<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/NCT03010358</url>
  </required_header>
  <id_info>
    <org_study_id>STUDY00016140</org_study_id>
    <secondary_id>NCI-2016-02029</secondary_id>
    <secondary_id>STUDY00016140</secondary_id>
    <nct_id>NCT03010358</nct_id>
  </id_info>
  <brief_title>Entospletinib and Obinutuzumab in Treating Patients With Relapsed Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or Non-Hodgkin Lymphoma</brief_title>
  <official_title>A Phase I/II Study of Syk Inhibitor Entospletinib (GS-9973) in Combination With Obinutuzumab in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) and B-Cell Malignancies</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Alexey Danilov, MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Gilead Sciences</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Oregon Health and Science University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>OHSU Knight Cancer Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase I/II trial studies the side effect and best dose of entospletinib when giving&#xD;
      together with obinutuzumab and to see how well they work in treating patients with chronic&#xD;
      lymphocytic leukemia, small lymphocytic lymphoma, or non-Hodgkin lymphoma that has come back.&#xD;
      Entospletinib may stop the growth of cancer cells by blocking some of the enzymes need for&#xD;
      cell growth. Monoclonal antibodies, such as obinutuzumab, may interfere with the ability of&#xD;
      cancer cells to grow and spread. Giving entospletinib and obinutuzumab together may work&#xD;
      better in treating patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, or&#xD;
      non-Hodgkin lymphoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To evaluate the safety and tolerability of entospletinib administered in combination with&#xD;
      obinutuzumab in patients with relapsed/refractory chronic lymphocytic leukemia/small&#xD;
      lymphocytic lymphoma (CLL/SLL) and non-Hodgkin lymphoma (NHL), and identify the dose for&#xD;
      phase 2 expansion. (Phase I) II. To evaluate the efficacy of entospletinib in combination&#xD;
      with obinutuzumab in patients with relapsed or refractory CLL/SLL, as measured by complete&#xD;
      response (CR) rate. (Phase II)&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. Objective response rate (ORR, defined as complete remission, complete response with&#xD;
      incomplete marrow recovery, partial remission and nodular partial response). (Phase II) II.&#xD;
      Event free survival defined as the interval between the date of first study treatment and the&#xD;
      date of objective signs of disease recurrence, subsequent anti-leukemic therapy, or death,&#xD;
      whichever is first reported. (Phase II) III. Safety and tolerability of entospletinib in&#xD;
      combination with obinutuzumab by adverse events (AEs). (Phase II)&#xD;
&#xD;
      EXPLORATORY OBJECTIVES:&#xD;
&#xD;
      I. Peripheral blood B-cell depletion and recovery. II. Pharmacodynamics effects of in vivo&#xD;
      administration of entospletinib on NFkappaB activation and expression of anti-apoptotic&#xD;
      proteins in CLL cells.&#xD;
&#xD;
      III. Association of established biomarkers (chromosomal abnormalities, immunoglobulin heavy&#xD;
      chain [IGHV] mutational status, p53 mutational status) with response (ORR and event-free&#xD;
      survival [EFS]) to entospletinib (ENTO) in combination with obinutuzumab in patients with&#xD;
      relapsed/refractory CLL.&#xD;
&#xD;
      OUTLINE: This is a phase I, dose-escalation study of entospletinib followed by a phase II&#xD;
      study.&#xD;
&#xD;
      Patients receive entospletinib orally (PO) either once a day (QD) or twice a day (BID) on&#xD;
      days -7 to -1 (run-in phase) depending on the assigned dose level. Patients also receive&#xD;
      obinutuzumab intravenously (IV) on days 1, 2, 8, and 15 of the first cycle and on day 1 of&#xD;
      all subsequent cycles. Treatment with obinutuzumab repeats every 28 days for up to 6 cycles&#xD;
      and daily treatment with entospletinib continues every 28 days for up to 12 cycles in the&#xD;
      absence of disease progression or unexpected toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up every 3 months for 12 months&#xD;
      then every 6 months thereafter. In the event of study closure, patients who are receiving&#xD;
      study drug at the time of closure will complete an abbreviated End of Treatment (EOT) visit.&#xD;
      No additional follow up will occur.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 17, 2017</start_date>
  <completion_date type="Actual">April 29, 2021</completion_date>
  <primary_completion_date type="Actual">April 29, 2021</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Maximum Tolerated Dose (MTD) of Entospletinib in Combination With Obinutuzumab</measure>
    <time_frame>Up to 28 days</time_frame>
    <description>The dose of obinutuzumab remains fixed in standard doses while the dose of entospletinib will be escalated. The starting dose of entospletinib will be 200 mg (twice-daily) and escalated to the second dose level 400 mg (twice-daily). MTD is the dose associated with a total of 6 patients treated with less than 2 dose limiting toxicities (DLT), or a total of 3 patients treated with less than 1 DLT. DLT is defined as 1) grade 3 or higher non-hematological toxicity (except grade 3 nausea, vomiting or diarrhea that was reversible within 72 hours with supportive care; grade 3 infusion-related toxicity; asymptomatic grade 3-4 laboratory abnormalities that are reversible to grade 2 or less within 72 hours; grade 3 tumor lysis syndrome or hyponatremia); 2) grade 4 neutropenia lasting &gt;7 days or febrile neutropenia; or 3) grade 4 thrombocytopenia/anemia or grade 3 thrombocytopenia with bleeding. The dosage follows the 3+3 traditional escalation rules.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Complete Response (CR) Defined as the Percentage of Subjects Who Achieve CR</measure>
    <time_frame>Up to 45 months</time_frame>
    <description>Response for CLL/SLL measured using Modified International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 (IWCLL) guidelines. Response for hairy cell leukemia was measured using Consensus resolution: proposed criteria published in Leukemia 1987.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Objective Response Rate (ORR)</measure>
    <time_frame>Up to 45 months</time_frame>
    <description>Defined as percentage of participants with complete remission, complete response with incomplete marrow recovery, partial remission and nodular partial response. Response for CLL/SLL measured using Modified International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 (IWCLL) guidelines. Response for hairy cell leukemia was measured using Consensus resolution: proposed criteria published in Leukemia 1987.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Event Free Survival (EFS)</measure>
    <time_frame>The interval between the date of first study treatment and the date of objective signs of disease recurrence, subsequent anti leukemic therapy, or death, whichever is first reported, assessed up to 45 months.</time_frame>
    <description>Will be summarized descriptively using the Kaplan-Meier estimate. EFS will be censored if entospletinib is discontinued for other reasons (such as drug is no longer available).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants Who Experienced Adverse Events</measure>
    <time_frame>Up to 45 months</time_frame>
    <description>Will be assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All adverse events (AEs) will be coded by system organ class, Medical Dictionary for Regulatory Activities (MedDRA) preferred term, and severity grade using NCI CTCAE (version 4.03).</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Peripheral Blood B-cell Depletion and Recovery</measure>
    <time_frame>Up to 45 months</time_frame>
    <description>Will be summarized using descriptive statistics.</description>
  </other_outcome>
  <other_outcome>
    <measure>Pharmacodynamics Parameters of NFkappaB Activation and Expression of Anti-apoptotic Proteins in Chronic Lymphocytic Leukemia (CLL) Cells</measure>
    <time_frame>Up to 45 months</time_frame>
    <description>Pharmacokinetic parameters including peak and trough levels will be determined by noncompartmental method(s) using the pharmacokinetic profile of entospletinib and obinutuzumab.</description>
  </other_outcome>
  <other_outcome>
    <measure>Biomarkers (Chromosomal Abnormalities, IGHV Mutational Status, p53 Mutational Status)</measure>
    <time_frame>Up to 45 months</time_frame>
    <description>Will be assessed by IgH somatic hypermutation assay version 2.0. Will associate with response (ORR) to entospletinib (ENTO) in combination with obinutuzumab in patients with relapsed/refractory CLL.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">24</enrollment>
  <condition>Anemia</condition>
  <condition>B-Cell Prolymphocytic Leukemia</condition>
  <condition>Grade 1 Follicular Lymphoma</condition>
  <condition>Grade 2 Follicular Lymphoma</condition>
  <condition>Grade 3a Follicular Lymphoma</condition>
  <condition>Hairy Cell Leukemia</condition>
  <condition>Lymphoplasmacytic Lymphoma</condition>
  <condition>Mantle Cell Lymphoma</condition>
  <condition>Marginal Zone Lymphoma</condition>
  <condition>Recurrent Chronic Lymphocytic Leukemia</condition>
  <condition>Recurrent Small Lymphocytic Lymphoma</condition>
  <condition>Refractory Chronic Lymphocytic Leukemia</condition>
  <condition>Refractory Small Lymphocytic Lymphoma</condition>
  <condition>Richter Syndrome</condition>
  <arm_group>
    <arm_group_label>Treatment (entospletinib, obinutuzumab)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive entospletinib PO either QD or BID on days -7 to -1 (run-in phase) depending on the assigned dose level. Patients also receive obinutuzumab IV on days 1, 2, 8, and 15 of the first cycle, and on day 1 of subsequent cycles. Treatment with obinutuzumab repeats every 28 days for up to 6 cycles and daily treatment with entospletinib continues every 28 days for up to 12 cycles in the absence of disease progression or unexpected toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Entospletinib</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (entospletinib, obinutuzumab)</arm_group_label>
    <other_name>ENTO</other_name>
    <other_name>GS 9973</other_name>
    <other_name>GS-9973</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Laboratory Biomarker Analysis</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Treatment (entospletinib, obinutuzumab)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Obinutuzumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (entospletinib, obinutuzumab)</arm_group_label>
    <other_name>Anti-CD20 Monoclonal Antibody R7159</other_name>
    <other_name>GA-101</other_name>
    <other_name>GA101</other_name>
    <other_name>Gazyva</other_name>
    <other_name>huMAB(CD20)</other_name>
    <other_name>R7159</other_name>
    <other_name>RO 5072759</other_name>
    <other_name>RO-5072759</other_name>
    <other_name>RO5072759</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Pharmacological Study</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Treatment (entospletinib, obinutuzumab)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Phase I portion of the study: Histologically or flow cytometry confirmed diagnosis of&#xD;
             B-CLL/SLL according to National Cancer Institute (NCI)-Working Group (WG) 1996&#xD;
             guidelines&#xD;
&#xD;
          -  Phase I portion of the study: The following types of NHL as documented by medical&#xD;
             records and with histology based on criteria established by the World Health&#xD;
             Organization (WHO):&#xD;
&#xD;
               -  Mantle cell lymphoma (MCL)&#xD;
&#xD;
               -  Follicular lymphoma (FL) - grades 1-3a&#xD;
&#xD;
               -  Lymphoplasmacytic lymphoma (LPL)&#xD;
&#xD;
               -  Marginal zone lymphoma (MZL)&#xD;
&#xD;
               -  CLL in Richter's transformation&#xD;
&#xD;
               -  B-cell prolymphocytic leukemia&#xD;
&#xD;
          -  Phase I portion of the study: Patients with histologically confirmed classical hairy&#xD;
             cell leukemia (HCL)&#xD;
&#xD;
          -  Phase II portion of the study - histologically or flow cytometry confirmed diagnosis&#xD;
             of BCLL/SLL according to NCI-WG 1996 guidelines; patients who lack CD23 expression on&#xD;
             their leukemia cells should be examined for (and found NOT to have) either t(11;14) or&#xD;
             cyclin D1 overexpression, to rule out mantle cell lymphoma&#xD;
&#xD;
          -  Patients underwent &gt;= 1 prior chemotherapy-based or immunotherapy-based regimen or&#xD;
             targeted therapy (e.g., inhibitors of BTK, PI3K etc.) administered for &gt;= 2 cycles,&#xD;
             and have had either documented disease progression or no response (stable disease) to&#xD;
             the most recent treatment regimen&#xD;
&#xD;
          -  Patients with CLL/SLL must demonstrate active disease meeting at least 1 of the&#xD;
             International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria for&#xD;
             requiring treatment:&#xD;
&#xD;
               -  A minimum of any one of the following constitutional symptoms:&#xD;
&#xD;
                    -  Unintentional weight loss &gt; 10% within the previous 6 months prior to&#xD;
                       screening&#xD;
&#xD;
                    -  Extreme fatigue (unable to work or perform usual activities)&#xD;
&#xD;
                    -  Fevers of greater than 100.5 Fahrenheit (F) for &gt;= 2 weeks without evidence&#xD;
                       of infection&#xD;
&#xD;
                    -  Night sweats without evidence of infection&#xD;
&#xD;
               -  Evidence of progressive marrow failure as manifested by the development of, or&#xD;
                  worsening of anemia or thrombocytopenia&#xD;
&#xD;
               -  Massive (i.e., &gt; 6 cm below the left costal margin), progressive or symptomatic&#xD;
                  splenomegaly&#xD;
&#xD;
               -  Massive nodes or clusters (i.e., &gt; 10 cm in longest diameter) or progressive&#xD;
                  lymphadenopathy&#xD;
&#xD;
               -  Progressive lymphocytosis with an increase of &gt; 50% over a 2-month period, or an&#xD;
                  anticipated doubling time of less than 6 months&#xD;
&#xD;
               -  Autoimmune anemia or thrombocytopenia that is poorly responsive to&#xD;
                  corticosteroids&#xD;
&#xD;
          -  Patients with HCL must be intolerant of or not candidates for purine analog-based&#xD;
             therapy, or failed to achieve response (CR or partial response [PR]) or relapsed&#xD;
             within 2 years of such therapy, AND meet the standard treatment initiation criteria&#xD;
             (absolute neutrophil count [ANC] =&lt; 1000/uL, hemoglobin [Hgb] =&lt; 10 g/dL, platelet&#xD;
             count =&lt; 100,000/uL); patients with indolent lymphoma (FL, LPL, MZL) and patients with&#xD;
             B-cell prolymphocytic leukemia must have an indication for treatment in the opinion of&#xD;
             the investigator; patients with MCL and patients with CLL in Richter's transformation&#xD;
             should have previously received or not be candidates for high dose&#xD;
             chemotherapy/autologous stem cell transplant&#xD;
&#xD;
          -  For diseases other than CLL, LPL, and HCL, presence of radiographically measurable&#xD;
             lymphadenopathy or extra-nodal lymphoid malignancy (defined as the presence of &gt;= 1&#xD;
             lesion that measures &gt;= 2.0 cm in the longest dimension [LD] and &gt;= 1.0 cm in the&#xD;
             longest perpendicular dimension [LPD] as assessed by computed tomography [CT] or&#xD;
             magnetic resonance imaging [MRI]); for LPL, measurable disease will be defined as&#xD;
             serum monoclonal IgM &gt; 0.5 g/dL or meeting at least 1 of the recommendations from the&#xD;
             Second International Workshop on LPL for requiring treatment&#xD;
&#xD;
          -  Patients must have Eastern Cooperative Oncology Group (ECOG) performance status =&lt; 2&#xD;
&#xD;
          -  Direct bilirubin =&lt; 2 X institutional upper limit of normal (ULN) (unless due to known&#xD;
             Gilbert's syndrome or compensated hemolysis directly attributable to CLL)&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) less than 2.5 X&#xD;
             institutional ULN&#xD;
&#xD;
          -  Estimated creatinine clearance (CrCL) using the Cockcroft-Gault equation &gt;= 50 mL/min&#xD;
&#xD;
          -  Platelets &gt;= 50,000/mm^3 independent of transfusion support, with no active bleeding&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) &gt;= 1000/mm^3, unless due to disease involvement in the&#xD;
             bone marrow&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior therapeutic intervention with any of the following:&#xD;
&#xD;
               -  Therapeutic anticancer antibodies within 4 weeks (rituximab), except within 6&#xD;
                  months for obinutuzumab or a similar investigational type II monoclonal antibody;&#xD;
&#xD;
               -  Radio- or toxin-immunoconjugates within 10 weeks;&#xD;
&#xD;
               -  Inhibitors of BTK (ibrutinib), PI-3K (idelalisib), BH3-mimetic venetoclax,&#xD;
                  lenalidomide and other &quot;targeted&quot; therapy (including but not limited to&#xD;
                  investigational BTK and PI-3K inhibitors, etc.) - within 6 half-lives (i.e., 36&#xD;
                  hours for ibrutinib)&#xD;
&#xD;
               -  All other chemotherapy, radiation therapy within 3 weeks prior to initiation of&#xD;
                  therapy&#xD;
&#xD;
               -  SYK inhibitors at any time&#xD;
&#xD;
          -  Inadequate recovery from adverse events related to prior therapy to grade =&lt; 1&#xD;
             (excluding grade 2 alopecia and neuropathy)&#xD;
&#xD;
          -  Chronic use of corticosteroids in excess of prednisone 30 mg/day or its equivalent&#xD;
&#xD;
          -  Stem cell transplant recipients must have no evidence of and not receive treatment for&#xD;
             graft-versus-host disease&#xD;
&#xD;
          -  Concomitant use or use in the prior two weeks of moderate or strong CYP3A and CYP2C9&#xD;
             inducers or strong CYP2C9 inhibitors, including nutraceutical preparations, e.g.,&#xD;
             grapefruit juice and St John's wort&#xD;
&#xD;
          -  History prior malignancy except:&#xD;
&#xD;
               -  Malignancy treated with curative intent and no known active disease present for&#xD;
                  &gt;= 2 years prior to initiation of therapy on current study&#xD;
&#xD;
               -  Adequately treated non-melanoma skin cancer or lentigo maligna (melanoma in situ)&#xD;
                  without evidence of disease&#xD;
&#xD;
               -  Adequately treated in situ carcinomas (e.g., cervical, esophageal, etc.) without&#xD;
                  evidence of disease&#xD;
&#xD;
               -  Asymptomatic prostate cancer managed with &quot;watch and wait&quot; strategy&#xD;
&#xD;
               -  Myelodysplastic syndrome which is clinically well controlled and no evidence of&#xD;
                  the cytogenetic abnormalities characteristic of myelodysplasia on the bone marrow&#xD;
                  at screening&#xD;
&#xD;
          -  Uncontrolled immune hemolysis or thrombocytopenia (positive direct antiglobulin test&#xD;
             in absence of hemolysis or history of immune-mediated cytopenias are not exclusions)&#xD;
&#xD;
          -  History of human immunodeficiency virus (HIV) infection or active hepatitis B or C&#xD;
&#xD;
          -  Major surgery (requiring general anesthesia) within 2 weeks prior to initiation of&#xD;
             therapy&#xD;
&#xD;
          -  Inability to swallow and retain an oral medication; patients with clinically&#xD;
             significant medical condition of malabsorption, inflammatory bowel disease, chronic&#xD;
             conditions which manifest with diarrhea, refractory nausea, vomiting or any other&#xD;
             condition that will interfere significantly with drug absorption are excluded;&#xD;
             patients must also have adequate venous access&#xD;
&#xD;
          -  Need for ongoing therapy with proton pump inhibitors; H2 antagonists are allowed&#xD;
&#xD;
          -  Active uncontrolled infection&#xD;
&#xD;
          -  Women who are pregnant or lactating&#xD;
&#xD;
          -  Fertile men or women of childbearing potential unless 1) permanently sterile or 2)&#xD;
             using a highly effective measure of contraception such as condoms in males and&#xD;
             consistent and correct use of one of the following in females: intrauterine device,&#xD;
             tubal sterilization, Essure micro-insert system, vasectomy in the male partner;&#xD;
             effective contraception is required for males during treatment with study drug and to&#xD;
             continue for 3 months after the last dose of either entospletinib or obinutuzumab,&#xD;
             whichever is later; for women, effective contraception is required to continue for 18&#xD;
             months after the last dose of obinutuzumab or for 30 days after the last dose of&#xD;
             entospletinib, whichever is later&#xD;
&#xD;
               -  Definition of childbearing potential: for this study, a female subject is&#xD;
                  considered of childbearing potential until becoming post-menopausal unless&#xD;
                  permanently sterile or with medically documented ovarian failure; women are&#xD;
                  considered to be in a postmenopausal state when &gt;= 54 years of age with cessation&#xD;
                  of previously occurring menses for &gt;= 12 months without an alternative cause;&#xD;
                  women of any age with amenorrhea of &gt;= 12 months may also be considered&#xD;
                  post-menopausal if their follicle stimulating hormone (FSH) level is in the&#xD;
                  post-menopausal range and they are not using hormonal contraception or hormonal&#xD;
                  replacement therapy; permanent sterilization in females includes hysterectomy,&#xD;
                  bilateral oophorectomy, or bilateral salpingectomy in a female subject of any&#xD;
                  age; permanent sterilization in males include bilateral orchiectomy or medical&#xD;
                  documentation of alternative explanation&#xD;
&#xD;
          -  Any condition for which participation in the study is judged by the Investigator to be&#xD;
             detrimental to the patient with inter-current illness or psychiatric/social situations&#xD;
             that would jeopardize compliance with study requirements&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Craig Okada, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>OHSU Knight Cancer Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>OHSU Knight Cancer Institute</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97239</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <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>Consensus resolution: proposed criteria for evaluation of response to treatment in hairy cell leukemia. Leukemia. 1987 Apr;1(4):405. No abstract available.</citation>
    <PMID>3669765</PMID>
  </reference>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>January 3, 2017</study_first_submitted>
  <study_first_submitted_qc>January 3, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 5, 2017</study_first_posted>
  <results_first_submitted>April 29, 2022</results_first_submitted>
  <results_first_submitted_qc>July 20, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">August 8, 2023</results_first_posted>
  <last_update_submitted>July 20, 2023</last_update_submitted>
  <last_update_submitted_qc>July 20, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 8, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>OHSU Knight Cancer Institute</investigator_affiliation>
    <investigator_full_name>Alexey Danilov, MD</investigator_full_name>
    <investigator_title>Adjunct Associate Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Lymphoma, Follicular</mesh_term>
    <mesh_term>Leukemia, Lymphoid</mesh_term>
    <mesh_term>Leukemia, Lymphocytic, Chronic, B-Cell</mesh_term>
    <mesh_term>Lymphoma, Mantle-Cell</mesh_term>
    <mesh_term>Leukemia, Hairy Cell</mesh_term>
    <mesh_term>Leukemia, Prolymphocytic</mesh_term>
    <mesh_term>Waldenstrom Macroglobulinemia</mesh_term>
    <mesh_term>Leukemia, Prolymphocytic, B-Cell</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Obinutuzumab</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>February 5, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/58/NCT03010358/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>One (1) participant was initially enrolled onto the study Dose Escalation phase, but was removed from study due to subsequent discovery of transformed disease at the time of screening. This participant is not included in safety nor efficacy analysis sets.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Phase 1, Dose 1</title>
          <description>Received entospletinib at Dose Level 1: 400 mg daily (200 mg twice daily) in combination with obinutuzumab during Dose Escalation phase of study.</description>
        </group>
        <group group_id="P2">
          <title>Phase 1, Dose 2</title>
          <description>Received entospletinib at Dose Level 2: 800 mg daily (400 mg twice daily) in combination with obinutuzumab during Dose Escalation phase of study.</description>
        </group>
        <group group_id="P3">
          <title>Phase 2, MTD</title>
          <description>Received entospletinib at Maximum Tolerated Dose (MTD) in combination with obinutuzumab during Dose Expansion phase of study.&#xD;
The MTD was determined to be 800 mg daily (400 mg twice daily).</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Stage 1 - Dose Escalation</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Stage 2 - Dose Expansion</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="15"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="14"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Phase 1, Dose 1</title>
          <description>Received entospletinib at Dose Level 1: 400 mg daily (200 mg twice daily) in combination with obinutuzumab during Dose Escalation phase of study.</description>
        </group>
        <group group_id="B2">
          <title>Phase 1, Dose 2</title>
          <description>Received entospletinib at Dose Level 2: 800 mg daily (400 mg twice daily) in combination with obinutuzumab during Dose Escalation phase of study.</description>
        </group>
        <group group_id="B3">
          <title>Phase 2, MTD</title>
          <description>Received entospletinib at Maximum Tolerated Dose (MTD) in combination with obinutuzumab during Dose Expansion phase of study.&#xD;
The MTD was determined to be 800 mg daily (400 mg twice daily).</description>
        </group>
        <group group_id="B4">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="6"/>
            <count group_id="B2" value="3"/>
            <count group_id="B3" value="14"/>
            <count group_id="B4" value="23"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="10"/>
                    <measurement group_id="B4" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="61.03" spread="15.67"/>
                    <measurement group_id="B2" value="68.03" spread="3.82"/>
                    <measurement group_id="B3" value="67.07" spread="8.22"/>
                    <measurement group_id="B4" value="65.62" spread="10.02"/>
                  </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="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="5"/>
                    <measurement group_id="B4" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="9"/>
                    <measurement group_id="B4" value="17"/>
                  </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 group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="10"/>
                    <measurement group_id="B4" value="18"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="3"/>
                  </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 group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="12"/>
                    <measurement group_id="B4" value="19"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="4"/>
                  </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="6"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="14"/>
                    <measurement group_id="B4" value="23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Maximum Tolerated Dose (MTD) of Entospletinib in Combination With Obinutuzumab</title>
        <description>The dose of obinutuzumab remains fixed in standard doses while the dose of entospletinib will be escalated. The starting dose of entospletinib will be 200 mg (twice-daily) and escalated to the second dose level 400 mg (twice-daily). MTD is the dose associated with a total of 6 patients treated with less than 2 dose limiting toxicities (DLT), or a total of 3 patients treated with less than 1 DLT. DLT is defined as 1) grade 3 or higher non-hematological toxicity (except grade 3 nausea, vomiting or diarrhea that was reversible within 72 hours with supportive care; grade 3 infusion-related toxicity; asymptomatic grade 3-4 laboratory abnormalities that are reversible to grade 2 or less within 72 hours; grade 3 tumor lysis syndrome or hyponatremia); 2) grade 4 neutropenia lasting &gt;7 days or febrile neutropenia; or 3) grade 4 thrombocytopenia/anemia or grade 3 thrombocytopenia with bleeding. The dosage follows the 3+3 traditional escalation rules.</description>
        <time_frame>Up to 28 days</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Phase 1, Dose 1-2</title>
            <description>2 groups of patients in phase 1 study.&#xD;
Phase 1, Dose 1 received entospletinib at Dose Level 1: 400 mg daily (200 mg twice daily) in combination with obinutuzumab during Dose Escalation phase of study. Phase 1, Dose 2 received entospletinib at Dose Level 2: 800 mg daily (400 mg twice daily) in combination with obinutuzumab during Dose Escalation phase of study.</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Tolerated Dose (MTD) of Entospletinib in Combination With Obinutuzumab</title>
          <description>The dose of obinutuzumab remains fixed in standard doses while the dose of entospletinib will be escalated. The starting dose of entospletinib will be 200 mg (twice-daily) and escalated to the second dose level 400 mg (twice-daily). MTD is the dose associated with a total of 6 patients treated with less than 2 dose limiting toxicities (DLT), or a total of 3 patients treated with less than 1 DLT. DLT is defined as 1) grade 3 or higher non-hematological toxicity (except grade 3 nausea, vomiting or diarrhea that was reversible within 72 hours with supportive care; grade 3 infusion-related toxicity; asymptomatic grade 3-4 laboratory abnormalities that are reversible to grade 2 or less within 72 hours; grade 3 tumor lysis syndrome or hyponatremia); 2) grade 4 neutropenia lasting &gt;7 days or febrile neutropenia; or 3) grade 4 thrombocytopenia/anemia or grade 3 thrombocytopenia with bleeding. The dosage follows the 3+3 traditional escalation rules.</description>
          <units>mg orally twice-daily</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="400"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Complete Response (CR) Defined as the Percentage of Subjects Who Achieve CR</title>
        <description>Response for CLL/SLL measured using Modified International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 (IWCLL) guidelines. Response for hairy cell leukemia was measured using Consensus resolution: proposed criteria published in Leukemia 1987.</description>
        <time_frame>Up to 45 months</time_frame>
        <population>Efficacy evaluable population: participants with CLL (Phase I/Phase II)</population>
        <group_list>
          <group group_id="O1">
            <title>All Research Participants</title>
            <description>The Outcome Measure was assessed in aggregate, combining participants from both phases of the study, as per the planned protocol.&#xD;
Phase 1, Dose 1 received entospletinib at Dose Level 1: 400 mg daily (200 mg twice daily) in combination with obinutuzumab during Dose Escalation phase of study.&#xD;
Phase 1, Dose 2 received entospletinib at Dose Level 2: 800 mg daily (400 mg twice daily) in combination with obinutuzumab during Dose Escalation phase of study.&#xD;
Phase 2, MTD: Received entospletinib at Maximum Tolerated Dose (MTD) in combination with obinutuzumab during Dose Expansion phase of study. The MTD was determined to be 800 mg daily (400 mg twice daily).</description>
          </group>
        </group_list>
        <measure>
          <title>Complete Response (CR) Defined as the Percentage of Subjects Who Achieve CR</title>
          <description>Response for CLL/SLL measured using Modified International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 (IWCLL) guidelines. Response for hairy cell leukemia was measured using Consensus resolution: proposed criteria published in Leukemia 1987.</description>
          <population>Efficacy evaluable population: participants with CLL (Phase I/Phase II)</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14.3" lower_limit="3.0" upper_limit="36.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Objective Response Rate (ORR)</title>
        <description>Defined as percentage of participants with complete remission, complete response with incomplete marrow recovery, partial remission and nodular partial response. Response for CLL/SLL measured using Modified International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 (IWCLL) guidelines. Response for hairy cell leukemia was measured using Consensus resolution: proposed criteria published in Leukemia 1987.</description>
        <time_frame>Up to 45 months</time_frame>
        <population>Efficacy evaluable population: participants with CLL (Phase I/Phase II)</population>
        <group_list>
          <group group_id="O1">
            <title>All Research Participants</title>
            <description>The Outcome Measure was assessed in aggregate, combining participants from both phases of the study, as per the planned protocol.&#xD;
Phase 1, Dose 1 received entospletinib at Dose Level 1: 400 mg daily (200 mg twice daily) in combination with obinutuzumab during Dose Escalation phase of study.&#xD;
Phase 1, Dose 2 received entospletinib at Dose Level 2: 800 mg daily (400 mg twice daily) in combination with obinutuzumab during Dose Escalation phase of study.&#xD;
Phase 2, MTD: Received entospletinib at Maximum Tolerated Dose (MTD) in combination with obinutuzumab during Dose Expansion phase of study. The MTD was determined to be 800 mg daily (400 mg twice daily).</description>
          </group>
        </group_list>
        <measure>
          <title>Objective Response Rate (ORR)</title>
          <description>Defined as percentage of participants with complete remission, complete response with incomplete marrow recovery, partial remission and nodular partial response. Response for CLL/SLL measured using Modified International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 (IWCLL) guidelines. Response for hairy cell leukemia was measured using Consensus resolution: proposed criteria published in Leukemia 1987.</description>
          <population>Efficacy evaluable population: participants with CLL (Phase I/Phase II)</population>
          <units>Percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="66.7" lower_limit="43.0" upper_limit="85.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Event Free Survival (EFS)</title>
        <description>Will be summarized descriptively using the Kaplan-Meier estimate. EFS will be censored if entospletinib is discontinued for other reasons (such as drug is no longer available).</description>
        <time_frame>The interval between the date of first study treatment and the date of objective signs of disease recurrence, subsequent anti leukemic therapy, or death, whichever is first reported, assessed up to 45 months.</time_frame>
        <population>Efficacy evaluable population: participants with CLL (Phase I/Phase II)</population>
        <group_list>
          <group group_id="O1">
            <title>All Research Participants</title>
            <description>The Outcome Measure was assessed in aggregate, combining participants from both phases of the study, as per the planned protocol.&#xD;
Phase 1, Dose 1 received entospletinib at Dose Level 1: 400 mg daily (200 mg twice daily) in combination with obinutuzumab during Dose Escalation phase of study.&#xD;
Phase 1, Dose 2 received entospletinib at Dose Level 2: 800 mg daily (400 mg twice daily) in combination with obinutuzumab during Dose Escalation phase of study.&#xD;
Phase 2, MTD: Received entospletinib at Maximum Tolerated Dose (MTD) in combination with obinutuzumab during Dose Expansion phase of study. The MTD was determined to be 800 mg daily (400 mg twice daily).</description>
          </group>
        </group_list>
        <measure>
          <title>Event Free Survival (EFS)</title>
          <description>Will be summarized descriptively using the Kaplan-Meier estimate. EFS will be censored if entospletinib is discontinued for other reasons (such as drug is no longer available).</description>
          <population>Efficacy evaluable population: participants with CLL (Phase I/Phase II)</population>
          <units>Months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="24.0" lower_limit="16" upper_limit="28"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants Who Experienced Adverse Events</title>
        <description>Will be assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All adverse events (AEs) will be coded by system organ class, Medical Dictionary for Regulatory Activities (MedDRA) preferred term, and severity grade using NCI CTCAE (version 4.03).</description>
        <time_frame>Up to 45 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Phase 1, Dose 1 (400 mg Entospletinib Daily)</title>
            <description>Patients receive entospletinib PO either QD or BID on days -7 to -1 (run-in phase) according to dose level 1 (200 mg twice daily). Patients also receive obinutuzumab IV on days 1, 2, 8, and 15 of the first cycle, and on day 1 of subsequent cycles. Treatment with obinutuzumab repeats every 28 days for up to 6 cycles and daily treatment with entospletinib continues every 28 days for up to 12 cycles in the absence of disease progression or unexpected toxicity.&#xD;
Entospletinib: Given PO&#xD;
Laboratory Biomarker Analysis: Correlative studies&#xD;
Obinutuzumab: Given IV&#xD;
Pharmacological Study: Correlative studies</description>
          </group>
          <group group_id="O2">
            <title>Phase 2 and MTD (800 mg Entospletinib Daily)</title>
            <description>Patients receive entospletinib PO either QD or BID on days -7 to -1 (run-in phase) according to dose level 2 (400 mg twice daily). Patients also receive obinutuzumab IV on days 1, 2, 8 and 15 of the first cycle, and on day 1 of subsequent cycles. Treatment with obinutuzumab repeats every 28 days for up to 6 cycles and daily treatment with entospletinib continues every 28 days for up to 12 cycles in the absence of disease progression or unexpected toxicity. Entospletinib is administered PO.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants Who Experienced Adverse Events</title>
          <description>Will be assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All adverse events (AEs) will be coded by system organ class, Medical Dictionary for Regulatory Activities (MedDRA) preferred term, and severity grade using NCI CTCAE (version 4.03).</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="17"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Peripheral Blood B-cell Depletion and Recovery</title>
        <description>Will be summarized using descriptive statistics.</description>
        <time_frame>Up to 45 months</time_frame>
        <population>Data for this outcome was not collected due to PI transition.</population>
        <group_list>
          <group group_id="O1">
            <title>All Research Participants</title>
            <description>The Outcome Measure was assessed in aggregate, combining participants from both phases of the study, as per the planned protocol.&#xD;
Phase 1, Dose 1 received entospletinib at Dose Level 1: 400 mg daily (200 mg twice daily) in combination with obinutuzumab during Dose Escalation phase of study.&#xD;
Phase 1, Dose 2 received entospletinib at Dose Level 2: 800 mg daily (400 mg twice daily) in combination with obinutuzumab during Dose Escalation phase of study.&#xD;
Phase 2, MTD: Received entospletinib at Maximum Tolerated Dose (MTD) in combination with obinutuzumab during Dose Expansion phase of study. The MTD was determined to be 800 mg daily (400 mg twice daily).</description>
          </group>
        </group_list>
        <measure>
          <title>Peripheral Blood B-cell Depletion and Recovery</title>
          <description>Will be summarized using descriptive statistics.</description>
          <population>Data for this outcome was not collected due to PI transition.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Pharmacodynamics Parameters of NFkappaB Activation and Expression of Anti-apoptotic Proteins in Chronic Lymphocytic Leukemia (CLL) Cells</title>
        <description>Pharmacokinetic parameters including peak and trough levels will be determined by noncompartmental method(s) using the pharmacokinetic profile of entospletinib and obinutuzumab.</description>
        <time_frame>Up to 45 months</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Biomarkers (Chromosomal Abnormalities, IGHV Mutational Status, p53 Mutational Status)</title>
        <description>Will be assessed by IgH somatic hypermutation assay version 2.0. Will associate with response (ORR) to entospletinib (ENTO) in combination with obinutuzumab in patients with relapsed/refractory CLL.</description>
        <time_frame>Up to 45 months</time_frame>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Up to 45 months. For the participants, the median follow-up time for adverse events was 17 months.</time_frame>
      <desc>Per protocol; &quot;Safety data will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (v 4.03).&quot; Since Phase 2 and the subset of Phase I patients who received MTD both received 800 mg daily, these are reported together. Those who received 400 mg daily were reported separately.</desc>
      <group_list>
        <group group_id="E1">
          <title>Phase 1, Dose 1 (400 mg Entospletinib Daily)</title>
          <description>Patients receive entospletinib PO either QD or BID on days -7 to -1 (run-in phase) according to dose level 1 (200 mg twice daily). Patients also receive obinutuzumab IV on days 1, 2, 8, and 15 of the first cycle, and on day 1 of subsequent cycles. Treatment with obinutuzumab repeats every 28 days for up to 6 cycles and daily treatment with entospletinib continues every 28 days for up to 12 cycles in the absence of disease progression or unexpected toxicity.</description>
        </group>
        <group group_id="E2">
          <title>Phase 2 and MTD (800 mg Entospletinib Daily)</title>
          <description>Patients receive entospletinib PO either QD or BID on days -7 to -1 (run-in phase) according to dose level 2 (400 mg twice daily). Patients also receive obinutuzumab IV on days 1, 2, 8 and 15 of the first cycle, and on day 1 of subsequent cycles. Treatment with obinutuzumab repeats every 28 days for up to 6 cycles and daily treatment with entospletinib continues every 28 days for up to 12 cycles in the absence of disease progression or unexpected 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="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Acute Coronary Syndrome</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Infusion Related Reaction</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Infections and infestations - Other, specify</sub_title>
                <description>SARS-COV2 Infection</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Infections and infestations - Other, specify</sub_title>
                <description>Pneumonia</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Interoperative Hemorrhage</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Tumor Lysis Syndrome</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</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="6" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="17" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Infusion related reaction</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="13" subjects_affected="11" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Bronchial infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Nail infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Otitis externa</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Rhinitis infective</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="6" subjects_affected="3" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Tooth infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Upper respiratory infection</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="17" subjects_affected="7" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Wound infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="9" subjects_affected="3" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" events="11" subjects_affected="4" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" events="13" subjects_affected="5" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="10" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" events="45" subjects_affected="10" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="13" subjects_affected="5" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Tumor lysis syndrome</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="17"/>
              </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>Bria Thurlow</name_or_title>
      <organization>OHSU Knight Cancer Institute</organization>
      <phone>503-494-4292</phone>
      <email>thurlow@ohsu.edu</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03010358
org study id: STUDY00016140
secondary id: NCI-2016-02029
secondary id: STUDY00016140
nct id: NCT03010358
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This phase I/II trial studies the side effect and best dose of entospletinib when giving
      together with obinutuzumab and to see how well they work in treating patients with chronic
      lymphocytic leukemia, small lymphocytic lymphoma, or non-Hodgkin lymphoma that has come back.
      Entospletinib may stop the growth of cancer cells by blocking some of the enzymes need for
      cell growth. Monoclonal antibodies, such as obinutuzumab, may interfere with the ability of
      cancer cells to grow and spread. Giving entospletinib and obinutuzumab together may work
      better in treating patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, or
      non-Hodgkin lymphoma.
PRIMARY OBJECTIVES:

      I. To evaluate the safety and tolerability of entospletinib administered in combination with
      obinutuzumab in patients with relapsed/refractory chronic lymphocytic leukemia/small
      lymphocytic lymphoma (CLL/SLL) and non-Hodgkin lymphoma (NHL), and identify the dose for
      phase 2 expansion. (Phase I) II. To evaluate the efficacy of entospletinib in combination
      with obinutuzumab in patients with relapsed or refractory CLL/SLL, as measured by complete
      response (CR) rate. (Phase II)

      SECONDARY OBJECTIVES:

      I. Objective response rate (ORR, defined as complete remission, complete response with
      incomplete marrow recovery, partial remission and nodular partial response). (Phase II) II.
      Event free survival defined as the interval between the date of first study treatment and the
      date of objective signs of disease recurrence, subsequent anti-leukemic therapy, or death,
      whichever is first reported. (Phase II) III. Safety and tolerability of entospletinib in
      combination with obinutuzumab by adverse events (AEs). (Phase II)

      EXPLORATORY OBJECTIVES:

      I. Peripheral blood B-cell depletion and recovery. II. Pharmacodynamics effects of in vivo
      administration of entospletinib on NFkappaB activation and expression of anti-apoptotic
      proteins in CLL cells.

      III. Association of established biomarkers (chromosomal abnormalities, immunoglobulin heavy
      chain [IGHV] mutational status, p53 mutational status) with response (ORR and event-free
      survival [EFS]) to entospletinib (ENTO) in combination with obinutuzumab in patients with
      relapsed/refractory CLL.

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

      Patients receive entospletinib orally (PO) either once a day (QD) or twice a day (BID) on
      days -7 to -1 (run-in phase) depending on the assigned dose level. Patients also receive
      obinutuzumab intravenously (IV) on days 1, 2, 8, and 15 of the first cycle and on day 1 of
      all subsequent cycles. Treatment with obinutuzumab repeats every 28 days for up to 6 cycles
      and daily treatment with entospletinib continues every 28 days for up to 12 cycles in the
      absence of disease progression or unexpected toxicity.

      After completion of study treatment, patients are followed up every 3 months for 12 months
      then every 6 months thereafter. In the event of study closure, patients who are receiving
      study drug at the time of closure will complete an abbreviated End of Treatment (EOT) visit.
      No additional follow up will occur.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum Tolerated Dose (MTD) of Entospletinib in Combination With Obinutuzumab
time frame: Up to 28 days
description: The dose of obinutuzumab remains fixed in standard doses while the dose of entospletinib will be escalated. The starting dose of entospletinib will be 200 mg (twice-daily) and escalated to the second dose level 400 mg (twice-daily). MTD is the dose associated with a total of 6 patients treated with less than 2 dose limiting toxicities (DLT), or a total of 3 patients treated with less than 1 DLT. DLT is defined as 1) grade 3 or higher non-hematological toxicity (except grade 3 nausea, vomiting or diarrhea that was reversible within 72 hours with supportive care; grade 3 infusion-related toxicity; asymptomatic grade 3-4 laboratory abnormalities that are reversible to grade 2 or less within 72 hours; grade 3 tumor lysis syndrome or hyponatremia); 2) grade 4 neutropenia lasting >7 days or febrile neutropenia; or 3) grade 4 thrombocytopenia/anemia or grade 3 thrombocytopenia with bleeding. The dosage follows the 3+3 traditional escalation rules.
measure: Complete Response (CR) Defined as the Percentage of Subjects Who Achieve CR
time frame: Up to 45 months
description: Response for CLL/SLL measured using Modified International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 (IWCLL) guidelines. Response for hairy cell leukemia was measured using Consensus resolution: proposed criteria published in Leukemia 1987.
measure: Objective Response Rate (ORR)
time frame: Up to 45 months
description: Defined as percentage of participants with complete remission, complete response with incomplete marrow recovery, partial remission and nodular partial response. Response for CLL/SLL measured using Modified International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 (IWCLL) guidelines. Response for hairy cell leukemia was measured using Consensus resolution: proposed criteria published in Leukemia 1987.
measure: Event Free Survival (EFS)
time frame: The interval between the date of first study treatment and the date of objective signs of disease recurrence, subsequent anti leukemic therapy, or death, whichever is first reported, assessed up to 45 months.
description: Will be summarized descriptively using the Kaplan-Meier estimate. EFS will be censored if entospletinib is discontinued for other reasons (such as drug is no longer available).
measure: Number of Participants Who Experienced Adverse Events
time frame: Up to 45 months
description: Will be assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All adverse events (AEs) will be coded by system organ class, Medical Dictionary for Regulatory Activities (MedDRA) preferred term, and severity grade using NCI CTCAE (version 4.03).
measure: Peripheral Blood B-cell Depletion and Recovery
time frame: Up to 45 months
description: Will be summarized using descriptive statistics.
measure: Pharmacodynamics Parameters of NFkappaB Activation and Expression of Anti-apoptotic Proteins in Chronic Lymphocytic Leukemia (CLL) Cells
time frame: Up to 45 months
description: Pharmacokinetic parameters including peak and trough levels will be determined by noncompartmental method(s) using the pharmacokinetic profile of entospletinib and obinutuzumab.
measure: Biomarkers (Chromosomal Abnormalities, IGHV Mutational Status, p53 Mutational Status)
time frame: Up to 45 months
description: Will be assessed by IgH somatic hypermutation assay version 2.0. Will associate with response (ORR) to entospletinib (ENTO) in combination with obinutuzumab in patients with relapsed/refractory CLL.
arm group label: Treatment (entospletinib, obinutuzumab)
arm group type: Experimental
description: Patients receive entospletinib PO either QD or BID on days -7 to -1 (run-in phase) depending on the assigned dose level. Patients also receive obinutuzumab IV on days 1, 2, 8, and 15 of the first cycle, and on day 1 of subsequent cycles. Treatment with obinutuzumab repeats every 28 days for up to 6 cycles and daily treatment with entospletinib continues every 28 days for up to 12 cycles in the absence of disease progression or unexpected toxicity.
intervention type: Drug
intervention name: Entospletinib
description: Given PO
arm group label: Treatment (entospletinib, obinutuzumab)
other name: ENTO
other name: GS 9973
other name: GS-9973
intervention type: Other
intervention name: Laboratory Biomarker Analysis
description: Correlative studies
arm group label: Treatment (entospletinib, obinutuzumab)
intervention type: Biological
intervention name: Obinutuzumab
description: Given IV
arm group label: Treatment (entospletinib, obinutuzumab)
other name: Anti-CD20 Monoclonal Antibody R7159
other name: GA-101
other name: GA101
other name: Gazyva
other name: huMAB(CD20)
other name: R7159
other name: RO 5072759
other name: RO-5072759
other name: RO5072759
intervention type: Other
intervention name: Pharmacological Study
description: Correlative studies
arm group label: Treatment (entospletinib, obinutuzumab)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Craig Okada, M.D.
role: Principal Investigator
affiliation: OHSU Knight Cancer Institute
facility: 
country: United States
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: Consensus resolution: proposed criteria for evaluation of response to treatment in hairy cell leukemia. Leukemia. 1987 Apr;1(4):405. No abstract available.
PMID: 3669765
responsible party type: Sponsor-Investigator
investigator affiliation: OHSU Knight Cancer Institute
investigator full name: Alexey Danilov, MD
investigator title: Adjunct Associate Professor
mesh term: Lymphoma
mesh term: Leukemia
mesh term: Lymphoma, Follicular
mesh term: Leukemia, Lymphoid
mesh term: Leukemia, Lymphocytic, Chronic, B-Cell
mesh term: Lymphoma, Mantle-Cell
mesh term: Leukemia, Hairy Cell
mesh term: Leukemia, Prolymphocytic
mesh term: Waldenstrom Macroglobulinemia
mesh term: Leukemia, Prolymphocytic, B-Cell
mesh term: Recurrence
mesh term: Obinutuzumab
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 