Lymphoma,Non-Hodgkin
Conditions
Keywords
Clinical trial, Phase III, Phosphatidylinositol-3-kinase, Non-Hodgkin's lymphoma, Indolent B-cell non-Hodgkin's lymphoma
Brief summary
The purpose of this study was to evaluate whether copanlisib in combination with rituximab is superior to placebo in combination with rituximab in prolonging progression free survival (PFS) in patients with relapsed iNHL who have received one or more lines of treatment, including rituximab and who either had a treatment-free interval of ≥ 12 months after completion of the last rituximab-containing treatment, or who are unwilling to receive chemotherapy/for whom chemotherapy is contraindicated on reason of age, comorbidities, and/or residual toxicity.
Interventions
Copanlisib is supplied as lyophilized preparation in a 6 mL injection vial. The total amount of copanlisib per vial is 60 mg. The solution for IV infusions is obtained after reconstitution with normal saline solution. Dosing will be administered on Days 1, 8 and 15 of each 28-day cycle. Copanlisib will be administered before rituximab.
DRUGPlacebo
Placebo is supplied as lyophilized preparation in a 6 mL injection vial. The developed placebo lyophilisate is equivalent to the 60 mg copanlisib formulation, with regard to the composition of excipients and the instructions for reconstitution and dose preparation. Placebo dosing will be administered on Days 1, 8 and 15 of each 28-day cycle. Placebo will be administered before rituximab.
DRUGRituximab
Rituximab dose 375 mg/m2 body surface weekly during Cycle 1 on Days 1, 8, 15 and 22, and then on Day 1 of Cycles 3, 5, 7 and 9.The solution for IV infusions is obtained after reconstitution of a calculated concentration of 1 to 4 mg/ml rituximab into an infusion bag containing sterile, pyrogen-free sodium chloride 9 mg/ml (0.9%) solution for injection or 5% D-Glucose in water.
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed diagnosis of Indolent non-Hodgkin's lymphoma (iNHL) in CD20 positive patients, with histological subtype limited to: * Follicular lymphoma(FL) grade1-2-3a * Small lymphocytic lymphoma(SLL) with absolute lymphocyte count \<5x10\*9/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) after the last rituximab-, rituximab biosimilars-, or anti-CD20 monoclonal antibody (e.g. obinutuzumab)-containing therapy (other previous treatment lines after rituximab are allowed). A previous regimen is defined as one of the following: at least 2 months of single-agent therapy (less than 2 months of therapy is allowed for patients who responded to single-agent rituximab, rituximab biosimilars, or anti-CD20 monoclonal antibody); at least 2 consecutive cycles of polychemotherapy; autologous transplant; radioimmunotherapy. Previous exposure to PI3K is acceptable (except to copanlisib) provided there is no resistance. Patients with prior intolerance to PI3K inhibitors other than copanlisib are eligible. * Non-WM must have at least one bi-dimensionally measurable lesion (which has not been previously irradiated) according to the Lugano Classification. For patients with splenic MZL (Marginal-zone lymphoma) 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 (ULN) 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 for central pathology(obtained within 5 years of the consent date) at Screening * Adequate baseline laboratory values collected no more than 7 days before starting study treatment * Left ventricular ejection fraction ≥ 45% * Patients must either: * have had a progression-free and treatment-free interval of at least 12 months after completion of the rituximab-, rituximab biosimilars-, or anti-CD20 monoclonal antibody-containing treatment OR * be considered unfit to receive chemotherapy on reason of age, concomitant morbidities, and/or residual toxicity from previous treatments, or unwillingness to receive chemotherapy. These patients must also have had a progression-free and treatment-free interval of at least 6 months after completion of the last rituximab-, rituximab biosimilars-, or anti-CD20 monoclonal antibody-containing treatment. Patients in whom chemotherapy is contraindicated are defined by one of the following features: * Age ≥ 80 years * Age \< 80 years and at least 1 of the following conditions: * at least 3 grade 3 CIRS-G comorbidities OR * at least 1 grade 4 CIRS-G comorbidity (if compatible to participation in the study).
Exclusion criteria
* Histologically confirmed diagnosis of follicular lymphoma grade 3b or transformed disease, or chronic lymphocytic leukemia * Progression free interval or treatment free interval of less than 12 months since the last rituximab-, rituximab biosimilars-, or anti-CD20 monoclonal antibody (e.g. obinutuzumab)-containing treatment(including maintenance with these drugs). For patients considered unwilling/unfit to receive chemotherapy : progression free interval or treatment free interval of less than 6 months since the last rituximab-, rituximab biosimilars-, or anti-CD20 monoclonal antibody-containing treatment (including maintenance with these drugs), as assessed by the investigator * History or concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function * Known lymphomatous involvement of the central nervous system * Patients with HbA1c \> 8.5% at Screening * Known history of human immunodeficiency virus (HIV) infection * Hepatitis B (HBV) or hepatitis C (HCV). Patients positive for HBsAg or HBcAb will be eligible if they are negative for HBV-DNA, these patients should receive prophylactic antiviral therapy. Patients positive for anti- HCV antibody will be eligible if they are negative for HCV-RNA * Documented evidence of resistance to prior treatment with idelalisib or other PI3K inhibitors. * Prior treatment with copanlisib * Cytomegalovirus (CMV) infection. Patients who are CMV PCR positive at baseline will not be eligible.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Based on Independent Central Review. | From first participant randomization (20-Aug-2015) up to data cut-off at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years and final analysis at 15-Nov-2024 up to 9 years | Progression-free survival (PFS) was defined as the time from randomization to progressive disease (PD) or death due to any cause, whichever was earlier according to the Lugano Classification and Response criteria in patients affected by Waldenström macroglobulinemia (kindly refer to the links in the Protocol section). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response Rate (CRR) | From first participant randomization (20-Aug-2015) up to data cut-off date at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years | Complete response rate (CRR) was defined as the percentage of participants who had a best response rating over the whole duration of the study (i.e., until the time of analysis of PFS) according to the Lugano Classification and for patients with Waldenström macroglobulinemia (WM) a response rating of Complete Response according to the Owen Criteria (kindly refer to the links in the Protocol section). |
| Duration of Response (DOR) | From first participant randomization (20-Aug-2015) up to data cut-off date at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years | Duration of response (DOR) was defined as the time (in days) from first observed tumor response Complete Response (CR), Very good partial response (VGPR), Partial Response (PR) or Minor Response (MR) until progression or death from any cause, whichever occurred earlier according to the Owen Criteria (kindly refer to the links in the Protocol section). Only patients with response in FAS were included in the analysis. |
| Disease Control Rate (DCR) | From first participant randomization (20-Aug-2015) up to data cut-off date at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years | Disease control rate was defined as the percentage of participants who had a best response rating as Complete Response (CR), Partial Response (PR) or stable disease (SD) according to the Lugano Classification and for patients with Waldenström macroglobulinemia (WM) as a response rating of CR, very good partial response (VGPR), PR, minor response (MR) or stable disease (SD) according to the Owen Criteria (kindly refer to the links in the Protocol section). |
| Time to Progression (TTP) | From first participant randomization (20-Aug-2015) up to data cut-off date at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years | Time to progression (TTP) was defined as the time (days) from date of randomization to date of first observed disease progression according to the Lugano Classification and Response criteria in patients affected by Waldenström macroglobulinemia (kindly refer to the links in the Protocol section). |
| Overall Survival (OS) | From randomization up to the final analysis at 15-Nov-2024 up to 9 years | Overall survival was defined as the time (in days) from randomization until death from any cause. |
| Objective Response Rate (ORR) | From first participant randomization (20-Aug-2015) up to data cut-off date at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years | Objective response rate (ORR) was defined as the percentage of participants who have a best response rating over the whole duration of the study (i.e. until time of analysis of PFS) of complete response (CR) or partial response (PR) according to the Lugano Classification and for patients with Waldenström macroglobulinemia (WM) a response rating of CR, very good partial response (VGPR), PR, or minor response (MR) according to the Owen Criteria (kindly refer to the links in the Protocol section). |
| Time to Improvement in DRS-P (Disease-Related Symptoms - Physical) of at Least 3 Points, as Measured by the Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 (FLymSI-18) Questionnaire. | From first participant randomization (20-Aug-2015) up to data cut-off date at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years | Time to improvement in DRS-P (Disease-Related Symptoms - Physical) was defined as the time (in days) from randomization to DRS-P improvement of at least three points. The Lymphoma Symptom Index-18 (FLymSI-18) questionnaire contains 18 items, each of which utilizes a Likert scale with 5 possible responses ranging from 0 'Not at all' to 4 'Very much' and was divided into a total score. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) at Primary Completion Date. | Up to 30 days after end of treatment with study drug, data reporting cut-off at 5 years from the first participant randomization date | Adverse events were considered to be treatment-emergent if they have started or worsened after first application of study medication up to 30 days after end of treatment with study medication. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) at 2-year Follow-up Cut-off Date. | Up to 30 days after end of treatment with study drug, data reporting cut-off at 7 years from the first participant randomization date | Adverse events were considered to be treatment-emergent if they have started or worsened after first application of study medication up to 30 days after end of treatment with study medication. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) at Final Analysis | Up to 30 days after end of treatment with study drug, data reporting cut-off at final analysis, up to 9 years | Adverse events were considered to be treatment-emergent if they have started or worsened after first application of study medication up to 30 days after end of treatment with study medication. |
| Time to Deterioration in DRS-P (Disease-Related Symptoms - Physical) of at Least Three Points, as Measured by the Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 (FLymSI-18) Questionnaire. | From first participant randomization (20-Aug-2015) up to data cut-off date at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years | Time to deterioration in DRS-P (Disease-Related Symptoms - Physical) of at least three points was defined as the time (in days) from randomization to DRS-P decline, progression, or death due to any reason, whichever occurred earlier. The Lymphoma Symptom Index-18 (FLymSI-18) questionnaire contains 18 items, each of which utilizes a Likert scale with 5 possible responses ranging from 0 'Not at all' to 4 'Very much' and was divided into a total score. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Chile, China, Colombia, France, Germany, Greece, Hong Kong, Hungary, Ireland, Italy, Japan, Lithuania, Malaysia, Mexico, New Zealand, Philippines, Poland, Portugal, Romania, Russia, Singapore, Slovakia, South Africa, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United States, Vietnam
Participant flow
Recruitment details
The study was conducted at multiple centers in North America, South America, South Africa, Europe, Asia, and Australia between 03 August 2015 (first participant first visit) and 15 November 2024 (last participant first visit).
Pre-assignment details
Overall, 652 were screened and total of 458 participants were randomized in a 2:1 ratio to study treatment: 307 participants to copanlisib/rituximab and 151 participants to placebo/rituximab.
Participants by arm
| Arm | Count |
|---|---|
| Copanlisib + Rituximab Copanlisib (60 mg) was administered intravenously (IV) (over approximately 1 h) on Days 1, 8, and 15 of each 28-day cycle. Rituximab (375 mg/m\^2) was administered weekly during Cycle 1 on Days 1, 8, 15, and 22, and then on Day 1 of Cycles 3, 5, 7, and 9. Copanlisib was administered before rituximab. | 307 |
| Placebo + Rituximab Placebo was administered intravenously (IV) (over approximately 1 h) on Days 1, 8, and 15 of each 28-day cycle. Rituximab (375 mg/m\^2) was administered weekly during Cycle 1 on Days 1, 8, 15, and 22, and then on Day 1 of Cycles 3, 5, 7, and 9. Placebo was administered before rituximab. | 151 |
| Total | 458 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Additional primary malignancy | 1 | 1 |
| Overall Study | AE associated with clinical disease progression | 1 | 4 |
| Overall Study | AE not associated with clinical disease progression | 117 | 12 |
| Overall Study | Death | 2 | 0 |
| Overall Study | Drug not administered | 3 | 2 |
| Overall Study | Failure to meet continuation criteria | 1 | 0 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Non-compliance to study drug | 1 | 0 |
| Overall Study | Other reason: Covid-19 pandemic related | 1 | 0 |
| Overall Study | Patient decision | 40 | 14 |
| Overall Study | Patient decision: COVID-19 pandemic related | 1 | 0 |
| Overall Study | Physician Decision | 2 | 8 |
| Overall Study | Progressive disease | 0 | 1 |
| Overall Study | Progressive disease - clinical progression | 6 | 6 |
| Overall Study | Progressive disease - radiological progression | 54 | 80 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Randomized by mistake with study treatment | 1 | 0 |
| Overall Study | Required procedure failed | 1 | 0 |
| Overall Study | Study terminated by sponsor | 19 | 2 |
| Overall Study | Switching to other therapy | 2 | 0 |
| Overall Study | Withdrawal by Subject | 51 | 16 |
Baseline characteristics
| Characteristic | Total | Placebo + Rituximab | Copanlisib + Rituximab |
|---|---|---|---|
| Age, Continuous | 61.9 years STANDARD_DEVIATION 11.7 | 61.5 years STANDARD_DEVIATION 11 | 62.0 years STANDARD_DEVIATION 12.1 |
| Eastern cooperative oncology group (ECOG) Performance Status (PS) 0 - Fully active | 277 Participants | 95 Participants | 182 Participants |
| Eastern cooperative oncology group (ECOG) Performance Status (PS) 1 - Restricted active | 168 Participants | 55 Participants | 113 Participants |
| Eastern cooperative oncology group (ECOG) Performance Status (PS) 2 - Ambulatory and capable of all self-care | 13 Participants | 1 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 55 Participants | 26 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 380 Participants | 118 Participants | 262 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 23 Participants | 7 Participants | 16 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 7 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 175 Participants | 50 Participants | 125 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 18 Participants | 7 Participants | 11 Participants |
| Race (NIH/OMB) White | 253 Participants | 89 Participants | 164 Participants |
| Sex: Female, Male Female | 220 Participants | 66 Participants | 154 Participants |
| Sex: Female, Male Male | 238 Participants | 85 Participants | 153 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 99 / 307 | 50 / 146 |
| other Total, other adverse events | 298 / 307 | 127 / 146 |
| serious Total, serious adverse events | 161 / 307 | 32 / 146 |
Outcome results
Primary
Progression Free Survival (PFS) Based on Independent Central Review.
Progression-free survival (PFS) was defined as the time from randomization to progressive disease (PD) or death due to any cause, whichever was earlier according to the Lugano Classification and Response criteria in patients affected by Waldenström macroglobulinemia (kindly refer to the links in the Protocol section).
Time frame: From first participant randomization (20-Aug-2015) up to data cut-off at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years and final analysis at 15-Nov-2024 up to 9 years
Population: All randomized participants (FAS=full analysis set) were included.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Copanlisib + Rituximab | Progression Free Survival (PFS) Based on Independent Central Review. | At data cut-off=31-Aug-2020 | 21.5 Months |
| Copanlisib + Rituximab | Progression Free Survival (PFS) Based on Independent Central Review. | At data cut-off=31-Aug-2022 | 23.2 Months |
| Copanlisib + Rituximab | Progression Free Survival (PFS) Based on Independent Central Review. | At data cut-off=15-Nov-2024 | 22.4 Months |
| Placebo + Rituximab | Progression Free Survival (PFS) Based on Independent Central Review. | At data cut-off=31-Aug-2020 | 13.8 Months |
| Placebo + Rituximab | Progression Free Survival (PFS) Based on Independent Central Review. | At data cut-off=31-Aug-2022 | 13.8 Months |
| Placebo + Rituximab | Progression Free Survival (PFS) Based on Independent Central Review. | At data cut-off=15-Nov-2024 | 14.0 Months |
Comparison: At primary completion datep-value: 0.00000295% CI: [0.393, 0.688]Log Rank
Comparison: At 2-year follow-up cut-off datep-value: 0.00000395% CI: [0.431, 0.722]Log Rank
Comparison: At final analysisp-value: 0.00019995% CI: [0.502, 0.823]Log Rank
Secondary
Complete Response Rate (CRR)
Complete response rate (CRR) was defined as the percentage of participants who had a best response rating over the whole duration of the study (i.e., until the time of analysis of PFS) according to the Lugano Classification and for patients with Waldenström macroglobulinemia (WM) a response rating of Complete Response according to the Owen Criteria (kindly refer to the links in the Protocol section).
Time frame: From first participant randomization (20-Aug-2015) up to data cut-off date at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years
Population: All randomized participants (FAS) were included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Copanlisib + Rituximab | Complete Response Rate (CRR) | At data cut-off=31-Aug-2022 | 34.2 Percentage of participants |
| Copanlisib + Rituximab | Complete Response Rate (CRR) | At data cut-off=31-Aug-2020 | 33.9 Percentage of participants |
| Placebo + Rituximab | Complete Response Rate (CRR) | At data cut-off=31-Aug-2020 | 14.6 Percentage of participants |
| Placebo + Rituximab | Complete Response Rate (CRR) | At data cut-off=31-Aug-2022 | 15.2 Percentage of participants |
Comparison: At primary completion datep-value: <0.00000195% CI: [11.57, 26.96]Cochran-Mantel-Haenszel
Comparison: At 2-year follow-up cut-off datep-value: 0.00000195% CI: [11.11, 26.73]Cochran-Mantel-Haenszel
Secondary
Disease Control Rate (DCR)
Disease control rate was defined as the percentage of participants who had a best response rating as Complete Response (CR), Partial Response (PR) or stable disease (SD) according to the Lugano Classification and for patients with Waldenström macroglobulinemia (WM) as a response rating of CR, very good partial response (VGPR), PR, minor response (MR) or stable disease (SD) according to the Owen Criteria (kindly refer to the links in the Protocol section).
Time frame: From first participant randomization (20-Aug-2015) up to data cut-off date at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years
Population: All randomized participants (FAS) were included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Copanlisib + Rituximab | Disease Control Rate (DCR) | At data cut-off=31-Aug-2020 | 89.3 Percentage of participants |
| Copanlisib + Rituximab | Disease Control Rate (DCR) | At data cut-off=31-Aug-2022 | 89.3 Percentage of participants |
| Placebo + Rituximab | Disease Control Rate (DCR) | At data cut-off=31-Aug-2020 | 84.8 Percentage of participants |
| Placebo + Rituximab | Disease Control Rate (DCR) | At data cut-off=31-Aug-2022 | 84.8 Percentage of participants |
Comparison: At primary completion datep-value: 0.09733995% CI: [-2.26, 11.12]Cochran-Mantel-Haenszel
Comparison: At 2-year follow-up cut-off datep-value: 0.09733995% CI: [-2.26, 11.12]Cochran-Mantel-Haenszel
Secondary
Duration of Response (DOR)
Duration of response (DOR) was defined as the time (in days) from first observed tumor response Complete Response (CR), Very good partial response (VGPR), Partial Response (PR) or Minor Response (MR) until progression or death from any cause, whichever occurred earlier according to the Owen Criteria (kindly refer to the links in the Protocol section). Only patients with response in FAS were included in the analysis.
Time frame: From first participant randomization (20-Aug-2015) up to data cut-off date at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years
Population: All randomized participants (FAS) were included.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Copanlisib + Rituximab | Duration of Response (DOR) | At data cut-off=31-Aug-2020 | 20.4 Months |
| Copanlisib + Rituximab | Duration of Response (DOR) | At data cut-off=31-Aug-2022 | 25.9 Months |
| Placebo + Rituximab | Duration of Response (DOR) | At data cut-off=31-Aug-2020 | 17.3 Months |
| Placebo + Rituximab | Duration of Response (DOR) | At data cut-off=31-Aug-2022 | 15.2 Months |
Comparison: At primary completion datep-value: 0.03037195% CI: [0.481, 1.018]Log Rank
Comparison: At 2-year follow-up cut-off datep-value: 0.05197695% CI: [0.547, 1.059]Log Rank
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) at 2-year Follow-up Cut-off Date.
Adverse events were considered to be treatment-emergent if they have started or worsened after first application of study medication up to 30 days after end of treatment with study medication.
Time frame: Up to 30 days after end of treatment with study drug, data reporting cut-off at 7 years from the first participant randomization date
Population: Participants in safety analysis set (SAF) with evaluable data reported.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Copanlisib + Rituximab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) at 2-year Follow-up Cut-off Date. | Any TEAEs | 307 Participants |
| Copanlisib + Rituximab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) at 2-year Follow-up Cut-off Date. | Any copanlisib- or placebo-related TEAE | 295 Participants |
| Copanlisib + Rituximab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) at 2-year Follow-up Cut-off Date. | Any rituximab-related TEAE | 218 Participants |
| Placebo + Rituximab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) at 2-year Follow-up Cut-off Date. | Any TEAEs | 137 Participants |
| Placebo + Rituximab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) at 2-year Follow-up Cut-off Date. | Any copanlisib- or placebo-related TEAE | 98 Participants |
| Placebo + Rituximab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) at 2-year Follow-up Cut-off Date. | Any rituximab-related TEAE | 93 Participants |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) at Final Analysis
Adverse events were considered to be treatment-emergent if they have started or worsened after first application of study medication up to 30 days after end of treatment with study medication.
Time frame: Up to 30 days after end of treatment with study drug, data reporting cut-off at final analysis, up to 9 years
Population: Participants in safety analysis set (SAF) with evaluable data reported.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Copanlisib + Rituximab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) at Final Analysis | Any TEAEs | 307 Participants |
| Copanlisib + Rituximab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) at Final Analysis | Any copanlisib- or placebo-related TEAE | 295 Participants |
| Copanlisib + Rituximab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) at Final Analysis | Any rituximab-related TEAE | 218 Participants |
| Placebo + Rituximab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) at Final Analysis | Any TEAEs | 137 Participants |
| Placebo + Rituximab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) at Final Analysis | Any copanlisib- or placebo-related TEAE | 98 Participants |
| Placebo + Rituximab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) at Final Analysis | Any rituximab-related TEAE | 93 Participants |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) at Primary Completion Date.
Adverse events were considered to be treatment-emergent if they have started or worsened after first application of study medication up to 30 days after end of treatment with study medication.
Time frame: Up to 30 days after end of treatment with study drug, data reporting cut-off at 5 years from the first participant randomization date
Population: Participants in safety analysis set (SAF) with evaluable data reported.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Copanlisib + Rituximab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) at Primary Completion Date. | Any TEAEs | 307 Participants |
| Copanlisib + Rituximab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) at Primary Completion Date. | Any copanlisib- or placebo-related TEAE | 293 Participants |
| Copanlisib + Rituximab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) at Primary Completion Date. | Any rituximab-related TEAE | 218 Participants |
| Placebo + Rituximab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) at Primary Completion Date. | Any TEAEs | 134 Participants |
| Placebo + Rituximab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) at Primary Completion Date. | Any copanlisib- or placebo-related TEAE | 95 Participants |
| Placebo + Rituximab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) at Primary Completion Date. | Any rituximab-related TEAE | 92 Participants |
Secondary
Objective Response Rate (ORR)
Objective response rate (ORR) was defined as the percentage of participants who have a best response rating over the whole duration of the study (i.e. until time of analysis of PFS) of complete response (CR) or partial response (PR) according to the Lugano Classification and for patients with Waldenström macroglobulinemia (WM) a response rating of CR, very good partial response (VGPR), PR, or minor response (MR) according to the Owen Criteria (kindly refer to the links in the Protocol section).
Time frame: From first participant randomization (20-Aug-2015) up to data cut-off date at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years
Population: All randomized participants (FAS) were included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Copanlisib + Rituximab | Objective Response Rate (ORR) | At data cut-off=31-Aug-2020 | 80.8 Percentage of participants |
| Copanlisib + Rituximab | Objective Response Rate (ORR) | At data cut-off=31-Aug-2022 | 80.5 Percentage of participants |
| Placebo + Rituximab | Objective Response Rate (ORR) | At data cut-off=31-Aug-2020 | 47.7 Percentage of participants |
| Placebo + Rituximab | Objective Response Rate (ORR) | At data cut-off=31-Aug-2022 | 49.7 Percentage of participants |
Comparison: At primary completion datep-value: <0.00000195% CI: [23.95, 42.03]Cochran-Mantel-Haenszel
Comparison: At 2-year follow-up cut-off datep-value: <0.00000195% CI: [21.63, 39.72]Cochran-Mantel-Haenszel
Secondary
Overall Survival (OS)
Overall survival was defined as the time (in days) from randomization until death from any cause.
Time frame: From randomization up to the final analysis at 15-Nov-2024 up to 9 years
Population: All randomized patients (FAS) were included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Copanlisib + Rituximab | Overall Survival (OS) | NA Months |
| Placebo + Rituximab | Overall Survival (OS) | NA Months |
p-value: 0.43645895% CI: [0.691, 1.368]Log Rank
Secondary
Time to Deterioration in DRS-P (Disease-Related Symptoms - Physical) of at Least Three Points, as Measured by the Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 (FLymSI-18) Questionnaire.
Time to deterioration in DRS-P (Disease-Related Symptoms - Physical) of at least three points was defined as the time (in days) from randomization to DRS-P decline, progression, or death due to any reason, whichever occurred earlier. The Lymphoma Symptom Index-18 (FLymSI-18) questionnaire contains 18 items, each of which utilizes a Likert scale with 5 possible responses ranging from 0 'Not at all' to 4 'Very much' and was divided into a total score.
Time frame: From first participant randomization (20-Aug-2015) up to data cut-off date at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years
Population: All randomized participants (FAS) were included.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Copanlisib + Rituximab | Time to Deterioration in DRS-P (Disease-Related Symptoms - Physical) of at Least Three Points, as Measured by the Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 (FLymSI-18) Questionnaire. | At data cut-off=31-Aug-2020 | 5.5 Months |
| Copanlisib + Rituximab | Time to Deterioration in DRS-P (Disease-Related Symptoms - Physical) of at Least Three Points, as Measured by the Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 (FLymSI-18) Questionnaire. | At data cut-off=31-Aug-2022 | 5.5 Months |
| Placebo + Rituximab | Time to Deterioration in DRS-P (Disease-Related Symptoms - Physical) of at Least Three Points, as Measured by the Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 (FLymSI-18) Questionnaire. | At data cut-off=31-Aug-2020 | 5.5 Months |
| Placebo + Rituximab | Time to Deterioration in DRS-P (Disease-Related Symptoms - Physical) of at Least Three Points, as Measured by the Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 (FLymSI-18) Questionnaire. | At data cut-off=31-Aug-2022 | 5.5 Months |
Comparison: At primary completion datep-value: 0.6926195% CI: [0.843, 1.331]Log Rank
Comparison: At 2-year follow-up cut-off datep-value: 0.66114595% CI: [0.841, 1.302]Log Rank
Secondary
Time to Improvement in DRS-P (Disease-Related Symptoms - Physical) of at Least 3 Points, as Measured by the Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 (FLymSI-18) Questionnaire.
Time to improvement in DRS-P (Disease-Related Symptoms - Physical) was defined as the time (in days) from randomization to DRS-P improvement of at least three points. The Lymphoma Symptom Index-18 (FLymSI-18) questionnaire contains 18 items, each of which utilizes a Likert scale with 5 possible responses ranging from 0 'Not at all' to 4 'Very much' and was divided into a total score.
Time frame: From first participant randomization (20-Aug-2015) up to data cut-off date at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years
Population: All randomized participants (FAS) were included.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Copanlisib + Rituximab | Time to Improvement in DRS-P (Disease-Related Symptoms - Physical) of at Least 3 Points, as Measured by the Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 (FLymSI-18) Questionnaire. | At data cut-off=31-Aug-2020 | NA Months |
| Copanlisib + Rituximab | Time to Improvement in DRS-P (Disease-Related Symptoms - Physical) of at Least 3 Points, as Measured by the Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 (FLymSI-18) Questionnaire. | At data cut-off=31-Aug-2022 | 38.5 Months |
| Placebo + Rituximab | Time to Improvement in DRS-P (Disease-Related Symptoms - Physical) of at Least 3 Points, as Measured by the Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 (FLymSI-18) Questionnaire. | At data cut-off=31-Aug-2020 | NA Months |
| Placebo + Rituximab | Time to Improvement in DRS-P (Disease-Related Symptoms - Physical) of at Least 3 Points, as Measured by the Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 (FLymSI-18) Questionnaire. | At data cut-off=31-Aug-2022 | 35.7 Months |
Comparison: At primary completion datep-value: 0.51003895% CI: [0.732, 1.355]Log Rank
Comparison: At 2-year follow-up cut-off datep-value: 0.4059795% CI: [0.768, 1.398]Log Rank
Secondary
Time to Progression (TTP)
Time to progression (TTP) was defined as the time (days) from date of randomization to date of first observed disease progression according to the Lugano Classification and Response criteria in patients affected by Waldenström macroglobulinemia (kindly refer to the links in the Protocol section).
Time frame: From first participant randomization (20-Aug-2015) up to data cut-off date at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years
Population: All randomized participants (FAS) were included.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Copanlisib + Rituximab | Time to Progression (TTP) | At data cut-off=31-Aug-2020 | 22.3 Months |
| Copanlisib + Rituximab | Time to Progression (TTP) | At data cut-off=31-Aug-2022 | 27.7 Months |
| Placebo + Rituximab | Time to Progression (TTP) | At data cut-off=31-Aug-2020 | 13.8 Months |
| Placebo + Rituximab | Time to Progression (TTP) | At data cut-off=31-Aug-2022 | 13.8 Months |
Comparison: At 2-year follow-up cut-off datep-value: <0.00000195% CI: [0.387, 0.659]Log Rank
Comparison: At primary completion datep-value: <0.00000195% CI: [0.357, 0.635]Log Rank