Phase III Copanlisib in Rituximab-refractory iNHL

To assess the safety of copanlisib.


Eligibility Criteria:
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