SL-401 (DT388IL3) is a novel cancer stem cell (CSC)-directed recombinant biologic agent that targets the interleukin-3 receptor (IL-3R). IL-3R is over-expressed on acute myeloid leukaemia (AML) stem cells relative to normal hematopoietic stem cells and on AML blasts. In pre-clinical studies, SL-401 targeted and eradicated CSCs and tumour bulk in both in vitro and in vivo assays, and prolonged the survival of immunosuppressed mice harbouring human AML xenografts.

In a Phase I dose escalation study in 74 patients with relapsed or refractory adult AML, de novo poor risk elderly AML or high risk myelodysplastic syndrome SL-401 was found to be well-tolerated at clinically active doses, with no treatment-related delayed recovery of the bone marrow. There were 2 complete remissions (CRs), 4 partial responses (PRs) and 14 minor responses (MRs) including 4 with >50% reduction in blasts. In addition, anti-tumour activity, defined as blast reductions or disease stabilisation, was seen in 46% of patients with relapsed or refractory AML, 55% of poor risk elderly AML and 43% of high risk MDS patients.

Durable CRs were induced in 2 patients with chemorefractory AML. One patient, who sustained a CR of >15 months duration, had a previous history of refractory AML, including two stem cell transplants, and had relapsed for a third time prior to entry onto this study. The second patient had a sustained CR of 8 months duration, after failing standard AML induction chemotherapy. This is consistent with the dual mechanism of action of SL-401 targeting both blasts and leukaemia stem cells.

In addition, the median survival was 3.2 months and the 12 months overall survival was 22%, which is favourable compared with historical 12-months survival of 2-8%. Also of note, SL-401 demonstrated a clinical anti-CSC effect as evidenced by a decrease in CSC activity in patient bone marrows (n=3), as determined by an ex vivo colony formation assay pre- and post-SL-401 treatment.

This study showed that SL-401 had demonstrated clinical activity, including durable CRs as well as blast reductions and disease stabilisation. Preliminary signals for a clinical anti-CSC effect and survival benefit in heavily pre-treated patients were also observed. SL-401 had a favourable safety profile and exhibited no myelosuppression. Given these promising results, Phase II studies of SL-401 are planned in patients with advanced AML and MDS. In parallel, SL-401 will be studied in additional Phase I trials as both single agent and in combination with other agents in IL-3R+ leukaemias including chronic myeloid leukaemias (CML).


Reference

M Konopleva, DE Hogge, DA Rizzieri et al Phase I Trial Results for SL-401, a Novel Cancer Stem Cell (CSC) Targeting Agent, Demonstrate Clinical Efficacy at Tolerable Doses In Patients with Heavily Pre-Treated AML, Poor Risk Elderly AML, and High Risk MDS Abstract 3298 presented at 52nd ASH, Orlando, FL, December 4-7, 2010.