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)].