Safety and Pharmacokinetics of Subcutaneous Blinatumomab (SC blinatumomab) for the Treatment of Adults with Relapsed or Refractory B Cell Precursor Acute Lymphoblastic Leukemia (R/R B-ALL); Results from a Phase 1b Study

Background: Blinatumomab, a BiTE® (bispecific T cell engager) immuno-oncology therapy, which redirects CD3+ T cells to engage and lyse CD19+ target cells, has demonstrated efficacy and a tolerable safety profile in patients (pts) with R/R B-ALL when administered as a 28-day continuous intravenous infusion (cIV). SC blinatumomab can simplify treatment administration, improve pt convenience, and reduce cost. Here, we present the dose-escalation results of a multicenter, single-arm, open-label, phase 1b study (NCT04521231) to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of SC blinatumomab in adults with R/R B-ALL. Methods: In this ongoing trial, 4 cohorts of up to 6 pts each were planned. Pts in each cohort received 2‒5 cycles of SC blinatumomab. Each cycle included a 26-day treatment period and a 1-week treatment-free interval. Pts in cohorts 1, 2, 3, and 4 received 40, 120, 250, or 500 µg of SC blinatumomab once daily, respectively, from days 1 to 7. This was followed by a thrice-weekly regimen of 250 µg SC blinatumomab for cohorts 1 and 2 and 500 and 1000 µg of SC blinatumomab for cohorts 3 and 4, respectively, from days 8 to 26 of cycle 1, and from days 1 to 26 for all subsequent cycles. Bone marrow (BM) evaluation was performed on day 27 of each cycle and additionally on day 12 of cycle 1 in cohorts 3 and 4. Results: Twenty pts were enrolled at the data cut-off of June 20, 2022 (6 in cohort 1, 3 in cohort 2, 5 in cohort 3, and 6 in cohort 4). Median age was 58 years (range, 19‒83). Ten pts (50%) were aged >55 years. The number of prior therapies ranged from 2 to 4. All pts had an Eastern Cooperative Oncology Group score of 0-1 at enrollment. Six pts were refractory to frontline or salvage therapy, 9 pts relapsed after chemotherapy, 3 pts relapsed after prior hematopoietic stem cell transplantation (HSCT), 1 pt relapsed after prior HSCT and anti-CD19 chimeric antigen receptor T cell therapy, and 1 pt relapsed after 2 prior HSCTs and blinatumomab therapy where initial residual disease was cleared with cIV blinatumomab enabling first HSCT. The median number of cycles of SC blinatumomab received was 1 (range, 1‒5). Seven pts received 1 cycle, 1 pt received 2, 1 pt received 4 and 2 pts received 5. Six pts ended treatment during cycle 1 and in 3 pts cycle 1 is ongoing. Median bone marrow blast count at the start of the study was 77% (range, 6‒100%). No dose-limiting toxicities were reported in any cohort. Seventeen pts had grade ≥3 treatment-emergent adverse events (TEAEs; Table). Six pts (30.0%) had neurotoxicity (NT) at any grade and 4 pts (20%) had NT at grade 3. Sixteen pts (80.0%) had cytokine release syndrome (CRS) at any grade and 2 pts (10.0%) had CRS at grade 3 (cohort 4; each event resolved within 48 h and subsequent cycle 1 dose was restarted). There was no incidence of NT or CRS at grade ≥4. Six pts ended treatment due to TEAEs, of which 4 pts were from cohort 1 (n=1, grade 5 herpes encephalitis unrelated to blinatumomab; n=1, injection site reaction in cycle 2 in pt with no response; n=1, hyperleukocytosis due to disease progression; n=1, face swelling due to progression of extramedullary disease) and 2 pts were from cohort 3 (n=1, grade 2 CRS, grade 3 liver enzyme elevation, and grade 3 NT [dysarthria and disorientation]; n=1, disease non-response). Preliminary PK results through cohort 3 (cohort 4 ongoing) showed that observed exposures (average concentrations at steady state [SS]) of SC blinatumomab were consistent with the efficacious exposures (SS concentration) of the approved regimen of cIV blinatumomab. The PD profile demonstrated that peripheral T cell redistribution and activation (CD3+ and CD8+ CD69+ T cells), transient cytokine elevation (IL-6, IL-10, IFN-γ), and CD19+ B cell depletion were consistent with the historical PD profile for cIV blinatumomab. Nine of 14 pts (64.3%) in cohorts 1‒3 (cohort 4 ongoing; 3 of 6 [50%], 2 of 3 [66%], 4 of 5 [80%] in cohorts 1, 2, and 3, respectively) achieved complete response with full or partial hematologic recovery within 2 cycles of SC blinatumomab without the presence of measurable residual disease (MRD<10-4). Conclusion: In this ongoing phase 1b dose-escalation study, SC blinatumomab demonstrated an acceptable safety profile and anti-leukemia activity in heavily pretreated pts with R/R B-ALL. PK exposures and PD profiles were consistent with those reported for the cIV regimen of blinatumomab, supporting the use of SC dosing of blinatumomab in this pt population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal