Copanlisib and Rituximab in Relapsed Indolent B-cell Non-Hodgkin's Lymphoma (iNHL)

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.