Results from Ongoing Phase 1/2 Clinical Trial of Tagraxofusp (SL-401) in Patients with Relapsed/Refractory Chronic Myelomonocytic Leukemia (CMML)
Authors: Patnaik Mrinal M. , Ali Haris , Gupta Vikas , Schiller Gary J. , Lee Sangmin , Yacoub Abdulraheem , Talpaz Moshe , Sardone Megan , Wysowskyj Halyna , Shemesh Shay , Chen Janice , Olguin Arturo , Brooks Christopher , Dunn Vanessa , Pardanani Animesh , Tefferi Ayalew , Verstovsek Srdan , Khoury Joseph David , Pemmaraju Naveen 
Published: October 2019

Abstract
Background: Patients with chronic myelomonocytic leukemia (CMML) have historically had poor outcomes, with overall response rates (ORR) of ~16% for hypomethylating agents (HMA) in first-line registration studies with a median overall survival (OS) of ~4-7 months in the relapsed/refractory (R/R) setting. Allogeneic stem cell transplant is not an option for the majority, due to older age at diagnosis and comorbidities. Tagraxofusp (Elzonris™, SL-401) is a novel targeted therapy directed to the interleukin-3 receptor-α (CD123), a target expressed on a variety of malignancies. In CMML, CD123 is expressed on malignant progenitor cells as well as microenvironmental plasmacytoid dendritic cell (pDC) infiltrates, now shown to be part of the malignant clone (Solary, EHA 2018). We thus hypothesized that therapeutic targeting of CD123-expressing malignant cells and infiltrating clonal pDCs may offer a novel therapeutic approach. Tagraxofusp has already demonstrated high levels of clinical activity against blastic plasmacytoid dendritic cell neoplasm (BPDCN), a CD123+ malignancy derived from pDCs.
Methods: This multicenter, two-stage Phase 1/2 trial is enrolling patients with relapsed/refractory (r/r) CMML or other myeloproliferative neoplasms (MPNs). Primary objectives include assessment of safety, determining optimal dose/regimen, and evaluating efficacy outcomes in patients with r/r CMML. In the Stage 1 dose escalation cohort (completed), tagraxofusp was administered as a daily IV infusion at 7, 9, and 12 mcg/kg/day, on days 1-3 every 21 days (cycle 1-4), every 28 days (cycles 5-7), and every 42 days (cycles 8+). In Stage 2 (ongoing), patients received the optimal dose determined in Stage 1 (12 mcg/kg; no MTD reached).
Results: As of July 2018, 18 patients with CMML (CMML-1 [n=10]; CMML-2 [n=8]) received tagraxofusp. 13 patients were treated in second-line setting and 5 patients were treated in third-line and beyond, with HMAs being the most commonly administered prior therapy. Median age was 70 years (range 42-80); 78% patients were male. 53% (9/17) of patients had baseline splenomegaly (range: 2 to 22 cm palpable below left costal margin (BCM) by physical exam). Most common treatment-related adverse events (TRAEs) were hypoalbuminemia and nausea (each 38%), vomiting (31%), fatigue, edema, and thrombocytopenia (each 25%). Most common ≥grade 3 TRAEs were thrombocytopenia (13%) and nausea (6%). Capillary leak syndrome was reported in 3 patients (19%; all grade 2). 100% (8/8) of patients with baseline splenomegaly had a spleen response, including 75% (6/8) who had reduction in splenomegaly of 50% or more. 60% (3/5) of patients with baseline spleen size ≥5cm had reduction in splenomegaly of 50% or more. Two patients treated with tagraxofusp achieved bone marrow CRs. 43% (6/14) of evaluable patients had a treatment duration of 6 months or more, including one at 8+ and one at 14+ months.
Conclusions: Tagraxofusp monotherapy resulted in significant reductions in spleen sizes along with bone marrow morphological responses in relapsed/refractory patients with CMML, with a manageable safety profile. Given CD123 expression on both neoplastic myeloid cells and pDCs infiltrates, tagraxofusp may offer a novel targeted approach for patients with CMML, an area of unmet medical need. Enrollment continues, and updated safety and efficacy data will be presented. A registrational trial in this patient population is planned. Clinical trial information: NCT02268253.

Disclosures
Ali: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte: Research Funding. Schiller:Celator/Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding. Lee:AstraZeneca: Consultancy; Clinipace: Consultancy; Karyopharm Therapeutics Inc: Consultancy; LAM Therapeutics: Research Funding; Amgen: Consultancy. Yacoub:Cara Therapeutics: Equity Ownership; Ardelyx, INC.: Equity Ownership; Dynavax: Equity Ownership; Inycte: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Sardone:Stemline Therapeutics: Employment, Equity Ownership. Wysowskyj:Stemline Therapeutics: Employment, Equity Ownership. Shemesh:Stemline Therapeutics: Employment, Equity Ownership. Chen:Stemline Therapeutics: Employment, Equity Ownership. Olguin:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics: Employment, Equity Ownership. Dunn:Stemline Therapeutics: Employment, Equity Ownership. Verstovsek:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Khoury:Stemline Therapeutics: Research Funding. Pemmaraju:celgene: Consultancy, Honoraria; novartis: Research Funding; Affymetrix: Research Funding; samus: Research Funding; cellectis: Research Funding; daiichi sankyo: Research Funding; stemline: Consultancy, Honoraria, Research Funding; plexxikon: Research Funding; abbvie: Research Funding; SagerStrong Foundation: Research Funding.