Clinical Trials /

Study of Copanlisib in Combination With Standard Immunochemotherapy in Relapsed Indolent Non-Hodgkin's Lymphoma (iNHL)

NCT02626455

Description:

The purpose of this study is to assess whether copanlisib in combination with standard immunochemotherapy (rituximab in combination with bendamustine [R-B] and rituximab in combination with a 4 drug combination of cyclophosphamide, doxorubicin, vincristine and prednisone/prednisolone [R-CHOP]) is effective and safe, compared with placebo in combination with standard immunochemotherapy (R-B or R-CHOP) in patients with relapsed iNHL who have received at least one, but at most three, lines of treatment, including rituximab-based immunochemotherapy and alkylating agents.

Related Conditions:
  • Follicular Lymphoma
  • Lymphoplasmacytic Lymphoma
  • Marginal Zone Lymphoma
  • Small Lymphocytic Lymphoma
  • Waldenstrom Macroglobulinemia
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Study of Copanlisib in Combination With Standard Immunochemotherapy in Relapsed Indolent Non-Hodgkin's Lymphoma (iNHL)
  • Official Title: A Phase III, Randomized, Double-blind, Controlled Multicenter Study of Intravenous PI3K Inhibitor Copanlisib in Combination With Standard Immunochemotherapy Versus Standard Immunochemotherapy in Patients With Relapsed Indolent Non-Hodgkin's Lymphoma (iNHL)

Clinical Trial IDs

  • ORG STUDY ID: 17833
  • SECONDARY ID: 2015-001088-38
  • NCT ID: NCT02626455

Conditions

  • Lymphoma, Non-Hodgkin

Interventions

DrugSynonymsArms
Copanlisib (BAY80-6946)Copanlisib + R-B or R-CHOP / Arm 1
PlaceboPlacebo + R-B or R-CHOP / Arm 2
RituximabCopanlisib + R-B or R-CHOP / Arm 1
CyclophosphamideCopanlisib + R-B or R-CHOP / Arm 1
DoxorubicinCopanlisib + R-B or R-CHOP / Arm 1
VincristineCopanlisib + R-B or R-CHOP / Arm 1
BendamustineCopanlisib + R-B or R-CHOP / Arm 1
PrednisoneCopanlisib + R-B or R-CHOP / Arm 1

Purpose

The purpose of this study is to assess whether copanlisib in combination with standard immunochemotherapy (rituximab in combination with bendamustine [R-B] and rituximab in combination with a 4 drug combination of cyclophosphamide, doxorubicin, vincristine and prednisone/prednisolone [R-CHOP]) is effective and safe, compared with placebo in combination with standard immunochemotherapy (R-B or R-CHOP) in patients with relapsed iNHL who have received at least one, but at most three, lines of treatment, including rituximab-based immunochemotherapy and alkylating agents.

Detailed Description

      Patients should be in need of and fit for immunochemotherapy and should not be resistant to
      rituximab (resistance defined as lack of response or progression within 6 months of the last
      date of rituximab administration, including rituximab, and/or rituximab biosimilars, and/or
      anti-CD20 monoclonal antibody).

      This study will be composed of two parts: Safety run-in and phase III part. The purpose of
      the safety run-in part of this study is to assess whether the drug being tested (copanlisib)
      in combination with standard immunochemotherapy (R-B or R-CHOP) is safe and at what dose
      level of the study drug (copanlisib - 45mg or 60 mg) patients are able to tolerate the study
      treatment combination. In addition to finding a safe and tolerable dose level for the phase
      III part of the study, efficacy will also be evaluated for patients that stay on the study
      treatment during the safety run-in. The phase III part of the study started with the
      determined recommended dose of copanlisib of 60 mg in combination with R-B.

      A maximum of 24 patients will take part in the safety run-in part of this study. In the phase
      III part approximately 520 patients will be randomly assigned to blinded treatment arms of
      copanlisib plus R-B or R-CHOP or placebo plus R-B or R-CHOP.
    

Trial Arms

NameTypeDescriptionInterventions
Copanlisib + R-B or R-CHOP / Arm 1ExperimentalCombination of copanlisib with standard immunochemotherapy (rituximab and bendamustine) [R-B] or rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone [R-CHOP] (safety run-in and phase III)
  • Copanlisib (BAY80-6946)
  • Rituximab
  • Cyclophosphamide
  • Doxorubicin
  • Vincristine
  • Bendamustine
  • Prednisone
Placebo + R-B or R-CHOP / Arm 2Placebo ComparatorCombination of placebo and R-B or R-CHOP (phase III only)
  • Placebo
  • Rituximab
  • Cyclophosphamide
  • Doxorubicin
  • Vincristine
  • Bendamustine
  • Prednisone

Eligibility Criteria

        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 / Waldenström 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety run-in_Determination of the recommended Phase-III dose (RP3D) of copanlisib in combination with standard immunochemotherapy assessed by the occurrence of dose-limiting toxicities / adverse events
Time Frame:At Cycle 1: 21 days or 28 days
Safety Issue:
Description:Progression free survival is defined as the time (in days) from randomization to disease progression or death from any cause (if no progression documented).

Secondary Outcome Measures

Measure:Safety run-in_Best Overall Response (BOR)
Time Frame:After Cycle 1: Up to 12 months
Safety Issue:
Description:
Measure:Safety run-in_Number of participants with treatment-emergent adverse events
Time Frame:Up to 13 months
Safety Issue:
Description:
Measure:Phase III_Objective tumor response rate (ORR)
Time Frame:Up to 52 months
Safety Issue:
Description:Proportion of patients who have a best overall response over the whole duration of the study (i.e. up to time of analysis of PFS) of complete response (CR) or partial response (PR) according to the Lugano Classification and for patients with Waldenström macroglobulinemia a best overall response of CR, very good partial response (VGPR), PR, or minor response (MR) according to the Owen Criteria.
Measure:Phase III_Duration of tumor response (DOR)
Time Frame:Up to 52 months
Safety Issue:
Description:Time (in days) from first observed tumor response (complete response [CR], very good partial response [VGPR], partial response [PR], or minor response [MR]) until PD or death from any cause, whichever is earlier. DOR will only be analyzed for patients with at least one CR, VGPR, PR, or MR.
Measure:Phase III_Complete tumor response rate (CRR)
Time Frame:Up to 52 months
Safety Issue:
Description:Proportion of patients who have a best overall response of CR during the study (i.e., up to time of analysis of PFS).
Measure:Phase III_Time to tumor progression (TTP)
Time Frame:Up to 52 months
Safety Issue:
Description:Time from randomization to PD or death related to PD, whichever is earlier.
Measure:Phase III_Time to next anti-lymphoma treatment (TTNT)
Time Frame:Up to 52 months
Safety Issue:
Description:Time from stop of study medication to start of new anti-lymphoma therapy.
Measure:Phase III_Overall survival (OS)
Time Frame:Up to 5 years after last patient´s first treatment
Safety Issue:
Description:The time (in days) from randomization until death from any cause.
Measure:Phase III_Time to improvement in disease-related physical symptoms measured by Lymphoma Symptom Index-18 questionnaire
Time Frame:Up to 52 months
Safety Issue:
Description:Time to improvement in disease-related physical symptoms (DRS-P) is defined as time from randomization to first increase in DRS-P score of at least 3 points from baseline before tumor progression. Will be evaluated for patients with a baseline DRS-P score of 30 points or less. The Lymphoma Symptom Index-18 (FLymSI-18) questionnaire measures disease-specific symptoms and/or treatment-related concerns in patients with advanced lymphoma.
Measure:Phase III_Time to deterioration in disease-related physical symptoms measured by Lymphoma Symptom Index-18 questionnaire
Time Frame:Up to 52 months
Safety Issue:
Description:Time to deterioration in disease-related physical symptoms (DRS-P) is defined as time (in days) from randomization to the earliest occurrence of 1) first reduction of DRS-P score from baseline ≥ 3 points, or 2) radiological progression or biochemical progression for Waldenström macroglobulinemia patients without lesions evaluable by imaging, or 3) death from any cause. The Lymphoma Symptom Index-18 (FLymSI-18) questionnaire measures disease-specific symptoms and/or treatment-related concerns in patients with advanced lymphoma.
Measure:Phase III_Number of participants with treatment-emergent adverse events
Time Frame:Up to 52 months
Safety Issue:
Description:

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Bayer

Trial Keywords

  • Clinical trial, Phase III
  • Phosphatidylinositol-3-kinase
  • Non-Hodgkin's lymphoma
  • Indolent B-cell non-Hodgkin's lymphoma

Last Updated

December 16, 2019