Phase 1b/2 study of blinatumomab in Japanese adults with relapsed/refractory acute lymphoblastic leukemia

Abstract

Adult patients with relapsed/refractory (R/R) B-precursor acute lymphoblastic leukemia (ALL) have a poor prognosis. Blinatumomab is a bispecific T-cell engager (BiTE) immuno-oncology therapy with dual specificity for CD19 and CD3 that redirects patients' CD3-positive cytotoxic T cells to lyse malignant and normal B cells. We conducted an open-label, phase 1b/2 study to determine the safety, pharmacokinetics, efficacy and recommended dose of blinatumomab in Japanese adults with R/R B-precursor ALL. Patients received 9 μg/day blinatumomab during week 1 and 28 μg/day during weeks 2-4, with a 2-week treatment-free interval (6-week cycle); patients received 28 μg/day blinatumomab in subsequent cycles. Primary endpoints were the incidence of dose-limiting toxicities (DLT) in phase 1b and complete remission (CR)/CR with partial hematologic recovery (CRh) within the first two cycles in phase 2. A total of 26 patients enrolled and 25 (96%) reported grade ≥3 adverse events (mostly cytopenias). There were no DLT. CR/CRh within two cycles was achieved by 4 of 5 patients (80%) in phase 1b and 8 of 21 patients (38%) in phase 2. Among patients with evaluable minimal residual disease, 4 (100%) in phase 1b and 3 (38%) in phase 2 had a complete MRD response. Median RFS for 8 patients who achieved CR/CRh in phase 2 was 5 (95% CI: 3.5-6.4) months; median OS was not estimable. There were no significant associations between maximum cytokine levels or percentage of specific cell types during cycle 1 and response. Consistent with global studies, blinatumomab appeared to be safe and efficacious in Japanese adults with R/R ALL.

Keywords: Japan; acute lymphoblastic leukemia; blinatumomab; clinical study; phase 1b; refractory; relapsed.

Conflict of interest statement

This clinical trial was funded by Amgen and Amgen Astellas BioPharma KK (ClinicalTrials.gov: NCT02412306). Blinatumomab was provided by Amgen. The funder contributed to the study design, data collection, data analysis and data interpretation, and funded a professional medical writer to assist with writing the report. The authors had full access to all data in the study and had final responsibility for the decision to submit for publication. Hitoshi Kiyoi has received research funding from Astellas, Celgene, Chugai, Eisai, FUJIFILM, Kyowa Hakko Kirin, Nippon Shinyaku, Novartis Pharma KK, Otsuka, Pfizer Japan, Sanofi, Sumitomo Dainippon, Takeda and Zenyaku Kogyo; and honoraria from Amgen, Astellas, Astellas BioPharma KK, Bristol‐Myers Squibb, Daiichi Sankyo and Novartis Pharma KK. Tomoko Hata, Iekuni Oh and Yasuhiro Nakashima have nothing to disclose. Yoshinobu Maeda has received research funding from Astellas. Hironobu Minami has received research funding from Chugai, and honoraria from Celgene, Astellas, Janssen and Novartis. Toshihiro Miyamoto has received honoraria from Amgen and Bristol‐Myers Squibb. Toru Sakura has received research funding from AbbVie GK, Astellas Pharma, Amgen Astellas BioPharma KK, Daiichi Sankyo and Otsuka. Hiroatsu Iida has received research funding from Chugai and honoraria from Astellas, Novartis, Celgene and Janssen. Abraham Anderson, Yuqi Chen, Joan D Morris and Catherine A. Tuglus are employees and stockholders of Amgen. Cedric Dos Santos and James Kalabus are ex‐employees and stockholders of Amgen. Yukio Kobayashi has received lecture fees/honoraria from Astellas.

© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Figures

Figure 1

Flow of patients through the study. A, Phase 1b part. B, Phase 2 part. aDeaths in the phase 1b part of the study were due to liver failure (1 patient), brain abscess (1 patient) and disease progression (3 patients). bDeaths in the phase 2 part of the study were due to tumor lysis syndrome (fatal adverse event, 1 patient) and disease progression (1 patient). cPatients still on study as of the data cutoff date (24 August 2017). alloHSCT, allogeneic hematopoietic stem cell transplantation

Figure 2

Cytokine levels grouped by patient response (CR/CRh) to blinatumomab treatment. Individual patient maximum cytokine levels in cycle 1 are shown with 1st, 2nd and 3rd quartiles (box) and outliers (whiskers). The horizontal line denotes the median. Results below the lower limit of quantitation (LLOQ, 125 pg/mL) were imputed to half of the LLOQ. CR, complete remission; CRh, complete remission with partial hematological recovery; IFN, interferon; IL, interleukin; TNF, tumor necrosis factor

Figure 3

Individual patient levels of T cells and B cells during cycle 1. A, CD3+ cells/mm3. B, CD3+CD4+ cells/mm2. C, CD3+CD8+ cells/mm2. D, Percentage of CD3− CD19+ cells

Figure 4

Baseline percentages of specific cell subsets grouped by patient response (CR/CRh) to blinatumomab treatment. CR, complete remission; CRh, complete remission with partial hematological recovery; NK, natural killer