Leukemia, Lymphocytic, Chronic, B-Cell
Conditions
Brief summary
Adult patients with chronic lymphocytic leukaemia who experience a relapse after at least two prior treatment regimens may be enrolled in this trial. The trial will examine whether monotherapy with BI 836826 is safe and tolerable at escalating dose levels.
Interventions
DRUGBI 836826
Monotherapy with BI 836826 at escalating dose levels administered as an intravenous infusion.
Sponsors
Boehringer Ingelheim
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
1. Diagnosis of relapsed or refractory chronic lymphocytic leukaemia. 2. At least two prior treatment regimens for chronic lymphocytic leukaemia. 3. At least one criterion for active disease as defined by the International Workshop on CLL. 4. Absolute lymphocyte count lower than 200 x 10\^9/l . 5. Eastern Cooperative Oncology Group (ECOG) Performance Status 0, 1 or 2. 6. Age 18 years or older. 7. Written informed consent which is consistent with International Conference on Harmonisation - Good Clinical Practice (ICH-GCP) guidelines and local legislation.
Exclusion criteria
1. Treatment with anti Cluster of Differentiation (CD) 20 therapy within 4 weeks, or alemtuzumab within 8 weeks, or any cytotoxic antileukemia therapy within 2 weeks, Ibrutinib or Idelalisib within 1 week prior to the first administration of the trial drug. 2. Prior allogeneic stem cell transplantation. 3. Active autoimmune haemolytic anemia. 4. Active autoimmune thrombocytopenia. 5. Known transformation to an aggressive B-cell malignancy. 6. Concurrent treatment with relevant doses of systemic glucocorticosteroids. 7. Prior history of malignancy other than chronic lymphocytic leukaemia (exceptions to this rule are defined in the clinical trial protocol). 8. Aspartate aminotransferase or alanine aminotransferase \> 2.5 x upper limit of normal. 9. Total bilirubin \> 1.5 x upper limit of normal. 10. Absolute Neutrophil Count \< 1.000/µl. 11. Platelets \< 25.000/µL. 12. Estimated Glomerular Filtration Rate \<45 mL/min. 13. Proteinuria Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or higher. 14. Significant concurrent disease. 15. Any infectious disease requiring treatment at the time of enrolment or within the previous 2 weeks. 16. Hepatitis B or C. 17. Human Immunodeficiency Virus (HIV) infection. 18. Cytomegalovirus (CMV) viremia. 19. Women of childbearing potential not using a highly effective method of birth control during the trial until one year after the last dose. 20. Pregnancy or breast feeding. 21. Known or suspected active alcohol or drug abuse. 22. Treatment with another investigational drug within the past four weeks before start of therapy or concomitantly with this trial. 23. Prior treatment with BI 836826. 24. Patients unable to comply with the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Dose-Limiting Toxicities Adverse Events (DLTs) | 14 days after first administration of BI836826 (MTD evaluation period) | Dose-Limiting Toxicities (DLTs) were defined as any drug-related non-haematologic adverse event of Common Terminology Criteria for AE (CTCAE) Grade 3 or higher, except infusion related reactions associated with the administration of BI 836826. In addition complications due to haematologic AEs were considered as DLTs and were added in more detail in an amendment later on. |
| Maximum Tolerated Dose (MTD) | 14 days after first administration of BI836826 (MTD evaluation period) | The maximum tolerated dose (MTD) was defined as the highest dose of BI 836826 studied for which the incidence of DLT was no more than 17% (i.e. 1 out of 6 patients) during the first treatment cycle. For those patients who received more than 1 cycle of BI 836826, all AEs corresponding to the DLT were considered for the purpose of confirming the MTD and for the selection of the recommended dose for treatment of the expansion cohort and for further development. All DLTs, occurring during the first or repeated treatment cycle were reported as significant AEs. As it was not possible to recruit a sufficient number of patients whilst the first part of the trial was still in progress, the recruitment was ended by the sponsor before the MTD or optimal biological dose (OBD) was reached. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Improved Platelet Count for at Least Two Subsequent Response Assessments | ≥8 day after a completed infusion of a cycle and before Chronic Lymphocytic Leukemia (CLL) therapy; data collected up to cut-off date 26Oct2016, Up to 1809 days | In patients with platelet counts below the limits of normal at baseline, improvement in this count during therapy potentially indicated a benefit for the patient. Number of patients with improved platelet count for at least two subsequent response assessments which fulfil International Workshop on Chronic Lymphocytic Leukemia (IWCLL) response criteria for Complete Remission (CR) or Partial Remission (PR). The response was assessed before Progressive Disease (PD) or start of new Chronic Lymphocytic Leukaemia (CLL) therapy. |
| Number of Patients With Improved Neutrophil Count for at Least Two Subsequent Response Assessments | ≥8 day after a completed infusion of a cycle and before Chronic Lymphocytic Leukemia (CLL) therapy; data collected up to cut-off date 26Oct2016, Up to 1809 days | In patients with neutrophil count below the limits of normal at baseline, improvement in this count during therapy potentially indicated a benefit for the patient. Number of patients with improved neutrophil count for at least two subsequent response assessments which fulfil International Workshop on Chronic Lymphocytic Leukemia (IWCLL) response criteria for Complete Remission (CR) or Partial Remission (PR). The response was assessed before Progressive Disease (PD) or start of new Chronic Lymphocytic Leukaemia (CLL) therapy. |
| Best Percentage Change From Baseline in Number of Lymphocytes in the Peripheral Blood | baseline and ≥8 day after a completed infusion of a cycle and before Chronic Lymphocytic Leukemia (CLL) therapy; data collected up to cut-off date 26Oct2016, Up to 1809 days | In most patients with relapsed or refractory chronic lymphocytic leukaemia (CLL), malignant B-cells represent the majority of lymphocytes in the peripheral blood. Reduction of CLL-cells was assessed in the peripheral blood by absolute lymphocyte count, and flow cytometry. The number of lymphocytes in the peripheral blood was analysed in terms of the best percentage change from baseline until start of subsequent CLL therapy or progressive disease (PD). |
| Progression-free Survival | Data collected up to cut-off date 26Oct2016, Up to 1809 days. | Progression-free survival (PFS) was defined as the time from the first administration of BI 836826 until disease progression or death, whichever occurred first. Disease progression= At least one of the following: * 50+% increase in blood lymphocytes over baseline with an absolute number of B-lymphocytes of at least 5x109/L * Progression of lymphadenopathy * 50+% increase in the previously noted enlargement of the liver or new appearance of hepatomegaly * 50+% increase in the previously noted enlargement of the spleen or new appearance of splenomegaly * 50+% Decrease of platelet counts or to less than 100x109/L secondary to CLL and unrelated to autoimmune cytopenia * Decrease of haemoglobin levels by more than 20 g/L, or to less than 100 g/L secondary to CLL and unrelated to autoimmune cytopenia T Transformation to a more aggressive histology, e.g. Richter syndrome. |
| Failure-free Survival | Data collected up to cut-off date 26Oct2016, Up to 1809 days. | Failure-free survival (FFS) was defined as the time from the first administration of BI 836826 until disease progression or death, or start of next Chronic Lymphocytic Leukemia (CLL) therapy, whichever occurred first. Disease progression= At least one of the following: * 50+% increase in blood lymphocytes over baseline with an absolute number of B-lymphocytes of at least 5x109/L * Progression of lymphadenopathy * 50+% increase in the previously noted enlargement of the liver or new appearance of hepatomegaly * 50+% increase in the previously noted enlargement of the spleen or new appearance of splenomegaly * 50+% Decrease of platelet counts or to less than 100x109/L secondary to CLL and unrelated to autoimmune cytopenia * Decrease of haemoglobin levels by more than 20 g/L, or to less than 100 g/L secondary to CLL and unrelated to autoimmune cytopenia T Transformation to a more aggressive histology, e.g. Richter syndrome. |
| Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Data collected up to cut-off date 26Oct2016 until Progressive disease (PD) to start of next Chronic Lymphocytic Leukaemia (CLL) therapy, Up to 1809 days. | Response was assessed according to the IWCLL (International Workshop on Chronic Lymphocytic Leukemia) guidelines based on laboratory data from the peripheral blood and clinical examination by the investigator after each cycle prior to administration of the next dose of BI 836826, at the end of the treatment (EOT) visit, and at all Follow-up Visits. Best overall response will be analysed descriptively. Frequency distributions will be used to examine this endpoint. |
| Number of Patients With Improved Haemoglobin Count for at Least Two Subsequent Response Assessments | ≥8 day after a completed infusion of a cycle and before Chronic Lymphocytic Leukemia (CLL) therapy; data collected up to cut-off date 26Oct2016, Up to 1809 days | In patients with haemoglobin counts below the limits of normal at baseline, improvement in this count during therapy potentially indicated a benefit for the patient. Number of patients with improved haemoglobin count for at least two subsequent response assessments which fulfil International Workshop on Chronic Lymphocytic Leukemia (IWCLL) response criteria for Complete Remission (CR) or Partial Remission (PR). The response was assessed before Progressive Disease (PD) or start of new Chronic Lymphocytic Leukaemia (CLL) therapy. |
Countries
Belgium, France, Germany
Participant flow
Recruitment details
This was a Phase-1,single arm,open-label,dose escalation trial, patients with advanced chronic lymphocytic leukemia. While the first part of the trial was still in progress, recruitment was ended by the sponsor before the maximum tolerated dose(MTD) or Optimal Biological Dose(OBD) was reached.
Pre-assignment details
All patients were screened for eligibility to participate in the trial. Patients attended specialist sites to ensure that all patients met all inclusion/exclusion criteria. Patients were not to be entered to trial treatment if any one of the specific entry criteria were not met.
Participants by arm
| Arm | Count |
|---|---|
| BI 836826 1 Milligram Patients were administered BI 836826-1 milligram solution for infusion after dilution intravenously as one single dose within a 14-day cycle | 3 |
| BI 836826 3 Milligram Patients were administered BI 836826-3 milligram solution for infusion after dilution intravenously as one single dose within a 14-day cycle | 3 |
| BI 836826 9 Milligram Patients were administered BI 836826-9 milligram solution for infusion after dilution intravenously as one or two doses within the first cycle followed by single doses within all following 14-day cycles | 6 |
| BI 836826 25 Milligram Patients were administered BI 836826-25 milligram solution for infusion after dilution intravenously as two doses within the first cycle followed by single doses within all following 14-day cycles | 6 |
| BI 836826 50 Milligram Patients were administered BI 836826-50 milligram solution for infusion after dilution intravenously as two doses within the first cycle followed by single doses within all following 14-day cycles | 3 |
| BI 836826 100 Milligram Patients were administered BI 836826-100 milligram solution for infusion after dilution intravenously as two doses within the first cycle followed by single doses within all following 14-day cycles | 3 |
| BI 836826 200 Milligram Patients were administered BI 836826-200 milligram solution for infusion after dilution intravenously as two doses within the first cycle followed by single doses within all following 14-day cycles | 6 |
| BI 836826 400 Milligram Patients were administered BI 836826-400 milligram solution for infusion after dilution intravenously as two doses within the first cycle followed by single doses within all following 14-day cycles | 3 |
| BI 836826 800 Milligram Patients were administered BI 836826-800 milligram solution for infusion after dilution intravenously as two doses within the first cycle followed by single doses within all following 14-day cycles | 4 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 1 | 2 | 1 | 0 | 0 | 0 | 1 |
| Overall Study | Dosage already reduced, AE still present | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Dose limiting toxicity | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 |
| Overall Study | Investigator decision | 0 | 1 | 0 | 1 | 0 | 0 | 1 | 0 | 1 |
| Overall Study | IV problems, administration not possible | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Low benefit and too many side effects | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | No adequate treatment response | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | No clinical benefit anymore | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | per protocol | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Progressive disease | 2 | 0 | 1 | 1 | 2 | 3 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 1 | 0 | 0 | 3 | 0 | 0 |
Baseline characteristics
| Characteristic | BI 836826 1 Milligram | Total | BI 836826 800 Milligram | BI 836826 400 Milligram | BI 836826 200 Milligram | BI 836826 100 Milligram | BI 836826 50 Milligram | BI 836826 25 Milligram | BI 836826 9 Milligram | BI 836826 3 Milligram |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 67.7 Years STANDARD_DEVIATION 8.4 | 66.5 Years STANDARD_DEVIATION 10.2 | 69.5 Years STANDARD_DEVIATION 6.5 | 70.7 Years STANDARD_DEVIATION 11.4 | 73.3 Years STANDARD_DEVIATION 5.4 | 61.0 Years STANDARD_DEVIATION 17 | 63.3 Years STANDARD_DEVIATION 13.2 | 58.7 Years STANDARD_DEVIATION 9.6 | 63.3 Years STANDARD_DEVIATION 10 | 74.3 Years STANDARD_DEVIATION 5.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 16 Participants | 2 Participants | 0 Participants | 4 Participants | 1 Participants | 2 Participants | 4 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 3 Participants | 21 Participants | 2 Participants | 3 Participants | 2 Participants | 2 Participants | 1 Participants | 2 Participants | 4 Participants | 2 Participants |
| Sex: Female, Male Female | 2 Participants | 11 Participants | 1 Participants | 0 Participants | 4 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 1 Participants | 26 Participants | 3 Participants | 3 Participants | 2 Participants | 2 Participants | 2 Participants | 6 Participants | 5 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 6 | 0 / 6 | 0 / 3 | 0 / 3 | 0 / 6 | 0 / 3 | 0 / 4 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 6 / 6 | 6 / 6 | 3 / 3 | 3 / 3 | 6 / 6 | 3 / 3 | 4 / 4 |
| serious Total, serious adverse events | 0 / 3 | 1 / 3 | 4 / 6 | 3 / 6 | 1 / 3 | 1 / 3 | 5 / 6 | 1 / 3 | 2 / 4 |
Outcome results
Primary
Maximum Tolerated Dose (MTD)
The maximum tolerated dose (MTD) was defined as the highest dose of BI 836826 studied for which the incidence of DLT was no more than 17% (i.e. 1 out of 6 patients) during the first treatment cycle. For those patients who received more than 1 cycle of BI 836826, all AEs corresponding to the DLT were considered for the purpose of confirming the MTD and for the selection of the recommended dose for treatment of the expansion cohort and for further development. All DLTs, occurring during the first or repeated treatment cycle were reported as significant AEs. As it was not possible to recruit a sufficient number of patients whilst the first part of the trial was still in progress, the recruitment was ended by the sponsor before the MTD or optimal biological dose (OBD) was reached.
Time frame: 14 days after first administration of BI836826 (MTD evaluation period)
Population: The trial was discontinued prematurely due to lack of recruitment before the MTD based on the frequency of patients with DLTs in the first treatment cycle was reached.
Primary
Number of Patients With Dose-Limiting Toxicities Adverse Events (DLTs)
Dose-Limiting Toxicities (DLTs) were defined as any drug-related non-haematologic adverse event of Common Terminology Criteria for AE (CTCAE) Grade 3 or higher, except infusion related reactions associated with the administration of BI 836826. In addition complications due to haematologic AEs were considered as DLTs and were added in more detail in an amendment later on.
Time frame: 14 days after first administration of BI836826 (MTD evaluation period)
Population: The maximum tolerated dose (MTD) evaluation set: This includes all patients who were documented to have received at least one dose of trial medication and were not replaced for the MTD evaluation.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BI 836826 1 Milligram | Number of Patients With Dose-Limiting Toxicities Adverse Events (DLTs) | Total with dose limiting toxicities adverse events | 0 Participants |
| BI 836826 3 Milligram | Number of Patients With Dose-Limiting Toxicities Adverse Events (DLTs) | Total with dose limiting toxicities adverse events | 0 Participants |
| BI 836826 9 Milligram | Number of Patients With Dose-Limiting Toxicities Adverse Events (DLTs) | Total with dose limiting toxicities adverse events | 0 Participants |
| BI 836826 25 Milligram | Number of Patients With Dose-Limiting Toxicities Adverse Events (DLTs) | Total with dose limiting toxicities adverse events | 0 Participants |
| BI 836826 50 Milligram | Number of Patients With Dose-Limiting Toxicities Adverse Events (DLTs) | Total with dose limiting toxicities adverse events | 0 Participants |
| BI 836826 100 Milligram | Number of Patients With Dose-Limiting Toxicities Adverse Events (DLTs) | Total with dose limiting toxicities adverse events | 0 Participants |
| BI 836826 200 Milligram | Number of Patients With Dose-Limiting Toxicities Adverse Events (DLTs) | Total with dose limiting toxicities adverse events | 1 Participants |
| BI 836826 400 Milligram | Number of Patients With Dose-Limiting Toxicities Adverse Events (DLTs) | Total with dose limiting toxicities adverse events | 0 Participants |
| BI 836826 800 Milligram | Number of Patients With Dose-Limiting Toxicities Adverse Events (DLTs) | Total with dose limiting toxicities adverse events | 1 Participants |
Secondary
Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria
Response was assessed according to the IWCLL (International Workshop on Chronic Lymphocytic Leukemia) guidelines based on laboratory data from the peripheral blood and clinical examination by the investigator after each cycle prior to administration of the next dose of BI 836826, at the end of the treatment (EOT) visit, and at all Follow-up Visits. Best overall response will be analysed descriptively. Frequency distributions will be used to examine this endpoint.
Time frame: Data collected up to cut-off date 26Oct2016 until Progressive disease (PD) to start of next Chronic Lymphocytic Leukaemia (CLL) therapy, Up to 1809 days.
Population: TS
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BI 836826 1 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Complete remission | 0 Participants |
| BI 836826 1 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Partial remission | 0 Participants |
| BI 836826 1 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Not evaluable | 0 Participants |
| BI 836826 1 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Complete remission with incomplete marrow recovery | 0 Participants |
| BI 836826 1 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Progressive disease | 0 Participants |
| BI 836826 1 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Stable disease | 3 Participants |
| BI 836826 3 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Stable disease | 3 Participants |
| BI 836826 3 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Complete remission | 0 Participants |
| BI 836826 3 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Progressive disease | 0 Participants |
| BI 836826 3 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Partial remission | 0 Participants |
| BI 836826 3 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Complete remission with incomplete marrow recovery | 0 Participants |
| BI 836826 3 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Not evaluable | 0 Participants |
| BI 836826 9 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Stable disease | 2 Participants |
| BI 836826 9 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Complete remission with incomplete marrow recovery | 0 Participants |
| BI 836826 9 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Not evaluable | 0 Participants |
| BI 836826 9 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Partial remission | 4 Participants |
| BI 836826 9 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Complete remission | 0 Participants |
| BI 836826 9 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Progressive disease | 0 Participants |
| BI 836826 25 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Complete remission | 0 Participants |
| BI 836826 25 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Progressive disease | 0 Participants |
| BI 836826 25 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Partial remission | 1 Participants |
| BI 836826 25 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Stable disease | 4 Participants |
| BI 836826 25 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Complete remission with incomplete marrow recovery | 0 Participants |
| BI 836826 25 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Not evaluable | 1 Participants |
| BI 836826 50 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Progressive disease | 0 Participants |
| BI 836826 50 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Complete remission | 0 Participants |
| BI 836826 50 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Partial remission | 0 Participants |
| BI 836826 50 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Stable disease | 3 Participants |
| BI 836826 50 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Not evaluable | 0 Participants |
| BI 836826 50 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Complete remission with incomplete marrow recovery | 0 Participants |
| BI 836826 100 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Progressive disease | 0 Participants |
| BI 836826 100 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Complete remission | 0 Participants |
| BI 836826 100 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Complete remission with incomplete marrow recovery | 0 Participants |
| BI 836826 100 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Partial remission | 0 Participants |
| BI 836826 100 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Stable disease | 3 Participants |
| BI 836826 100 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Not evaluable | 0 Participants |
| BI 836826 200 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Complete remission with incomplete marrow recovery | 0 Participants |
| BI 836826 200 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Complete remission | 0 Participants |
| BI 836826 200 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Not evaluable | 0 Participants |
| BI 836826 200 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Progressive disease | 0 Participants |
| BI 836826 200 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Stable disease | 2 Participants |
| BI 836826 200 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Partial remission | 4 Participants |
| BI 836826 400 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Partial remission | 2 Participants |
| BI 836826 400 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Progressive disease | 0 Participants |
| BI 836826 400 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Complete remission | 0 Participants |
| BI 836826 400 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Complete remission with incomplete marrow recovery | 0 Participants |
| BI 836826 400 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Not evaluable | 0 Participants |
| BI 836826 400 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Stable disease | 1 Participants |
| BI 836826 800 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Stable disease | 2 Participants |
| BI 836826 800 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Partial remission | 2 Participants |
| BI 836826 800 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Progressive disease | 0 Participants |
| BI 836826 800 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Complete remission with incomplete marrow recovery | 0 Participants |
| BI 836826 800 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Complete remission | 0 Participants |
| BI 836826 800 Milligram | Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria | Not evaluable | 0 Participants |
Secondary
Best Percentage Change From Baseline in Number of Lymphocytes in the Peripheral Blood
In most patients with relapsed or refractory chronic lymphocytic leukaemia (CLL), malignant B-cells represent the majority of lymphocytes in the peripheral blood. Reduction of CLL-cells was assessed in the peripheral blood by absolute lymphocyte count, and flow cytometry. The number of lymphocytes in the peripheral blood was analysed in terms of the best percentage change from baseline until start of subsequent CLL therapy or progressive disease (PD).
Time frame: baseline and ≥8 day after a completed infusion of a cycle and before Chronic Lymphocytic Leukemia (CLL) therapy; data collected up to cut-off date 26Oct2016, Up to 1809 days
Population: All patients who received at least one application of the drug BI 836826, had a baseline and at least one post-baseline assessment of the number of lymphocytes in the peripheral blood.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BI 836826 1 Milligram | Best Percentage Change From Baseline in Number of Lymphocytes in the Peripheral Blood | -11.39 Percentage of change (%) | Standard Deviation 31.39 |
| BI 836826 3 Milligram | Best Percentage Change From Baseline in Number of Lymphocytes in the Peripheral Blood | -21.20 Percentage of change (%) | Standard Deviation 10.08 |
| BI 836826 9 Milligram | Best Percentage Change From Baseline in Number of Lymphocytes in the Peripheral Blood | -48.21 Percentage of change (%) | Standard Deviation 57.39 |
| BI 836826 25 Milligram | Best Percentage Change From Baseline in Number of Lymphocytes in the Peripheral Blood | -48.15 Percentage of change (%) | Standard Deviation 34.01 |
| BI 836826 50 Milligram | Best Percentage Change From Baseline in Number of Lymphocytes in the Peripheral Blood | -49.35 Percentage of change (%) | Standard Deviation 31.44 |
| BI 836826 100 Milligram | Best Percentage Change From Baseline in Number of Lymphocytes in the Peripheral Blood | -81.81 Percentage of change (%) | Standard Deviation 11.03 |
| BI 836826 200 Milligram | Best Percentage Change From Baseline in Number of Lymphocytes in the Peripheral Blood | -79.22 Percentage of change (%) | Standard Deviation 39.94 |
| BI 836826 400 Milligram | Best Percentage Change From Baseline in Number of Lymphocytes in the Peripheral Blood | -93.40 Percentage of change (%) | Standard Deviation 9.76 |
| BI 836826 800 Milligram | Best Percentage Change From Baseline in Number of Lymphocytes in the Peripheral Blood | -47.14 Percentage of change (%) | Standard Deviation 103.29 |
Secondary
Failure-free Survival
Failure-free survival (FFS) was defined as the time from the first administration of BI 836826 until disease progression or death, or start of next Chronic Lymphocytic Leukemia (CLL) therapy, whichever occurred first. Disease progression= At least one of the following: * 50+% increase in blood lymphocytes over baseline with an absolute number of B-lymphocytes of at least 5x109/L * Progression of lymphadenopathy * 50+% increase in the previously noted enlargement of the liver or new appearance of hepatomegaly * 50+% increase in the previously noted enlargement of the spleen or new appearance of splenomegaly * 50+% Decrease of platelet counts or to less than 100x109/L secondary to CLL and unrelated to autoimmune cytopenia * Decrease of haemoglobin levels by more than 20 g/L, or to less than 100 g/L secondary to CLL and unrelated to autoimmune cytopenia T Transformation to a more aggressive histology, e.g. Richter syndrome.
Time frame: Data collected up to cut-off date 26Oct2016, Up to 1809 days.
Population: TS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BI 836826 1 Milligram | Failure-free Survival | 57.0 Days |
| BI 836826 3 Milligram | Failure-free Survival | 106.0 Days |
| BI 836826 9 Milligram | Failure-free Survival | 152.5 Days |
| BI 836826 25 Milligram | Failure-free Survival | 81.0 Days |
| BI 836826 50 Milligram | Failure-free Survival | 85.0 Days |
| BI 836826 100 Milligram | Failure-free Survival | 114.0 Days |
| BI 836826 200 Milligram | Failure-free Survival | 196.5 Days |
| BI 836826 400 Milligram | Failure-free Survival | 149.0 Days |
| BI 836826 800 Milligram | Failure-free Survival | 100.0 Days |
Secondary
Number of Patients With Improved Haemoglobin Count for at Least Two Subsequent Response Assessments
In patients with haemoglobin counts below the limits of normal at baseline, improvement in this count during therapy potentially indicated a benefit for the patient. Number of patients with improved haemoglobin count for at least two subsequent response assessments which fulfil International Workshop on Chronic Lymphocytic Leukemia (IWCLL) response criteria for Complete Remission (CR) or Partial Remission (PR). The response was assessed before Progressive Disease (PD) or start of new Chronic Lymphocytic Leukaemia (CLL) therapy.
Time frame: ≥8 day after a completed infusion of a cycle and before Chronic Lymphocytic Leukemia (CLL) therapy; data collected up to cut-off date 26Oct2016, Up to 1809 days
Population: Treated Set (TS): All patients who received at least one application of the drug BI 836826.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BI 836826 1 Milligram | Number of Patients With Improved Haemoglobin Count for at Least Two Subsequent Response Assessments | NO | 3 Participants |
| BI 836826 1 Milligram | Number of Patients With Improved Haemoglobin Count for at Least Two Subsequent Response Assessments | YES | 0 Participants |
| BI 836826 3 Milligram | Number of Patients With Improved Haemoglobin Count for at Least Two Subsequent Response Assessments | NO | 2 Participants |
| BI 836826 3 Milligram | Number of Patients With Improved Haemoglobin Count for at Least Two Subsequent Response Assessments | YES | 1 Participants |
| BI 836826 9 Milligram | Number of Patients With Improved Haemoglobin Count for at Least Two Subsequent Response Assessments | NO | 3 Participants |
| BI 836826 9 Milligram | Number of Patients With Improved Haemoglobin Count for at Least Two Subsequent Response Assessments | YES | 3 Participants |
| BI 836826 25 Milligram | Number of Patients With Improved Haemoglobin Count for at Least Two Subsequent Response Assessments | NO | 4 Participants |
| BI 836826 25 Milligram | Number of Patients With Improved Haemoglobin Count for at Least Two Subsequent Response Assessments | YES | 2 Participants |
| BI 836826 50 Milligram | Number of Patients With Improved Haemoglobin Count for at Least Two Subsequent Response Assessments | NO | 2 Participants |
| BI 836826 50 Milligram | Number of Patients With Improved Haemoglobin Count for at Least Two Subsequent Response Assessments | YES | 1 Participants |
| BI 836826 100 Milligram | Number of Patients With Improved Haemoglobin Count for at Least Two Subsequent Response Assessments | YES | 2 Participants |
| BI 836826 100 Milligram | Number of Patients With Improved Haemoglobin Count for at Least Two Subsequent Response Assessments | NO | 1 Participants |
| BI 836826 200 Milligram | Number of Patients With Improved Haemoglobin Count for at Least Two Subsequent Response Assessments | YES | 4 Participants |
| BI 836826 200 Milligram | Number of Patients With Improved Haemoglobin Count for at Least Two Subsequent Response Assessments | NO | 2 Participants |
| BI 836826 400 Milligram | Number of Patients With Improved Haemoglobin Count for at Least Two Subsequent Response Assessments | NO | 1 Participants |
| BI 836826 400 Milligram | Number of Patients With Improved Haemoglobin Count for at Least Two Subsequent Response Assessments | YES | 2 Participants |
| BI 836826 800 Milligram | Number of Patients With Improved Haemoglobin Count for at Least Two Subsequent Response Assessments | YES | 0 Participants |
| BI 836826 800 Milligram | Number of Patients With Improved Haemoglobin Count for at Least Two Subsequent Response Assessments | NO | 4 Participants |
Secondary
Number of Patients With Improved Neutrophil Count for at Least Two Subsequent Response Assessments
In patients with neutrophil count below the limits of normal at baseline, improvement in this count during therapy potentially indicated a benefit for the patient. Number of patients with improved neutrophil count for at least two subsequent response assessments which fulfil International Workshop on Chronic Lymphocytic Leukemia (IWCLL) response criteria for Complete Remission (CR) or Partial Remission (PR). The response was assessed before Progressive Disease (PD) or start of new Chronic Lymphocytic Leukaemia (CLL) therapy.
Time frame: ≥8 day after a completed infusion of a cycle and before Chronic Lymphocytic Leukemia (CLL) therapy; data collected up to cut-off date 26Oct2016, Up to 1809 days
Population: TS
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BI 836826 1 Milligram | Number of Patients With Improved Neutrophil Count for at Least Two Subsequent Response Assessments | NO | 2 Participants |
| BI 836826 1 Milligram | Number of Patients With Improved Neutrophil Count for at Least Two Subsequent Response Assessments | YES | 1 Participants |
| BI 836826 3 Milligram | Number of Patients With Improved Neutrophil Count for at Least Two Subsequent Response Assessments | YES | 3 Participants |
| BI 836826 3 Milligram | Number of Patients With Improved Neutrophil Count for at Least Two Subsequent Response Assessments | NO | 0 Participants |
| BI 836826 9 Milligram | Number of Patients With Improved Neutrophil Count for at Least Two Subsequent Response Assessments | NO | 1 Participants |
| BI 836826 9 Milligram | Number of Patients With Improved Neutrophil Count for at Least Two Subsequent Response Assessments | YES | 5 Participants |
| BI 836826 25 Milligram | Number of Patients With Improved Neutrophil Count for at Least Two Subsequent Response Assessments | NO | 2 Participants |
| BI 836826 25 Milligram | Number of Patients With Improved Neutrophil Count for at Least Two Subsequent Response Assessments | YES | 4 Participants |
| BI 836826 50 Milligram | Number of Patients With Improved Neutrophil Count for at Least Two Subsequent Response Assessments | YES | 1 Participants |
| BI 836826 50 Milligram | Number of Patients With Improved Neutrophil Count for at Least Two Subsequent Response Assessments | NO | 2 Participants |
| BI 836826 100 Milligram | Number of Patients With Improved Neutrophil Count for at Least Two Subsequent Response Assessments | YES | 2 Participants |
| BI 836826 100 Milligram | Number of Patients With Improved Neutrophil Count for at Least Two Subsequent Response Assessments | NO | 1 Participants |
| BI 836826 200 Milligram | Number of Patients With Improved Neutrophil Count for at Least Two Subsequent Response Assessments | NO | 1 Participants |
| BI 836826 200 Milligram | Number of Patients With Improved Neutrophil Count for at Least Two Subsequent Response Assessments | YES | 5 Participants |
| BI 836826 400 Milligram | Number of Patients With Improved Neutrophil Count for at Least Two Subsequent Response Assessments | NO | 0 Participants |
| BI 836826 400 Milligram | Number of Patients With Improved Neutrophil Count for at Least Two Subsequent Response Assessments | YES | 3 Participants |
| BI 836826 800 Milligram | Number of Patients With Improved Neutrophil Count for at Least Two Subsequent Response Assessments | YES | 1 Participants |
| BI 836826 800 Milligram | Number of Patients With Improved Neutrophil Count for at Least Two Subsequent Response Assessments | NO | 3 Participants |
Secondary
Number of Patients With Improved Platelet Count for at Least Two Subsequent Response Assessments
In patients with platelet counts below the limits of normal at baseline, improvement in this count during therapy potentially indicated a benefit for the patient. Number of patients with improved platelet count for at least two subsequent response assessments which fulfil International Workshop on Chronic Lymphocytic Leukemia (IWCLL) response criteria for Complete Remission (CR) or Partial Remission (PR). The response was assessed before Progressive Disease (PD) or start of new Chronic Lymphocytic Leukaemia (CLL) therapy.
Time frame: ≥8 day after a completed infusion of a cycle and before Chronic Lymphocytic Leukemia (CLL) therapy; data collected up to cut-off date 26Oct2016, Up to 1809 days
Population: TS
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BI 836826 1 Milligram | Number of Patients With Improved Platelet Count for at Least Two Subsequent Response Assessments | NO | 2 Participants |
| BI 836826 1 Milligram | Number of Patients With Improved Platelet Count for at Least Two Subsequent Response Assessments | YES | 1 Participants |
| BI 836826 3 Milligram | Number of Patients With Improved Platelet Count for at Least Two Subsequent Response Assessments | NO | 2 Participants |
| BI 836826 3 Milligram | Number of Patients With Improved Platelet Count for at Least Two Subsequent Response Assessments | YES | 1 Participants |
| BI 836826 9 Milligram | Number of Patients With Improved Platelet Count for at Least Two Subsequent Response Assessments | NO | 2 Participants |
| BI 836826 9 Milligram | Number of Patients With Improved Platelet Count for at Least Two Subsequent Response Assessments | YES | 4 Participants |
| BI 836826 25 Milligram | Number of Patients With Improved Platelet Count for at Least Two Subsequent Response Assessments | NO | 3 Participants |
| BI 836826 25 Milligram | Number of Patients With Improved Platelet Count for at Least Two Subsequent Response Assessments | YES | 3 Participants |
| BI 836826 50 Milligram | Number of Patients With Improved Platelet Count for at Least Two Subsequent Response Assessments | NO | 3 Participants |
| BI 836826 50 Milligram | Number of Patients With Improved Platelet Count for at Least Two Subsequent Response Assessments | YES | 0 Participants |
| BI 836826 100 Milligram | Number of Patients With Improved Platelet Count for at Least Two Subsequent Response Assessments | YES | 2 Participants |
| BI 836826 100 Milligram | Number of Patients With Improved Platelet Count for at Least Two Subsequent Response Assessments | NO | 1 Participants |
| BI 836826 200 Milligram | Number of Patients With Improved Platelet Count for at Least Two Subsequent Response Assessments | YES | 3 Participants |
| BI 836826 200 Milligram | Number of Patients With Improved Platelet Count for at Least Two Subsequent Response Assessments | NO | 3 Participants |
| BI 836826 400 Milligram | Number of Patients With Improved Platelet Count for at Least Two Subsequent Response Assessments | NO | 0 Participants |
| BI 836826 400 Milligram | Number of Patients With Improved Platelet Count for at Least Two Subsequent Response Assessments | YES | 3 Participants |
| BI 836826 800 Milligram | Number of Patients With Improved Platelet Count for at Least Two Subsequent Response Assessments | NO | 3 Participants |
| BI 836826 800 Milligram | Number of Patients With Improved Platelet Count for at Least Two Subsequent Response Assessments | YES | 1 Participants |
Secondary
Progression-free Survival
Progression-free survival (PFS) was defined as the time from the first administration of BI 836826 until disease progression or death, whichever occurred first. Disease progression= At least one of the following: * 50+% increase in blood lymphocytes over baseline with an absolute number of B-lymphocytes of at least 5x109/L * Progression of lymphadenopathy * 50+% increase in the previously noted enlargement of the liver or new appearance of hepatomegaly * 50+% increase in the previously noted enlargement of the spleen or new appearance of splenomegaly * 50+% Decrease of platelet counts or to less than 100x109/L secondary to CLL and unrelated to autoimmune cytopenia * Decrease of haemoglobin levels by more than 20 g/L, or to less than 100 g/L secondary to CLL and unrelated to autoimmune cytopenia T Transformation to a more aggressive histology, e.g. Richter syndrome.
Time frame: Data collected up to cut-off date 26Oct2016, Up to 1809 days.
Population: TS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BI 836826 1 Milligram | Progression-free Survival | 57.0 Days |
| BI 836826 3 Milligram | Progression-free Survival | 86.0 Days |
| BI 836826 9 Milligram | Progression-free Survival | 133.5 Days |
| BI 836826 25 Milligram | Progression-free Survival | 81.0 Days |
| BI 836826 50 Milligram | Progression-free Survival | 85.0 Days |
| BI 836826 100 Milligram | Progression-free Survival | 114.0 Days |
| BI 836826 200 Milligram | Progression-free Survival | 196.5 Days |
| BI 836826 400 Milligram | Progression-free Survival | 113.0 Days |
| BI 836826 800 Milligram | Progression-free Survival | 68.0 Days |