Lead-in Stage Results of a Pivotal Trial of SL-401, an Interleukin-3 Receptor (IL-3R) Targeting Biologic, in Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) or Acute Myeloid Leukemia (AML)
Authors: Sweet Kendra L. , Pemmaraju Naveen , Lane Andrew A , Stein Anthony S. , Vasu Sumithira , Blum William , Rizzieri David A. , Wang Eunice S. , Rowinsky Eric K. , Szarek Michael , Brooks Christopher L. , Disalvatore Sarah , Liu David , Duvic Madeleine , Schwartz Jonathan D. , Konopleva Marina 
Published: October 2019

Abstract
Background: SL-401 is a novel biologic delivering a truncated diphtheria toxin, a highly potent protein synthesis inhibitor, to the IL-3R that is overexpressed on cancer stem cells and tumor bulk in BPDCN, AML and other hematologic malignancies. The agent is being further evaluated in relapsed/refractory (r/r) BPDCN based on robust activity in BPDCN pts treated with a single cycle at 12 µg/kg/day x 5 (78% ORR, 55% CR; Frankel, Blood 2014). The objectives of the lead-in stage of this trial, which includes a pivotal evaluation in r/r BPDCN, were to evaluate the safety, pharmacokinetics (PK), and preliminary activity of multiple cycles, and confirm the dose for the BPDCN study and further AML studies.
Methods & Results: To date, 17 adults (9 BPDCN; 8 AML; median ages: All 63; BPDCN 69; AML 53), 15 of whom are evaluable for dose-limiting toxicity (DLT), have received 57+ cycles (range, 1-12+) of SL-401 as a 15 min infusion daily for up to 5 days every 3 weeks at 7 (6 pts/29+ cycles), 9 (3 pts/9 cycles) & 12 µg/kg/day (8 pts/19+ cycles). Two BPDCN pts had DLTs of capillary leak syndrome (CLS; Gr 5 [7 µg/kg/d]; Gr 4 [12 µg/kg/d]) in cycle 1 as manifested by decreased serum albumin during treatment followed by symptomatic CLS; both had rapid improvement of skin only disease but did not complete formal end-of-cycle assessments and are not evaluable for response. No other DLTs have occurred and the maximum tolerated dose (MTD) has not been identified. Measures, successful to date in preventing CLS, have been implemented to suspend dosing within a cycle for early CLS (manifested by weight gain and/or decreased albumin) and have allowed those pts to proceed to full 5-day dosing in subsequent cycles. Transient Gr 3 transaminase elevations, largely limited to cycle 1, have also occurred. Cumulative side effects have not been observed over multiple cycles. Five (71%) of 7 evaluable BPDCN pts had major objective responses, including complete responses. Four of 5 BPDCN pts with bone marrow involvement (range 15-80% blast count) had normalization to ≤ 5% blasts, and robust resolution of extensive, symptomatic skin lesions, lymphadenopathy, and soft tissue disease have also been noted, often within days of starting treatment. Several BPDCN pts with objective responses are receiving continued therapeutic benefit with successive cycles. Three r/r AML pts had stable disease for 6-12+ cycles, one of whom resolved transfusion dependence. Preliminary PK studies indicate inter-subject variability, increasing exposure from day 1 to 5 of cycle 1, and generally increased exposure in BPDCN relative to AML pts.
Conclusions: Multiple cycles of SL-401 are feasible and confer an acceptable safety profile at doses up to 12 µg/kg/day, which, along with safety measures to prevent CLS, will be used in a pivotal stage of this study in r/r BPDCN. Because of limited toxicity and evidence of protracted disease stabilization (up to 9+ mo) in several AML pts, further SL-401 dose escalation in AML is ongoing. Major responses in BPDCN and stabilization in AML indicate that targeting of IL-3R expressing cells via SL-401 has potential for sustained anticancer activity in aggressive myeloid malignancies.

Disclosures
Pemmaraju: Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Lane:Stemline Therapeutics, Inc.: Research Funding. Stein:Amgen: Speakers Bureau. Blum:Celator: Consultancy; Celgene: Consultancy; Boerhinger Ingelheim: Consultancy. Rizzieri:Teva: Other: ad board, Speakers Bureau; Celgene: Other: ad board, Speakers Bureau. Wang:Immunogen: Research Funding. Rowinsky:Stemline Therapeutics: Employment, Equity Ownership. Szarek:Stemline Therapeutics: Employment. Brooks:Stemline Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Disalvatore:Stemline Therapeutics: Employment. Liu:Stemline Therapeutics: Employment. Duvic:Cell Medica Ltd: Consultancy; Array Biopharma: Consultancy; Oncoceutics: Research Funding; Spatz Foundation: Research Funding; Rhizen Pharma: Research Funding; Allos (spectrum): Research Funding; Soligenics: Research Funding; Eisai: Research Funding; MiRagen Therapeutics: Consultancy; Huya Bioscience Int'l: Consultancy; Therakos: Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin, Co: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Research Funding; Tetralogics SHAPE: Research Funding. Schwartz:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding.