Leukemia, Lymphocytic, Chronic, B-Cell
Conditions
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
Interventions
DRUGBI 836826
DRUGIbrutinib
Standard of Care
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 3 |
| 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. | 3 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Not treated with BI 836826 | 1 | 0 |
| Overall Study | Other not defined above | 2 | 1 |
| Overall Study | Progressive disease | 1 | 0 |
| Overall Study | SD, PR-MRDpos or PR-L | 0 | 2 |
Baseline characteristics
| Characteristic | Dose Cohort BI 836826 200 Milligram (mg) + Ibrutinib | Total | Dose Cohort BI 836826 100 Milligram (mg) + Ibrutinib |
|---|---|---|---|
| Age, Continuous | 66.0 years STANDARD_DEVIATION 8.5 | 69.5 years STANDARD_DEVIATION 7.2 | 73.0 years STANDARD_DEVIATION 4.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 5 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 6 Participants | 3 Participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 2 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 2 / 3 | 3 / 3 |
Outcome results
Primary
Number of Participants With Dose Limiting Toxicities (DLTs) During the First Treatment Cycle
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.
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BI 836826 + Ibrutinib | Number of Participants With Dose Limiting Toxicities (DLTs) During the First Treatment Cycle | 0 Participants |
| Dose Cohort BI 836826 200 Milligram (mg) + Ibrutinib | Number of Participants With Dose Limiting Toxicities (DLTs) During the First Treatment Cycle | 0 Participants |
Primary
Recommended Phase 2 Dose of BI 836826 in Combination With Ibrutinib
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.
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.
Secondary
Maximum Tolerated Dose of BI 836826 in Combination With Ibrutinib
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.
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.