Results from Ongoing Phase 1/2 Trial of SL-401 in Patients with Myeloproliferative Neoplasms Including Chronic Myelomonocytic Leukemia and Primary Myelofibrosis

Background: SL-401 is a novel targeted therapy, comprised of recombinant IL-3 genetically fused to a truncated diphtheria toxin payload, directed to the interleukin-3 receptor α (CD123). CD123 is expressed by various cellular components of hematologic malignancies, including myeloproliferative neoplasms (MPN) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). CD123 is also expressed on immune plasmacytoid dendritic cells (pDCs), which have been shown to reside in the microenvironment of some malignancies, especially chronic myelomonocytic leukemia (CMML, 30-40%), where they may play a role in tumor growth. Accordingly, a therapy directed at CD123-expressing myeloid neoplastic cells and/or neighboring CD123-expressing pDCs could provide a therapeutic benefit. SL-401 is currently being evaluated in patients with MPN or MDS/MPN, including CMML and primary myelofibrosis (PMF). Preliminary results from this ongoing trial are reported here.

Methods & Results: This is a multicenter, single-arm Phase 1/2 trial of patients with MPN receiving SL-401 who have relapsed or are unable to tolerate standard therapy. In Stage 1 dose escalation (enrollment completed), patients received SL-401 as a daily IV infusion at 7, 9, or 12 mcg/kg/day on days 1-3 of a 21, 28 or 42-day cycle (cycles 1-4, 5-7, >8, respectively) in a standard 3x3 design. In Stage 2 (ongoing), patients receive SL-401 at the dose determined in Stage 1. Primary objectives include characterization of the safety profile, including determination of the maximum tolerated or tested dose, and overall response rate (ORR). In Stage 1, no DLT or MTD was reached. The 12 mcg/kg dose was selected for Stage 2. Nineteen (19) patients received SL-401 (MF, n=11; CMML-1, n=5; CMML-2, n=2; systemic mastocytosis (SM), n=1), 13 of whom received SL-401 at the 12 µg/kg dose. The median age was 69 years (range: 42-81) with a median of 1 prior line of therapy. Median number of SL-401 cycles was 3 (range: 1-11+). The most common treatment-related adverse events (TRAEs) were fatigue (6/19; 32%), thrombocytopenia (5/19; 26%), anemia (5/19; 26%), hypoalbuminemia (4/19; 21%), and capillary leak syndrome (CLS) (4/19; 21%). CLS was reported in 4 patients: grade 2 (n=3) and grade 3 (n=1). All events resolved and patients remained on study. The most common ≥ grade 3 TRAEs were anemia (4/19; 21%) and thrombocytopenia (3/19; 15.7%). SL-401 monotherapy achieved a complete response (CR) in a CMML-1 patient (receiving SL-401 for 10⁺ months, ongoing). There were also 7 patients with stable disease (SD) (1-8 months duration), including in 1 PMF patient with pre-treatment platelet count <50,000. Sixty percent (60%; 3/5) of patients with SD who received SL-401 at the 12 mcg/kg dose experienced spleen reductions (of 46%, 29% and 21%) by physical exam. CD123 analyses and patient enrollment in Stage 2 are ongoing.

Conclusions: SL-401 has been well-tolerated in patients with MPN and CMML, with primary TRAEs being fatigue, thrombocytopenia, anemia, hypoalbuminemia, and capillary leak syndrome (21% [4/19] including 1 grade 3 event). Early signs of activity include one CR (receiving SL-401 for 10⁺ months, ongoing), and 7 SDs (which include 3 spleen reductions of 21%-46% at the 12 mcg/kg dose). Given CD123 expression on myeloid neoplastic cells as well as pDCs within the microenvironment, SL-401 may offer a novel, targeted therapeutic approach in patients with certain MPNs of unmet medical need. CD123 analyses are ongoing and patient enrollment continues in Stage 2 of this Phase 1/2 trial. Clinical trial information: NCT02268253.