Background: Prognosis in smokers with LASCCHN remains poor. Activating mutations of PI3K are linked to poor outcome and PI3K activation in response to RT is implicated in resistance to CRT. Methods: In this phase I study, the oral pan-PI3K inhibitor B combined with CRT was tested in pts with stage III/IV LASCCHN and ≥10 pack-year history of tobacco use treated with curative intent. Pts received B during a 2-week run-in phase and during CRT consisting of 70Gy/35fx of radiotherapy plus weekly cisplatin. Results: Twenty-three pts (19 m, 4 f) were enrolled. Four had stage III, 19 (83%) had stage IV disease. 18 were former smokers, 5 smoked currently. Primary tumor locations: Oral cavity (6, 26%), oropharynx (11, 48%), larynx (3, 13%), other 3 (13%). HPV was pos in 14 cases. Among 7 pts enrolled on dose level 1 (DL1) (B 40mg daily, CDDP 30mg/m²/IMRT), 1 pt experienced gr 4 rash. Among 6 patients on DL2 (B 40mg daily, CDDP 35 mg/m²/IMRT), DLTs were observed in 4 cases (gr 3 neutropenia, LFT abn, mucositis, rash). Ten additional pts were enrolled at the RP2D (DL1). Additional gr 3 AEs included anorexia, anemia, dysphagia and confusion. One pt experienced grade 4 hyperamylasemia. With a median follow-up of 12 months (range 3-24), 2 pts (2/9%) had recurrence, one of whom died .Five pts had a response to buparlisib alone during the run-in phase assessed clinically or radiographically. To date, targeted NexGen sequencing was available in 8 pts. 4/5 cases with response to B alone had sequencing results and demonstrated mutations in FANCD2/EP300; FANCA/FGFR3; FANCI/FLT1 and PIC3CA/EP300. The patient who died had PIC3CA/STL11 mutations. Conclusions: B was tolerable in combination with CRT and appears to have promising activity. Genetic analysis is ongoing and may be helpful to identify patients suitable for this approach. Clinical trial information: NCT02113878