Trial Outcomes & Findings for 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 (NCT NCT02759016)

Last Updated: 2020-09-29

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

7 participants

Primary outcome timeframe

First treatment cycle, 4 weeks from first administration of BI 836826.

Results posted on

2020-09-29

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	Dose Cohort BI 836826 100 Milligram (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 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.	Dose Cohort BI 836826 200 Milligram (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 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.
Overall Study STARTED	4	3
Overall Study Treated With BI 836826 and Ibrutinib	3	3
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	4	3

Reasons for withdrawal

Reasons for withdrawal
Measure	Dose Cohort BI 836826 100 Milligram (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 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.	Dose Cohort BI 836826 200 Milligram (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 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.
Overall Study Not treated with BI 836826	1	0
Overall Study Progressive disease	1	0
Overall Study SD, PR-MRDpos or PR-L	0	2
Overall Study Other not defined above	2	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Dose Cohort BI 836826 100 Milligram (mg) + Ibrutinib n=3 Participants 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.	Dose Cohort BI 836826 200 Milligram (mg) + Ibrutinib n=3 Participants 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 n=6 Participants Total of all reporting groups
Age, Continuous	73.0 years STANDARD_DEVIATION 4.4 • n=5 Participants	66.0 years STANDARD_DEVIATION 8.5 • n=7 Participants	69.5 years STANDARD_DEVIATION 7.2 • n=5 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Sex: Female, Male Male	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	2 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: First treatment cycle, 4 weeks from first administration of BI 836826.

Population: 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.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: First treatment cycle, 4 weeks from first administration of BI 836826.

Population: 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.

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.

Outcome measures

Outcome measures
Measure	BI 836826 + Ibrutinib n=3 Participants 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.	Dose Cohort BI 836826 200 Milligram (mg) + Ibrutinib n=3 Participants 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.
Number of Participants With Dose Limiting Toxicities (DLTs) During the First Treatment Cycle	0 Participants	0 Participants

SECONDARY outcome

Timeframe: First treatment cycle, 4 weeks from first administration of BI 836826.

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

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.

Outcome measures

Outcome data not reported

Adverse Events

Dose Cohort BI 836826 100 Milligram (mg) + Ibrutinib

Serious events: 2 serious events

Other events: 3 other events

Deaths: 0 deaths

Dose Cohort BI 836826 200 Milligram (mg) + Ibrutinib

Serious events: 3 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Dose Cohort BI 836826 100 Milligram (mg) + Ibrutinib n=3 participants at risk 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.	Dose Cohort BI 836826 200 Milligram (mg) + Ibrutinib n=3 participants at risk 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.
Blood and lymphatic system disorders Neutropenia	33.3% 1/3 • 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. All participants who initiated at least one administration of BI 836826.	0.00% 0/3 • 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. All participants who initiated at least one administration of BI 836826.
Cardiac disorders Acute coronary syndrome	0.00% 0/3 • 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. All participants who initiated at least one administration of BI 836826.	33.3% 1/3 • 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. All participants who initiated at least one administration of BI 836826.
Gastrointestinal disorders Duodenal ulcer	0.00% 0/3 • 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. All participants who initiated at least one administration of BI 836826.	33.3% 1/3 • 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. All participants who initiated at least one administration of BI 836826.
Gastrointestinal disorders Intestinal ischaemia	0.00% 0/3 • 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. All participants who initiated at least one administration of BI 836826.	33.3% 1/3 • 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. All participants who initiated at least one administration of BI 836826.
Gastrointestinal disorders Intestinal obstruction	0.00% 0/3 • 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. All participants who initiated at least one administration of BI 836826.	33.3% 1/3 • 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. All participants who initiated at least one administration of BI 836826.
Infections and infestations Cellulitis	0.00% 0/3 • 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. All participants who initiated at least one administration of BI 836826.	33.3% 1/3 • 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. All participants who initiated at least one administration of BI 836826.
Infections and infestations Pseudomonal bacteraemia	0.00% 0/3 • 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. All participants who initiated at least one administration of BI 836826.	33.3% 1/3 • 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. All participants who initiated at least one administration of BI 836826.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	33.3% 1/3 • 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. All participants who initiated at least one administration of BI 836826.	0.00% 0/3 • 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. All participants who initiated at least one administration of BI 836826.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bowen's disease	0.00% 0/3 • 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. All participants who initiated at least one administration of BI 836826.	33.3% 1/3 • 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. All participants who initiated at least one administration of BI 836826.

Other adverse events

Additional Information

Boehringer Ingelheim, Call Center

Boehringer Ingelheim

Phone: 1-800-243-0127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place