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Letters to the Editor
A phase I study of the fully human, fragment crystal- lizable-engineered, anti-CD-33 monoclonal antibody BI 836858 in patients with previously-treated acute myeloid leukemia
In recent years, several research programs in acute myeloid leukemia (AML) have investigated the use of therapeutic monoclonal antibodies, which primarily elicit their effects through direct cell killing (apoptosis), via antibody-dependent cellular cytotoxicity (ADCC) or anti- body-dependent cellular phagocytosis (ADCP).1,2 Attention has been particularly focused on the myeloid differentiation antigen CD33,2 which is expressed on the surface of leukemic blast cells of almost all AML patients.1 While the activity of unconjugated anti-CD33 antibodies such as lintuzumab has been generally disap- pointing to date,3-6 clinical experience with gemtuzumab ozogamicin, a humanized anti-CD33 antibody-drug con- jugate, provides proof-of-principle for targeting CD33 in patients with AML.7,8
BI 836858 is a fully humanized IgG1 unconjugated anti-CD33 monoclonal antibody.1,9 Unlike lintuzumab, BI 836858 was fragment crystallizable (Fc)-engineered for increased binding to FcγRIIIa (CD16),9 a receptor found on the surface of natural killer (NK) cells and known to be involved in ADCC signaling.1,10 Accordingly, BI 836858 demonstrated superior ADCC to lintuzumab in AML cells in the laboratory.9 Here, we report the findings of a phase I dose escalation study of BI 836858 in patients with relapsed or refractory (R/R) AML, according to World Health Organization 2016 cri- teria (clinicaltrials gov. Identifier: NCT01690624).
Details of the study are available on request. Briefly, BI 836858 was administered as an intravenous (i.v.) infusion every 7 days in a 14-day treatment cycle (days 1 and 8). Premedication was obligatory prior to the first three administrations (acetaminophen/paracetamol; anti- histamine; glucocorticoid). The starting dose of BI 836858 was 10 mg, and in the absence of dose-limiting toxicities (DLT), dose escalation up to 320 mg was planned. Patients could receive up to eight repeated administrations of BI 836858 and in the case of clinical benefit and acceptable tolerability were allowed to con- tinue treatment beyond that until disease progression. In the first seven patients, infusions were administered over a 3-hour period; however, due to the occurrence of a high number of infusion-related reactions (IRR), administra- tion was adapted to a stepwise rate-controlled infusion with an increased premedication glucocorticoid dose (100 mg prednisolone or equivalent). If no IRR were apparent after first administration, the dose was reduced to 50 mg for adminstrations two to four, 25 mg for administration 5 and zero thereafter. Also, the protocol was adapted according to tumor load; patients with >5,000 leukocytes/mL peripheral blood were excluded. The primary endpoints for the study were the maximum tolerated dose (MTD) and number of patients with DLT during the MTD evaluation period (the first 2 treatment cycles). Secondary efficacy endpoints included best over- all response according to International Working Group Criteria and progression-free survival (PFS), defined as the time from first treatment with BI 836858 until disease progression, relapse or death.
Fifty-five patients were screened and 27 were treated with BI 836858 (10-40 mg; Table 1). The median duration of treatment was 21 days (range, 1-99 days), with a medi- an of three infusions given (range, 1-14 infusions). The DLT evaluation period was not completed by 13 patients
for reasons other than DLT (progressive disease, n=7; fatal intracranial hemorrhage, n=1; other adverse event [AE], n=2; patient refusal, n=1; not evaluable per proto- col, n=1; persistent disease/lack of efficacy, n=1), there- fore the MTD analysis set comprised 14 patients. Two patients in the 10 mg cohort had DLT. One patient had drug-related grade 3 elevated alanine aminotransferase (ALT) and aspartate transaminase (AST) 2 days after the first dose of BI 836858, which resolved within 8 days and 5 days, respectively. No change was made to study treat- ment for this patient. A second patient had a treatment- related grade 3 liver function test increased 3 days after the first dose of BI 836858, which resolved within 6 days. BI 836858 was discontinued in this patient. Following protocol amendment, no further DLT were reported in the 10, 20 or 40 mg dose cohorts. The MTD was not reached because the study was prematurely terminated by the sponsor, based on interim pharmacodynamic eval- uations.
The most common AE were febrile neutropenia (44%), nausea (44%), IRR (41%) and anemia (37%; Table 2). Febrile neutropenia (41%) was the most fre- quent grade 3 AE. Grade 4 AE were reported in six patients (22%). Seventeen (63%) patients had AE con- sidered related to BI 836858 (9 in the 10 mg cohort, 5 in the 20 mg cohort, and 3 in the 40 mg cohort). The most common were IRR (11 patients [41%]). The rate of IRR was higher prior to adaptation of the infusion protocol (57% vs. 35% after adaptation) with all IRR occurring in patients with a white blood cell (WBC) count of >10x103/mL. The majority of IRR occurred during the first six infusions. All cases of IRR were manageable with established supportive care measures. No patients expe- rienced AE that led to dose reductions. Six (22%) patients discontinued treatment due to AE, including one with grade 3 febrile neutropenia (20 mg dosing cohort), one with grade 2 leukocytosis (10 mg), one grade 3 cardiac failure (40 mg), one grade 3 IRR (20 mg), one grade 3 liver function test increased (10 mg) and one patient with a grade 4 neutrophil count decreased (10 mg). Twenty- three patients (85%) had serious AE (SAE); five SAE were considered to be related to the study drug and were recorded in four patients (grade 3 IRR; grade 3 IRR and grade 3 liver function test increased; grade 3 non-cardiac chest pain; grade 3 elevated ALT/AST). Sixteen patients died during the study (8 during the on-treatment period; 4 of which were due to disease progression and 4 were due to unknown reasons). None of the deaths were relat- ed to study treatment. Special search categories for AE (i.e., user-defined search categories) were used for this study to adequately monitor the frequency and severity of anticipated AE (e.g., potential class effects). The most frequent user-defined AE were neutropenia (48%), nau- sea (44%), IRR (41%) and drug-related hepatic disorders (33%). Laboratory evaluation demonstrated that 24 (89%) patients had low WBC counts (grade 3: 33%; grade 4: 52%)
BI 836858 exhibited two-compartmental pharmacoki- netic behavior, with maximum plasma concentrations generally achieved at the end of the infusion (Table 3). From 10 to 40 mg BI 836858, maximum plasma concen- trations for patients with R/R AML patients increased in a dose-proportional manner (Online Supplementary Figure S1). BI 836858 exposure and apparent terminal half-life (t1/2) increased with increasing doses (Table 3). Total plas- ma clearance was low and decreased in a dose-dependent manner. The volume of distribution was small, at approx- imately 6-7 L. No accumulation of BI 836858 was observed in plasma after weekly doses of up to 20 mg.
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haematologica | 2022; 107(3)