<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/NCT04431635</url>
  </required_header>
  <id_info>
    <org_study_id>UMCC 2019.097</org_study_id>
    <secondary_id>BTCRC-LYM17-145</secondary_id>
    <secondary_id>HUM00166647</secondary_id>
    <nct_id>NCT04431635</nct_id>
  </id_info>
  <brief_title>Dose De-escalation Study of the PI3k Alpha/Delta Inhibitor, Copanlisib Given in Combination With the Immunotherapeutic Agents, Nivolumab and Rituximab in Patients With Relapsed/Refractory Indolent Lymphoma</brief_title>
  <official_title>Phase IB Dose De-escalation Study of the PI3k Alpha/Delta Inhibitor, Copanlisib Given in Combination With the Immunotherapeutic Agents, Nivolumab and Rituximab in Patients With Relapsed/Refractory Indolent Lymphoma.Big Ten Cancer Research Consortium BTCRC-LYM17-145</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Michigan Rogel Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bayer</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Michigan</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Big Ten Cancer Research Consortium</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Michigan Rogel Cancer Center</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>
      Patients with relapsed or refractory follicular or marginal zone lymphoma who have received&#xD;
      at least one prior line of therapy will receive&#xD;
&#xD;
        -  Copanlisib IV: day 1, 8, 15 every 28 days&#xD;
&#xD;
        -  Nivolumab IV: Cycle 1 days 1 and 15; then day 1 only&#xD;
&#xD;
        -  Rituximab IV: Cycle 1 days 1, 8, 15, 22; then day 1 (C2-6); then Q2 cycles (8-12)&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients with relapsed/refractory lymphoma generally have few if any curative options and&#xD;
      demonstrate poor response rates to standard salvage therapies. Novel regimens utilizing&#xD;
      molecular targets are needed to improve outcomes in this patient population. While studies&#xD;
      evaluating single agent small-molecule inhibitors have demonstrated activity in this setting,&#xD;
      combinations of these drugs are generally thought to be more efficacious due to targeting&#xD;
      separate mechanisms of action and decreased chance of developing resistance. The PD-1/PD-L1&#xD;
      axis is a molecular target that has been demonstrated to be up-regulated in several tumors&#xD;
      including malignant lymphoma. Several pre-clinical studies have demonstrated the importance&#xD;
      of this axis on clinical outcomes of patients afflicted with low grade lymphoma including FL.&#xD;
      Targeting this axis with specific inhibitors would appear to be a rationale way to improve&#xD;
      outcomes in patients afflicted with these diseases. PI3K inhibitors in addition to inhibiting&#xD;
      signaling, impart changes in the immune cells in the tumor microenvironment and would appear&#xD;
      to be a logical candidate to explore in combination with immunotherapy. Based on these&#xD;
      preliminary data, we believe that we have justification for proceeding with our proposed&#xD;
      phase I study to combine the PD-1 inhibitor, nivolumab, with the PI3K inhibitor, copanlisib,&#xD;
      and the CD20 antibody, rituximab, in patients with relapsed/refractory follicular and&#xD;
      marginal zone lymphoma. This work has the potential to provide a novel strategy to improve&#xD;
      upon the clinical response noted in this patient population.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">June 15, 2020</start_date>
  <completion_date type="Anticipated">June 2026</completion_date>
  <primary_completion_date type="Anticipated">June 2025</primary_completion_date>
  <phase>Phase 1</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>MTD (Maximum Tolerated Dose) of copanlisib given in combination with nivolumab and rituximab</measure>
    <time_frame>28 days</time_frame>
    <description>To estimate the MTD (Maximum Tolerated Dose) of copanlisib given in combination with nivolumab and rituximab</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Complete Response rate of the combination of copanlisib, nivolumab, and rituximab given at the MTD.</measure>
    <time_frame>1 year</time_frame>
    <description>To estimate the Complete Response (CR) rate of the combination of copanlisib, nivolumab, and rituximab given at the MTD as determined by Lyric criteria [Cheson 2016}</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Summarize Adverse Events</measure>
    <time_frame>Up to two years</time_frame>
    <description>Summarize all adverse events graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Response</measure>
    <time_frame>1 year</time_frame>
    <description>The rate of overall response, defined as either CR or PR within 1 year of initiation of therapy.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Response</measure>
    <time_frame>Up to two years</time_frame>
    <description>3. Duration of response, as calculated from the time of initial response (CR or PR, determined by Lyric criteria [Cheson 2016]) until disease progression or death due to any cause (whichever occurs first).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival</measure>
    <time_frame>Up to two years</time_frame>
    <description>4. Progression free survival, as calculated from the first dose of the combination to the occurrence of definitive disease progression (as defined by Cheson 2016) or death from any cause, whichever comes first.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Next Treatment</measure>
    <time_frame>Up to two years</time_frame>
    <description>Time to next treatment (TTNT) is defined as the time from end of primary treatment to institution of next therapy.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">35</enrollment>
  <condition>Indolent Lymphoma</condition>
  <arm_group>
    <arm_group_label>Arm A: Copanlisib, Nivolumab &amp; Rituximab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Copanlisib IV: day 1, 8, 15 every 28 days Nivolumab IV: Cycle 1 days 1 and 15; then day 1 only Rituximab IV: Cycle 1 days 1, 8, 15, 22; then day 1 (C2-6); then Q2 cycles (8-12)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Copanlisib</intervention_name>
    <description>Copanlisib IV: day 1, 8, 15 every 28 days</description>
    <arm_group_label>Arm A: Copanlisib, Nivolumab &amp; Rituximab</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>Nivolumab IV: Cycle 1 days 1 and 15; then day 1 only</description>
    <arm_group_label>Arm A: Copanlisib, Nivolumab &amp; Rituximab</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rituximab</intervention_name>
    <description>Rituximab IV: Cycle 1 days 1, 8, 15, 22; then day 1 (C2-6); then Q2 cycles (8-12)</description>
    <arm_group_label>Arm A: Copanlisib, Nivolumab &amp; Rituximab</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥18 years at the time of informed consent.&#xD;
&#xD;
          -  Diagnosis of relapsed or refractory indolent follicular or marginal zone lymphoma&#xD;
             established by histologic assessment by a hematopathologist that has relapsed after at&#xD;
             least one line of chemo-immunotherapy.&#xD;
&#xD;
               -  Immunohistochemistry of the biopsy or&#xD;
&#xD;
               -  Flow cytometry of the biopsy&#xD;
&#xD;
          -  ECOG Performance Status ≤ 2&#xD;
&#xD;
          -  Has an indication for treatment based on the presence of symptoms and/or GELF criteria&#xD;
             as referenced in appendix A.&#xD;
&#xD;
          -  Must have failed or not be a candidate for an autologous stem cell transplantation.&#xD;
&#xD;
          -  Women of childbearing potential must be willing to use appropriate contraception&#xD;
             (barrier and hormonal therapy) or abstain from heterosexual activity from the point of&#xD;
             registration through at least 12 months after the last dose of study drugs.&#xD;
&#xD;
             -- NOTE: Women of childbearing potential are those who have not been surgically&#xD;
             sterilized, have not been free of menses for ≥ 1 year, or her sole male partner has&#xD;
             had a vasectomy at least 6 months prior to screening.&#xD;
&#xD;
          -  Male subjects capable of fathering a child who have a female partner of childbearing&#xD;
             potential must agree to use appropriate method(s) of contraception or abstain from&#xD;
             heterosexual activity starting with the first dose of study drug through 1 month after&#xD;
             the last dose of the study drugs.&#xD;
&#xD;
          -  Adequate organ function defined as&#xD;
&#xD;
               -  Hepatic:&#xD;
&#xD;
                    -  Total Bilirubin ≤ 1.5 mg/dL&#xD;
&#xD;
                    -  AST and ALT ≤ 2.5 x ULN.&#xD;
&#xD;
               -  Renal: Creatinine &lt; 2.0 mg/dl or CrCL &gt; 30 mL/minute&#xD;
&#xD;
               -  Bone marrow function:&#xD;
&#xD;
                    -  ANC ≥ 1000/mm3 (500/mm3 if known bone marrow (BM) involvement)&#xD;
&#xD;
                    -  Platelet ≥ 75,000/mm3 (or 50,000/mm3 if known BM involvement)&#xD;
&#xD;
                    -  Hgb &gt; 9 g/dL (transfusions allowed to meet this criterion)&#xD;
&#xD;
          -  Adequate glycemic control as demonstrated by a baseline fasting blood sugar (BS) ≤ 150&#xD;
             mg/dL. If uncontrolled then patient must be referred to PCP or endocrinology for&#xD;
             medical management. Patient may be enrolled if adequate control is obtained prior to&#xD;
             day 1 of therapy.&#xD;
&#xD;
          -  Adequate blood pressure (BP) control as demonstrated by a baseline BP of &lt; 150/90. If&#xD;
             uncontrolled then patient must be referred to PCP for medical management. Patient may&#xD;
             be enrolled if adequate control is obtained prior to day 1 of therapy.&#xD;
&#xD;
          -  Prior treatment is allowed if&#xD;
&#xD;
               -  at least 4 weeks must have elapsed since last chemotherapy and/or radiation and&#xD;
                  the patient has recovered to ≤ grade 1 toxicity from all treatment related&#xD;
                  events.&#xD;
&#xD;
               -  at least 3 months must have passed since radio-immunotherapy.&#xD;
&#xD;
               -  at least 3 months have passed since date of stem cell infusion (autograft) and&#xD;
                  patient has recovered to ≤ grade 1 toxicities related to this procedure.&#xD;
&#xD;
          -  Prior treatment with a PD-1/PD-L1 and/or PI3K inhibitor is allowed unless patient&#xD;
             prior treatment was discontinued for intolerance.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnant or breastfeeding women. NOTE: Women of childbearing potential must have a&#xD;
             negative serum or urine pregnancy test within 7 days prior to study registration. If&#xD;
             the urine test is positive or cannot be confirmed as negative, a serum pregnancy test&#xD;
             will be required. NOTE: Breast milk cannot be stored for future use while the mother&#xD;
             is being treated on study.&#xD;
&#xD;
          -  Diagnosis of follicular grade 3b, post-transplant lymphoproliferative disorder (PTLD),&#xD;
             or presence of histologic transformation.&#xD;
&#xD;
          -  Subjects with LFT abnormalities at baseline (above values per inclusion criteria),&#xD;
             history of cirrhotic liver morphology or alcoholic cirrhosis, subjects who use&#xD;
             acetaminophen at doses in excess of 2 g every day and have evidence of compromised&#xD;
             hepatic reserve.&#xD;
&#xD;
          -  Primary or metastatic CNS disease prior to study enrollment&#xD;
&#xD;
          -  Uncontrolled current illness, including, but not limited to ongoing or active&#xD;
             infections, symptomatic congestive heart failure, unstable angina pectoris, unstable&#xD;
             cardiac arrhythmia, evidence of interstitial lung disease or active, noninfectious&#xD;
             pneumonitis including symptomatic and/or pneumonitis requiring treatment and/or&#xD;
             psychiatric illness or social situations that would limit compliance with study&#xD;
             requirements.&#xD;
&#xD;
          -  History of inflammatory bowel disease i.e. Crohn's disease, ulcerative colitis.&#xD;
&#xD;
          -  HIV infection. NOTE: HIV testing is required.&#xD;
&#xD;
          -  Active infection with Hepatitis B or C virus (defined as a positive Hepatitis B&#xD;
             surface antigen/ positive Hepatitis C antibody or detectable viral load by PCR).&#xD;
             Patients with positive antibody but negative viral loads will be eligible for study&#xD;
             participation but will require appropriate prophylaxis.&#xD;
&#xD;
        NOTE: Hepatitis B and C testing are required.&#xD;
&#xD;
          -  Screening rate-corrected (using Friderica's correction) QT interval (QTcF) must not be&#xD;
             &gt; 480 msec via a standard 12-lead ECG within 28 days prior to registration.&#xD;
&#xD;
          -  Concomitant therapy in the last 4 weeks of any of the following: cytotoxic&#xD;
             chemotherapy, immunosuppressive agents, other investigational therapies, or chronic&#xD;
             use of systemic corticosteroids (doses ≤ 10 mg/day prednisone or equivalent are&#xD;
             permitted).&#xD;
&#xD;
          -  Active or prior documented autoimmune or inflammatory disorders within the past 3&#xD;
             years prior to study registration. The following are exceptions to this criterion:&#xD;
&#xD;
               -  Subjects with vitiligo or alopecia&#xD;
&#xD;
               -  Subjects with hypothyroidism (eg. following Hashimoto syndrome) stable on hormone&#xD;
                  replacement or psoriasis not requiring systemic treatment.&#xD;
&#xD;
          -  Known allergy or reaction to any component of either study drug formulation.&#xD;
&#xD;
          -  Prior allogeneic stem cell transplant.&#xD;
&#xD;
          -  Receipt of live attenuated vaccine within 30 days before the first dose of study&#xD;
             treatment.&#xD;
&#xD;
          -  HbA1c &gt; 8.5% at Screening&#xD;
&#xD;
          -  Patient that require treatment with agents that are CYP3A4 inhibitors or strong CYP3A4&#xD;
             inducers. Patients who are on agents that fall into this category must be off for at&#xD;
             least two weeks prior to 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>Yasmin H Karimi, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>The University of Michigan Rogel Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Illinois Cancer Center</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Michigan Comprehensive Cancer Center</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Michigan Health System</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Nebraska Medical Center</name>
      <address>
        <city>Omaha</city>
        <state>Nebraska</state>
        <zip>68198</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rutgers Cancer Institute of New Jersey</name>
      <address>
        <city>New Brunswick</city>
        <state>New Jersey</state>
        <zip>08903</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>June 11, 2020</study_first_submitted>
  <study_first_submitted_qc>June 12, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 16, 2020</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">September 1, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rituximab</mesh_term>
    <mesh_term>Nivolumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </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/NCT04431635
org study id: UMCC 2019.097
secondary id: BTCRC-LYM17-145
secondary id: HUM00166647
nct id: NCT04431635
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Patients with relapsed or refractory follicular or marginal zone lymphoma who have received
      at least one prior line of therapy will receive

        -  Copanlisib IV: day 1, 8, 15 every 28 days

        -  Nivolumab IV: Cycle 1 days 1 and 15; then day 1 only

        -  Rituximab IV: Cycle 1 days 1, 8, 15, 22; then day 1 (C2-6); then Q2 cycles (8-12)
Patients with relapsed/refractory lymphoma generally have few if any curative options and
      demonstrate poor response rates to standard salvage therapies. Novel regimens utilizing
      molecular targets are needed to improve outcomes in this patient population. While studies
      evaluating single agent small-molecule inhibitors have demonstrated activity in this setting,
      combinations of these drugs are generally thought to be more efficacious due to targeting
      separate mechanisms of action and decreased chance of developing resistance. The PD-1/PD-L1
      axis is a molecular target that has been demonstrated to be up-regulated in several tumors
      including malignant lymphoma. Several pre-clinical studies have demonstrated the importance
      of this axis on clinical outcomes of patients afflicted with low grade lymphoma including FL.
      Targeting this axis with specific inhibitors would appear to be a rationale way to improve
      outcomes in patients afflicted with these diseases. PI3K inhibitors in addition to inhibiting
      signaling, impart changes in the immune cells in the tumor microenvironment and would appear
      to be a logical candidate to explore in combination with immunotherapy. Based on these
      preliminary data, we believe that we have justification for proceeding with our proposed
      phase I study to combine the PD-1 inhibitor, nivolumab, with the PI3K inhibitor, copanlisib,
      and the CD20 antibody, rituximab, in patients with relapsed/refractory follicular and
      marginal zone lymphoma. This work has the potential to provide a novel strategy to improve
      upon the clinical response noted in this patient population.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: MTD (Maximum Tolerated Dose) of copanlisib given in combination with nivolumab and rituximab
time frame: 28 days
description: To estimate the MTD (Maximum Tolerated Dose) of copanlisib given in combination with nivolumab and rituximab
measure: Complete Response rate of the combination of copanlisib, nivolumab, and rituximab given at the MTD.
time frame: 1 year
description: To estimate the Complete Response (CR) rate of the combination of copanlisib, nivolumab, and rituximab given at the MTD as determined by Lyric criteria [Cheson 2016}
measure: Summarize Adverse Events
time frame: Up to two years
description: Summarize all adverse events graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
measure: Overall Response
time frame: 1 year
description: The rate of overall response, defined as either CR or PR within 1 year of initiation of therapy.
measure: Duration of Response
time frame: Up to two years
description: 3. Duration of response, as calculated from the time of initial response (CR or PR, determined by Lyric criteria [Cheson 2016]) until disease progression or death due to any cause (whichever occurs first).
measure: Progression Free Survival
time frame: Up to two years
description: 4. Progression free survival, as calculated from the first dose of the combination to the occurrence of definitive disease progression (as defined by Cheson 2016) or death from any cause, whichever comes first.
measure: Time to Next Treatment
time frame: Up to two years
description: Time to next treatment (TTNT) is defined as the time from end of primary treatment to institution of next therapy.
arm group label: Arm A: Copanlisib, Nivolumab & Rituximab
arm group type: Experimental
description: Copanlisib IV: day 1, 8, 15 every 28 days Nivolumab IV: Cycle 1 days 1 and 15; then day 1 only Rituximab IV: Cycle 1 days 1, 8, 15, 22; then day 1 (C2-6); then Q2 cycles (8-12)
intervention type: Drug
intervention name: Copanlisib
description: Copanlisib IV: day 1, 8, 15 every 28 days
arm group label: Arm A: Copanlisib, Nivolumab & Rituximab
intervention type: Drug
intervention name: Nivolumab
description: Nivolumab IV: Cycle 1 days 1 and 15; then day 1 only
arm group label: Arm A: Copanlisib, Nivolumab & Rituximab
intervention type: Drug
intervention name: Rituximab
description: Rituximab IV: Cycle 1 days 1, 8, 15, 22; then day 1 (C2-6); then Q2 cycles (8-12)
arm group label: Arm A: Copanlisib, Nivolumab & Rituximab
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Yasmin H Karimi, MD
role: Principal Investigator
affiliation: The University of Michigan Rogel Cancer Center
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Lymphoma
mesh term: Rituximab
mesh term: Nivolumab
sharing ipd: No