S128 Poster abstracts Poster Session – Molecular targeted agents II, Thursday 1 December 2016 a subset of melanoma and AML patients), while CSF1R is a vital signaling component in Tumor Associated Macrophages (TAMs), controlling tumor infiltration and immunosuppressive functions. NMS-P088 is a novel indazole discovered and being developed by NMS, which potently and selectively targets CSF-1R, FLT3 and KIT, including oncogenic variants with both primary and secondary mutations. NMS-P088 has a highly favorable safety profile in 7-day repeated oral administration studies in rat and non-human primate (therapeutic window >5 compared with exposures required for potent in vivo efficacy). The low myelotoxicity observed in exploratory toxicological studies suggests that NMS-P088 is highly suited to combination with chemotherapeutic agents. Furthermore, the compound possesses excellent BBB penetration and no adverse effects on cardiac parameters were observed in telemetry studies in the dog at Cmax levels exceeding those required for efficacy. In human tumor cell lines in vitro, NMS-P088 potently and selectively arrested growth of FLT3-driven AMLs and KIT-driven GISTs, with IC50s in the low nanomolar range. Against a panel of BA/F3 cells driven by CSF1R or by diverse FLT3 or KIT mutants, including variants implicated in resistance to agents currently in clinic, NMS-P088 compared favorably with reference compounds such as gilteritinib, quizartinib, crenolanib and midostaurin for FLT3, imatinib for KIT and pexidartinib for CSF1R, in terms of both cell proliferation and signaling pathway inhibition. Potent inhibition of CSF1R-dependent signaling was also observed in the human THP1 monocytic and NKM-1 myeloid leukemia cell lines. Efficacy studies in mice bearing human MOLM-13 AML tumors revealed that oral administration of NMS-P088 significantly inhibited tumor growth and increased survival time, while combination with cytarabine was well tolerated and had a greater than additive effect on survival. The outstanding in vitro activity of NMS- P088 on gatekeeper resistance mutations was confirmed in vivo against BA/F3_FLT3-ITD(F691L) tumors, with growth inhibition values of 85% for 15 mg/kg NMS-P088 vs. 14% for 40 mg/kg quizartinib. Finally, NMS-P088 efficiently and dose-dependently decreased tissue infiltration of CSF1R expressing macrophages, consistent with potent in vivo inhibition of this kinase. Due to its high potency and its tolerability profile, NMS-P088 is a promising new agent for combination with chemotherapy in FLT3 and KIT- driven malignancies, and with immune targeting agents in settings where relief of macrophage-dependent immune suppression would yield clinical benefit. No conflict of interest. 389 Poster (Board P068) Preclinical activity of cyclin-dependent kinase 4/6 inhibitor in squamous cell carcinoma of the head and neck G. Van Caloen 1 . 1 Institut de Recherche Clinique et Exp ´ erimentale Pole MIRO, Universit´ e catholique de Louvain, Oncology, Brussels, Belgium Background: Beside alcohol and tobacco, Human Papillomavirus (HPV) is another cause of squamous cell carcinoma of the Head and Neck (SCCHN), especially when located in the oropharynx. HPV-positive (HPV+) and -negative (HPV−) SCCHN are different entities based on differences in clinical and molecular behaviors. HPV− SCCHN harbors alterations that enable them to circumvent the mitotic checkpoints through impaired cyclin-dependent kinase (CDK) activities. Implicated mechanisms are (i) inactivation of CDKN2A (58%) and (ii) CCND1 amplification (25%). p16 inactivation and/or Cyclin D1 overexpression, induce CDK4/6 activation and promote tumor proliferation. Therefore, there is a strong rationale to test CDK4/6 inhibitors in HPV− SCCHN. In contrast, HPV+ SCCHN is mediated by expression of the viral E6 and E7 oncoproteins, which cause deregulation of the cell cycle by inactivating the p53 and Retinoblastoma proteins, respectively. In this work, we are investigating the activity of a CDK4/6 inhibitor in HPV− and HPV+ pre-clinical SCCHN models and try to identify predictive biomarkers of response or resistance. Method: We evaluated the activity (MTT and BrdU assays) of Ribociclib, an orally active and highly selective CDK4/6 inhibitor, in 6 human HPV− and 2 HPV+ SCCHN cell lines. To identify potential predictive biomarkers, we compared gene expression profile (RNA seq) and protein expression (western blot) of sensitive and resistant cell lines. The in vivo efficacy of Ribociclib was investigated in 2 HPV-negative Patient derived Tumor Xenograft (PDTX) models. The first model was chemotherapy and anti-epidermal growth factor receptor (EGFR) treatment na¨ ıve, while the second model was resistant to chemotherapy, radiotherapy and anti-EGFR treatment. A clinical study phase I investigating CDK4/6 inhibitor effect combined to Cetuximab is ongoing in Cliniques Universtitaires Saint-Luc. Results: The IC 50 , derived from the viability test (MTT assay), of HPV− cell lines varied between 12.13 and 21.24 mM of Ribociclib, while the IC 50 of HPV+ cell lines was 18.26 and 19.10 mM of Ribociclib. A concentration of 0.5 mM Ribociclib induced cell cycle arrest in G0−G1 phase (BrdU assay) in the majority of HPV− cell lines but not in HPV+ ones. Evaluated by RNA seq and western blot, in silico analysis suggested that the most resistant HPV− cell lines had low expression of CDK6, RB and CDH1, coding for E-cadherin, and high expression of CDKN1A and VIM, coding for p21 and vimentin. In vivo, both PDTX models treated with Ribociclib had a significant growth delay compared to controls (p < 0.038 and p < 0.0001). Conclusion: Our data suggest that Ribociclib induces cell cycle arrest (G0−G1) and has a cytostatic effect on HPV− SCCHN cell lines. Ribociclib seems to be less active in HPV+ SCCHN. Further investigations are ongoing in different PDTX models to identify predictive biomarkers. No conflict of interest. 391 Poster/Poster in the spotlight (Board P070) Dose- and regimen-finding phase I study of NVP-HDM201 in patients (pts) with TP53 wild-type (wt) advanced tumors D. Hyman 1 , M. Chatterjee 2 , M.H.G. Langenberg 3 , C.C. Lin 4 , C. Su´ arez 5 , D. Tai 6 , P. Cassier 7 , N. Yamamoto 8 , V.A. De Weger 9 , S. Jeay 10 , C. Meille 11 , E. Halilovic 12 , L. Mariconti 11 , N. Guerreiro 11 , A. Kumar 13 , J.U. Wuerthner 11 , S. Bauer 14 . 1 Memorial Sloan Kettering Cancer Center, Department of Medicine, New York, USA; 2 University Hospital of W¨ urzburg, Department of Internal Medicine II, W ¨ urzburg, Germany; 3 UMC Utrecht Cancer Center, Department of Medical Oncology, Utrecht, Netherlands; 4 National Taiwan University Hospital, Department of Oncology, Taipei, Taiwan; 5 Vall d’Hebron University Hospital and Institute of Oncology, Universitat Aut` onoma de Barcelona, Department of Medical Oncology, Barcelona, Spain; 6 National Cancer Centre Singapore, Department of Medical Oncology, Singapore, Singapore; 7 Centre L ´ eon B´ erard, Department of Medical Oncology, Lyon, France; 8 National Cancer Center Hospital, Department of Experimental Therapeutics, Tokyo, Japan; 9 The Netherlands Cancer Institute, Department of Clinical Pharmacology, Amsterdam, Netherlands; 10 Novartis Pharma AG, Department of Oncology Research, Basel, Switzerland; 11 Novartis Pharma AG, Department of Translational Clinical Oncology, Basel, Switzerland; 12 Novartis Institutes for BioMedical Research, Department of Translational Clinical Oncology, Cambridge, USA; 13 Novartis Healthcare Private Limited, Department of Oncology Global Development, Hyderabad, India; 14 West German Cancer Centre, University of Duisburg-Essen, Department of Medical Oncology, Essen, Germany Background: HDM201 is a potent and selective small molecule that inhibits the interaction between HDM2 and p53, leading to tumor regression in preclinical models when administered as either low-dose continuous or high-dose pulsed regimens. This study aims to determine the optimal dose and regimen of HDM201 for further clinical development. Pts with solid and hematological tumors were enrolled in independent dose escalations; here we report results from pts with solid tumors. Material and Methods: First-in-human, multicenter, open-label, ongoing study of HDM201 in pts with advanced TP53 wt tumors, progressing on standard therapy or for whom no standard therapy exists (NCT02143635, sponsored by Novartis Pharmaceuticals Corporation). Four oral treatment regimens of HDM201 are explored: Regimen (Reg) 1 comprising Reg 1A (single dose [SD] on Day 1 in a 3-week [wk] cycle) and Reg 1B (SD on Days 1 and 8 in a 4-wk cycle); and Reg 2 comprising Reg 2A (SD every day for first 2 wks in a 4-wk cycle) and Reg 2C (SD every day for first wk in a 4-wk cycle). Results: As of the data cut-off (April 1, 2016), 74 pts received HDM201 (Reg 1; Reg 2: 38; 36 pts: 21% and 22% were still receiving treatment, respectively). For both regimens (Reg 1; Reg 2), common grade 3/4 adverse events (AEs) suspected to be study drug-related, typically occurring during Cycle 2, were anemia (8%; 17%), neutropenia (26%; 14%), and thrombocytopenia (24%; 28%); the latter two were dose limiting. Nevertheless, Cycle 2 hematological AEs were taken into account for decisions on dose escalation and regimen selection. Gastrointestinal toxicity was common but not dose limiting; the most common AE reported was nausea (66%; 36%). Median duration of exposure was similar: 8.4 wks (2.4–61.6) on Reg 1; 8.1 wks (2.3–61.4) on Reg 2. However, compared with Reg 2, the average plasma concentration per cycle reached with Reg 1 was closer to the predicted preclinical target efficacious levels required for tumor regression. HDM201 showed approximate dose-proportional pharmacokinetics. Expo- sure correlated with blood concentrations of GDF15 and hematological toxicity. Preliminary efficacy was observed at dose levels above or equivalent to predicted average concentrations for tumor stasis: Reg 1: 1 (3%) and 11 (29%) pts had a partial response and stable disease, respectively; Reg 2: 9 (25%) pts had stable disease. Conclusions: Preliminary data suggest that hematological toxicity is of late onset and is regimen-dependent; the pulse regimen (Reg 1) allows for higher cumulative dose. Clinical benefit was observed. Measures other than platelet transfusion are currently being investigated to