Background: Although the Stupp protocol (radiotherapy + temozolomide (TMZ)) remains the mainstay of glioblastoma (GBM) first line treatment after extended surgery, the prognosis is still poor. PARP inhibitors, such as olaparib, may improve GBM outcomes by enhancing cytotoxic effects of ionizing radiation and TMZ. The non-dividing nature of normal brain cells allows a dedicated tumor radiosensitization. We implemented a phase I/IIa trial to assess safety and efficacy of olaparib combined with TMZ concomitant with intensity modulated radiotherapy (IMRT) as a first line treatment in unresectable GBM patients (pts). We herein present results of the phase I step. Methods: Based on the Stupp protocol, 2 treatment periods were considered. The radiotherapy period (RT) occurs after surgery: pts received IMRT (60 Gy/30 fractions/6 wks), oral TMZ (75 mg/m²) during IMRT, and olaparib orally given at the same dose until 4 wks after the end of IMRT. For the maintenance period (MT) from 4 wks after IMRT, pts received TMZ (150 mg/m², days (D) 1-5 every 28 days, for 6 cycles) plus olaparib at the MT dose level up to disease progression or unacceptable toxicity. The phase I included 2 sequential dose escalations (DE1, DE2) of olaparib to split both periods for DLT (Dose Limiting Toxicities) assessment. Olaparib dose levels (DL) were: 50 mg Q12H D 1-3 (DL1), 100 mg Q12H D1-3 (DL2) or D1-5 (DL3), 200 mg Q12H D1-3 (DL4) or D1-5 (DL5) or 200 mg Q12H continuously (DL6). Pts in DE1 received olaparib only during RT to determine the MTD1 (Maximum-Tolerated Dose), by assessing DLT on this period. Next, after olaparib administered at MTD1 during RT, pts in DE2 received olaparib during MT to determine MTD2 (≤MTD1) during the MT period, assessing DLT from the first 2 cycles. DE1 and DE2 were performed by a TITE-CRM (TIme-To-Event Continual Reassessment Method). Results: From 2017 to 2021, 30 pts were enrolled: 20 (67%) men, median age 59 yrs [range 25-70]. 16 and 11 pts were assessable for determining MTD1 and MTD2, respectively. In DE1, 2 pts received olaparib at DL1, 6 at DL2, 6 at DL3, 1 at DL4 and 1 at DL5. 4 pts observed DLT (3 at DL3, 1 at DL5): thrombocytopenia G3-4 (n=4) + neutropenia G4 (n=2). MTD1 was defined as DL2 with estimated probability of DLT of 22.1% [95%CI 8-40.5]. In DE2, 2 pts were treated at DL1, 9 at DL2. 1 pt observed DLT at DL2: thrombocytopenia G4. MTD2 was defined as DL2 with estimated probability of DLT of 13.3% [0.2-0.35]. No interruption of IMRT for toxicity was observed. Excepted DLT, permanent olaparib discontinuation for toxicity was observed in 1 pt during RT and 2 pts during MT. Toxicity induced temporary TMZ interruption in 4 pts, none with permanent discontinuation. No toxic death was observed. Conclusions: Olaparib 100 mg Q12H D1-3 in concomitant with the Stupp protocol has an acceptable safety profile in unresectable GBM pts: it warrants efficacy determination, in the ongoing phase IIa step. Clinical trial information: NCT03212742.