Preliminary evidence of antitumour activity of Ipatasertib (Ipat) and Atezolizumab (ATZ) in glioblastoma patients (pts) with PTEN loss from the Phase 1 Ice-CAP trial (NCT03673787)
Abstract Aims Despite improved understanding of effector T-cell trafficking into the central nervous system, initial trials with anti-PD1/PD-L1 immune checkpoint inhibitors (ICIs) have failed to meet their primary endpoints. PTEN loss of function is frequent in GBM and has been correlated with not o...
Published in: | Neuro-Oncology |
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Main Authors: | , , , , , , , , , , , , , , , , , , |
Format: | Article in Journal/Newspaper |
Language: | English |
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Oxford University Press (OUP)
2021
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Online Access: | http://dx.doi.org/10.1093/neuonc/noab195.022 http://academic.oup.com/neuro-oncology/article-pdf/23/Supplement_4/iv10/40659895/noab195.022.pdf |
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croxfordunivpr:10.1093/neuonc/noab195.022 |
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Oxford University Press (via Crossref) |
op_collection_id |
croxfordunivpr |
language |
English |
topic |
Cancer Research Neurology (clinical) Oncology |
spellingShingle |
Cancer Research Neurology (clinical) Oncology Tiu, Crescens Welsh, Liam Jones, Timothy Zachariou, Anna Prout, Toby Turner, Alison Daly, Rob Tunariu, Nina Riisnaes, Ruth Gurel, Bora Crespo, Mateus Carreira, Suzanne Vivanco, Igor Jenkins, Ben Yap, Christina Minchom, Anna Banerji, Udai deBono, Johann Lopez, Juanita Preliminary evidence of antitumour activity of Ipatasertib (Ipat) and Atezolizumab (ATZ) in glioblastoma patients (pts) with PTEN loss from the Phase 1 Ice-CAP trial (NCT03673787) |
topic_facet |
Cancer Research Neurology (clinical) Oncology |
description |
Abstract Aims Despite improved understanding of effector T-cell trafficking into the central nervous system, initial trials with anti-PD1/PD-L1 immune checkpoint inhibitors (ICIs) have failed to meet their primary endpoints. PTEN loss of function is frequent in GBM and has been correlated with not only poor overall prognosis, but also impaired antitumour responses, including reduced T cell infiltration into tumour and reduced efficacy of ICIs. Ipatasertib is a novel, potent, selective, small-molecule inhibitor of Akt. We have shown that Ipatasertib efficiently depletes FOXP3+ regulatory T cells from the tumour microenvironment (TME) resulting in increased infiltration of effector T cells in solid tumours (Lopez 2020, AACR). We hypothesize that the use of AKT inhibition in PTEN glioblastomas may deplete the TME of suppressive immune cells, and render malignant brain tumours more responsive to ICIs. We present updated data for the combination of Ipat+ATZ in patients with glioblastoma. Method Patients with relapsed WHO grade IV GBM with stable neurological symptoms ≥5 days prior to enrolment, requiring <3mg Dexamethasone were recruited into two cohorts of this early phase, open-label, single-centre trial studying the combination of Ipatasertib (Ipat) and Atezolizumab (ATZ): a dose finding cohort (A2; n=9) and an expansion cohort (B3; n=7, recruitment ongoing). The Ice-CAP A2 cohort assessed safety, pharmacodynamic, and preliminary clinical activity of Ipat (200mg or 400mg OD) + ATZ (1200mg Q3W) in pts with potentially resectable relapsed WHO Grade IV GBM. Pts had a 14-21-day run-in phase of Ipat then surgical tumour resection. Combination Ipat+ATZ commenced post surgery. Patients who declined surgery or who were deemed high risk for surgery proceeded directly to combination. Patients in the expansion cohort B3 commenced directly on Ipat+ATZ at the RP2D of 400mg Ipat with ATZ. Results 16 evaluable recurrent GBM pts were enrolled across two cohorts. Median age 56 yrs (25-71 yrs). Median ECOG PS 1. Median lines of prior therapy 1 (range 1-4). 10 pts had PTEN loss by IHC (H<30) and/or PTEN mutations on next generation sequencing. No DLTs, treatment-related (TR) serious adverse events (AEs), or immune-related AEs were observed. Most common TR AEs were G1 diarrhoea (44%), mucositis (17%), rash (28%). Clinical benefit rate (CR, PR and SD> 6 cycles) at clinical cutoff date (23/02/21) in patients with PTEN aberration was 30% (3/10). 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 22 with no evidence of disease. Two other patients with PTEN loss with radiological stable disease per RANO criteria remain well on study for >6 cycles. Conclusion Combination Ipat+ATZ appears safe and tolerable in GBM pts, with 400mg Ipatasertib OD + 1200mg ATZ Q3W declared as RP2D. Early efficacy signals were detected with PTEN loss being a promising predictive biomarker for response to combination. An expansion cohort enriched with pts with PTEN loss is ongoing. |
format |
Article in Journal/Newspaper |
author |
Tiu, Crescens Welsh, Liam Jones, Timothy Zachariou, Anna Prout, Toby Turner, Alison Daly, Rob Tunariu, Nina Riisnaes, Ruth Gurel, Bora Crespo, Mateus Carreira, Suzanne Vivanco, Igor Jenkins, Ben Yap, Christina Minchom, Anna Banerji, Udai deBono, Johann Lopez, Juanita |
author_facet |
Tiu, Crescens Welsh, Liam Jones, Timothy Zachariou, Anna Prout, Toby Turner, Alison Daly, Rob Tunariu, Nina Riisnaes, Ruth Gurel, Bora Crespo, Mateus Carreira, Suzanne Vivanco, Igor Jenkins, Ben Yap, Christina Minchom, Anna Banerji, Udai deBono, Johann Lopez, Juanita |
author_sort |
Tiu, Crescens |
title |
Preliminary evidence of antitumour activity of Ipatasertib (Ipat) and Atezolizumab (ATZ) in glioblastoma patients (pts) with PTEN loss from the Phase 1 Ice-CAP trial (NCT03673787) |
title_short |
Preliminary evidence of antitumour activity of Ipatasertib (Ipat) and Atezolizumab (ATZ) in glioblastoma patients (pts) with PTEN loss from the Phase 1 Ice-CAP trial (NCT03673787) |
title_full |
Preliminary evidence of antitumour activity of Ipatasertib (Ipat) and Atezolizumab (ATZ) in glioblastoma patients (pts) with PTEN loss from the Phase 1 Ice-CAP trial (NCT03673787) |
title_fullStr |
Preliminary evidence of antitumour activity of Ipatasertib (Ipat) and Atezolizumab (ATZ) in glioblastoma patients (pts) with PTEN loss from the Phase 1 Ice-CAP trial (NCT03673787) |
title_full_unstemmed |
Preliminary evidence of antitumour activity of Ipatasertib (Ipat) and Atezolizumab (ATZ) in glioblastoma patients (pts) with PTEN loss from the Phase 1 Ice-CAP trial (NCT03673787) |
title_sort |
preliminary evidence of antitumour activity of ipatasertib (ipat) and atezolizumab (atz) in glioblastoma patients (pts) with pten loss from the phase 1 ice-cap trial (nct03673787) |
publisher |
Oxford University Press (OUP) |
publishDate |
2021 |
url |
http://dx.doi.org/10.1093/neuonc/noab195.022 http://academic.oup.com/neuro-oncology/article-pdf/23/Supplement_4/iv10/40659895/noab195.022.pdf |
long_lat |
ENVELOPE(56.603,56.603,66.196,66.196) ENVELOPE(-63.567,-63.567,-64.850,-64.850) |
geographic |
Ipat Lopez |
geographic_facet |
Ipat Lopez |
genre |
Ice cap |
genre_facet |
Ice cap |
op_source |
Neuro-Oncology volume 23, issue Supplement_4, page iv10-iv10 ISSN 1522-8517 1523-5866 |
op_rights |
https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model |
op_doi |
https://doi.org/10.1093/neuonc/noab195.022 |
container_title |
Neuro-Oncology |
container_volume |
23 |
container_issue |
Supplement_4 |
container_start_page |
iv10 |
op_container_end_page |
iv10 |
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1766028590575517696 |
spelling |
croxfordunivpr:10.1093/neuonc/noab195.022 2023-05-15T16:38:19+02:00 Preliminary evidence of antitumour activity of Ipatasertib (Ipat) and Atezolizumab (ATZ) in glioblastoma patients (pts) with PTEN loss from the Phase 1 Ice-CAP trial (NCT03673787) Tiu, Crescens Welsh, Liam Jones, Timothy Zachariou, Anna Prout, Toby Turner, Alison Daly, Rob Tunariu, Nina Riisnaes, Ruth Gurel, Bora Crespo, Mateus Carreira, Suzanne Vivanco, Igor Jenkins, Ben Yap, Christina Minchom, Anna Banerji, Udai deBono, Johann Lopez, Juanita 2021 http://dx.doi.org/10.1093/neuonc/noab195.022 http://academic.oup.com/neuro-oncology/article-pdf/23/Supplement_4/iv10/40659895/noab195.022.pdf en eng Oxford University Press (OUP) https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model Neuro-Oncology volume 23, issue Supplement_4, page iv10-iv10 ISSN 1522-8517 1523-5866 Cancer Research Neurology (clinical) Oncology journal-article 2021 croxfordunivpr https://doi.org/10.1093/neuonc/noab195.022 2022-04-15T06:26:42Z Abstract Aims Despite improved understanding of effector T-cell trafficking into the central nervous system, initial trials with anti-PD1/PD-L1 immune checkpoint inhibitors (ICIs) have failed to meet their primary endpoints. PTEN loss of function is frequent in GBM and has been correlated with not only poor overall prognosis, but also impaired antitumour responses, including reduced T cell infiltration into tumour and reduced efficacy of ICIs. Ipatasertib is a novel, potent, selective, small-molecule inhibitor of Akt. We have shown that Ipatasertib efficiently depletes FOXP3+ regulatory T cells from the tumour microenvironment (TME) resulting in increased infiltration of effector T cells in solid tumours (Lopez 2020, AACR). We hypothesize that the use of AKT inhibition in PTEN glioblastomas may deplete the TME of suppressive immune cells, and render malignant brain tumours more responsive to ICIs. We present updated data for the combination of Ipat+ATZ in patients with glioblastoma. Method Patients with relapsed WHO grade IV GBM with stable neurological symptoms ≥5 days prior to enrolment, requiring <3mg Dexamethasone were recruited into two cohorts of this early phase, open-label, single-centre trial studying the combination of Ipatasertib (Ipat) and Atezolizumab (ATZ): a dose finding cohort (A2; n=9) and an expansion cohort (B3; n=7, recruitment ongoing). The Ice-CAP A2 cohort assessed safety, pharmacodynamic, and preliminary clinical activity of Ipat (200mg or 400mg OD) + ATZ (1200mg Q3W) in pts with potentially resectable relapsed WHO Grade IV GBM. Pts had a 14-21-day run-in phase of Ipat then surgical tumour resection. Combination Ipat+ATZ commenced post surgery. Patients who declined surgery or who were deemed high risk for surgery proceeded directly to combination. Patients in the expansion cohort B3 commenced directly on Ipat+ATZ at the RP2D of 400mg Ipat with ATZ. Results 16 evaluable recurrent GBM pts were enrolled across two cohorts. Median age 56 yrs (25-71 yrs). Median ECOG PS 1. Median lines of prior therapy 1 (range 1-4). 10 pts had PTEN loss by IHC (H<30) and/or PTEN mutations on next generation sequencing. No DLTs, treatment-related (TR) serious adverse events (AEs), or immune-related AEs were observed. Most common TR AEs were G1 diarrhoea (44%), mucositis (17%), rash (28%). Clinical benefit rate (CR, PR and SD> 6 cycles) at clinical cutoff date (23/02/21) in patients with PTEN aberration was 30% (3/10). 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 22 with no evidence of disease. Two other patients with PTEN loss with radiological stable disease per RANO criteria remain well on study for >6 cycles. Conclusion Combination Ipat+ATZ appears safe and tolerable in GBM pts, with 400mg Ipatasertib OD + 1200mg ATZ Q3W declared as RP2D. Early efficacy signals were detected with PTEN loss being a promising predictive biomarker for response to combination. An expansion cohort enriched with pts with PTEN loss is ongoing. Article in Journal/Newspaper Ice cap Oxford University Press (via Crossref) Ipat ENVELOPE(56.603,56.603,66.196,66.196) Lopez ENVELOPE(-63.567,-63.567,-64.850,-64.850) Neuro-Oncology 23 Supplement_4 iv10 iv10 |