Study of Copanlisib in Combination With Standard Immunochemotherapy in Relapsed Indolent Non-Hodgkin's Lymphoma (iNHL)

Patients should be in need of and fit for immunochemotherapy and should not be resistant to
rituximab (resistance defined as lack of response or progression within 6 months of the last
date of rituximab administration, including rituximab maintenance). This study will be
composed of two parts: Safety run-in and phase III part.

The purpose of the safety run-in part of this study is to assess whether the drug being
tested (copanlisib) in combination with standard immunochemotherapy (R-B or R-CHOP) is safe
and at what dose level of the study drug (copanlisib - 45mg or 60 mg) patients are able to
tolerate the study treatment combination. In addition to finding a safe and tolerable dose
level for the phase III part of the study, efficacy will also be evaluated for patients that
stay on the study treatment during the safety run-in. The phase III part of the study started
with the determined recommended dose of copanlisib of 60 mg in combination with R-B.

A maximum of 24 patients will take part in the safety run-in part of this study. In the phase
III part approximately 520 patients will be randomly assigned to blinded treatment arms of
copanlisib plus R-B or R-CHOP or placebo plus R-B or R-CHOP.

Inclusion Criteria:

- Histologically confirmed diagnosis of B lymphocyte antigen CD20 positive iNHL with
histological subtype limited to:

- Follicular lymphoma G1-2-3a

- Small lymphocytic lymphoma with absolute lymphocyte count <5x10E9/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) or progressed after at least one but at most three
prior lines of therapy, including rituximab-based immunochemotherapy and alkylating
agents (if given concomitantly is considered one line of therapy). A previous regimen
is defined as one of the following: at least 2 months of single-agent therapy (less
than 2 months of therapy with single agent rituximab can be considered a previous
regimen in the case the patient responded to it); at least 2 consecutive cycles of
polychemotherapy; autologous transplant; or radioimmunotherapy. Previous exposure to
other PI3K Inhibitors (except copanlisib) is acceptable provided there is no
resistance (resistance defined as no response (response defined as partial response
[PR] or complete response [CR]) at any time during therapy, or progressive disease
(PD) after any response (PR/CR) or after stable disease within 6 months from the end
of the therapy with a PI3K inhibitor.

- Non-WM patients must have at least one bi-dimensionally measurable lesion (that has
not been previously irradiated) according to the Lugano Classification. For patients
with splenic MZL 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 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 at Screening

- Adequate baseline laboratory values as assessed within 7 days before starting study
treatment.

- Left ventricular ejection fraction ≥ 50%

Exclusion Criteria

- Histologically confirmed diagnosis of follicular lymphoma grade 3b or transformed
disease, or chronic lymphocytic leukemia. In patients with clinical suspicion of
transformed disease, a fresh biopsy is recommended.

- Rituximab resistance at any line of therapy (resistance defined as lack of response,
or progression within 6 months of the last date of rituximab administration, including
rituximab maintenance).

- HbA1c > 8.5% at Screening

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

- Known lymphomatous involvement of the central nervous system

- Known history of human immunodeficiency virus (HIV) infection

- Hepatitis B (HBV) or hepatitis C (HCV) infection. Patients positive for hepatitis B
surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) will be eligible if they
are negative for HBV-DNA, these patients should receive prophylactic antiviral therapy
as per rituximab label. Patients positive for anti-HCV antibody will be eligible if
they are negative for HCV-RNA.

- Cytomegalovirus (CMV) infection. Patients who are CMV PCR positive at baseline will
not be eligible.CMV PCR test is considered positive if, the result can be interpreted
as a CMV viremia according to local standard of care.

- Uncontrolled hypertension despite optimal medical management (per investigator´s
assessment)

- Congestive heart failure > New York Heart Association (NYHA) class 2