Study of Copanlisib in Combination With Standard Immunochemotherapy in Relapsed Indolent Non-Hodgkin's Lymphoma (iNHL)
- Conditions
- Lymphoma, Non-Hodgkin
- Interventions
- Registration Number
- NCT02626455
- Lead Sponsor
- Bayer
- Brief Summary
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. Combination treatment of copanlisib at the recommended/approved dose of 60 mg with R-B or R-CHOP was completed in April 2021.
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. Combination therapy (copanlisib/placebo with R-B or R-CHOP) will be administered for a maximum of 6 cycles (C1-C6). Copanlisib/placebo (study drug) monotherapy will be administered from C7 onwards.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 551
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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)
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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.
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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.
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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.
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Male or female patients ≥ 18 years of age
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Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
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Life expectancy of at least 3 months
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Availability of fresh tumor tissue and/or archival tumor tissue at Screening
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Adequate baseline laboratory values as assessed within 7 days before starting study treatment.
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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
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Copanlisib + R-B or R-CHOP / Arm 1 Copanlisib (BAY80-6946) Combination 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) Placebo + R-B or R-CHOP / Arm 2 Placebo Combination of placebo and R-B or R-CHOP (phase III only) Placebo + R-B or R-CHOP / Arm 2 Bendamustine Combination of placebo and R-B or R-CHOP (phase III only) Copanlisib + R-B or R-CHOP / Arm 1 Rituximab Combination 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 + R-B or R-CHOP / Arm 1 Cyclophosphamide Combination 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 + R-B or R-CHOP / Arm 1 Doxorubicin Combination 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 + R-B or R-CHOP / Arm 1 Vincristine Combination 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) Placebo + R-B or R-CHOP / Arm 2 Doxorubicin Combination of placebo and R-B or R-CHOP (phase III only) Copanlisib + R-B or R-CHOP / Arm 1 Bendamustine Combination 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 + R-B or R-CHOP / Arm 1 Prednisone Combination 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) Placebo + R-B or R-CHOP / Arm 2 Rituximab Combination of placebo and R-B or R-CHOP (phase III only) Placebo + R-B or R-CHOP / Arm 2 Cyclophosphamide Combination of placebo and R-B or R-CHOP (phase III only) Placebo + R-B or R-CHOP / Arm 2 Vincristine Combination of placebo and R-B or R-CHOP (phase III only) Placebo + R-B or R-CHOP / Arm 2 Prednisone Combination of placebo and R-B or R-CHOP (phase III only)
- Primary Outcome Measures
Name Time Method SRI: Occurrence of Dose-limiting Toxicities (DLT) At Cycle 1: 28 days for Copa+R-B or 21 days for Copa+R-CHOP Dose-limiting toxicity is defined as any of the following occurring during Cycle 1 at a given dose level and regarded by the investigator and/or the sponsor to be possibly, probably, or definitely related to copanlisib given in combination with R-B or R-CHOP. General: any grade 5 hematologic or non-hematologic toxicity or any delay of \>2 weeks of Cycle 2 due to study treatment-related toxicity; Non-hematologic DLT: any non-hematologic toxicity grade ≥ 3; Hematologic DLT: grade 4 absolute neutrophil count decrease lasting \>7 days, or grade 4 febrile neutropenia, or grade 4 platelet count decreased or grade 3 platelet count decreased with serious bleeding, or signs of serious bleeding and/or international normalized ratio (INR) increased or partial thromboplastin time (PTT) prolonged of grade 3.
Phase 3: Progression-free Survival (PFS) by Independent Central Review Approximately 6 years 4 months PFS is defined as the time from randomization to progressive disease (PD) or death from any cause (if no progression is documented).
- Secondary Outcome Measures
Name Time Method SRI: Best Overall Response Approximately 7 years 8 months Best overall response is defined as the best response achieved during the treatment and active follow-up periods; prior to end of study or start of new anti-tumor treatment, whichever occurs first.
SRI: Number of Subjects With Treatment-emergent Adverse Event (TEAE) Approximately 4 years 10 months A treatment-emergent AE is defined as any event arising or worsening after start of study drug administration until 30 days after the last study drug intake.
Phase 3: Objective Tumor Response Rate (ORR)-Independent Central Review Up to 6 years 4 months ORR, as assessed by independent central review, is defined as the percentage of participants who had a best response rating of CR or PR according to the Lugano classification and for subjects with LPL/WM, a response rating of CR, VGPR, PR, or MR according to the Owen criteria, over the whole duration of the study (i.e., until time of analysis of PFS).
Phase 3: ORR-Investigator Assessment Up to 6 years 4 months ORR, as assessed by investigator, is defined as the percentage of participants who had a best response rating of CR or PR according to the Lugano classification and for subjects with LPL/WM, a response rating of CR, VGPR, PR, or MR according to the Owen criteria, over the whole duration of the study (i.e., until time of analysis of PFS).
Phase 3: Duration of Tumor Response (DOR)-Independent Central Review Approximately 6 years 4 months DOR, as assessed by independent central review, is defined as the time (in days) from first observed tumor response (CR, VGPR, PR, or MR) until progression or death from any cause, whichever occurred earlier. The DOR was only defined for patients with at least 1 CR, VGPR, PR, or MR.
Phase 3: DOR-Investigator Assessment Approximately 6 years 4 months DOR, as assessed by investigator, is defined as the time (in days) from first observed tumor response (CR, VGPR, PR, or MR) until progression or death from any cause, whichever occurred earlier. The DOR was only defined for patients with at least 1 CR, VGPR, PR, or MR.
Phase 3: Complete Tumor Response Rate (CRR)-Independent Central Review Approximately 6 years 4 months CRR, as assessed by independent central review, is defined as the proportion of patients who had a best response rating of CR according to the Lugano classification, and for patients with LPL/WM, a response rating of CR according to the Owen criteria, over the whole duration of the study (i.e., until the time of analysis of PFS).
Phase 3: CRR-Investigator Assessment Approximately 6 years 4 months CRR, as assessed by investigator, is defined as the proportion of patients who had a best response rating of CR according to the Lugano classification, and for patients with LPL/WM, a response rating of CR according to the Owen criteria, over the whole duration of the study (i.e., until the time of analysis of PFS).
Phase 3: Disease Control Rate (DCR)-Independent Central Review Approximately 6 years 4 months DCR, as assessed by independent central review, is defined as the proportion of patients who had a best response rating of CR, VGPR, PR, MR, or stable disease (excluding unconfirmed early stable disease).
Phase 3: DCR-Investigator Assessment Approximately 6 years 4 months DCR, as assessed by investigator, is defined as the proportion of patients who had a best response rating of CR, VGPR, PR, MR, or stable disease (excluding unconfirmed early stable disease).
Phase 3: Time to Tumor Progression (TTP)-Independent Central Review Approximately 6 years 4 months TTP, as assessed by independent central review, is defined as the time from randomization to progression or death related to progression, whichever occurred earlier. Death related to progression was any death except for: death due to an AE unrelated to progression; or death with a specification of "other" as reason (which excludes PD).
Phase 3: TTP-Investigator Assessment Approximately 6 years 4 months TTP, as assessed by investigator, is defined as the time from randomization to progression or death related to progression, whichever occurred earlier. Death related to progression was any death except for: death due to an AE unrelated to progression; or death with a specification of "other" as reason (which excludes PD).
Phase 3: Time to Next Anti-lymphoma Treatment (TTNT) Approximately 6 years 4 months A new anti-lymphoma therapy is any new systemic anticancer treatment or radiotherapy for lymphoma, with a consolidation intent. TTNT was defined as the time from the date of randomization to the start of new anti-lymphoma therapy, where the date of randomization was considered Day 1.
Phase 3: Overall Survival (OS) Approximately 6 years 4 months Overall survival is defined as the time from randomization until death from any cause. The OS for patients alive at the time of the database cut-off date was censored to the last date they were known to be alive. Deaths that occurred after the database cut-off date, reported during data cleaning, were considered for establishing the last known alive date at data cut-off.
Phase 3: Time to Deterioration in Disease-related Symptoms-physical (DRS-P) of at Least 3 Points of Lymphoma Approximately 6 years 4 months Time to deterioration in DRS-P of at least 3 points, as measured by the FLymSI-18 questionnaire, was evaluated in all patients. It is defined as the time from randomization to DRS-P decline, progression, or death from any reason, whichever occurred earlier.
Phase 3: Time to Improvement in Disease-related Symptoms-physical (DRS-P) of at Least 3 Points of Lymphoma Approximately 6 years 4 months Time to improvement in DRS-P of at least 3 points, as measured by the FLymSI-18 questionnaire, was evaluated for all patients. It is defined as the time from randomization to DRS-P improvement of at least 3 points.
Phase 3: Number of Subjects With Treatment-emergent Adverse Event (TEAE) Approximately 4 years A treatment-emergent AE is defined as any event arising or worsening after start of study drug administration until 30 days after the last study drug intake.
Trial Locations
- Locations (201)
Memorial Sloan Kettering Cancer Center- Bergen
🇺🇸New York, New York, United States
Irmandade da Santa Casa de Misericordia de Porto Alegre | Hospital Sao Francisco - Centro Medico Pesquisa Clinica Cardiologia
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
Hospital de Clinicas de Porto Alegre | Clinical Research Center - Surgery Research Center
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
Tianjin Medical University Cancer Institute & Hospital
🇨🇳Tianjin, China
Rigshospitalet - Hjertesygdomme
🇩🇰København Ø, Denmark
Odense Universitetshospital - Hæmatologisk afdeling
🇩🇰Odense C, Denmark
Tampereen yliopistollinen sairaala
🇫🇮Tampere, Finland
Haematologie-Onkologie im Zentrum MVZ GmbH
🇩🇪Augsburg, Bayern, Germany
Universitaetsklinikum Muenster
🇩🇪Münster, Nordrhein-Westfalen, Germany
General Hospital of Athens LAIKO
🇬🇷Athens, Greece
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