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

Study Overview
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Brief Summary
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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

Official Title
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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

Conditions
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Leukemia, Lymphocytic, Chronic, B-Cell

Intervention / Treatment
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* Drug: BI 836826
* Drug: Ibrutinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 836826<br>BI 836826 administered in combination with Standard of Care Ibrutinib | Drug: BI 836826<br> <br> Drug: Ibrutinib<br>* Standard of Care<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | First treatment cycle, 4 weeks from first administration of BI 836826. | 
| 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. | First treatment cycle, 4 weeks from first administration of BI 836826. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | First treatment cycle, 4 weeks from first administration of BI 836826. |