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A phase II study to assess the safety and efficacy of the dual mTORC1/2 inhibitor vistusertib in relapsed, refractory DLBCL: dual mTORC1/2 inhibition in relapsed, refractory DLBCL

A phase II study to assess the safety and efficacy of the dual mTORC1/2 inhibitor vistusertib in relapsed, refractory DLBCL: dual mTORC1/2 inhibition in relapsed, refractory DLBCL
A phase II study to assess the safety and efficacy of the dual mTORC1/2 inhibitor vistusertib in relapsed, refractory DLBCL: dual mTORC1/2 inhibition in relapsed, refractory DLBCL
Patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) who are unfit for or relapsed post autologous stem‐cell transplantation have poor outcomes. Historically, mTORC1 inhibitors have produced responses in approximately 30% of patients in this setting. mTORC1 inhibitor efficacy may be limited by resistance mechanisms including AKT activation by mTORC2. To date, dual mTORC1/2 inhibitors targeting both the TORC1 and TORC2 complexes have not been investigated in DLBCL. This phase II trial investigated the oral dual mTORC1/2 inhibitors vistusertib in an intermittent dosing schedule of 125 mg b.d. for two days per week. Thirty patients received vistusertib and six received vistusertib‐rituximab for up to six cycles (28‐day cycles). Two partial responses were achieved on monotherapy. Duration of response were 57 and 62 days respectively for these patients. 19% had stable disease within six cycles. In the monotherapy arm, the median progression‐free survival was 1.69 (95% confidence interval 1.61‐2.14) months and median overall survival was 6.58 (95% CI 3.81‐not reached) months respectively. The median duration of response or stable disease across the trial duration was 153 days (95% confidence interval 112‐not reached). Tumour responses according to PET/CT versus CT were concordant. There were no differences noted in tumour volume response according to cell of origin by either gene expression profiling or immunohistochemistry. Vistusertib +/‐ rituximab was well tolerated; across 36 patients 86% of adverse events were grade (G) 1‐2. Common vistusertib‐related adverse events were similar to those described with mTORC1 inhibitors: nausea (47% G1‐2), diarrhoea (27% G1‐2, 6% G3), fatigue (30% G1‐2, 3% G3), mucositis (25% G1‐2, 6% G3), vomiting (17% G1‐2) and dyspepsia (14% G1‐2). Dual mTORC1/2 inhibitors do not clearly confer an advantage over mTORC1 inhibitors in relapsed or refractory DLBCL. Potential resistance mechanisms are discussed within.
0278-0232
352-359
Eyre, Toby
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Hildyard, Catherine
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Hamblin, Angela
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Ali, Ayesha
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Houlton, Aimee
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Hopkins, Louise
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Royston, Daniel
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Linton, Kim
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Pettitt, Andrew
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Rule, Simon
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Cwynarski, Kate
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Barrington, Sally
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Warbey, Victoria
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Wrench, David
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Barrans, Sharon
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Hirst, Caroline
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Panchal, Anesh
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Roudier, Martine
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Harrington, Elizabeth
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Davies, Andrew
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Collins, Graham
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Eyre, Toby
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Hildyard, Catherine
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Hamblin, Angela
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Ali, Ayesha
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Houlton, Aimee
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Hopkins, Louise
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Royston, Daniel
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Linton, Kim
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Pettitt, Andrew
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Rule, Simon
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Cwynarski, Kate
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Barrington, Sally
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Warbey, Victoria
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Wrench, David
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Barrans, Sharon
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Hirst, Caroline
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Panchal, Anesh
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Roudier, Martine
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Harrington, Elizabeth
23ee5ca1-6257-4dc3-88ad-984490ab9b30
Davies, Andrew
0fe6a40a-10d1-4ade-a7e6-d1dceb2470af
Collins, Graham
391da378-f898-4dc9-b182-e34e09575b0b

Eyre, Toby, Hildyard, Catherine, Hamblin, Angela, Ali, Ayesha, Houlton, Aimee, Hopkins, Louise, Royston, Daniel, Linton, Kim, Pettitt, Andrew, Rule, Simon, Cwynarski, Kate, Barrington, Sally, Warbey, Victoria, Wrench, David, Barrans, Sharon, Hirst, Caroline, Panchal, Anesh, Roudier, Martine, Harrington, Elizabeth, Davies, Andrew and Collins, Graham (2019) A phase II study to assess the safety and efficacy of the dual mTORC1/2 inhibitor vistusertib in relapsed, refractory DLBCL: dual mTORC1/2 inhibition in relapsed, refractory DLBCL. Hematological Oncology, 37 (4), 352-359. (doi:10.1002/hon.2662).

Record type: Article

Abstract

Patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) who are unfit for or relapsed post autologous stem‐cell transplantation have poor outcomes. Historically, mTORC1 inhibitors have produced responses in approximately 30% of patients in this setting. mTORC1 inhibitor efficacy may be limited by resistance mechanisms including AKT activation by mTORC2. To date, dual mTORC1/2 inhibitors targeting both the TORC1 and TORC2 complexes have not been investigated in DLBCL. This phase II trial investigated the oral dual mTORC1/2 inhibitors vistusertib in an intermittent dosing schedule of 125 mg b.d. for two days per week. Thirty patients received vistusertib and six received vistusertib‐rituximab for up to six cycles (28‐day cycles). Two partial responses were achieved on monotherapy. Duration of response were 57 and 62 days respectively for these patients. 19% had stable disease within six cycles. In the monotherapy arm, the median progression‐free survival was 1.69 (95% confidence interval 1.61‐2.14) months and median overall survival was 6.58 (95% CI 3.81‐not reached) months respectively. The median duration of response or stable disease across the trial duration was 153 days (95% confidence interval 112‐not reached). Tumour responses according to PET/CT versus CT were concordant. There were no differences noted in tumour volume response according to cell of origin by either gene expression profiling or immunohistochemistry. Vistusertib +/‐ rituximab was well tolerated; across 36 patients 86% of adverse events were grade (G) 1‐2. Common vistusertib‐related adverse events were similar to those described with mTORC1 inhibitors: nausea (47% G1‐2), diarrhoea (27% G1‐2, 6% G3), fatigue (30% G1‐2, 3% G3), mucositis (25% G1‐2, 6% G3), vomiting (17% G1‐2) and dyspepsia (14% G1‐2). Dual mTORC1/2 inhibitors do not clearly confer an advantage over mTORC1 inhibitors in relapsed or refractory DLBCL. Potential resistance mechanisms are discussed within.

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TORCH Original Article Hem Onc 2019 R1 - Accepted Manuscript
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Accepted/In Press date: 30 July 2019
e-pub ahead of print date: 5 August 2019

Identifiers

Local EPrints ID: 433237
URI: http://eprints.soton.ac.uk/id/eprint/433237
ISSN: 0278-0232
PURE UUID: 74477f45-8283-40dc-b91e-343f94fe4f90
ORCID for Andrew Davies: ORCID iD orcid.org/0000-0002-7517-6938

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Date deposited: 12 Aug 2019 16:30
Last modified: 16 Mar 2024 08:05

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Contributors

Author: Toby Eyre
Author: Catherine Hildyard
Author: Angela Hamblin
Author: Ayesha Ali
Author: Aimee Houlton
Author: Louise Hopkins
Author: Daniel Royston
Author: Kim Linton
Author: Andrew Pettitt
Author: Simon Rule
Author: Kate Cwynarski
Author: Sally Barrington
Author: Victoria Warbey
Author: David Wrench
Author: Sharon Barrans
Author: Caroline Hirst
Author: Anesh Panchal
Author: Martine Roudier
Author: Elizabeth Harrington
Author: Andrew Davies ORCID iD
Author: Graham Collins

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