8560 Background: FF-10832, a stable liposomal formulation of gemcitabine with a prolonged half-life (mean t 1/2 of 26 hours compared to ~3 hours for gemcitabine HCl), has demonstrated single agent activity in patients (pts) with solid tumors. In pre-clinical models, FF-10832 has yielded superior anti-tumor activity compared to gemcitabine alone and in combination with PD-1 inhibitors. Following a safety run-in, we investigated the clinical activity of FF-10832 in an expansion study, administered alone or in combination with pembrolizumab (PEM), in pts with advanced/metastatic (m) NSCLC (NCT05318573). Methods: In the open-label single arm safety run-in, 40 mg/m 2 FF-10832 and 200 mg PEM every 3 weeks was established as safe and tolerable in 12 pts including 6 mNSCLC patients with unlimited prior therapies. The trial was expanded using this regimen. Pts were randomized to receive FF-10832 alone (mono) or FF-10832 +PEM (combo). Eligibility stipulated up to 3 prior therapies in the advanced/metastatic setting with prior disease progression (PD) on platinum and PD-(L)1-directed therapy. Pts receiving FF-10832 monotherapy could add PEM to FF-10832 upon PD determined by RECIST 1.1. To be evaluable for anti-tumor activity, pts must have had at least one RECIST assessment ≥6 weeks after baseline. All pts were evaluable for safety. Results: A total of 41 NSCLC pts were treated with FF-10832 (N=21) or FF-1032+PEM (N=20); median # of prior therapies was 2 for both arms. RECIST evaluability was achieved in 30 pts (14/16; mono/combo); 11 pts (7/4; mono/combo) came off study before evaluation for anti-tumor activity. No objective responses were observed. Stable disease (SD) was recorded in 9/14 pts in the mono arm and 13/16 in the combo arm; 4 pts (1 mono/3 combo) with >20% tumor shrinkage. Median time on study for the mono and combo arms was 9 (1 – 48.1) and 12.1 (1.1 – 44) weeks, respectively. Median (95% CI) PFS in months: mono arm, 2.7 (1.4 – 4.3); combo arm, 2.8 (1.9 – 5.5). Five mono pts began FF-10832+PEM treatment upon PD, two that remain on combination therapy with SD for 23 and 33 weeks after progressing on FF-10832 monotherapy. Related AEs were similar in mono vs combo arms; those in ≥15% of pts in each arm included nausea, vomiting, fatigue, rash, infusion-related reaction, and anemia. Related grade ≥3 AEs occurred in 33% (mono) and 45% (combo) of pts. The only attributable grade ≥3 events in >1 pt were in the combo arm (n): anemia (3), fatigue (2), dyspnea (2), and lymphopenia (2). FF-10832 PK showed a profile consistent with that previously reported (terminal t 1/2, ~30 hours). Overall survival data are pending. Conclusions: FF-10832 alone or in combination with PEM in platinum-CPI refractory pts proved tolerable with a safety profile matching previous experience. There were no objective responses, but the majority of evaluable pts had SD at 1 st assessment, some with tumor shrinkage. Aggregate mPFS was 2.7 mos. Clinical trial information: NCT05318573 .

9581 Background: FF-10850 is a novel liposomal topotecan with increased intratumoral accumulation and robust pre-clinical activity. The prolonged t 1/2 (27 hours) supported a twice-monthly dosing schedule in the first in human dose finding trial (NCT04047251), with anti-tumor activity demonstrated in heavily pre-treated patients (pts) with solid tumors; pts remained on study up to 20 months. Common AEs were nausea and fatigue, with manageable hematologic toxicity. A Merkel cell carcinoma (MCC) pt maintained a PR for 33 weeks after progression on prior topotecan and PD-1-directed therapy. Because MCC pts who have progressed or are ineligible for anti-PD-1 therapy have few effective systemic treatment options, we evaluated FF-10850 in an MCC expansion cohort. Results are reported for all MCC pts on study. Methods: Pts ≥18 years with advanced MCC were treated with FF-10850 2 mg/m 2 IV on Days 1 and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Pts must have progressed on or have been ineligible for all standard therapy and treated with or ineligible for PD-1 based therapy. In expansion, pts who progressed on camptothecin therapy within 6 months were excluded; prior etoposide was allowed. Response was assessed by RECIST 1.1. Results: 12 pts [8M/4F; median age 70 (58-84), ECOG PS 0 (5)/PS 1 (7)] were treated. Baseline disease (n): unresectable stage IIIA (1), IV (10)/IVB (1). The median # of prior therapies was 1 (0-5), 1 had prior topotecan; 2 pts had no prior therapy, one due to rheumatoid arthritis (RA) and another due to solid organ transplant. Common drug-related AEs were anemia (50%), nausea (50%), fatigue (42%), and thrombocytopenia (25%). One pt each had related Gr 3 anemia and neutropenia; no related Gr 4 toxicity was observed. Three pts had infusion-related reactions; one that did not restart treatment. Two pts left study before RECIST evaluation: one withdrew to hospice care, and one died of an unrelated MI after the first dose of FF-10850 following a clinically significant anti-tumor response 2 weeks after the single dose. Best overall response in 10 RECIST evaluable pts was: 1CR, 1 PR, 4 SD and 4 PD; disease control rate (CR+PR+2 consecutive SD) was 50%. Three pts remain on study: one that achieved a CR after 2 cycles maintains CR after 14 cycles, and 2 pts maintain durable SD after 6-12 cycles. The median (range) time on study was 9.4 (3.1-50.9) weeks; median PFS and OS were 7.5 (95% CI:1.2-NR) and 10.7 (95% CI:2.1-NR) months, respectively. Conclusions: FF-10850 has demonstrated encouraging preliminary activity in both pre-treated and treatment naïve MCC. The regimen of 2 mg/m 2 every 2 weeks is tolerable with manageable hematologic side effects. PFS and OS in this small study compare favorably with that reported for cytotoxic agents in 2 nd line pts of 3 and 10 months, respectively. Further exploration of FF-10850 in MCC may offer a novel treatment option for this rare disease. Clinical trial information: NCT04047251 .

Background: Yttrium-90 FF-21101 (Y-90-FF-21101) is a radiopharmaceutical that targets P-cadherin as a therapy against solid tumors. A previously reported, first-in-human study determined that a dose of 25 mCi/m(2) was safe, and a patient with clear cell carcinoma of the ovary achieved a complete response. In this article, the authors report the results of Y-90-FF-21101 treatment in an ovarian carcinoma expansion cohort and in patients with selected solid tumors who had known high P-cadherin expression. Methods: The trial was conducted as an open-label study in patients with advanced/metastatic disease. Radiologic response and safety were evaluated in patients who received 25 mCi/m(2) intravenously once every three cycles of 28 days until they developed progressive disease. Evaluation of the ovarian cohort was conducted in a Simon two-stage manner to determine further enrollment. Results: Fifty-seven patients (20 with ovarian carcinoma) were enrolled and treated. Patients who had ovarian and solid tumors had received a median of five and three prior therapies, respectively. No complete or partial responses were observed, so the trial was ended. The median progression-free survival was 118 days for the ovarian cohort and 55 days for the solid-tumor cohort. The most common treatment-related adverse events were thrombocytopenia (40%) and neutropenia (54%). One patient each developed fatal veno-occlusive disease and intracranial hemorrhage. Patients with higher P-cadherin levels remained on the study longer. Conclusions: Y-90-FF-21101 did not meet the predefined efficacy criteria, and adverse events were consistent with Y-90 agents. These data may assist in the development of other P-cadherin-directed therapies

4092 Background: FF-10832 has demonstrated improved pre-clinical anti-tumor activity compared to gemcitabine (GEM). Associated factors may include its prolonged circulating half-life, tumor accumulation, and immune activation.The first in human dose finding trial of FF-10832 demonstrated a tolerable safety profile and anti-tumor activity in heavily pre-treated patients (pts) with solid tumors who progressed on prior gemcitabine. A biliary tract cancer (BTC) pt maintained a PR >60 weeks after progression on prior GEM based therapy. We subsequently enrolled an expansion cohort evaluating FF-10832 monotherapy in BTC and describe the results (NCT03440450). Methods: Pts ≥18 years with advanced BTC who had progressed on up to 3 lines of therapy were treated with FF-10832 40 mg/m 2 IV Day 1 Q 21 days until disease progression or unacceptable toxicity. Response was assessed by RECIST 1.1. Modulation of immune cells (flow cytometry/multiomics) and population PK were assessed. Results: 18 pts [12M/6F; median age 68 (34-79), ECOG PS 0 (3) PS 1 (15)] were treated; median # prior therapies, 2 (1-3); all had prior GEM and 16 had progressed on prior GEM. Pts received a median of 4 (1 - 22+) cycles with a median time on study of 10.4 (3.3 -77+) weeks. FF-10832 was well-tolerated. The most common drug-related AEs were nausea, pyrexia, and decreased appetite (39% each). No Gr 4 toxicity was observed; Gr 3 AEs in >1 pt included anemia (2) and muscular weakness (2). All AEs were successfully managed using standard therapies. Two pts withdrew and 1 pt died of cholangitic sepsis before 1 st evaluation. Best overall response in 15 remaining pts was 2 PR, 8 SD, 4 PD and 1 NE. The median PFS and OS were 3.4 and 9.1 months, respectively. Both PRs had received prior GEM/platinum-based therapy: 1) a gallbladder adenocarcinoma pt achieved a 48% decrease in target lesions with FF-10832 by cycle 2, which was maintained through cycle 10; dose was reduced to 30 mg/m 2 at cycle 5 for Gr 3 muscle weakness, 2) a hilar cholangiocarcinoma pt achieved a PR by cycle 2,with complete resolution of target lesions before withdrawing. Four additional pts maintained SD ≥ 6 cycles, with 2 continuing on therapy after 9 and 26 cycles. PK was similar to that previously reported (terminal t 1/2, 30 hours), with similar log decreases observed in Ki67+ regulatory T cells and increases observed in CD8+ cells, indicative of anti-tumor immune activation. Conclusions: FF-10832 is well-tolerated and has anti-tumor activity in pts with advanced BTC who progressed on prior GEM. Although preliminary, these results of a single agent therapy compare favorably to those reported for 2 nd line combination therapies. This warrants further investigation of FF-10832 efficacy and safety in BTC patients. Clinical trial information: NCT03440450 .

2615 Background: FF-10832 (FF832) [liposomal gemcitabine (GEM)] has demonstrated superior activity preclinically compared to GEM via preferential tumor accumulation & induction of antitumor immune responses. Further enhanced activity has been shown in combination with immune checkpoint inhibitors. We evaluated the tolerability & preliminary efficacy of FF832 in combination with the PD-1 antibody pembrolizumab (PEM) in a Phase 2a safety run-in study in patients (pts) with advanced solid tumors. Methods: Pts received 200 mg PEM followed by 40 mg/m2 FF832 on Day 1 of a 21-day cycle to validate the recommended Phase 2 dose (RP2D) for combination therapy; treatment was continued until disease progression or unacceptable toxicity. Response was assessed by RECIST 1.1 every 2 cycles. Tumor PD-L1 expression, mutational burden, and modulation of circulating immune cells were assessed, & population PK modeling performed. Results: Twelve pts [NSCLC (6), urothelial cancer, UC (4), renal cell carcinoma (2); 6M/6F; median age, 69 (42-82) & median # prior therapies, 5 (1-7); prior GEM (5), prior PEM (9)] received a median of 2 (1-8) cycles FF832+PEM. Median time on study was 6.1 (1.1–23.7) weeks. FF832+PEM was well-tolerated. Common AEs related to FF832 were Gr≤2 fatigue (50%) with 1 Gr 3, anemia (33%) with 2 Gr 3, & Gr ≤2 decreased appetite, diarrhea, ↑AST, ↑AlkPhos, muscular weakness, nausea, and pyrexia (25% each). Common AEs related to FF832+PEM were Gr≤2 fatigue (33%) & nausea (25%). Three pts had Gr≤2 infusion reactions with the first FF832 infusion; all resolved & were successfully rechallenged. FF832 dose was reduced to 30 mg/m2 after Cycle 1 in 3 pts due to Gr 3 rash (1), Gr 2 fatigue (1), & one DLT of Gr 3 malaise, pain, and arthralgia. Of 9 pts evaluable for response, one achieved an unconfirmed PR after one cycle (UC, prior GEM/PEM, 42%↓ in target lesions). Five pts had a best response of SD with 2 maintained for 6-8 cycles. Median PFS was 6 weeks (95%CI: 3.1–NR); median OS was 23.3 weeks (95%CI: 4–NR). An extended plasma t1/2 (~30 hours) & exposures consistent with FF832 monotherapy at the RP2D were observed. As with FF832 monotherapy, multi-log decreases were observed in circulating Ki67+ Tregs relative to total CD4+ cells while CD8+ cells increased, suggesting FF832+PEM could enhance shifts to a more immunocompetent tumor microenvironment. Conclusions: The safety and preliminary efficacy of FF832+PEM was demonstrated in heavily pre-treated pts with solid tumors whose disease progressed on prior GEM and/or PEM. Continuous GEM exposure from FF832 along with immune checkpoint blockade may improve antitumor activity. Evaluation of FF832 at the RP2D/schedule of 40 m/gm2 Q 21 days alone and in combination with PEM is ongoing in a randomized expansion study in pts with metastatic NSCLC and UC with prior disease progression on PD-1/L1 therapy. Clinical trial information: NCT05318573 .

BackgroundThe nucleoside FF-10502-01, structurally similar to but with different biologic effects than gemcitabine, shows promising activity both alone and combined with cisplatin in preclinical gemcitabine-resistant tumor models. We conducted an open-label, single-arm, 3 + 3 first-in-human trial to explore the safety, tolerability, and antitumor activity of FF-10502-01 in patients with solid tumors. MethodsPatients with inoperable metastatic tumors refractory to standard therapies were enrolled. Escalating intravenous FF-10502-01 doses (8-135 mg/m(2)) were administered weekly for 3 weeks in 28-day cycles until progressive disease or unacceptable toxicity was observed. Three expansion cohorts were subsequently evaluated. ResultsA phase 2 dose of 90 mg/m(2) was determined after evaluating 40 patients. Dose-limiting toxicities included hypotension and nausea. Phase 2a enrolled patients with cholangiocarcinoma (36), gallbladder cancer (10), and pancreatic/other tumors (20). Common adverse events were grade 1-2 rash, pruritus, fever, and fatigue. Grade 3 or 4 hematologic toxicities were observed at low incidences, including thrombocytopenia (5.1%) and neutropenia (2%). Confirmed partial responses (PRs) occurred in five patients with gemcitabine-refractory tumors, including three with cholangiocarcinoma and one each with gallbladder and urothelial cancer. Median progression-free and overall survival rates in patients with cholangiocarcinoma were 24.7 and 39.1 weeks, respectively. Prolonged progression-free survival in patients with cholangiocarcinoma was associated with BAP1 and PBRM1 mutations. ConclusionFF-10502-01 was well tolerated with manageable side effects and limited hematologic toxicity. Durable PRs and disease stabilizations were observed in heavily pretreated biliary tract patients who had received prior gemcitabine. FF-10502-01 is distinct from gemcitabine and may represent an effective therapy.

3101 Background: FF-10850 (liposomal topotecan) was developed using a unique dihydrosphingomyelin-based carrier to enhance tumor drug delivery and retention, leading to improved efficacy and safety. Preclinical studies demonstrated superior anti-tumor activity with less myelosuppression compared to topotecan, with a pharmacokinetic (PK) profile supporting a twice-monthly dosing schedule. Methods: Accelerated titration followed by a 3+3 dose escalation design was used to determine the safety, maximum tolerated dose (MTD), dose-limiting toxicities (DLT), PK, and recommended Phase 2 dose. FF-10850 was administered IV on Day 1 and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Results: Patients (pts) [n = 29; 4M/25F; median age, 64 (range, 37–79) and # prior therapies, 4 (range, 1–8)] received FF-10850 at doses of 1, 2, 2.5, 3, 3.5 and 5 mg/m2; median # of cycles, 2 (range, 1–11). FF-10850 was well-tolerated at doses up to 2 mg/m2. Common drug-related adverse events (AEs) included anemia (83%, 51% Gr≥3), thrombocytopenia (62%, 35% Gr≥3), neutropenia (59%, 45% Gr≥3), nausea (38%), fatigue (24%, 7% Gr≥3), alopecia (24%), and hypokalemia (17%, 3% Gr≥3). Dose-limiting Gr≥3 thrombocytopenia, neutropenia, anemia, and fatigue were observed at doses ≥2.5 mg/m2. Eight pts required dose reductions due to AEs. The median time on study was 8.3 (1.6–45) weeks, with a median PFS of 9.4 weeks and median OS at least 26 weeks. Of 24 pts evaluable for response, two achieved a partial response (PR). One pt with ovarian cancer treated at 3.5 mg/m2 achieved a complete response in target lesions by Cycle 2 with stable non-target lesions, and maintained response for > 30 weeks (8 cycles) before progressing; dose was reduced in this pt to 2.6 mg/m2 at Cycle 2 due to Gr 4 thrombocytopenia. Another pt with refractory metastatic Merkel cell carcinoma tolerated therapy well at 2 mg/m2 and achieved a 48% reduction in target lesions that was maintained for > 30 weeks (8 cycles). Stable disease was observed in an additional 9 pts for ≥10 weeks (5 ovarian, 2 uterine and 2 cervical); five who maintained disease control for ≥24-45 weeks including one (ovarian) who had previously progressed on topotecan. An extended plasma t1/2 for topotecan of 25-30 hours was observed with no apparent dose-dependency or accumulation; < 1% of circulating topotecan was in the free (released) form. Conclusions: FF-10850 was well-tolerated up to 2 mg/m2 with anti-tumor activity demonstrated in heavily pre-treated pts with solid tumors including ovarian cancer, and an improved PK profile allowing less frequent dosing compared to topotecan. Expansion is ongoing in pts with ovarian and Merkel cell carcinoma at the RP2D of 2 mg/m2 IV on Day 1 & 15 of a 28-day cycle. Clinical trial information: NCT04047251.

3097 Background: FF-10832 is a stable liposomal formulation of gemcitabine (GEM) shown to overcome resistance through increased plasma stability and enhanced tumor drug delivery. Macrophage uptake and immune activation in the tumor microenvironment (TME) play a role in the superior efficacy of FF-10832 compared to GEM, with selective, marrow-sparing biodistribution contributing to an improved safety profile. Methods: A 3+3 design determined the safety, maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics (PK), and recommended Phase 2 dose (RP2D). FF-10832 was administered IV once or twice per cycle on a 28 or 21-day schedule until disease progression or unacceptable toxicity. Circulating immune cell populations were measured over time by flow cytometry. Results: Patients (pts) [n = 73, 26M/47F; median age, 64 (range, 26–84); # prior therapies, 3 (1–11); prior GEM, 60%] received FF-10832 on Day 1 and 15 Q28 days (1.2–30 mg/m2), Day 1 and 8 Q21 days (12–23 mg/m2), or Day 1 only Q28 or 21 days (30–55 mg/m2); median # cycles = 2 (1–14) & time on study = 8.3 (4–60) weeks. Common drug-related adverse events were Grade (Gr) ≤2 rash (22%), nausea (22%, 1 Gr 3), and pyrexia (21%, 2 Gr 3). Dose-limiting Gr ≥3 cellulitis/skin ulcers were observed at ≥23 mg/m2 with twice per cycle dosing and those regimens discontinued. Dose frequency was reduced to Day 1 only, which was well-tolerated without significant skin toxicity. Gr ≥3 thrombocytopenia and pneumonitis were observed at 55 mg/m2 Q21 days and the MTD confirmed at 40 (Q21) and 48 mg/m2 (Q28). Median OS = 25.3 (95%CI: 16–27.1) weeks and PFS = 9.6 (95%CI: 7.9–17.6) weeks. Three of 35 evaluable pts achieved a partial response (PR): one pt with gallbladder cancer who previously progressed on GEM achieved a 50%↓ by Cycle 13 at 40 mg/m2 Q28 days & maintains response on study at 60 weeks; two pts with pancreatic cancer had ≥30%↓: one adenocarcinoma after 2 cycles at 4.8 mg/m2 Days 1 & 15 Q28 days, and one acinar cell after 7 cycles at 40 mg/m2 Q28 days who remains on study. Stable disease (SD) was observed in 16 pts; 9 for ≥20 weeks. AUC increased in proportion to dose without accumulation. An extended plasma t1/2 (hrs) for released (39) & total GEM (26) with a free fraction < 1% of total GEM concentrations suggests continuous release in the TME. Pts with PR or SD had dose and time-related log decreases in Ki67+ regulatory T cells relative to total CD4+ cells with increases in anti-tumor CD8+ cells, suggesting a shift to a more immunocompetent environment. Conclusions: FF-10832 was well-tolerated in heavily pre-treated pts with solid tumors, with evidence of anti-tumor activity in pts who progressed on prior GEM. Prolonged, continuous exposure and enhancement of anti-tumor immunity may contribute to improved efficacy. Expansion is ongoing in biliary tract cancer pts treated at the RP2D/schedule of 40 mg/m2 Day 1 of a 21-day cycle. Clinical trial information: NCT03440450.

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.

3073 Background: Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme that is aberrantly expressed in many solid tumors. High levels of LSD1 expression are often correlated with poor patient prognosis due to LSD1’s role in cancer cell proliferation, metastasis, and chemoresistance. Seclidemstat is a novel, selective, reversible and oral LSD1 inhibitor capable of inhibiting both LSD1’s catalytic and scaffolding functions. We report preliminary efficacy in AST from an ongoing phase 1 trial. Methods: SALA-003-AC19 (NCT03895684) is a phase 1 trial of single agent SP-2577 in pts with AST. All pts had progressive disease (PD) at time of study entry. Pts received oral SP-2577 twice a day under fasting condition, in 28-day cycles (C). The primary objective is safety and tolerability. Secondary objectives are to determine maximum-tolerated dose, preliminary efficacy, pharmacokinetics, and pharmacodynamics. Results: As of December 30, 2020, 19 pts with AST (10 sarcoma, 2 prostate, 2 ovarian, 2 pancreatic, 1 renal, 1 cervical, 1 breast) were enrolled. Pts received escalating doses of SP-2577 from 150 to 600 mg BID and the dose escalation is ongoing. The median age was 63 years (range, 21–79). 42% were male, and pts had received a median of 4 (range, 1–8) prior systemic therapies. The most common (>5%) grade 3 treatment-related adverse events were GI related including diarrhea (5.3%) and abdominal pain (5.3%). No grade 4 events were reported and there were no treatment-related deaths. Safety data will be presented after completion of phase 1. Three pts had at least one dose reduction. Among the 13 pts who were evaluable for response at end of C2, 7 pts (54%) had best response of stable disease (SD) with median time to progression (TTP) of 4.3 months (range, 2.1–11.5). Four of the 7 pts had genetic abnormalities that may demonstrate increased sensitization to SP-2577 according to preclinical studies. Characteristics of 7 pts with SD at C2 and beyond are shown in the table. Conclusions: Seclidemstat has shown activity among advanced sarcoma pts with a manageable safety profile. The dose escalation is ongoing and preliminary clinical data supports further exploration in FET-translocated sarcoma as single agent and in combination therapy. Clinical trial information: NCT03895684. [Table: see text]

78 Background: Overexpression of the cell-cell adhesion protein P-cadherin has been associated with a more aggressive cancer cell phenotype, cancer stem cell properties, tumor invasion and metastasis. We determined the safety and recommended Phase II dose of the yttrium-labeled P-cadherin-targeted 90Y-FF-21101 monoclonal antibody (mAb) in patients (pts) with advanced tumors, and focused our expansion study in advanced colorectal (CRC) and pancreatic-biliary cancers (non-CRC tumors). We report the safety, efficacy, and correlative pharmacokinetics (PK)/pharmacodynamics (PD) in this cohort. Methods: Pts enrolled must have progressed on all standard therapies. 25 mCi/m2 (8 mCi/mg mAb) 90Y-FF-21101 was administered intravenously every 12 weeks (wks) until disease progression or unacceptable toxicity. Disease response was assessed based on RECIST v1.1 every 8 wks (1 cycle = 28 days). Serum mAb PK, existence of anti-drug antibodies (ADA) and tumor P-cadherin expression were also evaluated. Results: 31 pts [mean age 63 (range, 39-89); 14F/17M; median number of prior therapies, 3 (range, 1-11)] with CRC (18) and non-CRC tumors [pancreatic (8), cholangiocarcinoma (3), duodenal (2)] received a median of 1 (range, 1-2) dose of 90Y-FF-21101. Median duration on study was 8.1 (3.9 – 27) wks (CRC) and 8 (1.1-17.1) wks (pancreatic-biliary). Myelosuppression was the most common treatment-related adverse event [thrombocytopenia (87%; Grade (Gr) 3/4 in 45%), lymphopenia (74%; Gr 3/4 in 61%), anemia (52%; Gr 3/4 in 13%), leukopenia (32%; Gr 3/4 in 16%)], in addition to fatigue (68%, 1 Gr 3) and nausea (39%, 1 Gr 3). Three pts required dose reduction to 20 mCi/m2 with subsequent infusion after Gr 3/4 thrombocytopenia [(pancreatic (2), CRC (1)]. The clinical benefit rate in pts with CRC based on stable disease (SD) for ≥8 wks is 43.8% (7/16 pts), with a median PFS of 8.1 wks and OS of 27 wks [median PFS, 7.9 wks; OS, 17.1 wks in non-CRC]. Longer-term SD was maintained in 2 pts with CRC for 17-24 wks; one continues on treatment. Enrollment is ongoing in the non-CRC cohort. FF-21101 has a mean t1/2 of approximately 65 hours, and post-treatment ADA titers have been observed in < 5% of pts. Tumor P-cadherin expression analysis by IHC demonstrated H-scores > 150 in 88% (14/16) of CRC pts, 75% (9/12) for non-CRC; 2 CRC pts with SD ≥17 wks had H-scores ≥190. Conclusions: 90Y-FF-21101 administered every 12 wks demonstrated expected toxicities and has been generally well-tolerated, with preliminary evidence of benefit demonstrated in heavily pre-treated pts with advanced CRC. The optimal dose and schedule for this radioimmunotherapeutic will continue to be explored, along with pre-treatment P-cadherin expression as a predictive biomarker for disease response. Clinical trial information: NCT02454010.

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.

Phase I Study of P-cadherin–targeted Radioimmunotherapy with Y-FF-21101 Monoclonal Antibody in Solid Tumors A C Vivek Subbiah, William Erwin, Osama Mawlawi, Asa McCoy, David Wages, Catherine Wheeler, Carlos Gonzalez-Lepera, Holly Liu, Homer Macapinlac, Funda Meric-Bernstam, David S. Hong, Shubham Pant, Dao Le, Elmer Santos, Jose Gonzalez, Jason Roszik, Takeaki Suzuki, Ruth Ann Subach, Timothy Madden, Mary Johansen, Fumiko Nomura, Hirokazu Satoh, Tadashi Matsuura, Masamichi Kajita, Eri Nakamura, Yuichi Funase, Satoshi Matsushima, and Gregory Ravizzini

AbstractPurpose: 90Y-FF-21101 is an Yttrium-90–conjugated, chimeric mAb that is highly specific for binding to human placental (P)-cadherin, a cell-to-cell adhesion molecule overexpressed and associated with cancer invasion and metastatic dissemination in many cancer types. We report the clinical activity of 90Y-FF-21101 in a first-in-human phase I study in patients with advanced solid tumors. Patients and Methods: The safety and efficacy of 90Y-FF-21101 were evaluated in a phase I 3+3 dose-escalation study in patients with advanced solid tumors (n = 15) over a dose range of 5–25 mCi/m2. Dosimetry using 111In-FF-21101 was performed 1 week prior to assess radiation doses to critical organs. Patients who demonstrated clinical benefit received repeated 90Y-FF-21101 administration every 4 months. Results: 111In-FF-21101 uptake was observed primarily in the spleen, kidneys, testes, lungs, and liver, with tumor uptake observed in the majority of patients. Organ dose estimates for all patients were below applicable limits. P-cadherin expression H-scores ranged from 0 to 242 with 40% of samples exhibiting scores ≥100. FF-21101 protein pharmacokinetics were linear with increasing antibody dose, and the mean half-life was 69.7 (±12.1) hours. Radioactivity clearance paralleled antibody clearance. A complete clinical response was observed in a patient with clear cell ovarian carcinoma, correlating with a high tumor P-cadherin expression. Stable disease was observed in a variety of other tumor types, without dose-limiting toxicity. Conclusions: The favorable safety profile and initial antitumor activity observed for 90Y-FF-21101 warrant further evaluation of this radioimmunotherapeutic (RIT) approach and provide initial clinical data supporting P-cadherin as a potential target for cancer treatment.

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 (IC 50 : 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 .

3008 Background: FF10502 is a synthetic pyrimidine nucleoside similar to gemcitabine (gem) with a sulfur in the pentose ring. FF10502 is a more potent inhibitor of DNA polymerase Beta than gem with activity in gem resistant patient (pt) derived xenograft models. FF10502 is avidly taken up into DNA and has greater activity against quiescent cells than gem. Methods: Pts > 18 years old with advanced disease who had progressed on standard of care were enrolled into 9 dose levels to determine maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) and subsequently into two expansion cohorts: biliary or solid tumors (ST). FF10502 at doses of 8 to 135 mg/m2 was administered iv on days 1, 8, 15 of a 28-day cycle until progressive disease or toxicity. PK/PD evaluations were performed on all pts. Response was assessed by RECIST 1.1. Results: 76 pts were treated; 35 pts in dose escalation, including 7 cholangiocarcinoma pts. MTD was 90 mg/m2. DLTs included 2 pts with hypotension at 135mg/m2 (G3 and G4) and 1 pt each with G3 fatigue and G2 rash at 100mg/m2. In expansion, 19 cholangiocarcinoma, 3 gallbladder and 19 other pts (13 pancreatic, 2 urothelial, and 1 each ovarian, prostate, NSCLC, SCCHN each) were treated. 1 pt with prior rituximab for ITP developed PML. G3 treatment-related low platelets occurred in 3 pts at 90mg/m2 after cycle 1. There were 5 partial responses (PRs), including 4 pts who had progressed on prior gemcitabine: 3 of 26 pts with cholangiocarcinoma, 1 urothelial carcinoma and 1 chondroblastic osteosarcoma. 7 cholangiocarcinoma pts stayed on therapy for ≥6 months. FF10502 incorporation intoperipheral blood cellular DNA was seen, andbiomarkeranalysisdata to identify pts with higher potential for clinical response will be presented. Conclusions: FF10502 is well tolerated in pts with advanced cancers refractory to standard therapies. Early signals of efficacy warranting further exploration were seen in heavily pretreated cholangiocarcinoma pts (median: 4 prior therapies). Patient selection based on differential effects of FF10502 on DNA polymerases will be explored. Clinical trial information: NCT02661542.

Background: FF10502-01 is a synthetic pyrimidine nucleoside analogue that is structurally similar to gemcitabine with a substitution of sulfur for oxygen in the pentose ring. FF-10502-01 showed potent anti-tumor activity in preclinical studies. In Capan-1 and SUIT-2 pancreatic ca xenograft models, FF-502-01 achieved superior tumor growth suppression and survival, respectively, compared to gemcitabine (gem), with less toxicity at clinically relevant doses. In gem-resistant pancreatic PDX models, FF-10502-01, alone and in combination with nab-paclitaxel (nab-pac), had higher efficacy and tolerability than gem/gem+nab-pac. Methods: We conducted a standard 3+3, dose-escalation phase 1 trial with FF-10502-01 to determine safety, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) i.e. FF-10502 incorporation into peripheral blood cellular DNA, and preliminary antitumor activity. Eligibility criteria included age u003e18 years, solid tumors refractory to standard treatment and adequate organ function. FF-10502-01 was administered IV over 60 minutes on days 1, 8, and 15 every 4 weeks. Planned dosing cohorts included 8, 12, 18, 27, 40, 60, 90, 135 and 200 mg/m 2 . Supportive medications such as anti-nausea prophylaxis were allowed. Results: 22 patients (pts) have been treated in 6 dose cohorts of 8-60 mg/m 2 . The median number of cycles received was 2 (range 1 to u003e12). Pts with the following cancers were enrolled: pancreatic (5 pts); ovarian and cholangiocarcinoma (3 each); parotid gland, prostate, and sarcoma (2 each); and endometrial, squamous cell carcinoma of the head and neck, anal, colon-neuroendocrine, and unknown primary (1 pt each). 11 pts were male and 11 female, median age 63 years (range 21-80), average number of prior cytotoxic therapies 3 (range 1-7) and 9 pts with prior gemcitabine therapy. Common related adverse events were Gr 1/2 nausea (43%), rash (38%), fever (29%), fatigue (19%), and vomiting despite prophylactic ondansetron and dexamethasone (14%). One pt had Gr 3 nausea (a DLT). Cytopenias have been minimal: 2 pts with Gr 1 and 2 anemia; with no neutropenia or thrombocytopenia. No pts have required dose reduction for toxicity. To date, an MTD has not been identified and enrollment continues. A pt with chondroblastic osteogenic sarcoma (18 mg/m 2 ) achieved an unconfirmed partial response (73% decrease) in a maxillary mass but developed progressive disease at another site. 3 currently active patients (1 each of acinar pancreatic, prostate, parotid gland), demonstrated durable stable disease for u003e 48, 40 and 28 weeks, respectively, at doses ranging from 8 to 27 mg/m 2 . FF-10502 plasma concentrations increased with dose. Additional PK and PD data will be presented. Conclusions: The pyrimidine nucleoside antimetabolite FF-10502-01 is well tolerated with prophylactic anti-emetics and demonstrated preliminary antitumor activity in heavily pretreated patients. Citation Format: Gerald Steven Falchook, Lindsay Bramwell, Lori Hannan, Deeksha Vishwamitra, Takayuki Yamada, Michele Rosner, David Wages, Thomas Myers, Linda Paradiso, Filip Janku. First-in-human phase 1 trial of pyrimidine anti-metabolite FF-10502-01 in patients with advanced cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT100. doi:10.1158/1538-7445.AM2017-CT100

Abstract Background: FF10502-01 is a synthetic pyrimidine nucleoside analogue that is structurally similar to gemcitabine with a substitution of sulfur for oxygen in the pentose ring. FF-10502-01 showed potent anti-tumor activity in preclinical studies. In Capan-1 and SUIT-2 pancreatic ca xenograft models, FF-502-01 achieved superior tumor growth suppression and survival, respectively, compared to gemcitabine (gem), with less toxicity at clinically relevant doses. In gem-resistant pancreatic PDX models, FF-10502-01, alone and in combination with nab-paclitaxel (nab-pac), had higher efficacy and tolerability than gem/gem+nab-pac. Methods: We conducted a standard 3+3, dose-escalation phase 1 trial with FF-10502-01 to determine safety, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) i.e. FF-10502 incorporation into peripheral blood cellular DNA, and preliminary antitumor activity. Eligibility criteria included age >18 years, solid tumors refractory to standard treatment and adequate organ function. FF-10502-01 was administered IV over 60 minutes on days 1, 8, and 15 every 4 weeks. Planned dosing cohorts included 8, 12, 18, 27, 40, 60, 90, 135 and 200 mg/m2. Supportive medications such as anti-nausea prophylaxis were allowed. Results: 22 patients (pts) have been treated in 6 dose cohorts of 8-60 mg/m2. The median number of cycles received was 2 (range 1 to >12). Pts with the following cancers were enrolled: pancreatic (5 pts); ovarian and cholangiocarcinoma (3 each); parotid gland, prostate, and sarcoma (2 each); and endometrial, squamous cell carcinoma of the head and neck, anal, colon-neuroendocrine, and unknown primary (1 pt each). 11 pts were male and 11 female, median age 63 years (range 21-80), average number of prior cytotoxic therapies 3 (range 1-7) and 9 pts with prior gemcitabine therapy. Common related adverse events were Gr 1/2 nausea (43%), rash (38%), fever (29%), fatigue (19%), and vomiting despite prophylactic ondansetron and dexamethasone (14%). One pt had Gr 3 nausea (a DLT). Cytopenias have been minimal: 2 pts with Gr 1 and 2 anemia; with no neutropenia or thrombocytopenia. No pts have required dose reduction for toxicity. To date, an MTD has not been identified and enrollment continues. A pt with chondroblastic osteogenic sarcoma (18 mg/m2) achieved an unconfirmed partial response (73% decrease) in a maxillary mass but developed progressive disease at another site. 3 currently active patients (1 each of acinar pancreatic, prostate, parotid gland), demonstrated durable stable disease for > 48, 40 and 28 weeks, respectively, at doses ranging from 8 to 27 mg/m2. FF-10502 plasma concentrations increased with dose. Additional PK and PD data will be presented. Conclusions: The pyrimidine nucleoside antimetabolite FF-10502-01 is well tolerated with prophylactic anti-emetics and demonstrated preliminary antitumor activity in heavily pretreated patients. Citation Format: Gerald Steven Falchook, Lindsay Bramwell, Lori Hannan, Deeksha Vishwamitra, Takayuki Yamada, Michele Rosner, David Wages, Thomas Myers, Linda Paradiso, Filip Janku. First-in-human phase 1 trial of pyrimidine anti-metabolite FF-10502-01 in patients with advanced cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT100. doi:10.1158/1538-7445.AM2017-CT100