Intravenous BI 836826 in Combination With Ibrutinib in Relapsed/Refractory CLL Patients Who Have Been Pre-treated With at Least One Prior Line of Systemic Therapy, and Who Are Eligible for Treatment With Ibrutinib

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02759016
• Collaborator: (none)
• Enrollment: 7
• Locations: 3
• Arm: 1
• Actual Duration (Months): 36.5
• Patients Per Site: 2.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Intravenous BI 836826 in combination with ibrutinib in relapsed/refractory Chronic Lymphocytic Leukemia (CLL) patients who have been pre-treated with at least one prior line of systemic therapy, and who are eligible for treatment with ibrutinib. Objectives of the trial are to determine the recommended Phase 2 dose of BI 836826, and to document the safety and tolerability of BI 836826 when given in combination with ibrutinib

Condition or Disease	Intervention/Treatment	Phase
Leukemia, Lymphocytic, Chronic, B-Cell	Drug: BI 836826; Drug: Ibrutinib	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 7 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase Ib, Open Label, Single Arm, Multi-center, Dose Escalation Trial of Intravenous BI 836826 in Combination With Ibrutinib in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia
• Actual Study Start Date: Jun 23, 2016
• Actual Primary Completion Date: Jun 3, 2019
• Actual Study Completion Date: Jul 9, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BI 836826 BI 836826 administered in combination with Standard of Care Ibrutinib	Drug: BI 836826; Drug: Ibrutinib; Standard of Care

Outcome Measures

Primary Outcome Measures

1. Recommended Phase 2 Dose of BI 836826 in Combination With Ibrutinib [First treatment cycle, 4 weeks from first administration of BI 836826.]

   The Recommended Phase 2 Dose (RP2D ) of BI 836826 in combination with ibrutinib would be either the Maximum Tolerated Dose (MTD) or a lower dose and would be determined by the safety review committee based on safety and efficacy considerations.

2. Number of Participants With Dose Limiting Toxicities (DLTs) During the First Treatment Cycle [First treatment cycle, 4 weeks from first administration of BI 836826.]

   Number of participants with Dose Limiting Toxicities (DLTs) during the first treatment cycle. DLT was defined as any non-hematologic adverse event (AE) of Grade ≥ 3 related to BI 836826 and/or ibrutinib except infusion-related reaction (any Grade), Grade 3 Aspartate Aminotransferase (AST)- and/or Alanine Aminotransferase (ALT) elevation without concomitant bilirubin, elevation or any other asymptomatic Grade 3 laboratory abnormality with spontaneous recovery within 1 week. The following hematologic AEs related to BI 836826 and/or ibrutinib were considered DLT: Grade 4 neutropenia with concomitant infection, Grade 4 febrile neutropenia, and Grade 3 febrile neutropenia not resolving within 72 hours with appropriate treatment (antibiotics, antivirals, antifungals, growth factor support), Grade 4 thrombocytopenia with clinically significant bleeding, Grade 4 anemia, any Grade 5 hematologic AE.

Secondary Outcome Measures

1. Maximum Tolerated Dose of BI 836826 in Combination With Ibrutinib [First treatment cycle, 4 weeks from first administration of BI 836826.]

   To determine the Maximum Tolerated Dose (MTD) of BI 836826 in combination with ibrutinib, participants were entered sequentially into dose cohorts starting at 100 mg of BI 836826 and escalating to the MTD in combination with ibrutinib (fixed dose of 420 mg daily). Stepwise dose escalation of BI 836826 was guided by a Bayesian Logistic Regression Model (BLRM) with overdose control. The BLRM estimates the MTD by updating estimates of the probability of observing a Dose Limiting Toxicity (DLT) in the first treatment cycle (4 weeks) for each dose level as participant information becomes available. The MTD would be considered reached if the following criteria were fulfilled. The posterior probability of the true DLT rate in the target interval [0.16 - 0.33) of the MTD is above 0.50 or at least 15 participants have been treated in the study, of which at least 6 at the MTD.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Diagnosis of Chronic Lymphocytic Leukemia (CLL) established according to International Workshop Chronic Lymphocytic Leukemia (IWCLL) criteria.

• Relapsed or refractory CLL pre-treated with at least one prior line of systemic therapy for CLL.

• Indication for treatment consistent with IWCLL criteria, i.e. at least one of the following criteria should be met

• Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia.

• Massive or progressive or symptomatic splenomegaly.

• Massive nodes or progressive or symptomatic lymphadenopathy.

• Progressive lymphocytosis in the absence of infection, with an increase in blood Absolute Lymphocyte Count (ALC) >=50% over a 2-month period, or a lymphocyte doubling time (LDT) of <6 months (as long as initial ALC was >=30000/µl).

• Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy.

• Constitutional symptoms, defined as any one or more of the following disease-related symptoms or signs:

• unintentional weight loss of 10% or more within the previous 6 months

• significant fatigue

• fevers higher than 100.5°F or 38.0°C for >=2 weeks without other evidence of infection

• night sweats for > 1 month without evidence of infection

• Clinically quantifiable disease burden defined as at least one of the following:

• either ALC >10 000/µL, or

• measurable lymphadenopathy

• quantifiable bone marrow infiltration documented in a bone marrow biopsy during screening

• Resolution of all clinically relevant acute non-hematologic toxic effects of any prior antitumor therapy resolved to Grade <=1

• Baseline laboratory data as defined as:

Hemoglobin (Hb): >=8g/dL Absolute Neutrophil Count (ANC): >=1000/µL Platelet (PLT):

=25000/µL Glomerular Filtration Rate (GFR) or Creatinine Clearance: >=30ml/min Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT): <3 x Upper Limit of Normal (ULN) Bilirubin - total: <1.5 x ULN Activated Partial Thromboplastin Time (aPTT), Prothrombin Time (PT) or International Normalized Ratio (INR): <=1.5 x ULN PT <=1.5 x ULN, INR <=1.5

• Male or female patients. Women of childbearing potential must agree to use highly effective methods of birth control during the trial and for at least 1 year after the last dose of BI 836826 and 1 month after the last dose of ibrutinib.

• Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 2.

• Age 18 years and older

• Eligible and able to secure sourcing for ibrutinib

• Written Informed Consent

• Further Inclusion criteria apply

Exclusion criteria:

• Known transformation of Chronic Lymphocytic Leukemia (CLL) to an aggressive B-cell malignancy at the time of screening

• Prior allogeneic stem cell transplant within one year or active graft vs. host disease.

• History of a non-CLL malignancy except for adequately treated in situ, stage 1 or 2 carcinoma in Complete Response (CR), or any other cancer that has been in CR for >=2 years after end of cancer treatment.

• Active, uncontrolled autoimmune cytopenia. Patients with autoimmune cytopenia which is controlled with corticosteroids at doses of <=20 mg prednisolone or equivalent may be enrolled.

• Previous CLL treatment with a CD37-targeting antibody or a CD37-antibody drug conjugate.

• Previous treatment with ibrutinib

• Previous treatment with another Bruton's Tyrosine Kinase (BTK) -inhibitor.

• Ongoing systemic immunosuppressive therapy other than corticosteroids.

• Active bacterial, viral, or fungal infection requiring systemic treatment at the time of study entry.

• Human Immunodeficiency Virus (HIV) infection

• Active hepatitis B or C as evidenced by detection of virus specific Deoxyribonucleic Acid (DNA) or Ribonucleic Acid (RNA).

• History of stroke or intracranial hemorrhage within 6 months prior to enrollment

• Chronic persistent atrial flutter or atrial fibrillation. Patients with intermittent atrial fibrillation may be enrolled if without episode for >= 6 months and without indication for anti-coagulation

• Requirement for chronic anticoagulation with warfarin or with direct oral anticoagulants at the time of screening.

• Chronic treatment (i.e. >7 days) with a strong Cytochrome P450 (CYP3A) inhibitor which cannot be terminated prior to the first dose of ibrutinib.

• Unstable angina pectoris, uncontrolled hypertension, uncontrolled asthma or other pulmonary disease

• Women who are pregnant, nursing, or who plan to become pregnant while in the trial

• Further Exclusion criteria apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope	Duarte	California	United States	91010
2	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
3	Oregon Health and Sciences University	Portland	Oregon	United States	97239

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

• Statistical Analysis Plan - Jul 30, 2018
• Study Protocol - Jul 18, 2018

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT02759016
• Other Study ID Numbers: 1270.15
• First Posted: May 3, 2016
• Last Update Posted: Sep 29, 2020
• Last Verified: Sep 1, 2020

• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; BI 836826

Study Results

Participant Flow

Recruitment Details	This trial was planned to consist of 2 parts. First part was a Phase Ib, open-label, single arm, multi-center, dose escalation trial to determine the maximum tolerated dose and the recommended Phase II dose of intravenous BI 836826 in combination with ibrutinib. Original protocol planned a Phase II part which was not conducted.
Pre-assignment Detail	All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that the subjects strictly met all inclusion and none of the exclusion criteria. Abbreviations: SD=Stable Disease, PR-MRDpos=Minimal Residual Disease positive Partial Response, PR-L=Partial Response with Lymphocytosis.

Arm/Group Title	Dose Cohort BI 836826 100 Milligram (mg) + Ibrutinib	Dose Cohort BI 836826 200 Milligram (mg) + Ibrutinib
Arm/Group Description	Participants underwent a 2-week run-in phase with ibrutinib prior to the start of BI 836826. In combination with ibrutinib (420 mg daily dose, orally administered) BI 836826 was administered intravenously as a rate controlled injection in 4-week cycles, every two weeks for the first 16 weeks (Cycles 1-4), and every 4 weeks starting at week 17 (Cycle 5) until week 48 (Cycle 12). BI 836826 was administered in Cycle 1 on day 1 (10 mg), days 2 and 8 (50% of the assigned dose on each day), day 15 (100% of the assigned dose), in Cycles 2-4 on days 1 and 15 of each cycle (100% of the assigned dose), in Cycles 5-12 on day 1 (100% of the assigned dose). Participants could have initiated 12 cycles with BI 836826 and could be treated with ibrutinib unless progression, unacceptable toxicity, or withdrawal of consent occurred earlier. Continued treatment beyond Cycle 12 (up to a maximum of 24 treatment cycles) was possible for participants with a pre-specified response status at end of Cycle 12.	Participants underwent a 2-week run-in phase with ibrutinib prior to the start of BI 836826. In combination with ibrutinib (420 mg daily dose, orally administered) BI 836826 was administered intravenously as a rate controlled injection in 4-week cycles, every two weeks for the first 16 weeks (Cycles 1-4), and every 4 weeks starting at week 17 (Cycle 5) until week 48 (Cycle 12). BI 836826 was administered in Cycle 1 on day 1 (10 mg), days 2 and 8 (50% of the assigned dose on each day), day 15 (100% of the assigned dose), in Cycles 2-4 on days 1 and 15 of each cycle (100% of the assigned dose), in Cycles 5-12 on day 1 (100% of the assigned dose). Participants could have initiated 12 cycles with BI 836826 and could be treated with ibrutinib unless progression, unacceptable toxicity, or withdrawal of consent occurred earlier. Continued treatment beyond Cycle 12 (up to a maximum of 24 treatment cycles) was possible for participants with a pre-specified response status at end of Cycle 12.
Period Title: Overall Study
STARTED	4	3
Treated With BI 836826 and Ibrutinib	3	3
COMPLETED	0	0
NOT COMPLETED	4	3

Baseline Characteristics

Arm/Group Title	Dose Cohort BI 836826 100 Milligram (mg) + Ibrutinib	Dose Cohort BI 836826 200 Milligram (mg) + Ibrutinib	Total
Arm/Group Description	Participants underwent a 2-week run-in phase with ibrutinib prior to the start of BI 836826. In combination with ibrutinib (420 mg daily dose, orally administered) BI 836826 was administered intravenously as a rate controlled injection in 4-week cycles, every two weeks for the first 16 weeks (Cycles 1-4), and every 4 weeks starting at week 17 (Cycle 5) until week 48 (Cycle 12). BI 836826 was administered in Cycle 1 on day 1 (10 mg), days 2 and 8 (50% of the assigned dose on each day), day 15 (100% of the assigned dose), in Cycles 2-4 on days 1 and 15 of each cycle (100% of the assigned dose), in Cycles 5-12 on day 1 (100% of the assigned dose). Participants could have initiated 12 cycles with BI 836826 and could be treated with ibrutinib unless progression, unacceptable toxicity, or withdrawal of consent occurred earlier. Continued treatment beyond Cycle 12 (up to a maximum of 24 treatment cycles) was possible for participants with a pre-specified response status at end of Cycle 12.	Participants underwent a 2-week run-in phase with ibrutinib prior to the start of BI 836826. In combination with ibrutinib (420 mg daily dose, orally administered) BI 836826 was administered intravenously as a rate controlled injection in 4-week cycles, every two weeks for the first 16 weeks (Cycles 1-4), and every 4 weeks starting at week 17 (Cycle 5) until week 48 (Cycle 12). BI 836826 was administered in Cycle 1 on day 1 (10 mg), days 2 and 8 (50% of the assigned dose on each day), day 15 (100% of the assigned dose), in Cycles 2-4 on days 1 and 15 of each cycle (100% of the assigned dose), in Cycles 5-12 on day 1 (100% of the assigned dose). Participants could have initiated 12 cycles with BI 836826 and could be treated with ibrutinib unless progression, unacceptable toxicity, or withdrawal of consent occurred earlier. Continued treatment beyond Cycle 12 (up to a maximum of 24 treatment cycles) was possible for participants with a pre-specified response status at end of Cycle 12.	Total of all reporting groups
Overall Participants	3	3	6
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	73.0 (4.4)	66.0 (8.5)	69.5 (7.2)
Sex: Female, Male (Count of Participants)
Female	2 66.7%	1 33.3%	3 50%
Male	1 33.3%	2 66.7%	3 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 33.3%	0 0%	1 16.7%
Not Hispanic or Latino	2 66.7%	3 100%	5 83.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	3 100%	3 100%	6 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Recommended Phase 2 Dose of BI 836826 in Combination With Ibrutinib
Description	The Recommended Phase 2 Dose (RP2D ) of BI 836826 in combination with ibrutinib would be either the Maximum Tolerated Dose (MTD) or a lower dose and would be determined by the safety review committee based on safety and efficacy considerations.
Time Frame	First treatment cycle, 4 weeks from first administration of BI 836826.

Outcome Measure Data

Analysis Population Description

As the study was prematurely discontinued, recruitment of participants into the dose escalation part was not fully completed, the MTD was not reached and hence the RP2D could not be determined.

Arm/Group Title	BI 836826 + Ibrutinib
Arm/Group Description	Treatment group "BI 836826 + ibrutinib" comprises all dose cohorts during the dose escalation phase, that is, "Dose cohort BI 836826 100 mg + ibrutinib" and "Dose cohort BI 836826 200 mg + ibrutinib". Participants underwent a 2-week run-in phase with ibrutinib prior to the start of BI 836826. In combination with ibrutinib (420 mg daily dose, orally administered) BI 836826 was administered intravenously in Cycle (=4 weeks) 1 on day 1 (10 mg), days 2 and 8 (50% of the assigned dose on each day), day 15 (100% of the assigned dose), in Cycles 2-4 on days 1 and 15 of each cycle (100% of the assigned dose), in Cycles 5-12 on day 1 (100% of the assigned dose). Participants could have initiated 12 cycles with BI 836826 and could be treated with ibrutinib unless progression, unacceptable toxicity, or withdrawal of consent occurred earlier. Continued treatment beyond Cycle 12 (up to 24 treatment cycles) was possible for participants with a pre-specified response status at end of Cycle 12.
Measure Participants	0

2. Primary Outcome

Title	Number of Participants With Dose Limiting Toxicities (DLTs) During the First Treatment Cycle
Description	Number of participants with Dose Limiting Toxicities (DLTs) during the first treatment cycle. DLT was defined as any non-hematologic adverse event (AE) of Grade ≥ 3 related to BI 836826 and/or ibrutinib except infusion-related reaction (any Grade), Grade 3 Aspartate Aminotransferase (AST)- and/or Alanine Aminotransferase (ALT) elevation without concomitant bilirubin, elevation or any other asymptomatic Grade 3 laboratory abnormality with spontaneous recovery within 1 week. The following hematologic AEs related to BI 836826 and/or ibrutinib were considered DLT: Grade 4 neutropenia with concomitant infection, Grade 4 febrile neutropenia, and Grade 3 febrile neutropenia not resolving within 72 hours with appropriate treatment (antibiotics, antivirals, antifungals, growth factor support), Grade 4 thrombocytopenia with clinically significant bleeding, Grade 4 anemia, any Grade 5 hematologic AE.
Time Frame	First treatment cycle, 4 weeks from first administration of BI 836826.

Outcome Measure Data

Analysis Population Description

All participants who were documented to have initiated at least one dose of BI 836826 and were not replaced for the Maximum Tolerated Dose (MTD) evaluation.

Arm/Group Title	Dose Cohort BI 836826 100 Milligram (mg) + Ibrutinib	Dose Cohort BI 836826 200 Milligram (mg) + Ibrutinib
Arm/Group Description	Participants underwent a 2-week run-in phase with ibrutinib prior to the start of BI 836826. In combination with ibrutinib (420 mg daily dose, orally administered) BI 836826 was administered intravenously as a rate controlled injection in 4-week cycles, every two weeks for the first 16 weeks (Cycles 1-4), and every 4 weeks starting at week 17 (Cycle 5) until week 48 (Cycle 12). BI 836826 was administered in Cycle 1 on day 1 (10 mg), days 2 and 8 (50% of the assigned dose on each day), day 15 (100% of the assigned dose), in Cycles 2-4 on days 1 and 15 of each cycle (100% of the assigned dose), in Cycles 5-12 on day 1 (100% of the assigned dose). Participants could have initiated 12 cycles with BI 836826 and could be treated with ibrutinib unless progression, unacceptable toxicity, or withdrawal of consent occurred earlier. Continued treatment beyond Cycle 12 (up to a maximum of 24 treatment cycles) was possible for participants with a pre-specified response status at end of Cycle 12.	Participants underwent a 2-week run-in phase with ibrutinib prior to the start of BI 836826. In combination with ibrutinib (420 mg daily dose, orally administered) BI 836826 was administered intravenously as a rate controlled injection in 4-week cycles, every two weeks for the first 16 weeks (Cycles 1-4), and every 4 weeks starting at week 17 (Cycle 5) until week 48 (Cycle 12). BI 836826 was administered in Cycle 1 on day 1 (10 mg), days 2 and 8 (50% of the assigned dose on each day), day 15 (100% of the assigned dose), in Cycles 2-4 on days 1 and 15 of each cycle (100% of the assigned dose), in Cycles 5-12 on day 1 (100% of the assigned dose). Participants could have initiated 12 cycles with BI 836826 and could be treated with ibrutinib unless progression, unacceptable toxicity, or withdrawal of consent occurred earlier. Continued treatment beyond Cycle 12 (up to a maximum of 24 treatment cycles) was possible for participants with a pre-specified response status at end of Cycle 12.
Measure Participants	3	3
Number [Participants]	0 0%	0 0%

3. Secondary Outcome

Title	Maximum Tolerated Dose of BI 836826 in Combination With Ibrutinib
Description	To determine the Maximum Tolerated Dose (MTD) of BI 836826 in combination with ibrutinib, participants were entered sequentially into dose cohorts starting at 100 mg of BI 836826 and escalating to the MTD in combination with ibrutinib (fixed dose of 420 mg daily). Stepwise dose escalation of BI 836826 was guided by a Bayesian Logistic Regression Model (BLRM) with overdose control. The BLRM estimates the MTD by updating estimates of the probability of observing a Dose Limiting Toxicity (DLT) in the first treatment cycle (4 weeks) for each dose level as participant information becomes available. The MTD would be considered reached if the following criteria were fulfilled. The posterior probability of the true DLT rate in the target interval [0.16 - 0.33) of the MTD is above 0.50 or at least 15 participants have been treated in the study, of which at least 6 at the MTD.
Time Frame	First treatment cycle, 4 weeks from first administration of BI 836826.

Outcome Measure Data

Analysis Population Description

As the study was prematurely discontinued, recruitment of participants into the dose escalation part was not fully completed and the MTD was not reached.

Arm/Group Title	BI 836826 + Ibrutinib
Arm/Group Description	Treatment group "BI 836826 + ibrutinib" comprises all dose cohorts during the dose escalation phase, that is, "Dose cohort BI 836826 100 mg + ibrutinib" and "Dose cohort BI 836826 200 mg + ibrutinib". Participants underwent a 2-week run-in phase with ibrutinib prior to the start of BI 836826. In combination with ibrutinib (420 mg daily dose, orally administered) BI 836826 was administered intravenously in Cycle (=4 weeks) 1 on day 1 (10 mg), days 2 and 8 (50% of the assigned dose on each day), day 15 (100% of the assigned dose), in Cycles 2-4 on days 1 and 15 of each cycle (100% of the assigned dose), in Cycles 5-12 on day 1 (100% of the assigned dose). Participants could have initiated 12 cycles with BI 836826 and could be treated with ibrutinib unless progression, unacceptable toxicity, or withdrawal of consent occurred earlier. Continued treatment beyond Cycle 12 (up to 24 treatment cycles) was possible for participants with a pre-specified response status at end of Cycle 12.
Measure Participants	0

Adverse Events

Time Frame	On-treatment period + Residual Effect Period, that is, from first administration of BI 836826 until the end of the Residual Effect Period (30 days after the last infusion of BI 836826), up to 22 treatment cycles = 22 * 4 weeks + 30 days = 646 days.
Adverse Event Reporting Description	All participants who initiated at least one administration of BI 836826.
Arm/Group Title	Dose Cohort BI 836826 100 Milligram (mg) + Ibrutinib		Dose Cohort BI 836826 200 Milligram (mg) + Ibrutinib
Arm/Group Description	Participants underwent a 2-week run-in phase with ibrutinib prior to the start of BI 836826. In combination with ibrutinib (420 mg daily dose, orally administered) BI 836826 was administered intravenously as a rate controlled injection in 4-week cycles, every two weeks for the first 16 weeks (Cycles 1-4), and every 4 weeks starting at week 17 (Cycle 5) until week 48 (Cycle 12). BI 836826 was administered in Cycle 1 on day 1 (10 mg), days 2 and 8 (50% of the assigned dose on each day), day 15 (100% of the assigned dose), in Cycles 2-4 on days 1 and 15 of each cycle (100% of the assigned dose), in Cycles 5-12 on day 1 (100% of the assigned dose). Participants could have initiated 12 cycles with BI 836826 and could be treated with ibrutinib unless progression, unacceptable toxicity, or withdrawal of consent occurred earlier. Continued treatment beyond Cycle 12 (up to a maximum of 24 treatment cycles) was possible for participants with a pre-specified response status at end of Cycle 12.		Participants underwent a 2-week run-in phase with ibrutinib prior to the start of BI 836826. In combination with ibrutinib (420 mg daily dose, orally administered) BI 836826 was administered intravenously as a rate controlled injection in 4-week cycles, every two weeks for the first 16 weeks (Cycles 1-4), and every 4 weeks starting at week 17 (Cycle 5) until week 48 (Cycle 12). BI 836826 was administered in Cycle 1 on day 1 (10 mg), days 2 and 8 (50% of the assigned dose on each day), day 15 (100% of the assigned dose), in Cycles 2-4 on days 1 and 15 of each cycle (100% of the assigned dose), in Cycles 5-12 on day 1 (100% of the assigned dose). Participants could have initiated 12 cycles with BI 836826 and could be treated with ibrutinib unless progression, unacceptable toxicity, or withdrawal of consent occurred earlier. Continued treatment beyond Cycle 12 (up to a maximum of 24 treatment cycles) was possible for participants with a pre-specified response status at end of Cycle 12.
All Cause Mortality
	Dose Cohort BI 836826 100 Milligram (mg) + Ibrutinib		Dose Cohort BI 836826 200 Milligram (mg) + Ibrutinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/3 (0%)
Serious Adverse Events
	Dose Cohort BI 836826 100 Milligram (mg) + Ibrutinib		Dose Cohort BI 836826 200 Milligram (mg) + Ibrutinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)		3/3 (100%)
Blood and lymphatic system disorders
Neutropenia	1/3 (33.3%)		0/3 (0%)
Cardiac disorders
Acute coronary syndrome	0/3 (0%)		1/3 (33.3%)
Gastrointestinal disorders
Duodenal ulcer	0/3 (0%)		1/3 (33.3%)
Intestinal ischaemia	0/3 (0%)		1/3 (33.3%)
Intestinal obstruction	0/3 (0%)		1/3 (33.3%)
Infections and infestations
Cellulitis	0/3 (0%)		1/3 (33.3%)
Pseudomonal bacteraemia	0/3 (0%)		1/3 (33.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	1/3 (33.3%)		0/3 (0%)
Bowen's disease	0/3 (0%)		1/3 (33.3%)
Other (Not Including Serious) Adverse Events
	Dose Cohort BI 836826 100 Milligram (mg) + Ibrutinib		Dose Cohort BI 836826 200 Milligram (mg) + Ibrutinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		3/3 (100%)
Blood and lymphatic system disorders
Anaemia	2/3 (66.7%)		1/3 (33.3%)
Increased tendency to bruise	1/3 (33.3%)		0/3 (0%)
Lymphopenia	0/3 (0%)		2/3 (66.7%)
Neutropenia	1/3 (33.3%)		1/3 (33.3%)
Thrombocytopenia	1/3 (33.3%)		1/3 (33.3%)
Ear and labyrinth disorders
Ear pain	0/3 (0%)		1/3 (33.3%)
Eye disorders
Vision blurred	1/3 (33.3%)		0/3 (0%)
Gastrointestinal disorders
Abdominal pain upper	0/3 (0%)		1/3 (33.3%)
Constipation	0/3 (0%)		1/3 (33.3%)
Diarrhoea	1/3 (33.3%)		2/3 (66.7%)
Haemorrhoids	0/3 (0%)		1/3 (33.3%)
Lip swelling	1/3 (33.3%)		0/3 (0%)
Nausea	1/3 (33.3%)		1/3 (33.3%)
Oral pain	0/3 (0%)		1/3 (33.3%)
General disorders
Chest pain	0/3 (0%)		1/3 (33.3%)
Fatigue	1/3 (33.3%)		2/3 (66.7%)
Malaise	0/3 (0%)		1/3 (33.3%)
Pain	1/3 (33.3%)		0/3 (0%)
Pyrexia	2/3 (66.7%)		0/3 (0%)
Hepatobiliary disorders
Hyperbilirubinaemia	2/3 (66.7%)		0/3 (0%)
Infections and infestations
Bronchitis	0/3 (0%)		1/3 (33.3%)
Conjunctivitis	0/3 (0%)		1/3 (33.3%)
Nail infection	0/3 (0%)		1/3 (33.3%)
Pneumonia	1/3 (33.3%)		0/3 (0%)
Respiratory syncytial virus infection	0/3 (0%)		1/3 (33.3%)
Upper respiratory tract infection	2/3 (66.7%)		3/3 (100%)
Urinary tract infection	0/3 (0%)		1/3 (33.3%)
Vulvovaginal mycotic infection	0/3 (0%)		1/3 (33.3%)
Injury, poisoning and procedural complications
Arthropod bite	0/3 (0%)		1/3 (33.3%)
Contusion	0/3 (0%)		1/3 (33.3%)
Incision site pain	0/3 (0%)		1/3 (33.3%)
Infusion related reaction	3/3 (100%)		1/3 (33.3%)
Investigations
Blood creatinine increased	2/3 (66.7%)		0/3 (0%)
White blood cell count decreased	0/3 (0%)		1/3 (33.3%)
Metabolism and nutrition disorders
Hypercalcaemia	1/3 (33.3%)		0/3 (0%)
Hyperglycaemia	0/3 (0%)		1/3 (33.3%)
Hypophosphataemia	0/3 (0%)		1/3 (33.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/3 (33.3%)		2/3 (66.7%)
Back pain	1/3 (33.3%)		0/3 (0%)
Bone pain	0/3 (0%)		1/3 (33.3%)
Joint swelling	1/3 (33.3%)		0/3 (0%)
Muscle spasms	1/3 (33.3%)		0/3 (0%)
Musculoskeletal stiffness	0/3 (0%)		1/3 (33.3%)
Myalgia	0/3 (0%)		1/3 (33.3%)
Pain in jaw	1/3 (33.3%)		0/3 (0%)
Nervous system disorders
Neuropathy peripheral	1/3 (33.3%)		0/3 (0%)
Reproductive system and breast disorders
Atrophic vulvovaginitis	0/3 (0%)		1/3 (33.3%)
Vaginal haemorrhage	0/3 (0%)		1/3 (33.3%)
Respiratory, thoracic and mediastinal disorders
Cough	0/3 (0%)		2/3 (66.7%)
Nasal congestion	0/3 (0%)		1/3 (33.3%)
Oropharyngeal pain	0/3 (0%)		1/3 (33.3%)
Productive cough	1/3 (33.3%)		0/3 (0%)
Rhinorrhoea	0/3 (0%)		1/3 (33.3%)
Skin and subcutaneous tissue disorders
Alopecia	0/3 (0%)		1/3 (33.3%)
Ecchymosis	1/3 (33.3%)		1/3 (33.3%)
Erythema	1/3 (33.3%)		0/3 (0%)
Vascular disorders
Hypertension	1/3 (33.3%)		0/3 (0%)
Hypotension	0/3 (0%)		1/3 (33.3%)

Limitations/Caveats

Development of BI 836826 was discontinued (strategic decision). Recruitment was subsequently terminated, the Phase II part of the trial was eliminated from the protocol, participants on treatment were allowed to complete the trial as per protocol.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.