<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/NCT03755947</url>
  </required_header>
  <id_info>
    <org_study_id>HAL 306/2018</org_study_id>
    <nct_id>NCT03755947</nct_id>
  </id_info>
  <brief_title>Ibrutinib, Obinutuzumab and Venetoclax for Patients With Chronic Lymphocytic Leukemia</brief_title>
  <official_title>Sequential Triple Therapy With Ibrutinib, Obinutuzumab and Venetoclax in First and Second Line for Patients With Chronic Lymphocytic Leukemia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Grupo Cooperativo de Hemopatías Malignas</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Grupo Cooperativo de Hemopatías Malignas</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background: Chronic Lymphocytic Leukemia (CLL) is the most common leukemia in the occidental&#xD;
      countries. Until now, it is considered a chronic disease without a cure. The development of&#xD;
      new molecular therapies have showed that the cure may be an option. This protocol propose a&#xD;
      triple sequential therapy with three direct therapies for the leukemic cell: an inhibitor of&#xD;
      Bruton´s tyrosine kinase (ibrutinib), a second generation monoclonal antibody versus CD20&#xD;
      (obinutuzumab) and a BCL-2 inhibitor (venetoclax) as treatment of first or second line in&#xD;
      CLL.&#xD;
&#xD;
      Objective: Negativize the minimal residual disease and by this way obtain longer survivals&#xD;
      (overall survival and relapse free survival).&#xD;
&#xD;
      Design: This is a multicenter, longitudinal, experimental, open, non-randomized and&#xD;
      non-comparable study coordinated by the &quot;Grupo Cooperativo de Hemopatías Malignas&quot; situated&#xD;
      on Hospital Angeles Lomas in Huixquilucan, México. The study, is a phase II clinical study&#xD;
      that will employ three target therapy drugs in sequencing phases. It will start with a BTK&#xD;
      inhibitor as induction, later an anti-CD20 will be used for consolidation and it will end&#xD;
      with a BH3 analog as maintenance for one year. The primary outcome is the negativization of&#xD;
      minimal residual disease.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The international recommendations indicate that the first line of treatment for patients &lt;65&#xD;
      years old and with no significant comorbidities (fit patients) the known regime of FCR with&#xD;
      recommendation of category 1 and later bendamustine with antiCD20 or ibrutinib. For patients&#xD;
      &gt;65 years old or not fit for intensive treatment it is recommended chlorambucil with&#xD;
      obinutuzumab, monotherapy with ibrutinib, bendamustine with antiCD20 or chlorambucil with&#xD;
      another antiCD20 like rituximab or ofatumumab. In case of patients with high-risk alterations&#xD;
      of relapse due to positive MRD at the end of the treatment it is recommended a maintenance&#xD;
      schedule with lenalidomide.&#xD;
&#xD;
      The antibodies against CD20 have shown through the years its activity in diverse alterations&#xD;
      of B-cells. Rituximab was approved in 1998 for B-cells Non-Hodgkin lymphomas including CLL.&#xD;
      Currently there are new anti-CD20 with more activity than rituximab. One of them is&#xD;
      obinutuzumab which, by the monoclonal antibody engineering shows a greater affinity to the&#xD;
      union of the epitope CD20 generating increased cellular cytotoxicity.&#xD;
&#xD;
      Bruton's tyrosine kinase (BTK), generates signaling cascades for the cell survival by the&#xD;
      NF-KB and MAP kinases way, which leads to the transduction of the B cell receptor (BCR).&#xD;
      Ibrutinib is a molecule that inhibits BTK inducing apoptosis in the B cells being currently&#xD;
      used in the diverse mature B cell neoplasms.&#xD;
&#xD;
      Another therapeutic target is the BCL-2 protein (B-cell lymphoma 2) which is a key regulator&#xD;
      in the apoptotic and it's compromised in the B cell neoplasms. Venetoclax is a mimetic drug&#xD;
      to BH3 that blocks the function of BCL-2.&#xD;
&#xD;
      Based in the old and new drugs described in CLL, there is a great number of combinations that&#xD;
      can be applied in the different phases of the disease as well as by risk stages and physical&#xD;
      state of the patient. Before this scenario diverse CLL study groups proposes the strategy of&#xD;
      sequencing in three phases (triple T) trying to prevent the development of leukemic&#xD;
      subclones, minimize the use of chemotherapy that generates secondary mutations in CLL and&#xD;
      other neoplasms. These type of treatment counts with the advantage of: 1) being available for&#xD;
      patients physically fit or not due to the a limited toxicity of the drugs, 2) applying in an&#xD;
      out-of-hospital environment and 3) adjusting the treatment according to the response to&#xD;
      generate an effective cost in the new drugs. Thus, it is proposed the cytoreduction&#xD;
      sequencing for 1 to 2 cycles, induction for 6 to 12 months and the MRD maintenance that could&#xD;
      go from one year up to undefined with ibrutinib, obinutuzumab and venetoclax in that order.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 1, 2018</start_date>
  <completion_date type="Actual">February 1, 2021</completion_date>
  <primary_completion_date type="Actual">December 31, 2020</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>
    <intervention_model_description>This is a multicenter, longitudinal, experimental, open, non-randomized and non-comparable study</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Best response obtained</measure>
    <time_frame>Two months after finishing the triple sequencing therapy</time_frame>
    <description>The best response obtained will be defined as CR with negative MRD by the iwCLL response criteria measured subsequent a cytoreduction treatment, induction and consolidation with the triple sequencing therapy with Ibrutinib, Obinutuzumab and Venetoclax in patients with chronic lymphocytic leukemia.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>Three years</time_frame>
    <description>Defined as the time since the end of treatment to time of death in the patients diagnosed with chronic lymphocytic leukemia in treatment with a triple sequencing therapy with Ibrutinib, Obinutuzumab and Venetoclax</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relapse-Free Survival</measure>
    <time_frame>Three years</time_frame>
    <description>Defined as the time since the end of treatment to time to relapse in the patients diagnosed with chronic lymphocytic leukemia in treatment with a triple sequencing therapy with Ibrutinib, Obinutuzumab and Venetoclax</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of AcuteToxicity</measure>
    <time_frame>Two years</time_frame>
    <description>Adverse effects associated to triple sequencing therapy with Ibrutinib, Obinutuzumab and Venetoclax</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of Late Toxicity</measure>
    <time_frame>Three years</time_frame>
    <description>Adverse effects associated to triple sequencing therapy with Ibrutinib, Obinutuzumab and Venetoclax on long term follow up.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">3</enrollment>
  <condition>B-Cell Chronic Lymphocytic Leukemia</condition>
  <condition>B-Cell Chronic Lymphocytic Leukemia in Relapse (Diagnosis)</condition>
  <arm_group>
    <arm_group_label>IGV</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Cytoreduction 3 cycles (I) Ibrutinib, [Imbruvica, Janssen]&#xD;
Induction 6 cycles (G) Obinutuzumab, [Gazyva, Roche]&#xD;
Consolidation 12 cycles (V) Venetoclax, [Venclexta, Abbvie].</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ibrutinib</intervention_name>
    <description>Ibrutinib Oral Capsule [Imbruvica] Tablets 120 mg. Oral. 420mg/day, day 1 to 28, every 28 days. 3 cycles.</description>
    <arm_group_label>IGV</arm_group_label>
    <other_name>Imbruvica</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Obinutuzumab</intervention_name>
    <description>Obinutuzumab Injection. Intravenous Solution [Gazyva] Parenteral. 1000 mg, day 1 of every cycle, every 28 days. 6 cycles.</description>
    <arm_group_label>IGV</arm_group_label>
    <other_name>Gazyva</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Venetoclax</intervention_name>
    <description>Venetoclax Oral Tablets [Venclexta] Tablets 100 mg. Oral. 400 mg/day. Day 1 to 28, every 28 days. 12 cycles.</description>
    <arm_group_label>IGV</arm_group_label>
    <other_name>Venclexta</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients diagnosed with B cell chronic lymphocytic leukemia according to 2017 WHO&#xD;
             criteria by immunophenotype/immunohistochemistry with active disease according to the&#xD;
             2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria and do&#xD;
             not present TP53 mutation and/or del(17)p. (Cohort 1).&#xD;
&#xD;
          -  Patients diagnosed with relapsed/refractory chronic lymphocytic leukemia that have&#xD;
             previously received at least one line of treatment that does not include the drugs in&#xD;
             the study scheme. (Cohort 2).&#xD;
&#xD;
          -  Functional stage of 0 - 2 measured by the Eastern Cooperative Oncology Group (ECOG)&#xD;
             scale.&#xD;
&#xD;
          -  Creatinine depuration ≥ 30 ml/min measured in a 24-hour urine recollection or&#xD;
             utilizing the CKD-EPI formula.&#xD;
&#xD;
          -  Proper liver function: total bilirubin ≤ 1.5 x upper limit of normal (ULN) or ≤ 3 x&#xD;
             ULN in patients with Gilbert syndrome, alanine aminotransferase (ALT) and aspartate&#xD;
             aminotransferase (AST) ≤ 3.0 x ULN.&#xD;
&#xD;
          -  Capacity and willingness to provide a written informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  T cell lymphocytic leukemia diagnosis.&#xD;
&#xD;
          -  TP53 mutation and/or del(17)p presence.&#xD;
&#xD;
          -  Non-controlled systematic active infection (viral, bacterial and/or fungic).&#xD;
&#xD;
          -  Patients with known infection by human immunodeficiency virus (HIV).&#xD;
&#xD;
          -  Active infection by hepatitis B (defined as the presence of detectable HBV's DNA, HBe&#xD;
             antigen or HBs antigen). Patients with serological evidence of previous vaccination&#xD;
             (HBsAg negative, anti-HBs positive antibodies, anti-HBc negative antibodies) are&#xD;
             eligible. The patients that are HBsAg negative/ anti-Hbs positive antibodies but&#xD;
             anti-HBc positive antibodies are eligible, if the HBV DNA is negative, and the HBV-DNA&#xD;
             PCR is realized every 12 months after the last cycle of treatment.&#xD;
&#xD;
          -  Active infection by hepatitis C, defined by the ribonucleic acid (RNA) of hepatitis C&#xD;
             is detectable in plasma by polymerase chain reaction (PCR).&#xD;
&#xD;
          -  Significant cardiovascular diseases such as uncontrolled or symptomatic arrhythmias,&#xD;
             congestive heart failure or acute myocardial infarction within 2 months prior to&#xD;
             screening, or any class 3 or 4 heart disease according to the functional&#xD;
             classification of the NYHA.&#xD;
&#xD;
          -  Diagnosis of previous malignancies for 2 years, with exception of patients with basal&#xD;
             or squamous cell carcinoma or &quot;in situ&quot; carcinoma of cervix or breast.&#xD;
&#xD;
          -  Requiring therapy with inhibitors or potent inducers of CYP3A4 and CYP3A5 inhibitors.&#xD;
&#xD;
          -  Anticoagulant therapy with acenocoumarol or warfarin.&#xD;
&#xD;
          -  History of cerebrovascular accident or intracranial hemorrhage within 6 months prior&#xD;
             to screening.&#xD;
&#xD;
          -  History of allergic reaction or severe anaphylaxis to humanized or murine monoclonal&#xD;
             antibodies.&#xD;
&#xD;
          -  Pregnant or lactating women.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Grupo Cooperativo de Hemopatías Malignas</name>
      <address>
        <city>Huixquilucan</city>
        <state>Estado De México</state>
        <zip>52763</zip>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Mexico</country>
  </location_countries>
  <reference>
    <citation>Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, Hillmen P, Keating M, Montserrat E, Chiorazzi N, Stilgenbauer S, Rai KR, Byrd JC, Eichhorst B, O'Brien S, Robak T, Seymour JF, Kipps TJ. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018 Jun 21;131(25):2745-2760. doi: 10.1182/blood-2017-09-806398. Epub 2018 Mar 14.</citation>
    <PMID>29540348</PMID>
  </reference>
  <reference>
    <citation>Rai KR, Jain P. Chronic lymphocytic leukemia (CLL)-Then and now. Am J Hematol. 2016 Mar;91(3):330-40. doi: 10.1002/ajh.24282.</citation>
    <PMID>26690614</PMID>
  </reference>
  <reference>
    <citation>Garcia Marco JA, Giraldo Castellano P, Lopez Jimenez J, Rios Herranz E, Sastre Moral JL, Terol Castera MJ, Bosch Albareda F; en representacion del Grupo Espanol de Leucemia Linfatica Cronica (GELLC); Sociedad Espan ola de Hematologi a y Hemoterapia. [National guidelines for the management of patients with chronic lymphocytic leukemia. Sociedad Espan ola de Hematologi a y Hemoterapia and Grupo Espan ol de Leucemia Linfoci tica Cro nica]. Med Clin (Barc). 2013 Aug 17;141(4):175.e1-8. doi: 10.1016/j.medcli.2013.04.041. Epub 2013 Jul 3. Spanish.</citation>
    <PMID>23830547</PMID>
  </reference>
  <reference>
    <citation>Cartron G, de Guibert S, Dilhuydy MS, Morschhauser F, Leblond V, Dupuis J, Mahe B, Bouabdallah R, Lei G, Wenger M, Wassner-Fritsch E, Hallek M. Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study. Blood. 2014 Oct 2;124(14):2196-202. doi: 10.1182/blood-2014-07-586610. Epub 2014 Aug 20.</citation>
    <PMID>25143487</PMID>
  </reference>
  <reference>
    <citation>Farooqui MZ, Valdez J, Martyr S, Aue G, Saba N, Niemann CU, Herman SE, Tian X, Marti G, Soto S, Hughes TE, Jones J, Lipsky A, Pittaluga S, Stetler-Stevenson M, Yuan C, Lee YS, Pedersen LB, Geisler CH, Calvo KR, Arthur DC, Maric I, Childs R, Young NS, Wiestner A. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol. 2015 Feb;16(2):169-76. doi: 10.1016/S1470-2045(14)71182-9. Epub 2014 Dec 31.</citation>
    <PMID>25555420</PMID>
  </reference>
  <reference>
    <citation>Byrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Devereux S, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Pocock C, Thornton P, Caligaris-Cappio F, Robak T, Delgado J, Schuster SJ, Montillo M, Schuh A, de Vos S, Gill D, Bloor A, Dearden C, Moreno C, Jones JJ, Chu AD, Fardis M, McGreivy J, Clow F, James DF, Hillmen P; RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014 Jul 17;371(3):213-23. doi: 10.1056/NEJMoa1400376. Epub 2014 May 31.</citation>
    <PMID>24881631</PMID>
  </reference>
  <reference>
    <citation>Barr PM, Robak T, Owen C, Tedeschi A, Bairey O, Bartlett NL, Burger JA, Hillmen P, Coutre S, Devereux S, Grosicki S, McCarthy H, Li J, Simpson D, Offner F, Moreno C, Zhou C, Styles L, James D, Kipps TJ, Ghia P. Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2. Haematologica. 2018 Sep;103(9):1502-1510. doi: 10.3324/haematol.2018.192328. Epub 2018 Jun 7.</citation>
    <PMID>29880603</PMID>
  </reference>
  <reference>
    <citation>Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, Kipps TJ, Anderson MA, Brown JR, Gressick L, Wong S, Dunbar M, Zhu M, Desai MB, Cerri E, Heitner Enschede S, Humerickhouse RA, Wierda WG, Seymour JF. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016 Jan 28;374(4):311-22. doi: 10.1056/NEJMoa1513257. Epub 2015 Dec 6.</citation>
    <PMID>26639348</PMID>
  </reference>
  <reference>
    <citation>Cramer P, von Tresckow J, Bahlo J, Robrecht S, Langerbeins P, Al-Sawaf O, Engelke A, Fink AM, Fischer K, Tausch E, Seiler T, Fischer von Weikersthal L, Hebart H, Kreuzer KA, Bottcher S, Ritgen M, Kneba M, Wendtner CM, Stilgenbauer S, Eichhorst B, Hallek M. Bendamustine followed by obinutuzumab and venetoclax in chronic lymphocytic leukaemia (CLL2-BAG): primary endpoint analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol. 2018 Sep;19(9):1215-1228. doi: 10.1016/S1470-2045(18)30414-5. Epub 2018 Aug 13.</citation>
    <PMID>30115596</PMID>
  </reference>
  <reference>
    <citation>Fischer K, Al-Sawaf O, Fink A-M, et al. Venetoclax and obinutuzumab in chronic lymphocytic leukemia. Blood. 2017;129(19):2702-2705. Blood. 2017 Jul 13;130(2):232. doi: 10.1182/blood-2017-05-787366. No abstract available.</citation>
    <PMID>28705863</PMID>
  </reference>
  <reference>
    <citation>Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, D'Rozario J, Assouline S, Owen C, Gerecitano J, Robak T, De la Serna J, Jaeger U, Cartron G, Montillo M, Humerickhouse R, Punnoose EA, Li Y, Boyer M, Humphrey K, Mobasher M, Kater AP. Venetoclax-Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med. 2018 Mar 22;378(12):1107-1120. doi: 10.1056/NEJMoa1713976.</citation>
    <PMID>29562156</PMID>
  </reference>
  <reference>
    <citation>Hallek M. Signaling the end of chronic lymphocytic leukemia: new frontline treatment strategies. Blood. 2013 Nov 28;122(23):3723-34. doi: 10.1182/blood-2013-05-498287. Epub 2013 Sep 24. Erratum In: Blood. 2014 Jun 26;123(26):4153.</citation>
    <PMID>24065239</PMID>
  </reference>
  <verification_date>February 2021</verification_date>
  <study_first_submitted>November 20, 2018</study_first_submitted>
  <study_first_submitted_qc>November 26, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 28, 2018</study_first_posted>
  <last_update_submitted>February 1, 2021</last_update_submitted>
  <last_update_submitted_qc>February 1, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">February 2, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>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>Venetoclax</mesh_term>
    <mesh_term>Obinutuzumab</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03755947
org study id: HAL 306/2018
nct id: NCT03755947
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
Background: Chronic Lymphocytic Leukemia (CLL) is the most common leukemia in the occidental
      countries. Until now, it is considered a chronic disease without a cure. The development of
      new molecular therapies have showed that the cure may be an option. This protocol propose a
      triple sequential therapy with three direct therapies for the leukemic cell: an inhibitor of
      Bruton´s tyrosine kinase (ibrutinib), a second generation monoclonal antibody versus CD20
      (obinutuzumab) and a BCL-2 inhibitor (venetoclax) as treatment of first or second line in
      CLL.

      Objective: Negativize the minimal residual disease and by this way obtain longer survivals
      (overall survival and relapse free survival).

      Design: This is a multicenter, longitudinal, experimental, open, non-randomized and
      non-comparable study coordinated by the "Grupo Cooperativo de Hemopatías Malignas" situated
      on Hospital Angeles Lomas in Huixquilucan, México. The study, is a phase II clinical study
      that will employ three target therapy drugs in sequencing phases. It will start with a BTK
      inhibitor as induction, later an anti-CD20 will be used for consolidation and it will end
      with a BH3 analog as maintenance for one year. The primary outcome is the negativization of
      minimal residual disease.
The international recommendations indicate that the first line of treatment for patients <65
      years old and with no significant comorbidities (fit patients) the known regime of FCR with
      recommendation of category 1 and later bendamustine with antiCD20 or ibrutinib. For patients
      >65 years old or not fit for intensive treatment it is recommended chlorambucil with
      obinutuzumab, monotherapy with ibrutinib, bendamustine with antiCD20 or chlorambucil with
      another antiCD20 like rituximab or ofatumumab. In case of patients with high-risk alterations
      of relapse due to positive MRD at the end of the treatment it is recommended a maintenance
      schedule with lenalidomide.

      The antibodies against CD20 have shown through the years its activity in diverse alterations
      of B-cells. Rituximab was approved in 1998 for B-cells Non-Hodgkin lymphomas including CLL.
      Currently there are new anti-CD20 with more activity than rituximab. One of them is
      obinutuzumab which, by the monoclonal antibody engineering shows a greater affinity to the
      union of the epitope CD20 generating increased cellular cytotoxicity.

      Bruton's tyrosine kinase (BTK), generates signaling cascades for the cell survival by the
      NF-KB and MAP kinases way, which leads to the transduction of the B cell receptor (BCR).
      Ibrutinib is a molecule that inhibits BTK inducing apoptosis in the B cells being currently
      used in the diverse mature B cell neoplasms.

      Another therapeutic target is the BCL-2 protein (B-cell lymphoma 2) which is a key regulator
      in the apoptotic and it's compromised in the B cell neoplasms. Venetoclax is a mimetic drug
      to BH3 that blocks the function of BCL-2.

      Based in the old and new drugs described in CLL, there is a great number of combinations that
      can be applied in the different phases of the disease as well as by risk stages and physical
      state of the patient. Before this scenario diverse CLL study groups proposes the strategy of
      sequencing in three phases (triple T) trying to prevent the development of leukemic
      subclones, minimize the use of chemotherapy that generates secondary mutations in CLL and
      other neoplasms. These type of treatment counts with the advantage of: 1) being available for
      patients physically fit or not due to the a limited toxicity of the drugs, 2) applying in an
      out-of-hospital environment and 3) adjusting the treatment according to the response to
      generate an effective cost in the new drugs. Thus, it is proposed the cytoreduction
      sequencing for 1 to 2 cycles, induction for 6 to 12 months and the MRD maintenance that could
      go from one year up to undefined with ibrutinib, obinutuzumab and venetoclax in that order.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: This is a multicenter, longitudinal, experimental, open, non-randomized and non-comparable study
primary purpose: Treatment
masking: None (Open Label)
measure: Best response obtained
time frame: Two months after finishing the triple sequencing therapy
description: The best response obtained will be defined as CR with negative MRD by the iwCLL response criteria measured subsequent a cytoreduction treatment, induction and consolidation with the triple sequencing therapy with Ibrutinib, Obinutuzumab and Venetoclax in patients with chronic lymphocytic leukemia.
measure: Overall Survival
time frame: Three years
description: Defined as the time since the end of treatment to time of death in the patients diagnosed with chronic lymphocytic leukemia in treatment with a triple sequencing therapy with Ibrutinib, Obinutuzumab and Venetoclax
measure: Relapse-Free Survival
time frame: Three years
description: Defined as the time since the end of treatment to time to relapse in the patients diagnosed with chronic lymphocytic leukemia in treatment with a triple sequencing therapy with Ibrutinib, Obinutuzumab and Venetoclax
measure: Rate of AcuteToxicity
time frame: Two years
description: Adverse effects associated to triple sequencing therapy with Ibrutinib, Obinutuzumab and Venetoclax
measure: Rate of Late Toxicity
time frame: Three years
description: Adverse effects associated to triple sequencing therapy with Ibrutinib, Obinutuzumab and Venetoclax on long term follow up.
arm group label: IGV
arm group type: Experimental
description: Cytoreduction 3 cycles (I) Ibrutinib, [Imbruvica, Janssen]
Induction 6 cycles (G) Obinutuzumab, [Gazyva, Roche]
Consolidation 12 cycles (V) Venetoclax, [Venclexta, Abbvie].
intervention type: Drug
intervention name: Ibrutinib
description: Ibrutinib Oral Capsule [Imbruvica] Tablets 120 mg. Oral. 420mg/day, day 1 to 28, every 28 days. 3 cycles.
arm group label: IGV
other name: Imbruvica
intervention type: Drug
intervention name: Obinutuzumab
description: Obinutuzumab Injection. Intravenous Solution [Gazyva] Parenteral. 1000 mg, day 1 of every cycle, every 28 days. 6 cycles.
arm group label: IGV
other name: Gazyva
intervention type: Drug
intervention name: Venetoclax
description: Venetoclax Oral Tablets [Venclexta] Tablets 100 mg. Oral. 400 mg/day. Day 1 to 28, every 28 days. 12 cycles.
arm group label: IGV
other name: Venclexta
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: Mexico
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PMID: 24065239
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Leukemia, Lymphoid
mesh term: Leukemia, Lymphocytic, Chronic, B-Cell
mesh term: Venetoclax
mesh term: Obinutuzumab