Phase-3 Studie mit Copanlisib in Kombination mit einer Standard-Immunotherapie bei wiederauftretendem indolentem non-Hodgkin-Lymphom (iNHL).

Drug: Copanlisib (BAY80-6946);Drug: Placebo;Drug: Rituximab;Drug: Cyclophosphamide;Drug: Doxorubicin;Drug: Vincristine;Drug: Bendamustine;Drug: Prednisone

Gender: All
Maximum age: N/A
Minimum age: 18 Years

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 / Waldenstr?m 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, and/or rituximab biosimilars, and/or
anti-CD20 monoclonal antibody (e.g. obinutuzumab) -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, or rituximab
biosimilars, or anti-CD20 monoclonal antibody 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, or rituximab biosimilars, or anti-CD20 monoclonal antibody (e.g.
obinutuzumab) resistance at any line of therapy (resistance defined as lack of
response, or progression within 6 months of the last date of rituximab, or rituximab
biosimilars, or anti-CD20 monoclonal antibody administration, including maintenance
with these drugs).

- 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