SL-401, a Targeted Therapy Directed to the Interleukin-3 Receptor on Cancer Stem Cells and Tumor Bulk, Has Broad Clinical Activity and Tolerability as a Single Agent in Patients with Advanced Hematological Malignancies

Study Design: Eighty-five patients with advanced hematologic cancers, including relapsed or refractory AML (n = 59), de novo AML unfit for chemotherapy (n = 11), high-risk MDS (n = 7), CML in accelerated or blast phase failing prior tyrosine kinase-containing therapy (n = 3), and relapsed/refractory BPDCN (n = 5), were enrolled in a multicenter study at four study sites in the US and Canada. Among the patients with relapsed or refractory AML, the numbers of patients receiving SL-401 as 2nd, 3rd, or >3rd line therapy were 24, 16, and 19, respectively. The median age for all patients was 65 (range, 7-84) years. Patients received a single cycle of SL-401 as a 15-minute intravenous infusion in one of two dosing regimens to determine the maximum tolerated dose (MTD) and assess antitumor activity. In Regimen A, 45 patients received doses ranging from 4 to 12.5 µg/kg every other day for up to 6 doses. In Regimen B, 40 patients received doses ranging from 7.1 to 22.1 µg/kg daily for up to 5 doses. Results: A single cycle of SL-401 demonstrated single agent activity in patients with relapsed or refractory AML, including 2 durable complete responses (CRs) of 8 and >25 months duration and 5 partial responses (PRs). Overall survival (OS) was also notable among patients who received one cycle of SL-401 as ≥3rd line therapy for AML (n = 35); the median OS was 3.6 months (95% CI: 2.3, 6.1 months). Moreover, at therapeutically relevant doses, defined as the MTD (16.6 µg/kg/day) or one or two dose levels below the MTD (9.4 or 12.5 µg/kg/day), the median OS among AML patients who received SL-401 as ≥3rd line therapy (n = 16) was 5.6 months (95% CI: 2.5, 10.8 months). These OS values compared favorably to historical results of 1.5 months median OS for patients treated with standard chemotherapy. Major responses were also noted in patients with de novo AML who were unfit for chemotherapy and high risk MDS. In addition, three heavily pre-treated patients with BPDCN, which is known to express high levels of the IL-3R, had CRs of 1, 5, and >9 months (ongoing) duration, while an additional BPDCN patient had a PR. SL-401 was well tolerated. The MTD was not achieved with Regimen A, whereas the MTD for Regimen B was 16.6 µg/kg/day, with hypoalbuminemia and edema, manifestations of capillary leak, as the doselimiting toxicity (DLT) at the 22.1 µg/kg/day dose level. Other ≥Grade 3 AEs included transient (i.e., lasting ≤2 weeks) hepatic transaminase elevations. Notably, there was no evidence of treatment-related bone marrow suppression. Conclusion: SL-401 demonstrated single-agent anti-tumor activity and was well-tolerated in heavily pretreated patients with advanced AML, as well as in patients with MDS and BPDCN. In advanced AML, improved OS was observed among patients who received a single cycle of SL-401 as ≥3rd line treatment, a disease setting in which there is no standard therapy. SL401 may be an attractive treatment option for these patients given their susceptibility to severe myelosuppression and therefore often poor candidates for myelosupressive therapies that have limited benefit on clinical response and OS in this setting. Based on these positive findings, SL-401 will be advanced into a single-arm Phase 2b trial to treat patients with relapsed/refractory BPDCN, as well as a randomized Phase 2b trial to treat patients with AML in the 3rd line setting. In the BPDCN study, patients will be treated with multiple cycles of single-agent SL-401. In the AML study, patients will be randomized to treatment with either multiple cycles of single-agent SL-401 or physician’s choice, which will consist of available standard therapeutic agents. Single-agent SL-401 will also be studied in other malignancies where IL-3R is also overexpressed, including hairy cell leukemia, basophilic leukemia, and systemic mastocytosis. In addition, the efficacy and safety of SL401-based combination therapy will be evaluated in earlier lines of AML given the lack of overlapping side effects between SL-401 and traditional chemotherapy for AML.