<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/NCT04433182</url>
  </required_header>
  <id_info>
    <org_study_id>FIL_Copa-RB</org_study_id>
    <nct_id>NCT04433182</nct_id>
  </id_info>
  <brief_title>Copanlisib With Rituximab-Bendamustine in Patients With Relapsed-Refractory Diffuse Large B-cell Lymphoma</brief_title>
  <official_title>Copanlisib in Combination With Rituximab-Bendamustine in Patients With Relapsed-Refractory Diffuse Large B-cell Lymphoma: a Multicentric Phase II Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Fondazione Italiana Linfomi - ETS</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Fondazione Italiana Linfomi - ETS</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a multicentric single arm phase II trial, to investigate the efficacy (in terms of&#xD;
      PFS) of the combination regimen rituximab-bendamustine in association with copanlisib in&#xD;
      patients affected by relapsed/refractory DLBCL, not eligible to HDC and ASCT or relapsed&#xD;
      after intensified regimens.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The primary objective of this study is to evaluate the efficacy, in terms of Progression Free&#xD;
      Survival (12m-PFS) at 12 months, of a treatment with copanlisib in combination with a&#xD;
      standard rituximab-bendamustine regimen in patients with relapsed-refractory DLBCL, who have&#xD;
      received at least one, but no more than three lines of treatment, including rituximab-based&#xD;
      immunochemotherapy, not eligible for high-dose chemotherapy and ASCT or T-cell CAR-T therapy,&#xD;
      or relapsed after these treatments.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">August 18, 2020</start_date>
  <completion_date type="Anticipated">August 1, 2024</completion_date>
  <primary_completion_date type="Anticipated">July 1, 2023</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>Progression-free survival (PFS)</measure>
    <time_frame>4 years</time_frame>
    <description>Progression-Free Survival (PFS) will be defined as the time between the date of enrolment and the date of disease progression, relapse or death from any cause. Responding patients according to Response Criteria for NHL with PET and patients who are lost to follow-up will be censored at their last assessment date.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>4 years</time_frame>
    <description>Time between the date of enrolment and the date of death from any cause. Patients who have not died at the time of the final analysis will be censored at the date of the last contact.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate (ORR)</measure>
    <time_frame>End of treament (EOT), 30 months</time_frame>
    <description>ORR will be defined as the sum of CR + PR</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Complete Response Rate (CRR)</measure>
    <time_frame>End of induction (EOI), 18 months</time_frame>
    <description>CRR will be defined as the proportion of patients achieving a CR</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response (DOR)</measure>
    <time_frame>4 years</time_frame>
    <description>DOR is measured from the date when criteria for response are met (CR or PR) until the date of progression or relapse. Patients without relapse or progression will be censored at their last assessment date.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Conversion rate from SD/PR to PR/CR with maintenance</measure>
    <time_frame>End of treatment (after maintenance), 30 months</time_frame>
    <description>Conversion rate from SD/PR to PR/CR with maintenance</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluation of adverse events according to the current version of the CTCAE criteria</measure>
    <time_frame>4 years</time_frame>
    <description>Evaluation of adverse events according to the current version of the CTCAE criteria</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">37</enrollment>
  <condition>Diffuse Large B-cell Lymphoma</condition>
  <arm_group>
    <arm_group_label>Single arm Copa-RB</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Induction phase with Copanlisib, Rituximab and Bendamustina. Maintenance phase (for patients who reach at least SD after induction) with Copanlisib in monotherapy.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Copanlisib</intervention_name>
    <description>Induction phase: 6 cycles of Copa-RB every 28 days according to the following schedule&#xD;
Copanlisib (Copa): 60 mg/day i.v. on days 1,8,15&#xD;
Rituximab (R): 375 mg/sqm i.v. day 1*&#xD;
Bendamustine (B): 90 mg/sqm i.v. days 1-2*&#xD;
note: during cycle 1 rituximab can be administered on day 2: in this case bendamustine will be administered on days 2-3; in the case of a frail patient or a patient with high tumor burden copanlisib could be administered on day 1, rituximab on day 2 and bendamustine on days 3-4, at physician discretion.&#xD;
Maintenance phase: patients who reach at least SD after induction will receive a maintenance with copanlisib in monotherapy according to the following schedule:&#xD;
• Copanlisib: 60 mg/day i.v. on days 1 and 15 in 28-day cycles for 1 year</description>
    <arm_group_label>Single arm Copa-RB</arm_group_label>
    <other_name>ALIQOPA</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Histologically confirmed diagnosis of DLBCL (de-novo DLBCL or DLBCL transformed by&#xD;
             indolent lymphoma) including:&#xD;
&#xD;
               -  DLBCL, NOS including GCB type, ABC type;&#xD;
&#xD;
               -  T-cell rich large B-cell Lymphoma;&#xD;
&#xD;
               -  Epstein-Barr virus-positive DLBCL, NOS;&#xD;
&#xD;
               -  High-grade B-cell Lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double-&#xD;
                  hit or triple-hit lymphoma);&#xD;
&#xD;
               -  High-grade B-cell lymphoma NOS;&#xD;
&#xD;
               -  Intravascular B-cell Lymphoma;&#xD;
&#xD;
               -  Extranodal DLBCL;&#xD;
&#xD;
               -  DLBCL coexistent with either follicular lymphoma of any grade or marginal-zone&#xD;
                  lymphoma;&#xD;
&#xD;
               -  FL grade 3b. Patients must be CD20 positive. New biopsy at relapse time is&#xD;
                  recommended, but not mandatory.&#xD;
&#xD;
          2. Patients must have relapsed (recurrence after complete response or presented&#xD;
             progression after partial response) or refractory after at least ≥ 1 (but &lt; 4) prior&#xD;
             lines of therapy, including rituximab-based immunochemotherapy.&#xD;
&#xD;
             A previous regimen is defined as one of the following: at least 2 months of&#xD;
             single-agent therapy; at least 2 consecutive cycles of polychemotherapy; autologous&#xD;
             transplant; radioimmunotherapy.&#xD;
&#xD;
          3. Patients must not be eligible to high-dose chemotherapy (HDC) and autologous stem cell&#xD;
             transplantation (ASCT) or relapsed after that.&#xD;
&#xD;
          4. Patients must not be eligible to CAR T-cell therapy or relapsed after that.&#xD;
&#xD;
          5. Patients must have at least one bi-dimensionally measurable lesion (that has not been&#xD;
             previously irradiated) according to the 2014 Lugano criteria.&#xD;
&#xD;
          6. Male or female patient ≥ 18 years of age.&#xD;
&#xD;
          7. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 if not related to&#xD;
             lymphoma disease.&#xD;
&#xD;
          8. Ann Arbor stage II-IV disease.&#xD;
&#xD;
          9. Life expectancy of at least 3 months.&#xD;
&#xD;
         10. 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 6 months after last administration of bendamustine or&#xD;
             copanlisib or 12 months after last rituximab dose. 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 method (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;
         11. Adequate liver, renal and bone marrow function, assessed by baseline laboratory values&#xD;
             as assessed within 7 days before starting study treatment; as assessed by the&#xD;
             following (ULN= upper level of normality):&#xD;
&#xD;
               -  Total bilirubin ≤ 1.5 x ULN (&lt; 3 x ULN for patients with Gilbert-Meulengracht&#xD;
                  syndrome, patients with cholestasis due to compressive adenopathies of the&#xD;
                  hepatic hilum or documented liver involvement by lymphoma).&#xD;
&#xD;
               -  Alanine transaminase (ALT or GPT) and aspartate aminotransferase (AST or GOT) &lt;&#xD;
                  2.5 x ULN (&lt; 5x ULN for patients with documented liver involvement or with&#xD;
                  biliary obstruction due to lymphoma).&#xD;
&#xD;
               -  Lipase ≤ 1.5 x ULN.&#xD;
&#xD;
               -  Glomerular filtration rate (GFR) ≥ 30mL/min/1.73 m2 according to the Modification&#xD;
                  of Diet in Renal Disease (MDRD) abbreviated formula. If not on target, this&#xD;
                  evaluation may be repeated once after at least 24 hours either according to the&#xD;
                  MDRD abbreviated formula or by 24-hour sampling. If the latter result is within&#xD;
                  acceptable range, it may be used to fulfil the inclusion criteria instead.&#xD;
&#xD;
               -  International normalized ratio (INR) ≤ 1.5 and partial thromboplastin time (PTT)&#xD;
                  ≤ 1.5 x ULN. PTT can be used instead of INR if PTT ≤ 1.5 x ULN.&#xD;
&#xD;
               -  Platelet count ≥ 75,000/mm3. For patients with lymphomatous bone marrow&#xD;
                  infiltration (local assessment) or splenomegaly, platelet count ≥ 50,000/mm3.&#xD;
                  Platelet transfusion should not be given less than 7 days before the exam&#xD;
                  collection.&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) ≥ 1,000/mm3 (unless neutropenia related to&#xD;
                  lymphomatous bone marrow infiltration).&#xD;
&#xD;
               -  Hemoglobin (Hb) ≥ 8 g/dL (unless anemia related to active lymphoma).&#xD;
&#xD;
         12. Left ventricular ejection fraction ≥ 45%.&#xD;
&#xD;
         13. Ability to understand and willingness to sign written informed consent. Signed&#xD;
             informed consent must be obtained before any study specific procedure.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Patients who meet any of the following criteria at the time of screening will be excluded.&#xD;
&#xD;
          -  Previous assignment to treatment during this study. Patients permanently withdrawn&#xD;
             from study participation will not be allowed to re-enter the study.&#xD;
&#xD;
          -  Previous (within 28 days or less than 5 half-lives of the drug before start of study&#xD;
             treatment) or concomitant participation in another clinical study with investigational&#xD;
             medicinal product(s).&#xD;
&#xD;
        Excluded medical conditions:&#xD;
&#xD;
          1. Primary mediastinal B-cell Lymphoma (PMBCL)&#xD;
&#xD;
          2. DLBCL with concomitant HHV8 positivity or chronic inflammation&#xD;
&#xD;
          3. ALK positive DLBCL&#xD;
&#xD;
          4. Known lymphomatous involvement of the central nervous system&#xD;
&#xD;
          5. Congestive heart failure &gt; New York Heart Association (NYHA) class 2&#xD;
&#xD;
          6. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3&#xD;
             months).&#xD;
&#xD;
          7. Myocardial infarction less than 6 months before start of test drug&#xD;
&#xD;
          8. Uncontrolled arterial hypertension despite optimal medical management&#xD;
&#xD;
          9. HbA1c&gt; 8.5%&#xD;
&#xD;
         10. Arterial or venous thrombotic or embolic events such as cerebrovascular accident&#xD;
             (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism&#xD;
             within 3 months before the start of study medication. Patients with venous thrombotic&#xD;
             events related to lymphoma vascular infiltration or compressive disease are eligible&#xD;
             providing no signs of pulmonary embolism&#xD;
&#xD;
         11. Non-healing wound, ulcer, or bone fracture&#xD;
&#xD;
         12. Active, clinically serious infections &gt; CTCAE Grade 2&#xD;
&#xD;
         13. History of, or current autoimmune disease&#xD;
&#xD;
         14. Known history of Human immunodeficiency virus (HIV) infection. All patients must be&#xD;
             screened for HIV up to 28 days prior to study drug start using a blood test for HIV&#xD;
             according to local regulations.&#xD;
&#xD;
         15. DLBCL with concomitant primitive or secondary immunodeficiency&#xD;
&#xD;
         16. Hepatitis B (HBV) or hepatitis C (HCV). All patients must be screened for HBV and HCV&#xD;
             up to 28 days prior to study drug start using the routine hepatitis virus laboratorial&#xD;
             panel. Patients positive for HBsAg are excluded. Patients positive for HBcAb will be&#xD;
             eligible if they are negative for HBV-DNA, these patients should receive prophylactic&#xD;
             antiviral therapy. Patients positive for anti-HCV antibody will be eligible if they&#xD;
             are negative for HCV-RNA&#xD;
&#xD;
         17. CMV PCR positive at baseline&#xD;
&#xD;
         18. Previous or concurrent history of malignancies other than DLBCL within 5 years prior&#xD;
             to study treatment except for curatively treated:&#xD;
&#xD;
               -  Cervical carcinoma in situ&#xD;
&#xD;
               -  Non-melanoma skin cancer&#xD;
&#xD;
               -  Superficial bladder cancer (Ta [non-invasive tumor], Tis [carcinoma in situ] and&#xD;
                  T1 [tumor invades lamina propria])&#xD;
&#xD;
               -  Localized prostate cancer&#xD;
&#xD;
         19. Patients with seizure disorder requiring medication&#xD;
&#xD;
         20. Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding&#xD;
             event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication&#xD;
&#xD;
         21. Proteinuria of ≥ CTCAE Grade 3 as assessed by a 24h protein quantification or&#xD;
             estimated by urine protein: creatinine ratio &gt; 3.5 on a random urine sample&#xD;
&#xD;
         22. History or concurrent condition of interstitial lung disease of any severity and/or&#xD;
             severely impaired lung function (as judged by the investigator)&#xD;
&#xD;
         23. Concurrent diagnosis of pheochromocytoma&#xD;
&#xD;
         24. 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;
        Patients who meet any of the following criteria at the time of screening will be excluded.&#xD;
&#xD;
          -  Previous assignment to treatment during this study. Patients permanently withdrawn&#xD;
             from study participation will not be allowed to re-enter the study.&#xD;
&#xD;
          -  Previous (within 28 days or less than 5 half-lives of the drug before start of study&#xD;
             treatment) or concomitant participation in another clinical study with investigational&#xD;
             medicinal product(s).&#xD;
&#xD;
        Excluded medical conditions:&#xD;
&#xD;
          1. Primary mediastinal B-cell Lymphoma (PMBCL)&#xD;
&#xD;
          2. DLBCL with concomitant HHV8 positivity or chronic inflammation&#xD;
&#xD;
          3. ALK positive DLBCL&#xD;
&#xD;
          4. Known lymphomatous involvement of the central nervous system&#xD;
&#xD;
          5. Congestive heart failure &gt; New York Heart Association (NYHA) class 2&#xD;
&#xD;
          6. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3&#xD;
             months).&#xD;
&#xD;
          7. Myocardial infarction less than 6 months before start of test drug&#xD;
&#xD;
          8. Uncontrolled arterial hypertension despite optimal medical management&#xD;
&#xD;
          9. HbA1c&gt; 8.5%&#xD;
&#xD;
         10. Arterial or venous thrombotic or embolic events such as cerebrovascular accident&#xD;
             (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism&#xD;
             within 3 months before the start of study medication. Patients with venous thrombotic&#xD;
             events related to lymphoma vascular infiltration or compressive disease are eligible&#xD;
             providing no signs of pulmonary embolism&#xD;
&#xD;
         11. Non-healing wound, ulcer, or bone fracture&#xD;
&#xD;
         12. Active, clinically serious infections &gt; CTCAE Grade 2&#xD;
&#xD;
         13. History of, or current autoimmune disease&#xD;
&#xD;
         14. Known history of Human immunodeficiency virus (HIV) infection. All patients must be&#xD;
             screened for HIV up to 28 days prior to study drug start using a blood test for HIV&#xD;
             according to local regulations.&#xD;
&#xD;
         15. DLBCL with concomitant primitive or secondary immunodeficiency&#xD;
&#xD;
         16. Hepatitis B (HBV) or hepatitis C (HCV). All patients must be screened for HBV and HCV&#xD;
             up to 28 days prior to study drug start using the routine hepatitis virus laboratorial&#xD;
             panel. Patients positive for HBsAg are excluded. Patients positive for HBcAb will be&#xD;
             eligible if they are negative for HBV-DNA, these patients should receive prophylactic&#xD;
             antiviral therapy. Patients positive for anti-HCV antibody will be eligible if they&#xD;
             are negative for HCV-RNA&#xD;
&#xD;
         17. CMV PCR positive at baseline&#xD;
&#xD;
         18. Previous or concurrent history of malignancies other than DLBCL within 5 years prior&#xD;
             to study treatment except for curatively treated:&#xD;
&#xD;
               -  Cervical carcinoma in situ&#xD;
&#xD;
               -  Non-melanoma skin cancer&#xD;
&#xD;
               -  Superficial bladder cancer (Ta [non-invasive tumor], Tis [carcinoma in situ] and&#xD;
                  T1 [tumor invades lamina propria])&#xD;
&#xD;
               -  Localized prostate cancer&#xD;
&#xD;
         19. Patients with seizure disorder requiring medication&#xD;
&#xD;
         20. Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding&#xD;
             event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication&#xD;
&#xD;
         21. Proteinuria of ≥ CTCAE Grade 3 as assessed by a 24h protein quantification or&#xD;
             estimated by urine protein: creatinine ratio &gt; 3.5 on a random urine sample&#xD;
&#xD;
         22. History or concurrent condition of interstitial lung disease of any severity and/or&#xD;
             severely impaired lung function (as judged by the investigator)&#xD;
&#xD;
         23. Concurrent diagnosis of pheochromocytoma&#xD;
&#xD;
         24. 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;
         25. Unresolved toxicity higher than CTCAE Grade 1 attributed to any prior&#xD;
             therapy/procedure, excluding alopecia&#xD;
&#xD;
         26. Known hypersensitivity to any of the test drugs, test drug classes, or excipients in&#xD;
             the formulation&#xD;
&#xD;
         27. Substance abuse, medical, psychological or social conditions that may interfere with&#xD;
             the patient's participation in the study or evaluation of the study results&#xD;
&#xD;
         28. Any illness or medical conditions that are unstable or could jeopardize the safety of&#xD;
             patients and their compliance in the study e.g., uncontrolled diabetes, uncontrolled&#xD;
             dyslipidemia, etc.)&#xD;
&#xD;
        Excluded previous therapies and medications:&#xD;
&#xD;
          -  Prior treatment with copanlisib.&#xD;
&#xD;
          -  Prior exposure to idelalisib or other PI3K inhibitors, less than 28 days before start&#xD;
             of treatment, unless evidence of progression since last treatment&#xD;
&#xD;
          -  Prior treatment with bendamustine: subjects treated with bendamustine at least 24&#xD;
             months before, with a response &gt; one year to bendamustine containing regimen, will be&#xD;
             eligible&#xD;
&#xD;
          -  Ongoing immunosuppressive therapy.&#xD;
&#xD;
          -  Radiotherapy or immuno-/chemotherapy less than 2-4 weeks before start of treatment&#xD;
             (corticosteroids are allowed) and use of myeloid growth factors within 14 days prior&#xD;
             to treatment&#xD;
&#xD;
          -  platelet transfusion less than 7 days before start of treatment&#xD;
&#xD;
          -  Systemic continuous corticosteroid therapy at a daily dose higher than 15 mg&#xD;
             prednisone or equivalent is not allowed. Previous corticosteroid therapy must be&#xD;
             stopped or reduced to the allowed dose 7 days before performing the screening PET or&#xD;
             PET/CT and/or CT/MRI, whichever is performed first, and again prior to the first study&#xD;
             drug administration. If a patient is on chronic corticosteroid therapy,&#xD;
             corticosteroids should be de-escalated to the maximum allowed dose after the patient&#xD;
             has signed the IC. Patients may be using topical or inhaled corticosteroids. A&#xD;
             pre-phase with corticosteroids is allowed to control the disease in case of systemic&#xD;
             symptoms and/or compressive disease with a maximum of prednisone 100 mg (or&#xD;
             equivalent) daily for a maximum of 15 days prior start of treatment.&#xD;
&#xD;
          -  Autologous transplant less than 2 months before start of treatment. Prior Autologous&#xD;
             stem cell performed more than 2 months before start of treatment is allowed.&#xD;
&#xD;
          -  History of having received an allogeneic bone marrow or organ transplant.&#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.&#xD;
&#xD;
          -  Anti-arrhythmic therapy (beta blockers or digoxin are permitted).&#xD;
&#xD;
          -  Use of CYP3A4 inhibitors and inducers. Copanlisib is primarily metabolized by CYP3A4.&#xD;
             Therefore, concomitant use of strong inhibitors of CYP3A4 (e.g., ketoconazole,&#xD;
             itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir and saquinavir), and&#xD;
             strong inducers of CYP3A4 (e.g., rifampin, phenytoin, carbamazepine, phenobarbital,&#xD;
             St. John's Wort) are not permitted from Day -28 of Cycle 1 until restaging at the end&#xD;
             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>Umberto Vitolo</last_name>
    <role>Principal Investigator</role>
    <affiliation>Ematologia, Candiolo Cancer Institute. FPO-IRCCS</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Ospedale Monsignor Raffaele Dimiccoli - Ematologia</name>
      <address>
        <city>Barletta</city>
        <state>Barletta-Andria-Trani</state>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centro Riferimento Oncologico - S.O.C. Oncologia Medica A</name>
      <address>
        <city>Aviano</city>
        <state>Pordenone</state>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ematologia, Candiolo Cancer Institute. FPO-IRCCS</name>
      <address>
        <city>Candiolo</city>
        <state>Torino</state>
        <zip>10060</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>AOU Ospedali Riuniti - Clinica di Ematologia</name>
      <address>
        <city>Ancona</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>ASST Spedali Civili - Ematologia</name>
      <address>
        <city>Brescia</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Arnas Nuovo Ospedale Garibaldi Nesima - U.O.C. Ematologia</name>
      <address>
        <city>Catania</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>A.O. S. Croce e Carle - S.C. di Ematologia e Trapianto di Midollo Osseo</name>
      <address>
        <city>Cuneo</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ospedale Vito Fazzi - Ematologia</name>
      <address>
        <city>Lecce</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Azienda Ospedali Riuniti Papardo-Piemonte - S.C. Ematologia</name>
      <address>
        <city>Messina</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>I.R.C.C.S. Istituto Oncologico Veneto - Oncologia 1</name>
      <address>
        <city>Padova</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>AOU Policlinico Giaccone - Ematologia</name>
      <address>
        <city>Palermo</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>IRCCS Policlinico S. Matteo di Pavia - Divisione di Ematologia</name>
      <address>
        <city>Pavia</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ospedale Guglielmo da Saliceto - U.O.Ematologia</name>
      <address>
        <city>Piacenza</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Azienda Ospedaliera Sant'Andrea - Ematologia</name>
      <address>
        <city>Roma</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Policlinico Umberto I - Università &quot;La Sapienza&quot; Istituto Ematologia -Dipartimento di Medicina Traslazionale e di Precisione</name>
      <address>
        <city>Roma</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Azienda Ospedaliera S. Maria di Terni - S.C. Oncoematologia</name>
      <address>
        <city>Terni</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Azienda Ospedaliero Universitaria Città della Salute e della Scienza - S.C.Ematologia</name>
      <address>
        <city>Torino</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ospedale Ca' Foncello - S.C di Ematologia</name>
      <address>
        <city>Treviso</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>June 9, 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>March 30, 2023</last_update_submitted>
  <last_update_submitted_qc>March 30, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 31, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Diffuse Large B-cell Lymphoma</keyword>
  <keyword>Relapsed-Refractory</keyword>
  <keyword>DLBCL</keyword>
  <keyword>Copanlisib</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Lymphoma, B-Cell</mesh_term>
    <mesh_term>Lymphoma, Large B-Cell, Diffuse</mesh_term>
  </condition_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/NCT04433182
org study id: FIL_Copa-RB
nct id: NCT04433182
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
This is a multicentric single arm phase II trial, to investigate the efficacy (in terms of
      PFS) of the combination regimen rituximab-bendamustine in association with copanlisib in
      patients affected by relapsed/refractory DLBCL, not eligible to HDC and ASCT or relapsed
      after intensified regimens.
The primary objective of this study is to evaluate the efficacy, in terms of Progression Free
      Survival (12m-PFS) at 12 months, of a treatment with copanlisib in combination with a
      standard rituximab-bendamustine regimen in patients with relapsed-refractory DLBCL, who have
      received at least one, but no more than three lines of treatment, including rituximab-based
      immunochemotherapy, not eligible for high-dose chemotherapy and ASCT or T-cell CAR-T therapy,
      or relapsed after these treatments.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Progression-free survival (PFS)
time frame: 4 years
description: Progression-Free Survival (PFS) will be defined as the time between the date of enrolment and the date of disease progression, relapse or death from any cause. Responding patients according to Response Criteria for NHL with PET and patients who are lost to follow-up will be censored at their last assessment date.
measure: Overall Survival (OS)
time frame: 4 years
description: Time between the date of enrolment and the date of death from any cause. Patients who have not died at the time of the final analysis will be censored at the date of the last contact.
measure: Overall Response Rate (ORR)
time frame: End of treament (EOT), 30 months
description: ORR will be defined as the sum of CR + PR
measure: Complete Response Rate (CRR)
time frame: End of induction (EOI), 18 months
description: CRR will be defined as the proportion of patients achieving a CR
measure: Duration of response (DOR)
time frame: 4 years
description: DOR is measured from the date when criteria for response are met (CR or PR) until the date of progression or relapse. Patients without relapse or progression will be censored at their last assessment date.
measure: Conversion rate from SD/PR to PR/CR with maintenance
time frame: End of treatment (after maintenance), 30 months
description: Conversion rate from SD/PR to PR/CR with maintenance
measure: Evaluation of adverse events according to the current version of the CTCAE criteria
time frame: 4 years
description: Evaluation of adverse events according to the current version of the CTCAE criteria
arm group label: Single arm Copa-RB
arm group type: Experimental
description: Induction phase with Copanlisib, Rituximab and Bendamustina. Maintenance phase (for patients who reach at least SD after induction) with Copanlisib in monotherapy.
intervention type: Drug
intervention name: Copanlisib
description: Induction phase: 6 cycles of Copa-RB every 28 days according to the following schedule
Copanlisib (Copa): 60 mg/day i.v. on days 1,8,15
Rituximab (R): 375 mg/sqm i.v. day 1*
Bendamustine (B): 90 mg/sqm i.v. days 1-2*
note: during cycle 1 rituximab can be administered on day 2: in this case bendamustine will be administered on days 2-3; in the case of a frail patient or a patient with high tumor burden copanlisib could be administered on day 1, rituximab on day 2 and bendamustine on days 3-4, at physician discretion.
Maintenance phase: patients who reach at least SD after induction will receive a maintenance with copanlisib in monotherapy according to the following schedule:
• Copanlisib: 60 mg/day i.v. on days 1 and 15 in 28-day cycles for 1 year
arm group label: Single arm Copa-RB
other name: ALIQOPA
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Umberto Vitolo
role: Principal Investigator
affiliation: Ematologia, Candiolo Cancer Institute. FPO-IRCCS
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Italy
responsible party type: Sponsor
mesh term: Lymphoma
mesh term: Lymphoma, B-Cell
mesh term: Lymphoma, Large B-Cell, Diffuse
sharing ipd: No