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7035 Background: Myeloablative allogeneic hematopoietic cell transplantation (AHCT) is potentially curative for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but toxicities of conditioning limit its use in older or frail patients. Non-myeloablative (NMA) conditioning achieves better tolerability, at the expense of higher rates of relapse. We have developed a first-in-class monoclonal antibody (mAb), JSP191, which inhibits stem cell factor binding to CD117 (c-Kit), thereby depleting normal and MDS/AML disease-initiating hematopoietic stem cells (HSC). In pre-clinical models, anti-CD117 mAbs potently synergize with low dose total body radiation (TBI) to deplete HSC and facilitate donor cell engraftment. We reasoned that adding JSP191 to a standard NMA conditioning of 2 Gy TBI and fludarabine (Flu) would be safe and result in depletion of measurable residual disease (MRD) in older adults with high-risk MDS/AML entering AHCT. Methods: We report on the first 6 enrolled subjects in our Phase 1 trial (NCT#04429191) of JSP191/TBI/Flu as AHCT conditioning in MDS/AML patients, ≥ 60 years, with MRD detected by cytogenetics (cyto), difference from normal flow cytometry (flow), and/or next-generation sequencing (NGS). Primary endpoints are safety and tolerability of JSP191/TBI/Flu and JSP191 pharmacokinetics. Secondary endpoints include engraftment, donor chimerism, MRD clearance, GVHD, NRM, EFS, and OS at 1 year. JSP191 at 0.6 mg/kg was administered intravenously; serum concentration of JSP191 was used to confirm timing to begin Flu at 30 mg/m2/day x 3 days [Transplant Day (TD)-4, -3, -2] and TBI 2 Gy on TD0. Peripheral blood grafts from HLA-matched related or unrelated donors were administered on TD0 (10-13 days after JSP191). GVHD prophylaxis was tacrolimus, sirolimus, and mycophenolate mofetil. Results: All subjects are still on trial, and there have been no infusion toxicities and no JSP191-related serious adverse events. All subjects engrafted with neutrophil recovery TD+19 to TD+26, and showed ≥94% donor myeloid chimerism in the blood at TD+28. All 3 evaluable subjects with TD+90 follow up showed complete donor (≥95%) total and myeloid chimerism and MRD elimination (Table). Conclusions: These early results are the first to demonstrate that JSP191/TBI/Flu is safe, well-tolerated, and capable of clearing MDS/AML MRD in older adults undergoing NMA AHCT. Clinical trial information: NCT04429191. [Table: see text]

10045 Background: Genomic alterations of RET kinase, including chromosomal fusions and activating point mutations, have been identified as oncogenic drivers in pediatric and adult cancers. Multikinase inhibitors have modest activity against RET-altered cancers and are associated with significant toxicity. LOXO-292 is a potent, ATP-competitive, small molecule RET inhibitor with high selectivity for RET, preclinical activity in the brain and excellent pharmacokinetic properties. In an ongoing phase 1/2 study of adult and adolescent patients with advanced RET-altered cancers, LOXO-292 demonstrated marked antitumor activity and was well tolerated. Methods: Pediatric patients with RET-altered cancers who were unable to access LOXO-292 through a phase 1/2 clinical trial were enrolled using FDA-allowed, IRB-approved single patient protocols . Patients received LOXO-292 (capsule/liquid formulation) orally, continuously, at a starting dose of 90 mg/m2 BID. Response was assessed locally by investigators. Results: As of January 31, 2019, 4 female patients aged 13 months–8 years were enrolled from the Republic of Korea (papillary thyroid cancer, n = 1) and the USA (infantile myofibroma/hemangiopericytoma, n = 1; congenital mesoblastic nephroma/infantile fibrosarcoma, n = 1; lipofibromatosis, n = 1). All tumors harbored RET gene fusions (5′ partners: CCDC6, MYH10, SPECC1L, and NCOA4, respectively), detected by next-generation sequencing. Previous therapies included surgery/iodine 131 (n = 1); vandetanib (n = 1); surgery/chemotherapy (n = 1); 1 patient was treatment-naïve. Duration of treatment ranged from 3–120 days and all patients remain on treatment. There were no dose modifications or discontinuations due to adverse events. There were no treatment-related adverse events ≥ grade 3. Two patients who were evaluable for response had partial responses (both ongoing, 1 confirmed, 1 pending confirmation). Conclusions: These preliminary data from a real-world setting suggest that LOXO-292 is effective and safe in pediatric patients whose tumors harbor RET gene fusions.

9048Background: LOXO-292 is a novel, highly-selective, small molecule RET inhibitor in clinical development for pts with advanced cancers harboring oncogenic RET alterations (e.g. non-small cell lu...

10510 Background: Larotrectinib is the first selective small-molecule inhibitor of TRKA, B, and C in clinical development. Data from the adult phase I trial demonstrate prolonged responses in patients (pts) with TRK fusions and a favorable tolerability profile. Methods: This multicenter, rolling 6 phase I study enrolled pts with refractory solid or CNS tumors aged ≥ 1 month – 21 years. Pts were dosed orally BID on a continuous 28-day schedule either by capsule or solution. Pharmacokinetic (PK)-directed intra-subject dose escalation was permitted, with exposures targeting the adult recommended Phase II dose (RP2D) of 100 mg BID. The primary objective was to define the MTD / RP2D; secondary objectives included PK and efficacy using RECIST v1.1. Results: As of December 31, 2016, 17 pts (12 with TRK fusions, 5 without TRK fusions) with a median age of 5.2 years (0.4 – 18.3) were enrolled to 3 dose levels. Pts were enrolled with fusions of all 3 NTRK genes: NTRK1 (n=6), NTRK2 (n=1), and NTRK3 (n=5) in heterogeneous tumor diagnoses: infantile fibrosarcoma (IFS) (n=6), other sarcoma (n=4), and papillary thyroid cancer (n=2). Most common AEs regardless of attribution were vomiting, diarrhea, and fatigue. While 8 (47%) pts experienced grade 3-4 AEs, none were attributed to larotrectinib. No DLTs were observed and an MTD was not established. Both formulations delivered dose-dependent PK comparable to the adult RP2D at dose level 3. 12 pts (10 with TRK fusions, 2 without TRK fusions) remain on treatment with median follow-up of 2.8 months (0.7 – 8.4). Among TRK fusion pts, the vast majority have achieved confirmed RECIST responses regardless of tumor diagnoses. No responses were seen in pts without TRK fusions (n=4). 5 pts discontinued therapy, including 2 with TRK fusions: 1 pt with IFS had sufficient response to allow tumor resection, and 1 pt with IFS progressed with a documented acquired resistance mutation. Conclusions: Larotrectinib has demonstrated a favorable tolerability profile and histology-independent efficacy in pediatric pts harboring TRK fusions. Updated safety and efficacy data will be presented, including the RP2D, response rate, duration of response, and use of larotrectinib in the pre-surgical setting. Clinical trial information: NCT02637687.

TPS10583Background: The TRK family of neurotrophin receptors, TRKA, TRKB, and TRKC (encoded by NTRK1, NTRK2, and NTRK3 genes, respectively) and their neurotrophin ligands regulate growth, different...