Lymphoma, Non-Hodgkin
Conditions
Keywords
indolent Non-Hodgkin lymphoma, rituximab-refractory
Brief summary
To assess the safety of copanlisib.
Interventions
DRUGCopanlisib (BAY 80-6946)
60 mg of experimental drug in solution administered intravenously on Days 1, 8 and 15 of each 28-day treatment cycle
Sponsors
Bayer
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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 10\*9/L at the time of diagnosis and at study entry. * Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM). * Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal). * Patients must have received two or more prior lines of treatment. A previous regimen is defined as one of the following: at least two months of single-agent therapy, at least two consecutive cycles of polychemotherapy, autologous transplant, radioimmunotherapy. * Prior therapy must include rituximab and alkylating agents.Prior exposure to idelalisib or other PI3K inhibitors is acceptable (except to copanlisib) provided that there is no resistance. * Patients must be refractory to the last rituximab-based treatment, defined as no response or response lasting \< 6 months after completion of treatment. Time interval to assess refractoriness will be calculated between the end date (last day) of the last rituximab-containing regimen and the day of diagnosis confirmation of the subsequent relapse. * Patients must have at least one bi-dimensionally measurable lesion (which has not been previously irradiated) according to the Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification. * 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. * ECOG performance status ≤ 1 * Adequate bone marrow, liver and renal function
Exclusion criteria
* Histologically confirmed diagnosis of FL grade 3b. * Chronic lymphocytic leukemia (CLL). * Transformed disease (assessed by investigator): * histological confirmation of transformation, or * clinical and laboratory signs: rapid disease progression, high standardized uptake value (SUV) (\> 12) by positron emission tomography (PET) at baseline if PET scans are performed (optional). * Bulky disease - Lymph nodes or tumor mass (except spleen) \>= 7cm LD (longest diameter) * Known lymphomatous involvement of the central nervous system. * Uncontrolled arterial hypertension despite optimal medical management (per investigator's assessment). * Type I or II diabetes mellitus with HbA1c \> 8.5% at Screening. * Known history of human immunodeficiency virus (HIV) infection. * Active clinically serious infections \> CTCAE Grade 2 * Active Hepatitis B or hepatitis C * History or concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function (as judged by the investigator) * History of having received an allogeneic bone marrow or organ transplant * Positive cytomegalovirus (CMV) PCR test at baseline * Pregnant or breast-feeding patients
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAE)s | up to 7 years | Adverse event data were collected after signing the informed consent until 30 days after the last study drug administration (end of safety follow-up) |
| Number of Participants With Treatment-emergent Serious Adverse Events (TESAE)s | up to 7 years | Serious adverse event data were collected after signing the informed consent until 30 days after the last study drug administration (end of safety follow-up) |
| Number of Participants With Abnormal Laboratory Parameters | up to 7 years | \- Above threshold of 10% and reported as TEAEs - any event (Grade 1-4) |
| Number of Participants With Abnormal Vital Signs | up to 7 years | \- Reported as TEAEs - worst CTCAE grade total - |
Countries
Brazil, Bulgaria, Greece, Italy, Poland, Russia, South Africa, South Korea, Taiwan, Turkey (Türkiye)
Participant flow
Recruitment details
The study was conducted at 20 study centers in 10 countries/regions: Brazil (2), Bulgaria (1), Greece (1), Italy (2), Poland (1), Russian Federation (5), South Africa (1), South Korea (5), Taiwan (1) and Turkey (1) between 22 September 2015 (first patient first visit) and 26 October 2022 (last patient last visit).
Pre-assignment details
34 participants were screened. 9 participants were screening failures and 25 participants were randomized to study treatment: 17 to copanlisib and 8 to placebo. All randomized participants also received at least one dose of study treatment and were valid for safety analyses. After study unblinding 7 placebo participants switched to copanlisib.
Participants by arm
| Arm | Count |
|---|---|
| Copanlisib (BAY80-6946, Aliqopa) Participants who were randomized to copanlisib until end of the study | 17 |
| Placebo Participants who were randomized to placebo until switching from placebo to copanlisib after disease progression or after study unblinding | 8 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | AE associated with clinical disease progression | 2 | 1 |
| Overall Study | AE not associated with clinical diseaseprogression | 4 | 1 |
| Overall Study | Progressive disease - clinical progression | 1 | 4 |
| Overall Study | Progressive disease - radiological progression | 6 | 2 |
| Overall Study | withdrawal by patient | 4 | 0 |
Baseline characteristics
| Characteristic | Copanlisib (BAY80-6946, Aliqopa) | Placebo | Total |
|---|---|---|---|
| Age, Customized Adults (18-64 years) | 12 Participants | 5 Participants | 17 Participants |
| Age, Customized From 65-84 years | 5 Participants | 3 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 6 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Female | 7 Participants | 1 Participants | 8 Participants |
| Sex: Female, Male Male | 10 Participants | 7 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 17 | 1 / 8 | 2 / 7 | 4 / 24 |
| other Total, other adverse events | 17 / 17 | 7 / 8 | 7 / 7 | 24 / 24 |
| serious Total, serious adverse events | 6 / 17 | 1 / 8 | 5 / 7 | 11 / 24 |
Outcome results
Primary
Number of Participants With Abnormal Laboratory Parameters
\- Above threshold of 10% and reported as TEAEs - any event (Grade 1-4)
Time frame: up to 7 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Copanlisib (BAY80-6946, Aliqopa) | Number of Participants With Abnormal Laboratory Parameters | Platelet count decreased | 3 Participants |
| Copanlisib (BAY80-6946, Aliqopa) | Number of Participants With Abnormal Laboratory Parameters | Neutrophil count decreased | 4 Participants |
| Copanlisib (BAY80-6946, Aliqopa) | Number of Participants With Abnormal Laboratory Parameters | Hyperglycaemia | 6 Participants |
| Copanlisib (BAY80-6946, Aliqopa) | Number of Participants With Abnormal Laboratory Parameters | Neutropenia | 6 Participants |
| Copanlisib (BAY80-6946, Aliqopa) | Number of Participants With Abnormal Laboratory Parameters | Anaemia | 2 Participants |
| Copanlisib (BAY80-6946, Aliqopa) | Number of Participants With Abnormal Laboratory Parameters | ANY | 9 Participants |
| Placebo | Number of Participants With Abnormal Laboratory Parameters | Anaemia | 2 Participants |
| Placebo | Number of Participants With Abnormal Laboratory Parameters | Platelet count decreased | 0 Participants |
| Placebo | Number of Participants With Abnormal Laboratory Parameters | Hyperglycaemia | 0 Participants |
| Placebo | Number of Participants With Abnormal Laboratory Parameters | ANY | 1 Participants |
| Placebo | Number of Participants With Abnormal Laboratory Parameters | Neutropenia | 0 Participants |
| Placebo | Number of Participants With Abnormal Laboratory Parameters | Neutrophil count decreased | 0 Participants |
| Switched to Copanlisib | Number of Participants With Abnormal Laboratory Parameters | ANY | 3 Participants |
| Switched to Copanlisib | Number of Participants With Abnormal Laboratory Parameters | Hyperglycaemia | 4 Participants |
| Switched to Copanlisib | Number of Participants With Abnormal Laboratory Parameters | Anaemia | 4 Participants |
| Switched to Copanlisib | Number of Participants With Abnormal Laboratory Parameters | Neutrophil count decreased | 2 Participants |
| Switched to Copanlisib | Number of Participants With Abnormal Laboratory Parameters | Platelet count decreased | 2 Participants |
| Switched to Copanlisib | Number of Participants With Abnormal Laboratory Parameters | Neutropenia | 1 Participants |
| Treated With Copanlisib | Number of Participants With Abnormal Laboratory Parameters | Platelet count decreased | 5 Participants |
| Treated With Copanlisib | Number of Participants With Abnormal Laboratory Parameters | ANY | 12 Participants |
| Treated With Copanlisib | Number of Participants With Abnormal Laboratory Parameters | Hyperglycaemia | 10 Participants |
| Treated With Copanlisib | Number of Participants With Abnormal Laboratory Parameters | Neutropenia | 7 Participants |
| Treated With Copanlisib | Number of Participants With Abnormal Laboratory Parameters | Neutrophil count decreased | 6 Participants |
| Treated With Copanlisib | Number of Participants With Abnormal Laboratory Parameters | Anaemia | 6 Participants |
Primary
Number of Participants With Abnormal Vital Signs
\- Reported as TEAEs - worst CTCAE grade total -
Time frame: up to 7 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Copanlisib (BAY80-6946, Aliqopa) | Number of Participants With Abnormal Vital Signs | Blood pressure increased | 2 Participants |
| Copanlisib (BAY80-6946, Aliqopa) | Number of Participants With Abnormal Vital Signs | Electrocardiogram QT prolonged | 1 Participants |
| Placebo | Number of Participants With Abnormal Vital Signs | Electrocardiogram QT prolonged | 0 Participants |
| Placebo | Number of Participants With Abnormal Vital Signs | Blood pressure increased | 0 Participants |
| Switched to Copanlisib | Number of Participants With Abnormal Vital Signs | Blood pressure increased | 1 Participants |
| Switched to Copanlisib | Number of Participants With Abnormal Vital Signs | Electrocardiogram QT prolonged | 0 Participants |
| Treated With Copanlisib | Number of Participants With Abnormal Vital Signs | Blood pressure increased | 3 Participants |
| Treated With Copanlisib | Number of Participants With Abnormal Vital Signs | Electrocardiogram QT prolonged | 1 Participants |
Primary
Number of Participants With Treatment-emergent Adverse Events (TEAE)s
Adverse event data were collected after signing the informed consent until 30 days after the last study drug administration (end of safety follow-up)
Time frame: up to 7 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Copanlisib (BAY80-6946, Aliqopa) | Number of Participants With Treatment-emergent Adverse Events (TEAE)s | 17 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAE)s | 7 Participants |
| Switched to Copanlisib | Number of Participants With Treatment-emergent Adverse Events (TEAE)s | 7 Participants |
| Treated With Copanlisib | Number of Participants With Treatment-emergent Adverse Events (TEAE)s | 24 Participants |
Primary
Number of Participants With Treatment-emergent Serious Adverse Events (TESAE)s
Serious adverse event data were collected after signing the informed consent until 30 days after the last study drug administration (end of safety follow-up)
Time frame: up to 7 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Copanlisib (BAY80-6946, Aliqopa) | Number of Participants With Treatment-emergent Serious Adverse Events (TESAE)s | 6 Participants |
| Placebo | Number of Participants With Treatment-emergent Serious Adverse Events (TESAE)s | 1 Participants |
| Switched to Copanlisib | Number of Participants With Treatment-emergent Serious Adverse Events (TESAE)s | 5 Participants |
| Treated With Copanlisib | Number of Participants With Treatment-emergent Serious Adverse Events (TESAE)s | 11 Participants |