Open-label, Uncontrolled Phase II Trial of Intravenous PI3K Inhibitor BAY80-6946 in Patients With Relapsed, Indolent or Aggressive Non-Hodgkin's Lymphomas
Condition: Lymphoma, Non-Hodgkin
MeSH terms: Lymphoma; Lymphoma, Non-Hodgkin
Intervention: Copanlisib (Aliqopa, BAY80-6946)
Intervention description: BAY 80-6946 is administered in a normal saline solution, 100 mL, intravenously over 1h. No intravenous glucose preparations should be administered on the days of infusion. Dosing is weekly for the first 3 weeks (on Days 1, 8, and 15) of a 28-day cycle, followed by a 1-week break (i.e., no infusion on Day 22).
Part A: The individual dose will be 0.8 mg/kg (max. 65 mg) per infusion from Cycle 1 on. The maximum dose of 65 mg should never be exceeded.
Part B: The individual dose will be 60 mg per infusion from Cycle 1 on.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 227.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Clinical trial, phase II; Phosphatidylinositol 3-Kinase; Class I, Non-Hodgkin's lymphoma

Summary:

      The objective of the study (part A) is to evaluate the efficacy and safety of BAY80-6946 in
      patients with indolent or aggressive Non-Hodgkin's Lymphoma, who have progressed after
      standard therapy. 30 patients will be enrolled to both indolent and aggressive disease group.
      The objective of the study part B (CHRONOS-1) is to evaluate the efficacy and safety of
      BAY80-6946 in patients with relapsed/refractory follicular lymphoma. 120 patients will be
      enrolled in the part B of the study. Further objectives are to evaluate the pharmacokinetics
      and biomarkers. Quality of life will be a further objective of part B of the study.

      In a cohort of 20 patients (enrolled both in part A and B) an ECG substudy will be performed
      to assess the potential for cardiac toxicity and QT/QTc interval prolongation of BAY80-6946.

      After an up to 28-day screening period, eligible patients will start treatment with
      BAY80-6946 at a dose of 0.8 mg/kg (Part A) and at a dose of 60 mg (Part B).

      Treatment will be continued until disease has progressed or until another criterion is met
      for withdrawal from study. An end-of-treatment visit will be performed within 7 days after
      discontinuation of study treatment. Thirty to 35 days after last study drug administration, a
      safety followup visit will be performed for the collection of adverse events (AEs) and
      concomitant medication data. Patients will be contacted quarterly to determine overall
      survival status up to 4 years after last patient completed treatment. Patients who
      discontinue study drug for reasons other than disease progression will enter the Active
      Assessment Follow-up period. The end of study notification to Health Authorities will be
      based on the completion of the collection of survival data.

      The efficacy is measured by the decrease in tumor size. Tumor assessments will be done at
      Screening, every 8 weeks during Year 1, every 12 weeks during Year 2, and every 6 months
      during Year 3. Blood samples will be collected for pharmacokinetic analysis. Archival tumor
      tissue and blood samples will be collected for biomarker analysis (mandatory) and for central
      pathology review (part B), fresh biopsy tissue will also be collected if available.
    

Eligibility criteria:

        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)].