A phase 1/2 study of thiotepa-based immunochemotherapy in relapsed/refractory primary CNS lymphoma: the TIER trial

Christopher P. Fox; Ayesha S. Ali; Graham McIlroy; Steffi Thust; Nicolas Martinez-Calle; Aimee E. Jackson; Louise M. Hopkins; Catherine M. Thomas; Shireen Kassam; Josh Wright; Sridhar Chaganti; Jeffery Smith; Ian Chau; Dominic Culligan; Kim M. Linton; Graham P. Collins; Andres J.M. Ferreri; Andrew J. Davies; Rod Johnson; Dorothee P. Auer; Kate Cwynarski; David J. Lewis

doi:10.1182/bloodadvances.2021004779

A phase 1/2 study of thiotepa-based immunochemotherapy in relapsed/refractory primary CNS lymphoma: the TIER trial

Christopher P. Fox^*, Ayesha S. Ali, Graham McIlroy, Steffi Thust, Nicolas Martinez-Calle, Aimee E. Jackson, Louise M. Hopkins, Catherine M. Thomas, Shireen Kassam, Josh Wright, Sridhar Chaganti, Jeffery Smith, Ian Chau, Dominic Culligan, Kim M. Linton, Graham P. Collins, Andres J.M. Ferreri, Andrew J. Davies, Rod Johnson, Dorothee P. AuerKate Cwynarski, David J. Lewis

^*Corresponding author for this work

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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.

Original language	English
Pages (from-to)	4073-4082
Number of pages	10
Journal	Blood Advances
Volume	5
Issue number	20
Early online date	31 Aug 2021
DOIs	https://doi.org/10.1182/bloodadvances.2021004779
Publication status	Published - 26 Oct 2021

Bibliographical note

Funding Information:
Conflict-of-interest disclosure: C.P.F. received consultant fees and research funding from Roche and Adienne. J.S. received funding to attend EHA 2018 and ICML 2019 from AbbVie and Janssen. G.P.C. received consultant fees from Roche. A.J.M.F. received speaker’s fees from Adienne; received research grants from Bristol Myers Squibb, BeiGene, Pharmacyclics, Hutchison MediPharma, Amgen, Genmab, ADC Therapeutics, Gilead, Novartis, and Pfizer; participated in advisory boards for Gilead, Novartis, Juno, and PletixaPharm; and holds patents on NGR-human tumor necrosis factor-a in brain tumours and NGR-hTNF/R-CHOP in relapsed or refractory PCNSL and SNGR-hTNF in brain tumors. K.C. received consultant fees and research funding from Roche and Adienne. The remaining authors declare no competing financial interests.

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 Trials 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.

Publisher Copyright:
© 2021 by The American Society of Hematology.

ASJC Scopus subject areas

Hematology

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Fox, C. P., Ali, A. S., McIlroy, G., Thust, S., Martinez-Calle, N., Jackson, A. E., Hopkins, L. M., Thomas, C. M., Kassam, S., Wright, J., Chaganti, S., Smith, J., Chau, I., Culligan, D., Linton, K. M., Collins, G. P., Ferreri, A. J. M., Davies, A. J., Johnson, R., ... Lewis, D. J. (2021). A phase 1/2 study of thiotepa-based immunochemotherapy in relapsed/refractory primary CNS lymphoma: the TIER trial. Blood Advances, 5(20), 4073-4082. https://doi.org/10.1182/bloodadvances.2021004779

@article{975da0b732b942d5acb4947bd3c677d9,

title = "A phase 1/2 study of thiotepa-based immunochemotherapy in relapsed/refractory primary CNS lymphoma: the TIER trial",

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-na{\"i}ve 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.",

author = "Fox, {Christopher P.} and Ali, {Ayesha S.} and Graham McIlroy and Steffi Thust and Nicolas Martinez-Calle and Jackson, {Aimee E.} and Hopkins, {Louise M.} and Thomas, {Catherine M.} and Shireen Kassam and Josh Wright and Sridhar Chaganti and Jeffery Smith and Ian Chau and Dominic Culligan and Linton, {Kim M.} and Collins, {Graham P.} and Ferreri, {Andres J.M.} and Davies, {Andrew J.} and Rod Johnson and Auer, {Dorothee P.} and Kate Cwynarski and Lewis, {David J.}",

note = "Funding Information: Conflict-of-interest disclosure: C.P.F. received consultant fees and research funding from Roche and Adienne. J.S. received funding to attend EHA 2018 and ICML 2019 from AbbVie and Janssen. G.P.C. received consultant fees from Roche. A.J.M.F. received speaker{\textquoteright}s fees from Adienne; received research grants from Bristol Myers Squibb, BeiGene, Pharmacyclics, Hutchison MediPharma, Amgen, Genmab, ADC Therapeutics, Gilead, Novartis, and Pfizer; participated in advisory boards for Gilead, Novartis, Juno, and PletixaPharm; and holds patents on NGR-human tumor necrosis factor-a in brain tumours and NGR-hTNF/R-CHOP in relapsed or refractory PCNSL and SNGR-hTNF in brain tumors. K.C. received consultant fees and research funding from Roche and Adienne. The remaining authors declare no competing financial interests. 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 Trials 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. Publisher Copyright: {\textcopyright} 2021 by The American Society of Hematology.",

year = "2021",

month = oct,

day = "26",

doi = "10.1182/bloodadvances.2021004779",

language = "English",

volume = "5",

pages = "4073--4082",

journal = "Blood Advances",

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publisher = "American Society of Hematology",

number = "20",

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Fox, CP, Ali, AS, McIlroy, G, Thust, S, Martinez-Calle, N, Jackson, AE, Hopkins, LM, Thomas, CM, Kassam, S, Wright, J, Chaganti, S, Smith, J, Chau, I, Culligan, D, Linton, KM, Collins, GP, Ferreri, AJM, Davies, AJ, Johnson, R, Auer, DP, Cwynarski, K & Lewis, DJ 2021, 'A phase 1/2 study of thiotepa-based immunochemotherapy in relapsed/refractory primary CNS lymphoma: the TIER trial', Blood Advances, vol. 5, no. 20, pp. 4073-4082. https://doi.org/10.1182/bloodadvances.2021004779

TY - JOUR

T1 - A phase 1/2 study of thiotepa-based immunochemotherapy in relapsed/refractory primary CNS lymphoma

T2 - the TIER trial

AU - Fox, Christopher P.

AU - Ali, Ayesha S.

AU - McIlroy, Graham

AU - Thust, Steffi

AU - Martinez-Calle, Nicolas

AU - Jackson, Aimee E.

AU - Hopkins, Louise M.

AU - Thomas, Catherine M.

AU - Kassam, Shireen

AU - Wright, Josh

AU - Chaganti, Sridhar

AU - Smith, Jeffery

AU - Chau, Ian

AU - Culligan, Dominic

AU - Linton, Kim M.

AU - Collins, Graham P.

AU - Ferreri, Andres J.M.

AU - Davies, Andrew J.

AU - Johnson, Rod

AU - Auer, Dorothee P.

AU - Cwynarski, Kate

AU - Lewis, David J.

N1 - Funding Information: Conflict-of-interest disclosure: C.P.F. received consultant fees and research funding from Roche and Adienne. J.S. received funding to attend EHA 2018 and ICML 2019 from AbbVie and Janssen. G.P.C. received consultant fees from Roche. A.J.M.F. received speaker’s fees from Adienne; received research grants from Bristol Myers Squibb, BeiGene, Pharmacyclics, Hutchison MediPharma, Amgen, Genmab, ADC Therapeutics, Gilead, Novartis, and Pfizer; participated in advisory boards for Gilead, Novartis, Juno, and PletixaPharm; and holds patents on NGR-human tumor necrosis factor-a in brain tumours and NGR-hTNF/R-CHOP in relapsed or refractory PCNSL and SNGR-hTNF in brain tumors. K.C. received consultant fees and research funding from Roche and Adienne. The remaining authors declare no competing financial interests. 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 Trials 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. Publisher Copyright: © 2021 by The American Society of Hematology.

PY - 2021/10/26

Y1 - 2021/10/26

N2 - 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.

AB - 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.

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A phase 1/2 study of thiotepa-based immunochemotherapy in relapsed/refractory primary CNS lymphoma: the TIER trial

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Bibliographical note

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