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

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 leukemia (AML) stem cells relative to normal hematopoietic stem cells. IL-3R is also over-expressed on AML blasts. In pre-clinical studies, SL-401 targets and eradicates CSCs and tumor bulk in both in vitro and in vivo assays, and prolongs survival of immunosuppressed mice harboring human AML xenografts.

A Phase I dose escalation study was undertaken in 74 patients with relapsed or refractory adult AML (n=56), de novo poor risk elderly AML (n=11), or high risk myelodysplastic syndrome (MDS) (n=7). Thirty-three patients were >/= 2nd salvage. Cytogenetics were unfavorable (36%), intermediate (59%), favorable (0%), and not determined (5%). The median age was 65 years (range, 24–84). Patients received SL-401 via a 15 minute intravenous infusion in one of two dosing regimens for one cycle to determine the maximum tolerated dose (MTD) and to evaluate clinical activity. In Regimen A, 45 patients received doses ranging from 4 to 12.5 ug/kg every other day for up to six doses. In Regimen B, 29 patients received doses ranging from 7.1 to 22.1 ug/kg daily for up to 5 doses.

SL-401 was well-tolerated at clinically active doses. Grade 1–2 hypoalbuminemia was common (68%) but manageable and not dose-limiting. Other less common grade 1–2 adverse events (AEs) included fever and chills, largely infusion-related. Grade >/= 3 AEs included transaminase elevations (20%), mostly transient, and vascular leak (4%) which was the dose limiting toxicity (DLT) at 22.1 ug/kg daily × 5. The MTD was established at 16.6 ug/kg daily for 5 doses; no MTD was defined for the every other day schedule. Notably, there was no treatment-related delayed recovery of the bone marrow. This is consistent with the known over-expression of the drug's target, IL-3R, on leukemia versus normal hematopoietic stem cells. Absolute neutrophil count and hemoglobin remained stable, and near or above baseline pre-treatment levels, throughout therapy and up to day 30 post-infusion. Mean platelet counts were 58,000/uL pre-treatment, 30,000/uL at day 15, and back to baseline by day 30.

Overall, we observed 2 complete remissions (CRs), 4 partial responses (PRs) and 14 minor responses (MRs) including 4 with >50% reduction in blasts. In addition, anti-tumor activity, defined as blast reductions or disease stabilization, 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 complete remissions (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 leukemia stem cells. In addition, the median survival of >/= 2nd salvage AML patients was 3.2 months (95% CI: 2.0, 8.4) and the 12 months overall survival was 22% (95% CI: 5.1, 45.7) which is favorable 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.

SL-401 demonstrated clinical activity, including durable CRs as well as blast reductions and disease stabilization. Preliminary signals for a clinical anti-CSC effect and survival benefit in heavily pre-treated patients were also observed. SL-401 had a favorable 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+ leukemias including chronic myeloid leukemias (CML).

Konopleva:Stemline: Research Funding. Cirrito:Stemline: Employment, Equity Ownership, Patents & Royalties. Niecestro:Stemline: Consultancy, Equity Ownership. Bergstein:Stemline: Board of Directors, Employment, Equity Ownership, Patents & Royalties. Frankel:Stemline: Research Funding.