Open-label, Uncontrolled Phase II Trial of Intravenous PI3K Inhibitor BAY80-6946 in Patients With Relapsed, Indolent or Aggressive Non-Hodgkin's Lymphomas

Inclusion Criteria:

* Indolent NHL:

  * Histologically confirmed diagnosis of follicular lymphoma (FL) grades 1, 2 or 3a, marginal zone lymphoma (including nodal or splenic marginal zone B-cell lymphoma and mucosa-associated lymphoid tissue \[MALT\] lymphoma), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, chronic lymphocytic leukemia (CLL).
  * Relapsed after ≥ 2 prior chemotherapy- or immunotherapy-based regimens for indolent NHL, or refractory to 2 prior chemotherapy and/ or immunotherapy-based regimens.
* Aggressive NHL:

  * Histologically confirmed diagnosis of grade 3b follicular lymphoma (FL), transformed indolent lymphoma, diffuse large B-cell lymphoma (DLBCL), mediastinal large B-cell lymphoma, mantle cell lymphoma (MCL), peripheral T-cell lymphoma unspecified, or anaplastic large cell lymphoma primary systemic type, or angioimmunoblastic T cell lymphoma.
  * Relapsed after ≥ 2 prior chemotherapy regimens, including the following: First-line treatment with standard anthracycline-containing regimen (e.g., cyclophosphamide, doxorubicin, vincristine, and prednisone or equivalent). At least 1 additional combination chemotherapy regimen. Patients relapsed after or refractory to first prior chemotherapy- and/or immunotherapy-based regimen for aggressive NHL and not eligible for high-dose regimen followed by transplant. High-dose chemotherapy, or chemoradiotherapy with autologous stem cell transplantation is considered 1 regimen. Patients with CD20 expressing neoplastic cells must have received prior rituximab, if available.
  * Patients with transformed indolent lymphoma must have received at least 2 prior chemotherapy- and/or immunotherapy-based regimens
  * Consent to provide fresh tumor tissue during screening
* Indolent B-cell NHL lymphoma (study part B):

  * 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 109/L at the time of diagnosis and at study entry
    * Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM)
    * Marginal zone lymphoma (MZL) (splenic, nodal, or extranodal)
  * Relapsed or refractory after ≥ 2 prior lines of therapy (refractory defined as not responding to a standard regimen or progressing within 6 months of the last course of a standard regimen). Patients must have received Rituximab and alkylating agents.
* For all patients:

  * Male or female patients \> 18 years of age
  * ECOG performance status ≤ 2 (ECOG: Eastern Cooperative Oncology Group)
  * Life expectancy of at least 3 months
  * Adequate bone marrow, liver and renal function as assessed within 7 days before starting study treatment
  * Left ventricular ejection fraction (LVEF) ≥ lower limit of normal (LLN) for the Institution
  * Availability of archival tumor tissue

Exclusion Criteria:

* Uncontrolled hypertension (blood pressure ≥ 150/90 mmHg despite optimal medical management)
* Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks of start of study medication (CTCAE: Common Terminology Criteria for Adverse Events).
* History or concurrent condition of interstitial lung disease
* Unresolved toxicity higher than CTCAE grade 1 (NCI-CTC version 4.0) attributed to any prior therapy/procedure excluding alopecia. (NCI: National Cancer Institute)
* Prior treatment with PI3K inhibitors
* Systemic corticosteroid therapy (ongoing)
* Hepatitis B or C. All subjects must be screened for hepatitis B and C up to 28 days prior to study drug start using the hepatitis virus panel laboratorial routine. Subjects positive for HBsAg or HBcAb will be eligible if they are negative for HBV-DNA; subjects positive for HCV IgG will be eligible if they are negative for HCV RNA.
* For Part B:

  * Histologically confirmed diagnosis of follicular lymphoma grade 3b or transformed disease and chronic lymphocytic leukemia (CLL)
  * History or concurrent condition of interstitial lung disease or severely impaired pulmonary function
* Excluded medical conditions:

  * Previous or concurrent cancer that is distinct in primary site or histology from indolent B-cell NHL within 5 years prior to treatment start EXCEPT for curatively treated cervical cancer in situ, nonmelanoma skin cancer and superficial bladder tumors \[Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)\].
  * Hepatitis B or C. All subjects must be screened for hepatitis B and C up to 28 days prior to study drug start using the hepatitis virus panel laboratorial routine. Subjects positive for HBsAg or HBcAb will be eligible if they are negative for HBV-DNA; subjects positive for HCV IgG will be eligible if they are negative for HCV-RNA.
  * Type I or II diabetes mellitus with HbA1c \> 8.5% or fasting plasma glucose \> 160 mg/dL at screening.
  * Previous or concurrent cancer that is distinct in primary site or histology from indolent B-cell NHL within 5 years prior to treatment start EXCEPT for curatively treated cervical cancer in situ, nonmelanoma skin cancer and superficial bladder tumors \[Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)\].