A Phase 1 Study Investigating AFM11 in Patients with Relapsed/Refractory B Cell Precursor Acute Lymphoblastic Leukemia: Preliminary Results

Background

AFM11 is a bispecific, tetravalent T cell-engaging antibody construct binding to CD19 on B cell origin malignant cells such as B-precursor acute lymphoblastic leukemia (B-ALL) and to CD3 on T cells. By engaging CD3-positive T cells, AFM11 elicits T cell-mediated killing of CD19-positive (CD19+) leukemia and lymphoma cells. In vivo anti-tumor activity of AFM11 was investigated in a Raji tumor xenograft model in non-obese diabetic/severe combined immunodeficiency (NOD/scid) mice reconstituted with human peripheral blood mononuclear cells (PBMC). Tumor growth in all AFM11-treated animal groups was significantly reduced. In the highest dose group, all animals achieved complete tumor remission. (Reusch et al., 2015). An ongoing Phase 1 study assesses safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of AFM11 in patients with relapsed/refractory (R/R) CD19+ B-ALL.

Methods

Patients (pts) with relapsed or refractory CD19+ B-ALL are being enrolled into escalating cohorts of 1-6 pts. The primary objective of the study is to determine the maximum tolerated dose (MTD) of AFM11 administered as a 2-week continuous intravenous (CIV) infusion. AFM11 is administered over the first 2 weeks (wks) of each 4 wk cycle for up to 3 cycles. Pts with rapidly progressing disease receive pre-treatment with 200 mg cyclophosphamide and 10 mg/m2 dexamethasone over 3-5 days before initiating AFM11. A lower starting dose is employed during the first wk of cycle 1 and escalated to a target dose during the second wk of cycle 1 and all subsequent cycles. An accelerated titration design is used until toxicity is observed, followed by a classical 3+3 design. PD activity is assessed by flow cytometry of peripheral blood lymphocytes and serum cytokine measurements. Tumor response is evaluated by local bone marrow and peripheral blood laboratory results between days 15 and 18 of each cycle.

Results

As of June 29, 2018, fourteen pts (8 female/6 male) have been treated in 5 cohorts. The median age is 41.5 years (range 19-67) and the median number of prior therapies is 5 (range 1-12). AFM11 was well-tolerated with no dose-limiting toxicities (DLTs) observed in the first 5 cohorts. The study switched to 3+3 design in cohort 3 due to the occurrence of grade 2 AFM11-related events in cohort 2. Enrollment into cohort 6 is ongoing and the MTD has not yet been reached.

The most frequent (≥2 pts) AFM11-related adverse events were pyrexia (29%), myalgia (14%), and tremor (14%). Most of the events were Common Terminology Criteria for Adverse Events (CTCAE) v4.03 grade 1-2, with one grade 3 and no grade 4 events observed. Transient and reversible neurological events occurred in 3 of 14 (21%) pts: grade 1 paresthesia (n=1), grade 1/grade 2 tremor (n=1 each), grade 2 lethargy (n=1); and grade 3 altered state of consciousness (n=1). The grade 3 event occurred during the third cycle of treatment and was managed with treatment interruption and steroids and resolved within 48 hours. The pt then completed the third cycle at a reduced AFM11 dose without incident.

Peripheral B cell reductions were observed in multiple pts in cohorts 4 and 5 and notable cytokine release was detected in two pts. Two pts achieved complete remission with complete hematological recovery (CR): one pt in cohort 4 achieved CR after the first cycle and progressed 2 wks later; one pt in cohort 5 achieved CR after the first cycle which was sustained after the second and third cycles and was assessed as minimal residual disease (MRD) negative after cycle 3. As a result, this pt became eligible to receive stem cell transplantation upon study completion. Both CR pts had peripheral B-cell aplasia after the first few days of treatment. Updated data will be presented.

Conclusions

The CD19/CD3-targeting tetravalent bispecific T cell engager AFM11 was well-tolerated in pts with R/R B-ALL across the first 5 cohorts of an ongoing Phase 1 study, and the MTD has not been reached. Pyrexia was the most frequently observed related adverse event. Transient neurological events were observed and were consistent with those associated with other CD19-targeted therapies. Peripheral B cell reductions and complete remissions observed in pts treated in the higher dose cohorts suggest that AFM11 is active in pts with R/R B-ALL and that the study is nearing determination of the therapeutic dose and schedule.