BI836826 Dose Escalation in Relapsed Chronic Lymphocytic Leukaemia (CLL)

• BI 836826 (Drug): Monotherapy with BI 836826 at escalating dose levels administered as an intravenous infusion.

Primary outcomes

• 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 outcomes

• 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).
• 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.
• 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 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.
• 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.

Sex: All, ages: 18 Years to any

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

Participant flow

Outcome results

• Best Percentage Change From Baseline in Number of Lymphocytes in the Peripheral Blood (Secondary), Mean, Percentage of change (%): BI 836826 1 Milligram -11.39 +/- 31.39; BI 836826 3 Milligram -21.20 +/- 10.08; BI 836826 9 Milligram -48.21 +/- 57.39; BI 836826 25 Milligram -48.15 +/- 34.01; BI 836826 50 Milligram -49.35 +/- 31.44; BI 836826 100 Milligram -81.81 +/- 11.03; BI 836826 200 Milligram -79.22 +/- 39.94; BI 836826 400 Milligram -93.40 +/- 9.76; BI 836826 800 Milligram -47.14 +/- 103.29
• Number of Patients With Improved Haemoglobin Count for at Least Two Subsequent Response Assessments (Secondary), Count of participants, Participants: BI 836826 1 Milligram 3; BI 836826 3 Milligram 2; BI 836826 9 Milligram 3; BI 836826 25 Milligram 4; BI 836826 50 Milligram 2; BI 836826 100 Milligram 1; BI 836826 200 Milligram 2; BI 836826 400 Milligram 1; BI 836826 800 Milligram 4
• Number of Patients With Improved Platelet Count for at Least Two Subsequent Response Assessments (Secondary), Count of participants, Participants: BI 836826 1 Milligram 2; BI 836826 3 Milligram 2; BI 836826 9 Milligram 2; BI 836826 25 Milligram 3; BI 836826 50 Milligram 3; BI 836826 100 Milligram 1; BI 836826 200 Milligram 3; BI 836826 400 Milligram 0; BI 836826 800 Milligram 3
• Number of Patients With Improved Neutrophil Count for at Least Two Subsequent Response Assessments (Secondary), Count of participants, Participants: BI 836826 1 Milligram 1; BI 836826 3 Milligram 3; BI 836826 9 Milligram 5; BI 836826 25 Milligram 4; BI 836826 50 Milligram 1; BI 836826 100 Milligram 2; BI 836826 200 Milligram 5; BI 836826 400 Milligram 3; BI 836826 800 Milligram 1
• Best Overall Response According to 'International Workshop on Chronic Lymphocytic Leukemia' (IWCLL) Criteria (Secondary), Count of participants, Participants: BI 836826 1 Milligram 0; BI 836826 3 Milligram 0; BI 836826 9 Milligram 0; BI 836826 25 Milligram 0; BI 836826 50 Milligram 0; BI 836826 100 Milligram 0; BI 836826 200 Milligram 0; BI 836826 400 Milligram 0; BI 836826 800 Milligram 0
• Progression-free Survival (Secondary), Median, Days: BI 836826 1 Milligram 57.0 (15.0 to 316.0); BI 836826 3 Milligram 86.0 (59.0 to 141.0); BI 836826 9 Milligram 133.5 (79.0 to 281.0); BI 836826 25 Milligram 81.0 (29.0 to 134.0); BI 836826 50 Milligram 85.0 (16.0 to 106.0); BI 836826 100 Milligram 114.0 (44.0 to 133.0); BI 836826 200 Milligram 196.5 (98.0 to 247.0); BI 836826 400 Milligram 113.0 (106.0 to 799.0); BI 836826 800 Milligram 68.0 (51.0 to 74.0)
• Failure-free Survival (Secondary), Median, Days: BI 836826 1 Milligram 57.0 (29.0 to 316.0); BI 836826 3 Milligram 106.0 (59.0 to 141.0); BI 836826 9 Milligram 152.5 (85.0 to 281.0); BI 836826 25 Milligram 81.0 (29.0 to 134.0); BI 836826 50 Milligram 85.0 (25.0 to 106.0); BI 836826 100 Milligram 114.0 (54.0 to 133.0); BI 836826 200 Milligram 196.5 (127.0 to 247.0); BI 836826 400 Milligram 149.0 (120.0 to 799.0); BI 836826 800 Milligram 100.0 (68.0 to 141.5)
• Number of Patients With Dose-Limiting Toxicities Adverse Events (DLTs) (Primary), Count of participants, Participants: BI 836826 1 Milligram 0; BI 836826 3 Milligram 0; BI 836826 9 Milligram 0; BI 836826 25 Milligram 0; BI 836826 50 Milligram 0; BI 836826 100 Milligram 0; BI 836826 200 Milligram 1; BI 836826 400 Milligram 0; BI 836826 800 Milligram 1
• Maximum Tolerated Dose (MTD) (Primary)

Adverse events

Time frame: From the first dose of study medication until 6 weeks after last administration of BI 836826, up to 136 weeks

Serious adverse events by term

Other adverse events by term

172 more terms not shown.

Limitations and caveats: The trial was discontinued due to lack of recruitment before a formal maximum tolerated dose (MTD) was established based on the number of patients with Dose Limiting Toxicities (DLTs) in the first treatment cycle.

• Statistical Analysis Plan (PDF, 2016-10-13)
• Study Protocol (PDF, 2015-03-04)

• Boehringer Ingelheim, Study chair, Boehringer Ingelheim