Search

TPS11577 Background: Several sarcomas possess chromosomal translocations in FET family members ( FUS, EWSR1, and TAF15) responsible for cancer development. Sarcomas caused by FET family gene rearrangements include ES, desmoplastic round cell small tumors (DSRCT), myxoid liposarcoma (ML), and several others. Lysine specific demethylase 1 (LSD1) is a critical protein for sarcoma development and progression through its colocalization and/or association with several FET family oncogenic transcription factors. This suggests that pharmacologic inhibition of LSD1 may be a therapeutic strategy. Seclidemstat (SP-2577, Salarius Pharmaceuticals) is an oral, first-in-class, small molecule with reversible, noncompetitive inhibition of LSD1 (IC50: 25–50 nM). In vitro and in vivo data demonstrate seclidemstat, or analogs, modulate EWS/ETS transcriptional activity, down-regulating oncogene expression and up-regulating tumor-suppressor gene expression, leading to significant tumor growth inhibition in ES mouse xenograft studies. Seclidemstat has shown in in vitro ES cell lines near additivity efficacy when added to TC. In in vitro studies of other FET-translocated sarcomas, including ML (FUS/DDIT3 fusion) and clear cell sarcoma (EWS/ATF1 fusion), seclidemstat showed anti-proliferative activity. In an ongoing Phase 1 trial investigating single agent seclidemstat in advanced solid tumors (NCT03895684), three pts with metastatic FET-translocated sarcomas had a median progression-free survival of 5.7 months (range: 4.3–7.2) with a best response of stable disease despite having a median of 5 (range: 1–7) prior therapies. Methods: This dose expansion Phase 1 study (NCT03600649) assesses seclidemstat at 900 mg PO BID, the recommended Phase 2 dose, in two expansion cohorts: a single agent expansion in select sarcoma pts (n = 30) and a safety lead-in dose escalation and expansion (n = 24) of seclidemstat combined with TC in pts with ES. Pts must be ≥12 years old, have ECOG performance status of 0 or 1, with a life expectancy > 4 months. In the select sarcoma cohort, pts must have ML (n = 15) or other sarcomas with FET family translocations (n = 15) including DSRCT. One to 3 prior lines of therapy are allowed. In the ES combination cohort, up to 2 lines of prior therapy are allowed. Primary objective is safety/tolerability and secondary objective is efficacy. The trial is currently recruiting across 8 locations in the United States. Clinical trial information: NCT03600649.

11514 Background: Ewing sarcoma (ES), a rare bone and soft tissue sarcoma mainly of adolescents and young adults, is characterized by a chromosomal translocation resulting in a fusion oncoprotein. Lysine specific demethylase 1 (LSD1) has been shown to associate with the fusion oncoprotein and promote oncogenic transcriptional activity making LSD1 an attractive target for ES treatment. Seclidemstat is a novel, selective, reversible oral LSD1 inhibitor capable of inhibiting both LSD1’s catalytic and scaffolding functions. This is the first report of an LSD1 inhibitor in a Phase 1 trial focused exclusively on ES. Methods: SALA-002-EW16 is a Phase 1 trial of single agent seclidemstat in patients (pts) with relapsed or refractory (R/R) ES. This report describes the completed monotherapy dose escalation. Pts > 12 years received oral SP-2577 twice daily in 28-day cycles under fasting conditions at the assigned dose level. The primary objective was safety and tolerability. Secondary objectives include to determine maximum-tolerated dose (MTD), recommended Phase 2 dose (RP2D), preliminary efficacy, pharmacokinetics, and pharmacodynamics. Results: As of December 30, 2020, 27 pts with R/R ES were enrolled. Pts received escalating doses of SP-2577 at 75 (n = 1), 150 (n = 2), 300 (n = 4), 600 (n = 6), 900 (n = 8), or 1200 mg PO BID (n = 6). The median age was 25 years (range 15–68), 63% were male, and pts had received a median of 3 (range 2–12) prior systemic therapies. There were no treatment-related deaths. The most common ( > 5%) grade 3 treatment-related adverse events (TRAEs) were vomiting (15%), abdominal pain (11%), and hypokalemia (11%). One pt (4%) with grade 3 pancreatitis reported a grade 4 AE of elevated lipase. All remaining grade 3 TRAEs, including hematological TRAEs, were reported in only one pt each. Four pts discontinued study for an AE (weight loss, pancreatitis, vomiting, abdominal pain). Three pts had a dose reduction. The first cycle dose-limiting toxicities were gastrointestinal-related AEs observed in 2 pts at 1200 mg BID. Thus, the MTD/RP2D was established as 900 mg BID. Peak plasma concentrations occurred at a median of 4 hours (h) post-dose and median terminal half-life was 6 h; exposure was dose proportional through 900 mg BID. One pt at 600 mg BID achieved a reduction in target lesions starting at end of C2 with further target lesion tumor shrinkage through end of C4 and C6 (maximum 76% tumor shrinkage) with coincident new non-target lesion appearance at end of C2. Of pts evaluable for response at the end of C2 (12 pts), two additional pts (16.7%) at 600 mg BID and 900 mg BID had overall stable disease. Conclusions: Seclidemstat has a manageable safety profile with proof-of-concept preliminary activity in heavily pretreated pts with relapsed/refractory ES. These data support the planned Phase 2 expansion of seclidemstat as single agent and in combination with chemotherapy in ES and other sarcomas that share similar translocations. Clinical trial information: NCT03600649.

TPS11567 Background: Ewing sarcoma (ES) is a rare, aggressive bone and soft tissue cancer that predominantly afflicts adolescents and young adults. Novel therapeutic agents are needed as there are no approved targeted treatments for this disease. ES is characterized by a chromosomal translocation resulting in an EWS/ETS fusion oncoprotein, a transcription factor that results in aberrant gene expression leading to ES progression. Lysine specific demethylase 1 (LSD1) associates with EWS/ETS oncoproteins to alter gene expression and contribute to disease progression. Directly inhibiting EWS/ETS is challenging and little progress has been made, though targeting LSD1 presents a viable therapeutic strategy for ES. Seclidemstat (SP-2577, Salarius Pharmaceuticals) is a first-in-class, orally bioavailable, small molecule with reversible and noncompetitive selective inhibition of LSD1 at low nanomolar concentrations (IC50: 25-50 nM). Seclidemstat inhibits LSD1’s scaffolding functions and enzymatic activity to help reverse aberrant gene expression. In vitro data show that treatment with seclidemstat, or seclidemstat analog, modulates EWS/ETS transcriptional activity, down-regulating oncogene expression and up-regulating tumor-suppressor gene expression. In in vivo xenograft studies (e.g., SK-N-MC, A673), mice treated with seclidemstat show significant tumor growth inhibition/regression vs the control vehicle group. Methods: This phase 1/2 clinical study of seclidemstat is being conducted in relapsed or refractory ES (NCT03600649). The trial is an open-label, non-randomized dose-escalation/dose-expansion study designed to determine the maximum tolerated dose through single-patient dose escalation followed by traditional 3+3 design. The primary objective is to assess seclidemstat’s safety and tolerability while secondary objectives include pharmacokinetics, efficacy and exploratory pharmacodynamic markers. Patients must be ≥12 years old, have received at least 1 prior line of therapy including a prior camptothecin-based regimen, with a life expectancy > 4 months. All patients receive seclidemstat twice-daily (BID) as oral tablets until unacceptable toxicity or disease progression. Patients are followed for survival until the end of study. The trial is currently recruiting across 8 locations in the United States. Upon identification of the recommended phase 2 dose, that cohort will be expanded to enroll a total of 20 patients. Clinical trial information: NCT03600649 .

10533 Background: Despite advances in risk stratification and therapy, the post-induction disease free survival (DFS) and overall survival (OS) for children with low-risk acute myeloid leukemia (LR-AML) remain low with DFS and OS of 50% and 68%, respectively, on the standard arm of the recent Children’s Oncology Group (COG) trial, AAML1031. Additionally, current therapy for pediatric LR-AML contains anthracycline doses exceeding thresholds known to increase the risk of adverse cardiac effects. In an effort to decrease exposure to cardiotoxic therapy, the Aflac Cancer and Blood Disorders Center adopted an institutional practice to treat LR-AML patients with a regimen of intensified induction therapy with decreased anthracycline exposure (Aflac-AML consisting of ADE10, Mitox/HiDAC, HiDAC/VP, Capizzi II). The aim of this study is to describe the associated toxicities and outcomes of this regimen in pediatric LR-AML. Methods: We retrospectively reviewed medical records of patients diagnosed with de novo LR-AML and treated per the Aflac-AML regimen from 2011-2014. Charts were reviewed for cardiac outcomes, ICU admissions, and the rate of infectious toxicities. DFS and OS were determined using Kaplan-Meier survival analysis. Results: We identified 11 LR-AML patients treated with Aflac-AML therapy. Patients received a planned 317 mg/m2 cumulative anthracycline dose vs 442 mg/m2for those treated on AAML1031. There was no decrease in LVEF with a mean change of +2.17% for Aflac-AML patients from the time of diagnosis to therapy completion (p = 0.23). The primary infectious toxicities observed were febrile neutropenia and bacterial infections with a median of 36.4±6% documented bacterial infections per cycle. Fungal and viral infections were rare as were ICU admissions – median 4.5±4% per cycle – and there were no toxic mortalities. The 3-year DFS and OS from end of induction I for Aflac-AML patients were 72.7% and 90.9%, respectively. Conclusions: The Aflac-AML regimen resulted in short-term toxicities and outcomes comparable to current chemotherapy regimens for pediatric LR-AML but with reduced anthracycline exposure. These data support use of this regimen for pediatric LR-AML patients.