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

Autor: Eyre TA; Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, UK., Hildyard C; Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, UK., Hamblin A; Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, UK., Ali AS; Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK., Houlton A; Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK., Hopkins L; Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK., Royston D; Department of Cellular Pathology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK., Linton KM; Department of Medical Oncology, The Christie Hospital NHS Trust, Manchester, UK., Pettitt A; Department of Haematology, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK., Rule S; Department of Haematology, University of Plymouth Medical School, Plymouth, UK., Cwynarski K; Department of Haematology, University College London, London, UK., Barrington SF; Clinical PET Centre, St Thomas' Hospital, London, UK., Warbey V; Clinical PET Centre, St Thomas' Hospital, London, UK., Wrench D; Department of Haematology, Guy's and St Thomas' Hospital, London, UK., Barrans S; Haematological Malignancy Diagnostic Service, St James' University Hospital, Leeds, UK., Hirst CS; Translational Medicine, AstraZeneca Oncology R&D I Research and Early Development, Cambridge, UK., Panchal A; Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK., Roudier MP; Translational Medicine, AstraZeneca Oncology R&D I Research and Early Development, Cambridge, UK., Harrington EA; Translational Medicine, AstraZeneca Oncology R&D I Research and Early Development, Cambridge, UK., Davies A; Cancer Research UK Centre, Cancer Sciences Unit, University of Southampton, Southampton General Hospital, Southampton, UK., Collins GP; Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, UK.
Jazyk: angličtina
Zdroj: Hematological oncology [Hematol Oncol] 2019 Oct; Vol. 37 (4), pp. 352-359. Date of Electronic Publication: 2019 Sep 09.
DOI: 10.1002/hon.2662
Abstrakt: Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are unfit for or relapsed postautologous 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 inhibitor vistusertib in an intermittent dosing schedule of 125 mg b.d. for 2 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. Durations 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 was1.69 (95% confidence interval [CI] 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% CI 112-not reached). Tumour responses according to positron emission tomography/computed tomography versus computed tomography 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.
(© 2019 John Wiley & Sons, Ltd.)
Databáze: MEDLINE
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