A phase 1/2 study of thiotepa-based immunochemotherapy in relapsed/refractory primary CNS lymphoma: the TIER trial
A phase 1/2 study of thiotepa-based immunochemotherapy in relapsed/refractory primary CNS lymphoma: the TIER trial
Relapsed or refractory primary central nervous system lymphoma (rrPCNSL) confers a poor prognosis with no accepted standard of care. Very few prospective studies have been conducted in this patient group. This study was a multicenter phase 1/2 study that investigated thiotepa in combination with ifosfamide, etoposide, and rituximab (TIER) for the treatment of PCNSL relapsed or refractory to high-dose methotrexate-based chemotherapy. A 3 + 3 design investigated the recommended phase 2 dose of thiotepa for a single-stage phase 2 cohort by assessing the activity of 2 cycles of TIER against rrPCNSL. The primary outcome was overall response rate. The dose-finding study demonstrated that 50 mg/m2 of thiotepa could be safely delivered within the TIER regimen. No dose-limiting toxicities were encountered in phase 1, and TIER was well-tolerated by the 27 patients treated in phase 2. The most common grade 3 to 4 toxicities were neutropenia (56% of patients) and thrombocytopenia (39%). An overall response was confirmed in 14 patients (52%), which met the prespecified threshold for clinically relevant activity. The median progression-free survival was 3 months (95% confidence interval [CI], 2 to 6 months) and overall survival 5 months (95% CI, 3 to 9 months). Exploratory analyses suggest a greater benefit for thiotepa-naïve patients. Six patients successfully completed autologous stem cell transplantation (ASCT) consolidation, with 4 experiencing durable remissions after a median follow-up of 50 months. The TIER regimen can be delivered safely and is active against rrPCNSL. When it is followed by ASCT, it can provide durable remission and long-term survival. However, for the majority of patients, prognosis remains poor, and novel treatment strategies are urgently needed. This trial was registered at https://www.clinicaltrialsregister.eu/ctr-search/search as EudraCT 2014-000227-24 and ISRCTN 12857473.
Antineoplastic Combined Chemotherapy Protocols/adverse effects, Combined Modality Therapy, Hematopoietic Stem Cell Transplantation, Humans, Lymphoma, Non-Hodgkin/drug therapy, Prospective Studies, Thiotepa/therapeutic use, Transplantation, Autologous
4073-4082
Fox, Christopher P.
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Ali, Ayesha S.
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McIlroy, Graham
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Thust, Steffi
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Martinez-Calle, Nicolás
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Jackson, Aimee E.
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Hopkins, Louise M.
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Thomas, Catherine M.
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Kassam, Shireen
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Wright, Josh
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Chaganti, Sridhar
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Smith, Jeffery
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Chau, Ian
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Culligan, Dominic
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Linton, Kim M.
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Collins, Graham P.
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Ferreri, Andrés J. M.
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Lewis, David
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Davies, Andrew J.
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Johnson, Rod
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Auer, Dorothee P.
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Cwynarski, Kate
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26 October 2021
Fox, Christopher P.
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Ali, Ayesha S.
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McIlroy, Graham
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Thust, Steffi
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Martinez-Calle, Nicolás
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Jackson, Aimee E.
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Hopkins, Louise M.
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Thomas, Catherine M.
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Kassam, Shireen
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Wright, Josh
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Chaganti, Sridhar
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Smith, Jeffery
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Chau, Ian
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Culligan, Dominic
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Linton, Kim M.
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Collins, Graham P.
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Ferreri, Andrés J. M.
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Lewis, David
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Davies, Andrew J.
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Johnson, Rod
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Auer, Dorothee P.
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Cwynarski, Kate
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Fox, Christopher P., Ali, Ayesha S., McIlroy, Graham, Thust, Steffi, Martinez-Calle, Nicolás, Jackson, Aimee E., Hopkins, Louise M., Thomas, Catherine M., Kassam, Shireen, Wright, Josh, Chaganti, Sridhar, Smith, Jeffery, Chau, Ian, Culligan, Dominic, Linton, Kim M., Collins, Graham P., Ferreri, Andrés J. M., Lewis, David, Davies, Andrew J., Johnson, Rod, Auer, Dorothee P. and Cwynarski, Kate
(2021)
A phase 1/2 study of thiotepa-based immunochemotherapy in relapsed/refractory primary CNS lymphoma: the TIER trial.
Blood Advances, 5 (20), .
(doi:10.1182/bloodadvances.2021004779).
Abstract
Relapsed or refractory primary central nervous system lymphoma (rrPCNSL) confers a poor prognosis with no accepted standard of care. Very few prospective studies have been conducted in this patient group. This study was a multicenter phase 1/2 study that investigated thiotepa in combination with ifosfamide, etoposide, and rituximab (TIER) for the treatment of PCNSL relapsed or refractory to high-dose methotrexate-based chemotherapy. A 3 + 3 design investigated the recommended phase 2 dose of thiotepa for a single-stage phase 2 cohort by assessing the activity of 2 cycles of TIER against rrPCNSL. The primary outcome was overall response rate. The dose-finding study demonstrated that 50 mg/m2 of thiotepa could be safely delivered within the TIER regimen. No dose-limiting toxicities were encountered in phase 1, and TIER was well-tolerated by the 27 patients treated in phase 2. The most common grade 3 to 4 toxicities were neutropenia (56% of patients) and thrombocytopenia (39%). An overall response was confirmed in 14 patients (52%), which met the prespecified threshold for clinically relevant activity. The median progression-free survival was 3 months (95% confidence interval [CI], 2 to 6 months) and overall survival 5 months (95% CI, 3 to 9 months). Exploratory analyses suggest a greater benefit for thiotepa-naïve patients. Six patients successfully completed autologous stem cell transplantation (ASCT) consolidation, with 4 experiencing durable remissions after a median follow-up of 50 months. The TIER regimen can be delivered safely and is active against rrPCNSL. When it is followed by ASCT, it can provide durable remission and long-term survival. However, for the majority of patients, prognosis remains poor, and novel treatment strategies are urgently needed. This trial was registered at https://www.clinicaltrialsregister.eu/ctr-search/search as EudraCT 2014-000227-24 and ISRCTN 12857473.
Text
advancesadv2021004779
- Version of Record
More information
Accepted/In Press date: 7 May 2021
e-pub ahead of print date: 31 August 2021
Published date: 26 October 2021
Additional Information:
Acknowledgments
This work (the TIER trial) was supported by the Blood Cancer UK
(reference number 13069) and Cure Leukaemia Trials Acceleration
Programme, by the facilities funded through Birmingham Science
City Translational Medicine Clinical Research Infrastructure and Tri-
als Platform, and by Advantage West Midlands (part of the Science
City University of Warwick and University of Birmingham Research
Alliance). Thiotepa was provided free of charge by Adienne.
S.T. receives research funding from the Department of Health
National Institute for Health Research (NIHR) Biomedical
Research Centre (to University College London Hospital). G.P.C.
is supported by the NIHR Oxford Biomedical Research Centre
and Cancer Research UK Experimental Cancer Medicines Centre
Keywords:
Antineoplastic Combined Chemotherapy Protocols/adverse effects, Combined Modality Therapy, Hematopoietic Stem Cell Transplantation, Humans, Lymphoma, Non-Hodgkin/drug therapy, Prospective Studies, Thiotepa/therapeutic use, Transplantation, Autologous
Identifiers
Local EPrints ID: 453359
URI: http://eprints.soton.ac.uk/id/eprint/453359
ISSN: 2473-9529
PURE UUID: 7b222e3d-e258-4f8b-9d9a-a2e428c2fb97
Catalogue record
Date deposited: 13 Jan 2022 18:14
Last modified: 17 Mar 2024 03:14
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Contributors
Author:
Christopher P. Fox
Author:
Ayesha S. Ali
Author:
Graham McIlroy
Author:
Steffi Thust
Author:
Nicolás Martinez-Calle
Author:
Aimee E. Jackson
Author:
Louise M. Hopkins
Author:
Catherine M. Thomas
Author:
Shireen Kassam
Author:
Josh Wright
Author:
Sridhar Chaganti
Author:
Jeffery Smith
Author:
Ian Chau
Author:
Dominic Culligan
Author:
Kim M. Linton
Author:
Graham P. Collins
Author:
Andrés J. M. Ferreri
Author:
David Lewis
Author:
Rod Johnson
Author:
Dorothee P. Auer
Author:
Kate Cwynarski
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