A phase Ib, open label, dose escalation trial of the anti-CD37 monoclonal antibody, BI 836826, in combination with ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia

Abstract

SummaryBI 836826 is a chimeric immunoglobulin G1 antibody targeting CD37, a transmembrane protein expressed on normal and malignant B cells. This open-label, phase Ib, dose-escalation study was conducted to determine the recommended phase II dose (RP2D) of BI 836826 + ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Eligible patients received 420 mg/day of ibrutinib with escalating doses of BI 836826. BI 836826 was administered in 4-week cycles. After Cycle 12, patients achieving complete response (CR), CR with incomplete marrow recovery, or minimal residual disease-negative partial response could continue to receive BI 836826 + ibrutinib every 4 weeks for ≤ 12 additional cycles. Patients received either 100 mg (n = 3) or 200 mg (n = 3) BI 836826 + ibrutinib. In the 100 mg BI 836826 cohort, one patient received two cycles and two patients received 22 cycles of BI 836826. In the 200 mg BI 836826 cohort, patients received 12, 16 and 20 cycles of BI 836826, respectively. All patients discontinued BI 836826 and continued ibrutinib outside the trial. No dose-limiting toxicities were reported in the maximum tolerated dose (MTD) evaluation period. As the trial was discontinued before the MTD was reached, the RP2D was not determined. Grade 3/4 adverse events (AEs) were predominantly hematological. Pseudomonal bacteremia was the only drug-related AE of special interest. BI 836826 + ibrutinib did not exceed the MTD at doses up to 200 mg in patients with CLL. However, RP2D and MTD were not formally established, as the sponsor discontinued the trial.

Immunotherapeutic Strategies in Chronic Lymphocytic Leukemia: Advances and Challenges

“…The ability of re-converting the immune system from CLL patients to a more effective status has led to the addition of ibrutinib to other regimens, with significant improvement of tumor control. Preclinical and clinical results have already demonstrated the ability of ibrutinib in i) improving the efficacy of the novel mAbs cirmtuzumab ( 52 , 53 ), ianalumab ( 59 ) and BI 836826 ( 48 ), ii) enhancing the susceptibility of CLL cells to BiTE-mediated killing ( 66 , 67 ), and iii) potentiating the generation, functionality and curative effects of CAR T cells ( 88 , 89 ). Similarly, other agents capable of modulating the immune system, such as avadomide, have shown promising results when administered in combination with checkpoint inhibitors ( 23 ), thus leading to reconsider active immunotherapy as a potential therapeutic option for patients with CLL.…”

“…BI 836826 is another CD37-targeting mAb that has been Fc-engineered in order to improve its cytotoxic effects. BI 836826 has proven to be particularly effective in CLL patients with del(17p) and/or TP53 mutation in a phase 1 study, and more recently a clinical trial testing its combination with ibrutinib in relapsed or refractory CLL patients has been terminated ( 48 ). Last, the Fc-engineered DuoHexaBody-CD37 is a biparatopic (dual epitope-targeting) anti-CD37 mAb with the E430G mutation that exerts enhanced cytotoxic functions ( 49 ).…”

Current Status of Novel Agents for the Treatment of B Cell Malignancies: What’s Coming Next?

“…CD37 is expressed almost exclusively on hematopoietic cells with high expression on mature B-cells, including their malignant counterparts [ 331 ]. A large number of CD37 targeting agents have been developed including mAbs, ARCs, ADCs, and CAR-T cells [ 332 , 333 , 334 , 335 ]. Among them, the anti-CD37 BI856826, initially reported as a valid therapeutic target in B-NHL (NCT01403948) [ 336 ] and CLL (NCT02759016) [ 334 ], did not undergo further clinical development upon the decision of sponsors to discontinue the trials.…”

“…A large number of CD37 targeting agents have been developed including mAbs, ARCs, ADCs, and CAR-T cells [ 332 , 333 , 334 , 335 ]. Among them, the anti-CD37 BI856826, initially reported as a valid therapeutic target in B-NHL (NCT01403948) [ 336 ] and CLL (NCT02759016) [ 334 ], did not undergo further clinical development upon the decision of sponsors to discontinue the trials. A phase I/II study is evaluating the safety and efficacy of the ARC 177 Lutetium-lilotomab satetraxetan (betalutin) for treatment of relapsed B-NHL ( Table 4 ) [ 289 ].…”

Anti-CD37 α-amanitin–conjugated antibodies as potential therapeutic weapons for Richter syndrome

“…[9][10][11] CD37 has recently gained attention as a potential target, with consequent development of novel therapeutic agents [12][13][14][15][16] that have shown clinical efficacy in CLL and DLBCL when used in combination with rituximab, chemotherapy, or targeted compounds. [17][18][19][20][21] The increased interest and efficacy of anti-CD37-based therapies prompted the development of 3 different anti-CD37-ATACs (amanitin-based ADCs). These novel drugs are composed of a chimeric monoclonal IgG1 antibody specific for CD37, conjugated via either a proteolytic cleavable (anti-CD37-Ama 1 and anti-CD37-Ama 2) or a noncleavable (anti-CD37-Ama 3) linker to amanitin as the payload (supplemental Figure 1A, available on the Blood Web site).…”