Phase III Copanlisib in Rituximab-refractory iNHL

Inclusion Criteria:

- Histologically confirmed diagnosis of indolent B-cell NHL, with histological subtype
limited to the following:

- Follicular lymphoma (FL) grade 1-2-3a.

- Small lymphocytic lymphoma (SLL) with absolute lymphocyte count < 5 x 10*9/L at
the time of diagnosis and at study entry.

- Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM).

- Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal).

- Patients must have received two or more prior lines of treatment. A previous regimen
is defined as one of the following: at least two months of single-agent therapy, at
least two consecutive cycles of polychemotherapy, autologous transplant,
radioimmunotherapy.

- Prior therapy must include rituximab and alkylating agents.Prior exposure to
idelalisib or other PI3K inhibitors is acceptable (except to copanlisib) provided that
there is no resistance.

- Patients must be refractory to the last rituximab-based treatment, defined as no
response or response lasting < 6 months after completion of treatment. Time interval
to assess refractoriness will be calculated between the end date (last day) of the
last rituximab-containing regimen and the day of diagnosis confirmation of the
subsequent relapse.

- Patients must have at least one bi-dimensionally measurable lesion (which has not been
previously irradiated) according to the Recommendations for Initial Evaluation,
Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano
Classification.

- 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.

- ECOG performance status ≤ 1

- Adequate bone marrow, liver and renal function

Exclusion Criteria:

- Histologically confirmed diagnosis of FL grade 3b.

- Chronic lymphocytic leukemia (CLL).

- Transformed disease (assessed by investigator):

- histological confirmation of transformation, or

- clinical and laboratory signs: rapid disease progression, high standardized
uptake value (SUV) (> 12) by positron emission tomography (PET) at baseline if
PET scans are performed (optional).

- Bulky disease - Lymph nodes or tumor mass (except spleen) >= 7cm LD (longest diameter)

- Known lymphomatous involvement of the central nervous system.

- Uncontrolled arterial hypertension despite optimal medical management (per
investigator's assessment).

- Type I or II diabetes mellitus with HbA1c > 8.5% at Screening.

- Known history of human immunodeficiency virus (HIV) infection.

- Active clinically serious infections > CTCAE Grade 2

- Active Hepatitis B or hepatitis C

- History or concurrent condition of interstitial lung disease of any severity and/or
severely impaired lung function (as judged by the investigator)

- History of having received an allogeneic bone marrow or organ transplant

- Positive cytomegalovirus (CMV) PCR test at baseline

- Pregnant or breast-feeding patients