Abstract Background: Hyperactivation of the PI3K/AKT pathway correlates with impaired antitumour response, including reduced T cell infiltration into tumour and reduced efficacy of immune checkpoint inhibitors (ICIs). PTEN loss of function, often observed in GBM, may contribute to refractoriness of ICIs in this disease. Methods: The Ice-CAP A2 cohort assessed safety, pharmacodynamic, and preliminary clinical activity of Ipa (200mg or 400mg OD) + A (1200mg Q3W) in pts with potentially resectable relapsed WHO Grade IV GBM. Key inclusion criteria were stable neurological symptoms ≥5 days prior to enrolment, steroid requirement <3mg Dexamethasone. Pts had a 14-21-day run-in phase of Ipa then surgical tumour resection. Combination Ipa+A commenced post surgery. Dose-limiting toxicity (DLT) period included run-in phase to Cycle 1 completion (≤11 wks). Results: 10 evaluable pts were enrolled (3 had Ipa at 200mg, 7 at 400mg); median age 58 (range 25-70y), ECOG score 1; median duration of treatment 8 wks. 2 remain on treatment. No DLTs, treatment-related (TR) serious adverse events (AEs), or immune-related AEs were observed. Most common TR AEs were G1 diarrhoea (60%), mucositis (30%), rash (20%). 7 pts had PTEN loss and/or PTEN mutations. Clinical benefit rate in pts with PTEN aberration was 2/7 (29%): 1 pCR and 1 SD >12wks, both on 400mg Ipa. A 58-year-old man with PTEN loss had MRI at Cycle 5 showing worsening enhancement suggestive of disease progression. Resection of the lesion showed intense lymphocyte infiltration and pathological CR. He is currently on Cycle 18 with no evidence of disease. Conclusion: Combination Ipa+A appears safe and tolerable in GBM pts, with 400mg Ipa OD + 1200mg A Q3W declared as RP2D. PTEN loss may be a promising predictive biomarker for response to combination. An expansion cohort enriched with pts with PTEN loss is ongoing. Cytokine and FACS data will be presented at AACR Table 1.Clinical Benefit Rate of glioblastoma patients stratified according to PTEN aberrationsPTEN statusnBest responseClinical Benefit RatePTEN loss on IHC (H<30)51 pCRa2/7 (29%)1 SD >12 wks, ongoingb3 PDPTEN aberration on NGS but PTEN protein expression pending11 PDcPTEN loss of heterozygozity on PCR11 PDWild type PTEN on NGS or IHC (H≥30)33 PDLegend: IHC = immunohistochemistry; NGS = next generation sequencing; PCR = polymerase chain reaction;pCR = pathologic complete response; SD = stable disease; PD = progressive diseaseaExceptional responder with PTEN H=5 on IHC and splice site 75_79+2delGACCTGT on NGSb PTENY68*; c PTENQ298* Citation Format: Crescens Tiu, Andrea Biondo, Liam C. Welsh, Timothy L. Jones, Anna Zachariou, Toby Prout, Alison J. Turner, Robert Daly, Igor Vivanco, Christina Yap, Ben Jenkins, Mateus Crespo, Ruth Riisnaes, Suzanne Carreira, Bora Gurel, Nina Tunariu, Anna Minchom, Udai Banerji, Johann S. de Bono, Juanita S. Lopez. Results of the glioblastoma multiforme (GBM) cohort of phase 1 trial Ice-CAP (NCT03673787): Preliminary evidence of antitumour activity of Ipatasertib (Ipa) and Atezolizumab (A) in patients (pts) with PTEN loss [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT120.