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 last rituximab-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); 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 (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 last rituximab-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-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 containing treatment (including rituximab maintenance). For patients
considered unwilling/unfit to receive chemotherapy : progression free interval or
treatment free interval of less than 6 months since the last rituximab containing
treatment (including rituximab maintenance), 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