<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/NCT03789240</url>
  </required_header>
  <id_info>
    <org_study_id>190030</org_study_id>
    <secondary_id>19-C-0030</secondary_id>
    <nct_id>NCT03789240</nct_id>
  </id_info>
  <brief_title>Response-Adapted Therapy With Copanlisib and Rituximab in Untreated Follicular Lymphoma</brief_title>
  <official_title>A Phase 2 Study of Response-Adapted Therapy With Copanlisib and Rituximab in Untreated Follicular Lymphoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      The disease follicular lymphoma (FL) develops when the body makes abnormal B-cells. These&#xD;
      cells usually build up in the lymph nodes, but can also affect other parts of the body.&#xD;
      Researchers want to see if a combination of drugs can attack the cancer cells in people with&#xD;
      FL.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      To see if copanlisib plus rituximab is effective at slowing the growth of FL.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      People with FL who have not had prior treatment for their disease&#xD;
&#xD;
      Design:&#xD;
&#xD;
      Participants will be screened with:&#xD;
&#xD;
        -  Medical and cancer history&#xD;
&#xD;
        -  Physical exam&#xD;
&#xD;
        -  Review of symptoms and ability to perform daily activities&#xD;
&#xD;
        -  Blood and urine tests&#xD;
&#xD;
        -  Small amount of bone marrow removed by needle in the hip bone&#xD;
&#xD;
        -  Scans of the chest, abdomen, and pelvis. Some scans will use a radioactive tracer.&#xD;
&#xD;
      Participants will get the study drugs in 28-day cycles for up to 13 cycles. Both are given as&#xD;
      an intravenous (IV) infusion. Copanlisib is given over about 1 hour. Rituximab is given over&#xD;
      several hours.&#xD;
&#xD;
        -  For 1 cycle, they will get 3 weekly doses of copanlisib.&#xD;
&#xD;
        -  For the next cycle, they will get 3 weekly doses of copanlisib and 4 weekly doses of&#xD;
           rituximab.&#xD;
&#xD;
        -  For all other cycles, they will get 2-3 weekly doses of copanlisib and 1 dose of&#xD;
           rituximab.&#xD;
&#xD;
      Participants will repeat some screening tests during the cycles. They will give a cheek swab&#xD;
      and/or saliva sample and may have a tumor sample taken.&#xD;
&#xD;
      After treatment, some participants will have a few follow-up visits each year for 5 years,&#xD;
      then 1 each year. They will repeat screening tests.&#xD;
&#xD;
      Other participants will be contacted by phone every few months.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
        -  Follicular lymphoma (FL) is the most common indolent non-Hodgkin s lymphoma (NHL) with a&#xD;
           highly variable clinical course across patients&#xD;
&#xD;
        -  Standard frontline therapy for FL includes a monoclonal anti-CD20 antibody with or&#xD;
           without chemotherapy that can induce durable remissions but is generally not curable&#xD;
&#xD;
        -  The 20% of patients who relapse within 2 years of frontline chemotherapy have an&#xD;
           inferior overall survival; molecular profiles and gene-expression signatures can&#xD;
           identify patients at high-risk of early treatment failure but are incomplete and require&#xD;
           further validation&#xD;
&#xD;
        -  The phosphoinositide 3-kinase (PI3K) pathway is critically important in FL; agents that&#xD;
           target PI3K show good clinical activity in patients who relapse early after chemotherapy&#xD;
&#xD;
        -  Copanlisib is an intravenous therapy targeting both PI3K-alpha and PI3K-delta isoforms&#xD;
           and is FDA-approved for use in adults with relapsed and refractory FL&#xD;
&#xD;
        -  Induction therapy with copanlisib and rituximab may produce deep and durable remissions&#xD;
           in patients with FL without the use of cytotoxic agents&#xD;
&#xD;
        -  Circulating tumor DNA (ctDNA) is a promising modality for monitoring therapy&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      - To determine the complete response (CR) rate after copanlisib and rituximab as induction&#xD;
      therapy for patients with untreated follicular lymphoma&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
        -  Patients with histologically confirmed stage II-IV follicular lymphoma, grade 1-2 or 3a&#xD;
           that meet criteria for initiation of systemic therapy&#xD;
&#xD;
        -  No previous systemic therapy; prior local radiation permitted&#xD;
&#xD;
        -  ECOG performance status 0-2&#xD;
&#xD;
        -  Adequate bone marrow and organ function&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  Phase 2 study of up to 65 patients with untreated FL who meet standard criteria for&#xD;
           treatment&#xD;
&#xD;
        -  Patients will first be treated with a window of copanlisib monotherapy, followed by&#xD;
           induction therapy with copanlisib and rituximab for up to 6 cycles&#xD;
&#xD;
        -  Patients who achieve a CR after 6 cycles of induction therapy will stop treatment and be&#xD;
           monitored with computed tomography (CT) scans and plasma assays for circulating tumor&#xD;
           DNA (ctDNA). Patients who relapse &gt; 6 months from the end of induction can be re-treated&#xD;
           with 6 additional cycles of copanlisib and rituximab&#xD;
&#xD;
        -  Patients who achieve a partial response after 6 cycles of induction therapy will receive&#xD;
           an additional 6 cycles of extended induction therapy with copanlisib and rituximab&#xD;
&#xD;
        -  Patients who do not achieve at least a partial response after 6 cycles of induction&#xD;
           therapy will stop treatment and be monitored with CT scans and peripheral blood assays&#xD;
           for ctDNA&#xD;
&#xD;
        -  Patients who progress or relapse after induction therapy and meet criteria for salvage&#xD;
           therapy will be treated with standard chemotherapy and a monoclonal anti-CD20 antibody&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">August 22, 2019</start_date>
  <completion_date type="Anticipated">January 1, 2027</completion_date>
  <primary_completion_date type="Anticipated">January 1, 2027</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Acheivement of complete response</measure>
    <time_frame>Within 6 months of induction therapy completion</time_frame>
    <description>The response rate will be determined and reported along with a 95% confidence interval</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Safety of study treatments when given in combination</measure>
    <time_frame>Through study induction therapy period</time_frame>
    <description>Incidence of adverse events</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Continuous complete response rate</measure>
    <time_frame>At 30 months from study enrollment</time_frame>
    <description>The response rate will be determined and reported along with a 95% confidence interval</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">65</enrollment>
  <condition>Follicular Lymphoma</condition>
  <condition>Non-Hodgkin's Lymphoma</condition>
  <condition>NHL</condition>
  <arm_group>
    <arm_group_label>1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Window of treatment with Copanlisib 60mg via IV for a single 28 day cycle, once weekly for the first 3 weeks and then a 1 week break followed by induction therapy with copanlisib and rituximab. Induction therapy will be 6 cycles (28 days) of: copanlisib dose and administration same as window, rituximab 375mg/m2 via IV, once weekly for the first 4 weeks during cycle 1, subsequent cycles (cycles 2-6), rituximab will be dosed only once on day 1 of the cycle.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Rituximab</intervention_name>
    <description>Rituximab is administered at a dose of 375 mg/m2 via IV weekly for the first 4 weeks on Days 1, 8, 15, and 22 during cycle 1. With subsequent cycles (cycles 2-6), rituximab will be dosed only once on Day 1 of the cycle.</description>
    <arm_group_label>1</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Copanlisib</intervention_name>
    <description>Copanlisib is administered at a fixed dose of 60 mg via IV weekly for the first 3 weeks on Days 1, 8, and 15 followed by a 1-week break (no infusion on Day 22)</description>
    <arm_group_label>1</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
          -  Patients must have a confirmed histologic diagnosis of FL, grade 1-2 or 3a, according&#xD;
             to the criteria established by the most recent version of the World Health&#xD;
             Organization (WHO) classification system. Pathologic diagnosis must be confirmed by&#xD;
             Laboratory of Pathology, NCI&#xD;
&#xD;
          -  Stage II-IV disease. NOTE: Patients with stage I FL who have been treated with&#xD;
             radiation therapy and have subsequently relapsed are eligible.&#xD;
&#xD;
          -  No prior systemic treatment for FL with chemotherapy, targeted small molecule therapy,&#xD;
             or monoclonal antibody therapy prior to the first dose of copanlisib treatment.&#xD;
             Patients may have received prior radiation therapy only; radiation therapy must have&#xD;
             been completed &gt;12 weeks prior to the first dose of copanlisib. NOTE: Prior shortterm&#xD;
             (less than or equal to 7 days) use of corticosteroids for acute medical complications&#xD;
             related to sites of FL involvement is permitted.&#xD;
&#xD;
          -  Patients must meet standard criteria for initiation of systemic therapy as evidenced&#xD;
             by presence of one of the following:&#xD;
&#xD;
               -  Development of symptomatic enlarged lymph nodes or spleen&#xD;
&#xD;
               -  Development of B symptoms (fever, night sweats, weight loss) or severe pruritus&#xD;
&#xD;
               -  Development of significant serous pleural or pericardial effusions (small&#xD;
                  effusions seen only on CT scans are not indications for systemic therapy)&#xD;
&#xD;
               -  Development of bone marrow failure as a result of involvement by FL and not&#xD;
                  attributable to other causes; this would be manifest as a Hgb &lt; 9 g/dl, absolute&#xD;
                  neutrophil count &lt; 1 x 10^9/L, or platelet count &lt; 75 x 10^9/L&#xD;
&#xD;
               -  Critical organ involvement, organ compression (e.g., ureteric obstruction or&#xD;
                  epidural compression), or significant risk of future organ compressions&#xD;
&#xD;
               -  Increase in the size of lymph nodes on CT scans indicating progression of disease&#xD;
                  from previous CT scans&#xD;
&#xD;
          -  Adequate tissue from diagnostic biopsy; formalin fixed tissue block or 20 slides of&#xD;
             tumor sample (archival or fresh) must be available for performance of correlative&#xD;
             studies&#xD;
&#xD;
          -  Be greater than or equal to 8 years of age on day of signing informed consent. NOTE:&#xD;
             Because no dosing or adverse event data are currently available on the use of&#xD;
             (copanlisib) in patients &lt;18 years of age, children are excluded from this study&#xD;
&#xD;
          -  ECOG performance status 0-2&#xD;
&#xD;
          -  Adequate organ function as evidenced by the following laboratory parameters:&#xD;
&#xD;
               -  Absolute neutrophil count (ANC): &gt;= 1,500 /mm^3 (unless due to involvement by&#xD;
                  lymphoma or benign ethnic neutropenia)&#xD;
&#xD;
               -  Platelets: &gt;=75,000 / mcL (unless due to involvement by lymphoma; transfusions&#xD;
                  not permitted)&#xD;
&#xD;
               -  Hemoglobin: &gt;= 8 g/dL (transfusions permitted)&#xD;
&#xD;
               -  Renal function: Glomerular filtration rate (GFR) &gt;= 40 mL/min/1.73 m^2 as&#xD;
                  estimated by the Modification of Diet in Renal Disease (MDRD) abbreviated&#xD;
                  formula. If not on target, a 24-hour urine creatinine clearance can be used to&#xD;
                  directly measure.&#xD;
&#xD;
               -  Serum total bilirubin: less than or equal to 1.5 X ULN OR (&lt; 3 x ULN for patients&#xD;
                  with Gilbert syndrome, patients with cholestasis due to compressive adenopathies&#xD;
                  of the hepatic hilum or documented liver involvement or with biliary obstruction&#xD;
                  due to lymphoma)&#xD;
&#xD;
               -  AST (SGOT) and ALT (SGPT): less than or equal to 2.5 x ULN (less than or equal to&#xD;
                  5 x ULN for patients with liver involvement by lymphoma)&#xD;
&#xD;
               -  Lipase: less than or equal to 1.5 x ULN&#xD;
&#xD;
          -  Women of childbearing potential (WOCBP) and men must agree to use effective&#xD;
             contraception when sexually active. This applies for the time period between signing&#xD;
             of the informed consent form and for at least 1 month after the last dose of&#xD;
             copanlisib and&#xD;
&#xD;
             12 months after the last dose of rituximab, whichever is later, for WOCBP and for men&#xD;
             after the last administration of study treatment. NOTE: A woman is considered of&#xD;
             childbearing potential, (i.e., fertile), following menarche and until becoming&#xD;
             post-menopausal unless permanently sterile. Permanent sterilization methods include&#xD;
             but are not limited to hysterectomy, bilateral salpingectomy and bilateral&#xD;
             oophorectomy. A postmenopausal state is defined as no menses for continuous 12 months&#xD;
             without an alternative medical cause. A high follicle stimulating hormone (FSH) level&#xD;
             in the postmenopausal range may be used to confirm a post-menopausal state in women&#xD;
             not using hormonal contraception or hormonal replacement therapy. The investigator or&#xD;
             a designated associate is requested to advise the patient how to achieve highly&#xD;
             effective birth control (failure rate of less than 1%), e.g., intrauterine device&#xD;
             (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion,&#xD;
             vasectomized partner and sexual abstinence. The use of condoms by male patients is&#xD;
             required unless the female partner is permanently sterile.&#xD;
&#xD;
          -  Ability of patient to understand and the willingness to sign a written informed&#xD;
             consent document&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          -  Known lymphomatous involvement of the central nervous system&#xD;
&#xD;
          -  History of any known primary or acquired immunodeficiency syndrome (e.g., HIV)&#xD;
&#xD;
          -  CMV PCR positive at baseline&#xD;
&#xD;
          -  Hepatitis B surface antigen (HbsAg) or core antibody (HbcAb) positive with a positive&#xD;
             Hep B DNA Quantitative, HBV Viral Load result.&#xD;
&#xD;
        NOTE: Subjects with positive hepatitis B serology (HbsAg or HbcAb) may be enrolled onto the&#xD;
        study but they must have a negative Hep B DNA Quantitative, HBV Viral Load result before&#xD;
        enrollment.&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to the following that may&#xD;
             limit interpretation of results or that could increase risk to the patient at the&#xD;
             discretion of the investigator:&#xD;
&#xD;
               -  Active autoimmune disease that has required systemic treatment in the past 12&#xD;
                  months (i.e., with use of disease modifying agents, corticosteroids or&#xD;
                  immunosuppressive drugs). NOTE: Replacement therapy (e.g., thyroxine, insulin, or&#xD;
                  physiologic corticosteroid replacement therapy for adrenal or pituitary&#xD;
                  insufficiency, etc.) is not considered a form of systemic treatment.&#xD;
&#xD;
               -  History of (non-infectious) pneumonitis that required steroids, evidence of&#xD;
                  interstitial lung disease or active, non-infectious pneumonitis.&#xD;
&#xD;
               -  Active hepatitis C infection. NOTE: Subjects who are hepatitis C antibody&#xD;
                  positive will need to have a negative HCV PCR result before enrollment. Those&#xD;
                  with a positive PCR for hepatitis C are excluded.&#xD;
&#xD;
               -  Congestive heart failure &gt; New York Heart Association (NYHA) class 2&#xD;
&#xD;
               -  Unstable angina&#xD;
&#xD;
               -  Myocardial infarction in the past 6 months&#xD;
&#xD;
               -  Uncontrolled hypertension despite optimal medical management&#xD;
&#xD;
               -  Arterial thromboembolic events such as cerebrovascular accident (including&#xD;
                  transient ischemic attacks), in prior 3 months&#xD;
&#xD;
               -  Uncontrolled Type I or II diabetes despite optimal medical management&#xD;
&#xD;
               -  Any second malignancy that requires active systemic therapy&#xD;
&#xD;
               -  Known mental or physical illness that would interfere with cooperation with the&#xD;
                  requirements of the trial or confound the results or interpretation of the&#xD;
                  results of the trial and, in the opinion of the treating investigator, would make&#xD;
                  the patient inappropriate for entry into the study.&#xD;
&#xD;
          -  Severe hepatic impairment (Child-Pugh C)&#xD;
&#xD;
          -  Requirement to continue on any of the medications that are excluded&#xD;
&#xD;
          -  Organ compromise that, in the opinion of the PI, necessitates immediate cytoreductive&#xD;
             therapy&#xD;
&#xD;
          -  Pregnant or breast-feeding patients. Women of childbearing potential must have a serum&#xD;
             pregnancy test performed a maximum of 7 days before start of treatment, and a negative&#xD;
             result must be documented before start of treatment&#xD;
&#xD;
          -  Major surgical procedure or significant traumatic injury (as judged by the&#xD;
             investigator) within 28 days before start of treatment, or have not recovered from&#xD;
             major side effects, open biopsy within 7 days before start of treatment&#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>Mark J Roschewski, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Cancer Institute (NCI)</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>NCI Medical Oncology Referral Office</last_name>
    <phone>(240) 760-6050</phone>
    <email>NCIMO_Referrals@mail.nih.gov</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Mark J Roschewski, M.D.</last_name>
    <phone>(240) 760-6183</phone>
    <email>mark.roschewski@nih.gov</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>National Institutes of Health Clinical Center</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>For more information at the NIH Clinical Center contact National Cancer Institute Referral Office</last_name>
      <phone>888-624-1937</phone>
    </contact>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2019-C-0030.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <verification_date>August 4, 2023</verification_date>
  <study_first_submitted>December 18, 2018</study_first_submitted>
  <study_first_submitted_qc>December 27, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 28, 2018</study_first_posted>
  <last_update_submitted>August 30, 2023</last_update_submitted>
  <last_update_submitted_qc>August 30, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 31, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>BAY 80-6946</keyword>
  <keyword>PI3K Target</keyword>
  <keyword>Aliqopa</keyword>
  <keyword>Monoclonal Antibody</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Lymphoma, Follicular</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rituximab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>.All IPD recorded in the medical record will be shared with intramural investigators upon request. @@@@@@All large scale genomic sequencing data will be shared with subscribers to dbGaP.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_time_frame>Clinical data will be available during the study and indefinitely. @@@@@@Genomic data will be available once genomic data are uploaded per protocol GDS plan for as long as database is active.</ipd_time_frame>
    <ipd_access_criteria>Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. @@@@@@Genomic data will be made available via dbGaP through requests to the data custodians.</ipd_access_criteria>
  </patient_data>
  <!-- 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/NCT03789240
org study id: 190030
secondary id: 19-C-0030
nct id: NCT03789240
lead sponsor: 
is fda regulated drug: Yes
is fda regulated device: No
Background:

      The disease follicular lymphoma (FL) develops when the body makes abnormal B-cells. These
      cells usually build up in the lymph nodes, but can also affect other parts of the body.
      Researchers want to see if a combination of drugs can attack the cancer cells in people with
      FL.

      Objective:

      To see if copanlisib plus rituximab is effective at slowing the growth of FL.

      Eligibility:

      People with FL who have not had prior treatment for their disease

      Design:

      Participants will be screened with:

        -  Medical and cancer history

        -  Physical exam

        -  Review of symptoms and ability to perform daily activities

        -  Blood and urine tests

        -  Small amount of bone marrow removed by needle in the hip bone

        -  Scans of the chest, abdomen, and pelvis. Some scans will use a radioactive tracer.

      Participants will get the study drugs in 28-day cycles for up to 13 cycles. Both are given as
      an intravenous (IV) infusion. Copanlisib is given over about 1 hour. Rituximab is given over
      several hours.

        -  For 1 cycle, they will get 3 weekly doses of copanlisib.

        -  For the next cycle, they will get 3 weekly doses of copanlisib and 4 weekly doses of
           rituximab.

        -  For all other cycles, they will get 2-3 weekly doses of copanlisib and 1 dose of
           rituximab.

      Participants will repeat some screening tests during the cycles. They will give a cheek swab
      and/or saliva sample and may have a tumor sample taken.

      After treatment, some participants will have a few follow-up visits each year for 5 years,
      then 1 each year. They will repeat screening tests.

      Other participants will be contacted by phone every few months.
Background:

        -  Follicular lymphoma (FL) is the most common indolent non-Hodgkin s lymphoma (NHL) with a
           highly variable clinical course across patients

        -  Standard frontline therapy for FL includes a monoclonal anti-CD20 antibody with or
           without chemotherapy that can induce durable remissions but is generally not curable

        -  The 20% of patients who relapse within 2 years of frontline chemotherapy have an
           inferior overall survival; molecular profiles and gene-expression signatures can
           identify patients at high-risk of early treatment failure but are incomplete and require
           further validation

        -  The phosphoinositide 3-kinase (PI3K) pathway is critically important in FL; agents that
           target PI3K show good clinical activity in patients who relapse early after chemotherapy

        -  Copanlisib is an intravenous therapy targeting both PI3K-alpha and PI3K-delta isoforms
           and is FDA-approved for use in adults with relapsed and refractory FL

        -  Induction therapy with copanlisib and rituximab may produce deep and durable remissions
           in patients with FL without the use of cytotoxic agents

        -  Circulating tumor DNA (ctDNA) is a promising modality for monitoring therapy

      Objective:

      - To determine the complete response (CR) rate after copanlisib and rituximab as induction
      therapy for patients with untreated follicular lymphoma

      Eligibility:

        -  Patients with histologically confirmed stage II-IV follicular lymphoma, grade 1-2 or 3a
           that meet criteria for initiation of systemic therapy

        -  No previous systemic therapy; prior local radiation permitted

        -  ECOG performance status 0-2

        -  Adequate bone marrow and organ function

      Design:

        -  Phase 2 study of up to 65 patients with untreated FL who meet standard criteria for
           treatment

        -  Patients will first be treated with a window of copanlisib monotherapy, followed by
           induction therapy with copanlisib and rituximab for up to 6 cycles

        -  Patients who achieve a CR after 6 cycles of induction therapy will stop treatment and be
           monitored with computed tomography (CT) scans and plasma assays for circulating tumor
           DNA (ctDNA). Patients who relapse > 6 months from the end of induction can be re-treated
           with 6 additional cycles of copanlisib and rituximab

        -  Patients who achieve a partial response after 6 cycles of induction therapy will receive
           an additional 6 cycles of extended induction therapy with copanlisib and rituximab

        -  Patients who do not achieve at least a partial response after 6 cycles of induction
           therapy will stop treatment and be monitored with CT scans and peripheral blood assays
           for ctDNA

        -  Patients who progress or relapse after induction therapy and meet criteria for salvage
           therapy will be treated with standard chemotherapy and a monoclonal anti-CD20 antibody
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Acheivement of complete response
time frame: Within 6 months of induction therapy completion
description: The response rate will be determined and reported along with a 95% confidence interval
measure: Safety of study treatments when given in combination
time frame: Through study induction therapy period
description: Incidence of adverse events
measure: Continuous complete response rate
time frame: At 30 months from study enrollment
description: The response rate will be determined and reported along with a 95% confidence interval
arm group label: 1
arm group type: Experimental
description: Window of treatment with Copanlisib 60mg via IV for a single 28 day cycle, once weekly for the first 3 weeks and then a 1 week break followed by induction therapy with copanlisib and rituximab. Induction therapy will be 6 cycles (28 days) of: copanlisib dose and administration same as window, rituximab 375mg/m2 via IV, once weekly for the first 4 weeks during cycle 1, subsequent cycles (cycles 2-6), rituximab will be dosed only once on day 1 of the cycle.
intervention type: Biological
intervention name: Rituximab
description: Rituximab is administered at a dose of 375 mg/m2 via IV weekly for the first 4 weeks on Days 1, 8, 15, and 22 during cycle 1. With subsequent cycles (cycles 2-6), rituximab will be dosed only once on Day 1 of the cycle.
arm group label: 1
intervention type: Drug
intervention name: Copanlisib
description: Copanlisib is administered at a fixed dose of 60 mg via IV weekly for the first 3 weeks on Days 1, 8, and 15 followed by a 1-week break (no infusion on Day 22)
arm group label: 1
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Mark J Roschewski, M.D.
role: Principal Investigator
affiliation: National Cancer Institute (NCI)
last name: NCI Medical Oncology Referral Office
phone: (240) 760-6050
email: NCIMO_Referrals@mail.nih.gov
last name: Mark J Roschewski, M.D.
phone: (240) 760-6183
email: mark.roschewski@nih.gov
facility: 
status: Recruiting
contact: 
country: United States
url: https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2019-C-0030.html
description: NIH Clinical Center Detailed Web Page
responsible party type: Sponsor
mesh term: Lymphoma
mesh term: Lymphoma, Follicular
mesh term: Rituximab
sharing ipd: Yes
ipd description: .All IPD recorded in the medical record will be shared with intramural investigators upon request. @@@@@@All large scale genomic sequencing data will be shared with subscribers to dbGaP.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd time frame: Clinical data will be available during the study and indefinitely. @@@@@@Genomic data will be available once genomic data are uploaded per protocol GDS plan for as long as database is active.
ipd access criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. @@@@@@Genomic data will be made available via dbGaP through requests to the data custodians.