Copanlisib and Rituximab in Relapsed Indolent B-cell Non-Hodgkin's Lymphoma (iNHL)
Condition: Lymphoma,Non-Hodgkin
MeSH terms: Lymphoma; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell
Intervention: Copanlisib (Aliqopa, BAY80-6946); Placebo; Rituximab
Intervention description: Copanlisib is supplied as lyophilized preparation in a 6 mL injection vial. The total amount of copanlisib per vial is 60 mg. The solution for IV infusions is obtained after reconstitution with normal saline solution. Dosing will be administered on Days 1, 8 and 15 of each 28-day cycle. Copanlisib will be administered before rituximab.; Placebo is supplied as lyophilized preparation in a 6 mL injection vial. The developed placebo lyophilisate is equivalent to the 60 mg copanlisib formulation, with regard to the composition of excipients and the instructions for reconstitution and dose preparation. Placebo dosing will be administered on Days 1, 8 and 15 of each 28-day cycle. Placebo will be administered before rituximab.; Rituximab dose 375 mg/m2 body surface weekly during Cycle 1 on Days 1, 8, 15 and 22, and then on Day 1 of Cycles 3, 5, 7 and 9.The solution for IV infusions is obtained after reconstitution of a calculated concentration of 1 to 4 mg/ml rituximab into an infusion bag containing sterile, pyrogen-free sodium chloride 9 mg/ml (0.9%) solution for injection or 5% D-Glucose in water.
Intervention MeSH terms: Rituximab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 458.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Clinical trial, Phase III; Phosphatidylinositol-3-kinase; Non-Hodgkin's lymphoma; Indolent B-cell non-Hodgkin's lymphoma

Summary:

      The purpose of this study was to evaluate whether copanlisib in combination with rituximab is
      superior to placebo in combination with rituximab in prolonging progression free survival
      (PFS) in patients with relapsed iNHL who have received one or more lines of treatment,
      including rituximab and who either had a treatment-free interval of ≥ 12 months after
      completion of the last rituximab-containing treatment, or who are unwilling to receive
      chemotherapy/for whom chemotherapy is contraindicated on reason of age, comorbidities, and/or
      residual toxicity.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically confirmed diagnosis of Indolent non-Hodgkin's lymphoma (iNHL) in CD20
             positive patients, with histological subtype limited to:

               -  Follicular lymphoma(FL) grade1-2-3a

               -  Small lymphocytic lymphoma(SLL) with absolute lymphocyte count <5x10*9/L at study
                  entry

               -  Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM)

               -  Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal)

          -  Patients must have relapsed (recurrence after complete response or presented
             progression after partial response) after the last rituximab-, rituximab biosimilars-,
             or anti-CD20 monoclonal antibody (e.g. obinutuzumab)-containing therapy (other
             previous treatment lines after rituximab are allowed). A previous regimen is defined
             as one of the following: at least 2 months of single-agent therapy (less than 2 months
             of therapy is allowed for patients who responded to single-agent rituximab, rituximab
             biosimilars, or anti-CD20 monoclonal antibody); at least 2 consecutive cycles of
             polychemotherapy; autologous transplant; radioimmunotherapy. Previous exposure to PI3K
             is acceptable (except to copanlisib) provided there is no resistance. Patients with
             prior intolerance to PI3K inhibitors other than copanlisib are eligible.

          -  Non-WM must have at least one bi-dimensionally measurable lesion (which has not been
             previously irradiated) according to the Lugano Classification. For patients with
             splenic MZL (Marginal-zone lymphoma) this requirement may be restricted to
             splenomegaly alone since that is usually the only manifestation of measurable disease.

          -  Patients affected by WM who do not have at least one bi-dimensionally measurable
             lesion in the baseline radiologic assessment must have measurable disease, defined as
             presence of immunoglobulin M (IgM) paraprotein with a minimum IgM level ≥ 2 x upper
             limit of normal (ULN) and positive immunofixation test .

          -  Male or female patients ≥ 18 years of age

          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

          -  Life expectancy of at least 3 months

          -  Availability of fresh tumor tissue and/or archival tumor tissue for central
             pathology(obtained within 5 years of the consent date) at Screening

          -  Adequate baseline laboratory values collected no more than 7 days before starting
             study treatment

          -  Left ventricular ejection fraction ≥ 45%

          -  Patients must either:

               -  have had a progression-free and treatment-free interval of at least 12 months
                  after completion of the rituximab-, rituximab biosimilars-, or anti-CD20
                  monoclonal antibody-containing treatment OR

               -  be considered unfit to receive chemotherapy on reason of age, concomitant
                  morbidities, and/or residual toxicity from previous treatments, or unwillingness
                  to receive chemotherapy. These patients must also have had a progression-free and
                  treatment-free interval of at least 6 months after completion of the last
                  rituximab-, rituximab biosimilars-, or anti-CD20 monoclonal antibody-containing
                  treatment. Patients in whom chemotherapy is contraindicated are defined by one of
                  the following features:

                    -  Age ≥ 80 years

                    -  Age < 80 years and at least 1 of the following conditions:

                         -  at least 3 grade 3 CIRS-G comorbidities OR

                         -  at least 1 grade 4 CIRS-G comorbidity (if compatible to participation
                            in the study).

        Exclusion Criteria:

          -  Histologically confirmed diagnosis of follicular lymphoma grade 3b or transformed
             disease, or chronic lymphocytic leukemia

          -  Progression free interval or treatment free interval of less than 12 months since the
             last rituximab-, rituximab biosimilars-, or anti-CD20 monoclonal antibody (e.g.
             obinutuzumab)-containing treatment(including maintenance with these drugs). For
             patients considered unwilling/unfit to receive chemotherapy : progression free
             interval or treatment free interval of less than 6 months since the last rituximab-,
             rituximab biosimilars-, or anti-CD20 monoclonal antibody-containing treatment
             (including maintenance with these drugs), as assessed by the investigator

          -  History or concurrent condition of interstitial lung disease of any severity and/or
             severely impaired lung function

          -  Known lymphomatous involvement of the central nervous system

          -  Patients with HbA1c > 8.5% at Screening

          -  Known history of human immunodeficiency virus (HIV) infection

          -  Hepatitis B (HBV) or hepatitis C (HCV). Patients positive for HBsAg or HBcAb will be
             eligible if they are negative for HBV-DNA, these patients should receive prophylactic
             antiviral therapy. Patients positive for anti- HCV antibody will be eligible if they
             are negative for HCV-RNA

          -  Documented evidence of resistance to prior treatment with idelalisib or other PI3K
             inhibitors.

          -  Prior treatment with copanlisib

          -  Cytomegalovirus (CMV) infection. Patients who are CMV PCR positive at baseline will
             not be eligible.