen SL, Schulman P, Vinciguerra VP, Rai K, Rassenti LZ, Kipps TJ, Dighiero G, Schroeder HW Jr, Ferrarini M, Chiorazzi N. Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors. J Clin Invest. 1998 Oct 15;102(8):1515-25. doi: 10.1172/JCI3009.
PMID: 9788964
citation: Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL, Buchbinder A, Budman D, Dittmar K, Kolitz J, Lichtman SM, Schulman P, Vinciguerra VP, Rai KR, Ferrarini M, Chiorazzi N. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999 Sep 15;94(6):1840-7.
PMID: 10477712
citation: Oscier DG, Thompsett A, Zhu D, Stevenson FK. Differential rates of somatic hypermutation in V(H) genes among subsets of chronic lymphocytic leukemia defined by chromosomal abnormalities. Blood. 1997 Jun 1;89(11):4153-60.
PMID: 9166858
citation: Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999 Sep 15;94(6):1848-54.
PMID: 10477713
citation: Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, Rozman M, Marce S, Lopez-Guillermo A, Campo E, Montserrat E. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med. 2003 May 1;348(18):1764-75. doi: 10.1056/NEJMoa023143.
PMID: 12724482
citation: Lin K, Sherrington PD, Dennis M, Matrai Z, Cawley JC, Pettitt AR. Relationship between p53 dysfunction, CD38 expression, and IgV(H) mutation in chronic lymphocytic leukemia. Blood. 2002 Aug 15;100(4):1404-9. doi: 10.1182/blood-2001-11-0066. Erratum In: Blood 2002 Oct 1;100(7):2291.
PMID: 12149224
citation: Gahrton G, Juliusson G. Clinical implication of chromosomal aberrations in chronic B-lymphocytic leukaemia cells. Nouv Rev Fr Hematol (1978). 1988;30(5-6):389-92.
PMID: 3265508
citation: Bird ML, Ueshima Y, Rowley JD, Haren JM, Vardiman JW. Chromosome abnormalities in B cell chronic lymphocytic leukemia and their clinical correlations. Leukemia. 1989 Mar;3(3):182-91.
PMID: 2918755
citation: Krober A, Seiler T, Benner A, Bullinger L, Bruckle E, Lichter P, Dohner H, Stilgenbauer S. V(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood. 2002 Aug 15;100(4):1410-6.
PMID: 12149225
citation: Rozman C, Montserrat E. Bone marrow biopsy in chronic lymphocytic leukemia. Nouv Rev Fr Hematol (1978). 1988;30(5-6):369-71.
PMID: 3065734
citation: Pangalis GA, Boussiotis VA, Kittas C. B-chronic lymphocytic leukemia. Disease progression in 150 untreated stage A and B patients as predicted by bone marrow pattern. Nouv Rev Fr Hematol (1978). 1988;30(5-6):373-5.
PMID: 3222147
citation: Montserrat E, Vinolas N, Reverter JC, Rozman C. Natural history of chronic lymphocytic leukemia: on the progression and progression and prognosis of early clinical stages. Nouv Rev Fr Hematol (1978). 1988;30(5-6):359-61.
PMID: 3222145
citation: Shustik C, Mick R, Silver R, Sawitsky A, Rai K, Shapiro L. Treatment of early chronic lymphocytic leukemia: intermittent chlorambucil versus observation. Hematol Oncol. 1988 Jan-Mar;6(1):7-12. doi: 10.1002/hon.2900060103.
PMID: 3277904
citation: Liepman M, Votaw ML. The treatment of chronic lymphocytic leukemia with COP chemotherapy. Cancer. 1978 May;41(5):1664-9. doi: 10.1002/1097-0142(197805)41:53.0.co;2-q.
PMID: 647620
citation: Oken MM, Kaplan ME. Combination chemotherapy with cyclophosphamide, vincristine, and prednisone in the treatment of refractory chronic lymphocytic leukemia. Cancer Treat Rep. 1979 Mar;63(3):441-7. No abstract available.
PMID: 371799
citation: Hansen MM, Andersen E, Christensen BE, Christiansen I, Geisler C, Kristensen D, Jensen KB, Junker P. CHOP versus prednisolone + chlorambucil in chronic lymphocytic leukemia (CLL): preliminary results of a randomized multicenter study. Nouv Rev Fr Hematol (1978). 1988;30(5-6):433-6.
PMID: 3065739
citation: Raphael B, Andersen JW, Silber R, Oken M, Moore D, Bennett J, Bonner H, Hahn R, Knospe WH, Mazza J, et al. Comparison of chlorambucil and prednisone versus cyclophosphamide, vincristine, and prednisone as initial treatment for chronic lymphocytic leukemia: long-term follow-up of an Eastern Cooperative Oncology Group randomized clinical trial. J Clin Oncol. 1991 May;9(5):770-6. doi: 10.1200/JCO.1991.9.5.770.
PMID: 2016618
citation: Grever MR, Kopecky KJ, Coltman CA, Files JC, Greenberg BR, Hutton JJ, Talley R, Von Hoff DD, Balcerzak SP. Fludarabine monophosphate: a potentially useful agent in chronic lymphocytic leukemia. Nouv Rev Fr Hematol (1978). 1988;30(5-6):457-9.
PMID: 2464793
citation: Keating MJ, Kantarjian H, O'Brien S, Koller C, Talpaz M, Schachner J, Childs CC, Freireich EJ, McCredie KB. Fludarabine: a new agent with marked cytoreductive activity in untreated chronic lymphocytic leukemia. J Clin Oncol. 1991 Jan;9(1):44-9. doi: 10.1200/JCO.1991.9.1.44.
PMID: 1702145
citation: Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L, Hines J, Threatte GA, Larson RA, Cheson BD, Schiffer CA. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000 Dec 14;343(24):1750-7. doi: 10.1056/NEJM200012143432402.
PMID: 11114313
citation: O'Brien S, Kantarjian H, Beran M, Smith T, Koller C, Estey E, Robertson LE, Lerner S, Keating M. Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment. Blood. 1993 Sep 15;82(6):1695-700.
PMID: 8400226
citation: Anaissie E, Kontoyiannis DP, Kantarjian H, Elting L, Robertson LE, Keating M. Listeriosis in patients with chronic lymphocytic leukemia who were treated with fludarabine and prednisone. Ann Intern Med. 1992 Sep 15;117(6):466-9. doi: 10.7326/0003-4819-117-6-466.
PMID: 1354425
citation: Johnston JB, Verburg L, Shore T, Williams M, Israels LG, Begleiter A. Combination therapy with nucleoside analogs and alkylating agents. Leukemia. 1994 Apr;8 Suppl 1:S140-3.
PMID: 8152282
citation: Begleiter A, Pugh L, Israels LG, Johnston JB. Enhanced cytotoxicity and inhibition of DNA damage repair in irradiated murine L5178Y lymphoblasts and human chronic lymphocytic leukemia cells treated with 2'-deoxycoformycin and deoxyadenosine in vitro. Cancer Res. 1988 Jul 15;48(14):3981-6.
PMID: 3260129
citation: O'Brien SM, Kantarjian HM, Cortes J, Beran M, Koller CA, Giles FJ, Lerner S, Keating M. Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia. J Clin Oncol. 2001 Mar 1;19(5):1414-20. doi: 10.1200/JCO.2001.19.5.1414.
PMID: 11230486
citation: Flinn IW, Byrd JC, Morrison C, Jamison J, Diehl LF, Murphy T, Piantadosi S, Seifter E, Ambinder RF, Vogelsang G, Grever MR. Fludarabine and cyclophosphamide with filgrastim support in patients with previously untreated indolent lymphoid malignancies. Blood. 2000 Jul 1;96(1):71-5.
PMID: 10891432
citation: Hainsworth JD, Litchy S, Barton JH, Houston GA, Hermann RC, Bradof JE, Greco FA; Minnie Pearl Cancer Research Network. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2003 May 1;21(9):1746-51. doi: 10.1200/JCO.2003.09.027.
PMID: 12721250
citation: O'Brien SM, Kantarjian H, Thomas DA, Giles FJ, Freireich EJ, Cortes J, Lerner S, Keating MJ. Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol. 2001 Apr 15;19(8):2165-70. doi: 10.1200/JCO.2001.19.8.2165.
PMID: 11304768
citation: Byrd JC, Murphy T, Howard RS, Lucas MS, Goodrich A, Park K, Pearson M, Waselenko JK, Ling G, Grever MR, Grillo-Lopez AJ, Rosenberg J, Kunkel L, Flinn IW. Rituximab using a thrice weekly dosing schedule in B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity. J Clin Oncol. 2001 Apr 15;19(8):2153-64. doi: 10.1200/JCO.2001.19.8.2153.
PMID: 11304767
citation: Ladetto M, Bergui L, Ricca I, Campana S, Pileri A, Tarella C. Rituximab anti-CD20 monoclonal antibody induces marked but transient reductions of peripheral blood lymphocytes in chronic lymphocytic leukaemia patients. Med Oncol. 2000 Aug;17(3):203-10. doi: 10.1007/BF02780529.
PMID: 10962531
citation: Huhn D, von Schilling C, Wilhelm M, Ho AD, Hallek M, Kuse R, Knauf W, Riedel U, Hinke A, Srock S, Serke S, Peschel C, Emmerich B; German Chronic Lymphocytic Leukemia Study Group. Rituximab therapy of patients with B-cell chronic lymphocytic leukemia. Blood. 2001 Sep 1;98(5):1326-31. doi: 10.1182/blood.v98.5.1326.
PMID: 11520778
citation: List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D, Rimsza L, Heaton R, Knight R, Zeldis JB. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005 Feb 10;352(6):549-57. doi: 10.1056/NEJMoa041668.
PMID: 15703420
citation: List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, Powell B, Greenberg P, Thomas D, Stone R, Reeder C, Wride K, Patin J, Schmidt M, Zeldis J, Knight R; Myelodysplastic Syndrome-003 Study Investigators. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006 Oct 5;355(14):1456-65. doi: 10.1056/NEJMoa061292.
PMID: 17021321
citation: Richardson PG, Schlossman RL, Weller E, Hideshima T, Mitsiades C, Davies F, LeBlanc R, Catley LP, Doss D, Kelly K, McKenney M, Mechlowicz J, Freeman A, Deocampo R, Rich R, Ryoo JJ, Chauhan D, Balinski K, Zeldis J, Anderson KC. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood. 2002 Nov 1;100(9):3063-7. doi: 10.1182/blood-2002-03-0996.
PMID: 12384400
citation: Richardson PG, Blood E, Mitsiades CS, Jagannath S, Zeldenrust SR, Alsina M, Schlossman RL, Rajkumar SV, Desikan KR, Hideshima T, Munshi NC, Kelly-Colson K, Doss D, McKenney ML, Gorelik S, Warren D, Freeman A, Rich R, Wu A, Olesnyckyj M, Wride K, Dalton WS, Zeldis J, Knight R, Weller E, Anderson KC. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006 Nov 15;108(10):3458-64. doi: 10.1182/blood-2006-04-015909. Epub 2006 Jul 13.
PMID: 16840727
citation: Rajkumar SV, Hayman SR, Lacy MQ, Dispenzieri A, Geyer SM, Kabat B, Zeldenrust SR, Kumar S, Greipp PR, Fonseca R, Lust JA, Russell SJ, Kyle RA, Witzig TE, Gertz MA. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood. 2005 Dec 15;106(13):4050-3. doi: 10.1182/blood-2005-07-2817. Epub 2005 Aug 23.
PMID: 16118317
citation: Marriott JB, Clarke IA, Dredge K, Muller G, Stirling D, Dalgleish AG. Thalidomide and its analogues have distinct and opposing effects on TNF-alpha and TNFR2 during co-stimulation of both CD4(+) and CD8(+) T cells. Clin Exp Immunol. 2002 Oct;130(1):75-84. doi: 10.1046/j.1365-2249.2002.01954.x.
PMID: 12296856
citation: Mangiameli DP, Blansfield JA, Kachala S, Lorang D, Schafer PH, Muller GW, Stirling DI, Libutti SK. Combination therapy targeting the tumor microenvironment is effective in a model of human ocular melanoma. J Transl Med. 2007 Jul 18;5:38. doi: 10.1186/1479-5876-5-38.
PMID: 17640369
citation: Tai YT, Li XF, Catley L, Coffey R, Breitkreutz I, Bae J, Song W, Podar K, Hideshima T, Chauhan D, Schlossman R, Richardson P, Treon SP, Grewal IS, Munshi NC, Anderson KC. Immunomodulatory drug lenalidomide (CC-5013, IMiD3) augments anti-CD40 SGN-40-induced cytotoxicity in human multiple myeloma: clinical implications. Cancer Res. 2005 Dec 15;65(24):11712-20. doi: 10.1158/0008-5472.CAN-05-1657.
PMID: 16357183
citation: LeBlanc R, Hideshima T, Catley LP, Shringarpure R, Burger R, Mitsiades N, Mitsiades C, Cheema P, Chauhan D, Richardson PG, Anderson KC, Munshi NC. Immunomodulatory drug costimulates T cells via the B7-CD28 pathway. Blood. 2004 Mar 1;103(5):1787-90. doi: 10.1182/blood-2003-02-0361. Epub 2003 Sep 25.
PMID: 14512311
citation: Hernandez-Ilizaliturri FJ, Reddy N, Holkova B, Ottman E, Czuczman MS. Immunomodulatory drug CC-5013 or CC-4047 and rituximab enhance antitumor activity in a severe combined immunodeficient mouse lymphoma model. Clin Cancer Res. 2005 Aug 15;11(16):5984-92. doi: 10.1158/1078-0432.CCR-05-0577.
PMID: 16115943
citation: Pellagatti A, Jadersten M, Forsblom AM, Cattan H, Christensson B, Emanuelsson EK, Merup M, Nilsson L, Samuelsson J, Sander B, Wainscoat JS, Boultwood J, Hellstrom-Lindberg E. Lenalidomide inhibits the malignant clone and up-regulates the SPARC gene mapping to the commonly deleted region in 5q- syndrome patients. Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11406-11. doi: 10.1073/pnas.0610477104. Epub 2007 Jun 18.
PMID: 17576924
citation: Chanan-Khan A, Miller KC, Musial L, Lawrence D, Padmanabhan S, Takeshita K, Porter CW, Goodrich DW, Bernstein ZP, Wallace P, Spaner D, Mohr A, Byrne C, Hernandez-Ilizaliturri F, Chrystal C, Starostik P, Czuczman MS. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol. 2006 Dec 1;24(34):5343-9. doi: 10.1200/JCO.2005.05.0401. Epub 2006 Nov 6.
PMID: 17088571
citation: Ferrajoli A, Lee BN, Schlette EJ, O'Brien SM, Gao H, Wen S, Wierda WG, Estrov Z, Faderl S, Cohen EN, Li C, Reuben JM, Keating MJ. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood. 2008 Jun 1;111(11):5291-7. doi: 10.1182/blood-2007-12-130120. Epub 2008 Mar 11.
PMID: 18334676
citation: Andritsos LA, Johnson AJ, Lozanski G, Blum W, Kefauver C, Awan F, Smith LL, Lapalombella R, May SE, Raymond CA, Wang DS, Knight RD, Ruppert AS, Lehman A, Jarjoura D, Chen CS, Byrd JC. Higher doses of lenalidomide are associated with unacceptable toxicity including life-threatening tumor flare in patients with chronic lymphocytic leukemia. J Clin Oncol. 2008 May 20;26(15):2519-25. doi: 10.1200/JCO.2007.13.9709. Epub 2008 Apr 21.
PMID: 18427150
citation: Chen C, Paul H, Xu W, et al: A phase II study of lenalidomide in previously untreated, symptomatic chronic lymphocytic leukemia (CLL). Blood 112:23, 2008 (abstr 44).
citation: Byrd JC, Peterson BL, Morrison VA, Park K, Jacobson R, Hoke E, Vardiman JW, Rai K, Schiffer CA, Larson RA. Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood. 2003 Jan 1;101(1):6-14. doi: 10.1182/blood-2002-04-1258. Epub 2002 Jul 5.
PMID: 12393429
citation: Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, Hensel M, Hopfinger G, Hess G, von Grunhagen U, Bergmann M, Catalano J, Zinzani PL, Caligaris-Cappio F, Seymour JF, Berrebi A, Jager U, Cazin B, Trneny M, Westermann A, Wendtner CM, Eichhorst BF, Staib P, Buhler A, Winkler D, Zenz T, Bottcher S, Ritgen M, Mendila M, Kneba M, Dohner H, Stilgenbauer S; International Group of Investigators; German Chronic Lymphocytic Leukaemia Study Group. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010 Oct 2;376(9747):1164-74. doi: 10.1016/S0140-6736(10)61381-5.
PMID: 20888994
citation: Keating MJ, O'Brien S, Albitar M, Lerner S, Plunkett W, Giles F, Andreeff M, Cortes J, Faderl S, Thomas D, Koller C, Wierda W, Detry MA, Lynn A, Kantarjian H. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 20;23(18):4079-88. doi: 10.1200/JCO.2005.12.051. Epub 2005 Mar 14.
PMID: 15767648
citation: Brown JR, Abramson J, Hochberg E, Mikler E, Dalton V, Werner L, Reynolds H, Thompson C, McDonough SM, Kuang Y, Ritz J, Neuberg D, Freedman AS. A phase I study of lenalidomide in combination with fludarabine and rituximab in previously untreated CLL/SLL. Leukemia. 2010 Nov;24(11):1972-5. doi: 10.1038/leu.2010.199. Epub 2010 Sep 16. No abstract available.
PMID: 20844565
citation: Provan D, Bartlett-Pandite L, Zwicky C, Neuberg D, Maddocks A, Corradini P, Soiffer R, Ritz J, Nadler LM, Gribben JG. Eradication of polymerase chain reaction-detectable chronic lymphocytic leukemia cells is associated with improved outcome after bone marrow transplantation. Blood. 1996 Sep 15;88(6):2228-35.
PMID: 8822943
citation: Moreton P, Kennedy B, Lucas G, Leach M, Rassam SM, Haynes A, Tighe J, Oscier D, Fegan C, Rawstron A, Hillmen P. Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. J Clin Oncol. 2005 May 1;23(13):2971-9. doi: 10.1200/JCO.2005.04.021. Epub 2005 Feb 28.
PMID: 15738539
citation: Bosch F, Ferrer A, Lopez-Guillermo A, Gine E, Bellosillo B, Villamor N, Colomer D, Cobo F, Perales M, Esteve J, Altes A, Besalduch J, Ribera JM, Montserrat E; GELCAB (Grup per l'Estudi dels Limfomes a Catalunya i Balears). Fludarabine, cyclophosphamide and mitoxantrone in the treatment of resistant or relapsed chronic lymphocytic leukaemia. Br J Haematol. 2002 Dec;119(4):976-84. doi: 10.1046/j.1365-2141.2002.03959.x.
PMID: 12472576
citation: Boettcher S, Fischer K, Stilgenbauer S, Busch R, Fingerle-Rowson G, Fink AM et al. Quantitative MRD assessments predict progression-free survival in CLL patients treated with fludarabine and cyclophosphamide with or without rituximab - a prospective analysis in 471 patients from the randomized GCLLSG CLL8 trial. Blood 2008; 112: 11, abstract 326)
citation: Kay NE, Geyer SM, Call TG, Shanafelt TD, Zent CS, Jelinek DF, Tschumper R, Bone ND, Dewald GW, Lin TS, Heerema NA, Smith L, Grever MR, Byrd JC. Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia. Blood. 2007 Jan 15;109(2):405-11. doi: 10.1182/blood-2006-07-033274. Epub 2006 Sep 28.
PMID: 17008537
citation: Foon KA, Boyiadzis M, Land SR, Marks S, Raptis A, Pietragallo L, Meisner D, Laman A, Sulecki M, Butchko A, Schaefer P, Lenzer D, Tarhini A. Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009 Feb 1;27(4):498-503. doi: 10.1200/JCO.2008.17.2619. Epub 2008 Dec 15.
PMID: 19075274
citation: Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989 Mar;10(1):1-10. doi: 10.1016/0197-2456(89)90015-9.
PMID: 2702835
citation: Dufy DE, Santner TJ, Confidence intervals for binomial parameter based on multistage tests. Biometrics 43:81-93, 1987.
responsible party type: Sponsor
mesh term: Leukemia, Lymphocytic, Chronic, B-Cell
mesh term: Cyclophosphamide
mesh term: Rituximab
mesh term: Fludarabine
mesh term: Lenalidomide
provided document: 
participant flow: 
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outcome list: 
reported events: 
certain agreements: 
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