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6038 Background: Preclinical data suggest cell cycle checkpoint inhibition induces greater cell death in BRCA mutant HGSOC by causing replication stress and dysregulation of DNA damage responses. We hypothesized that prexasertib, a cell cycle checkpoint kinase 1 (CHK1) inhibitor, would be active in BRCA mutated HGSOC patients. Methods: We conducted a single center, two-stage phase II study of prexasertib (105mg/m2 IV every 2 weeks) in HGSOC patients with known germline or somatic BRCA mutations. The primary endpoint was RECIST response rate (RR). Progression-free survival (PFS) and safety (CTCAE v4) were secondary endpoints. Baseline research biopsies and blood samples were collected for exploratory biomarker endpoints. Results: Between February 2015 and July 2019, 22 heavily pretreated (median 5 prior systemic therapies [1-12]) women with BRCA mutant HGSOC (median age 58.7 [44-74.8]) received at least one dose of prexasertib. 13 (59%) patients were secondary platinum-resistant (median 8 [3-12] prior therapies) and 9 (41%) maintained platinum-sensitivity (median 4 [1-5] prior therapies). All but one received prior PARP inhibitor (PARPi) either in combination (10 [48%]) or as monotherapy (11 [52%]), with a median 5 month [mo; 1-29] PARPi-free interval prior to study entry. There was one complete response (41+mo, platinum-sensitive, no prior PARPi) and one partial response (9+mo, platinum-sensitive, 13.5mo PARPi-free interval) yielding an 11% RR (2/18 evaluable). No response was seen in platinum-resistant patients with prior PARPi. Median duration on study treatment was 4mo [1-9] among 21 patients with prior PARPi and 4mo [1.5-9] among 17 evaluable patients with prior PARPi. Common (>10%) grade 3/4 adverse events were neutropenia (82%), leukopenia (64%), and thrombocytopenia (14%); only one patient had grade 3 febrile neutropenia. 16 of 18 (89%) patients with grade 3/4 neutropenia received prophylactic growth factors for subsequent treatments. Conclusions: Prexasertib is tolerable and has modest activity in heavily pretreated BRCA mutant HGSOC patients. Further evaluation of predictive biomarkers for exceptional responders is ongoing. Clinical trial information: NCT02203513.

e18541 Background: Despite considerable advancements in the standard therapies including surgery, chemotherapy and radiotherapy, the clinical outcome for head and neck squamous cell carcinoma (HNSCC) remains poor due to tumor recurrence and metastasis. Molecular-targeted therapies have evolved as novel and promising treatment for HNSCC patients. Herein, we identified a CHK1 inhibitor, prexasertib, as a therapeutic target that enhanced the infiltration of innate and adaptive immune markers in the mice tumor immune microenvironment (TIME) and subsequently sensitizes the tumors. Methods: For this study we used syngeneic mouse model of HNSCC developed using mouse tonsil epithelial cells transformed with HRAS expression and PTPN13 knockdown to represent tobacco-induced HNSCC (MTE-Ras). In vitro drug activity of prexasertib was determined using immunoblotting, flow cytometry, cell proliferation and colony formation assays. The effect of prexasertib on TIME was quantified by Quantigene Plex panel and multiplex immunohistochemistry (mIHC). Results: We found that in vitro treatment with prexasertib increased the amount of DNA damage in the cancer cells and eventually lead to their death. Similarly, our in vivo data showed that treatment with prexasertib resulted in significant tumor regression and increased mice survival. At the molecular level, prexasertib treatment resulted in an upregulation of transcripts associated with T-cell activation, cytokines, chemokines and macrophages indicating an upregulation of inflammatory gene signature. This was further supported by our findings from mIHC staining of mice tumors showing increased infiltration of natural killer cells, natural killer T cells and dendritic cells, following prexasertib treatment. Interestingly, we also saw an increase in the Tregs after prexasertib treatment, which is indicative of an immunosuppressive environment, and we speculate this could be as a result of negative feedback following immune activation by prexasertib treatment. Conclusions: Our results uncover a previously unidentified role of prexasertib in regulating the innate and adaptive immune response in HNSCC, and therefore further corroborate CHK1 as a promising therapeutic target in HNSCC.

3091 Background: Prexasertib inhibits CHK1, a kinase involved in DNA repair and replication. LY3023414 inhibits PI3K/mTOR signaling, implicated in the development of malignant disease. Prexasertib + LY3023414 has resulted in enhanced antitumor activity in triple negative breast cancer (TNBC) in vitro models. Methods: This Phase 1b study in patients (pts) with solid tumors assessed escalating doses of prexasertib (60-105 mg/m2 IV every 14 days [q14d]) and LY3023414 (100-200 mg orally twice daily [BID]). Dose escalation ceased once the maximum tolerated dose of each monotherapy was reached. An initial expansion cohort (Arm E) explored prexasertib 105 mg/m2 q14d + LY3023414 200 mg BID. Subsequent expansion cohorts evaluated prexasertib 105 mg/m2 q14d + LY3023414 150 mg BID in pts with solid tumors with PIK3CA mutations (Arm E2) or TNBC (Arm E3). Results: Fifty pts were enrolled (escalation: n = 13; Arm E: n = 9; Arm E2: n = 15; Arm E3: n = 13). No dose-limiting toxicities (DLTs) were observed during escalation however DLT-equivalent toxicities were observed in 2 pts in Arm E (anemia, neutropenia, thrombocytopenia, oral mucositis, abdominal pain, fatigue). Due to toxicity, a reduced dose of LY3023414 (150 mg BID) was assessed in Arm E2/E3. In the 28 patients treated in Arms E2/E3, common treatment-related adverse events (any grade; grade ≥3) were: leukopenia/neutropenia (82%; 79%), thrombocytopenia (46%; 36%), nausea (46%; 0%), stomatitis (39%, 4%), vomiting (36%; 0%), and anemia (29%; 18%). Febrile neutropenia was reported in 25% of pts. Dose reductions in Arm E2/E3 were common. In escalation, 2 pts achieved a partial response (PR) and 3 pts achieved stable disease (SD). In Arm E, 78% of pts achieved SD. Of the pts evaluable at the time of data transfer, PRs were achieved in 1 pt with an unknown primary (Arm E2) and 2 pts with TNBC (Arm E3). Each agent’s pharmacokinetic profile was consistent with prior monotherapy data. Conclusions: Prexasertib + LY3023414 showed preliminary efficacy in heavily pretreated pts with solid tumors but was associated with toxicity, suggesting supportive care may be required. Clinical trial information: NCT02124148.

2579Background: CHK1 is a key kinase for DNA replication and repair. Prexasertib, a CHK1 inhibitor, enhanced the nonclinical activity of cisplatin and is predicted to potentiate the clinical activi...