Appleby, N, Eyre, TA, Cabes, M et al. (7 more authors) (2019) The STELLAR trial protocol: a prospective multicentre trial for Richter’s syndrome consisting of a randomised trial investigation CHOP-R with or without acalabrutinib for newly diagnosed RS and a single-arm platform study for evaluation of novel agents in relapsed disease. BMC Cancer, 19 (1). 471. ISSN 1471-2407
Abstract
Background
Transformation of chronic lymphocytic leukaemia (CLL) to diffuse large B-cell lymphoma (DLCBL) type Richter’s syndrome (RS) carries a dismal prognosis. Standard-of-care chemoimmunotherapy for de novo RS is inadequate with median survival of less than one year. Patients are frequently elderly or have co-morbidities limiting dose-intense chemotherapy. Treatment of relapsed/refractory (R/R) RS and RS emerging after CLL-directed therapy represent urgent unmet clinical needs.
Agents targeting Bruton’s tyrosine kinase (BTK) deliver improved outcomes for patients with high-risk CLL and expand effective treatments to frailer patients. Acalabrutinib is an oral, second-generation BTK inhibitor with a favourable toxicity profile and demonstrated activity in CLL and B-cell lymphomas. Combination of acalabrutinib with standard-of-care CHOP-R chemoimmunotherapy offers a sound rationale to test in a prospective trial for de novo RS.
Methods
The prospective multicentre STELLAR study is designed in two elements, consisting of a randomised study to evaluate the safety and activity of CHOP-R chemoimmunotherapy in combination with acalabrutinib in newly diagnosed RS and single-arm studies of novel agents for other RS patient cohorts.
Eligible patients with newly diagnosed DLBCL-type RS are randomised between six cycles of CHOP-R therapy and six cycles CHOP-R plus acalabrutinib, followed by acalabrutinib maintenance. The primary endpoint of the randomised component is progression free survival (PFS).
Cohort 1 enrols RS patients with progressive disease following chemoimmunotherapy for acalabrutinib monotherapy. Patients with RS diagnosed while on ibrutinib may enrol in Cohort 2, a single-arm study of CHOP-R plus acalabrutinib. The primary endpoint for the single-arm studies is overall response rate (ORR).
Secondary endpoints for all cohorts are overall survival (OS), quality of life and proportion of patients proceeding to stem cell transplantation.
The study will be accompanied by exploratory analysis of the mutational landscape of RS and the relationship between dynamic changes in sequential circulating tumour DNA samples and clinical outcomes.
Discussion
The STELLAR randomised trial evaluates the role of CHOP-R plus acalabrutinib in newly diagnosed RS patients. The single-arm platform studies enable the incorporation of promising novel therapies into the protocol. The STELLAR study has potential to identify novel biomarkers of treatment response in this high-risk malignancy.
Trial registration
EudraCT: 2017–004401-40, registered on the 31-Oct-2017.
IRSCTN: https://www.isrctn.com/ISRCTN52839057, registered on the 04-Mar-2019.
ClinicalTrials.gov: NCT03899337, registered on 02-April-2019.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The Author(s). 2019. This is an open access article under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) (https://creativecommons.org/licenses/by/4.0/) The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
Keywords: | Richter syndrome; Richter transformation, acalabrutinib; BTK inhibitor, chronic lymphocytic leukaemia; CHOP-R |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Experimental Haematology (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 17 Feb 2020 13:51 |
Last Modified: | 17 Feb 2020 13:51 |
Status: | Published |
Publisher: | BMC |
Identification Number: | 10.1186/s12885-019-5717-y |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:157196 |