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Single arm NCRI phase II study of CHOP in combination with Ofatumumab in induction and maintenance for patients with newly diagnosed Richter's syndrome.

ABSTRACT: Transformation of B-cell chronic lymphocytic leukaemia (B-CLL) to diffuse large B cell lymphoma (DLBCL) (Richter's syndrome (RS)) is a rare (2-15% of patients) but catastrophic complication of B-CLL. Dose-intense chemotherapy regimens investigated in small single institution trials, but with the exception of bone marrow transplantation for a minority of patients, little has improved the median overall survival of patients with RS beyond eight months. Patients are often elderly, immunosuppressed, possess co-morbidities and have a deteriorating performance status. TP53 disruption is a common molecular abnormality noted in RS and contributes to the tumour's chemotherapy resistance. Ofatumumab is a fully human anti-CD20 monoclonal IgG1? antibody that targets a unique epitope on B lymphocytes. It has displayed increased binding affinity and a longer dissociation time when compared to rituximab resulting in improved complement dependent cellular cytotoxicity (CDCC); a mechanism with the potential to overcome apoptosis-resistance in TP53 disruption. Given the prevalence of TP53 disruption in RS, Ofatumumab was considered a relatively non-toxic agent with a sound rationale to test in a prospective multicentre trial as an adjunct to CHOP induction and subsequent ofatumumab maintenance therapy in responding patients.The CHOP-OR study is a prospective phase II study to evaluate the safety, feasibility and activity of a CHOP chemotherapy in combination with ofatumumab in induction and subsequent maintenance for patients with newly diagnosed RS. The primary objective will be the overall response rate (ORR) in patients with RS after six cycles of CHOP-O. The secondary objectives include feasibility of recruitment, progression free survival (PFS), overall survival (OS) and toxicity. The study will be accompanied by exploratory analysis of the genomic landscape of RS in newly diagnosed patients.The CHOP-OR trial evaluates the safety, feasibility and activity of CHOP plus Ofatumumab induction and Ofatumumab maintenance in new RS patients. The study is currently recruiting and has met the interim analysis criteria, with more than 7 of the first 25 participants achieving a CR or PR after six cycles of CHOP-O. The study has the potential to identify predictive biomarkers for this treatment modality.NCT01171378.

SUBMITTER: Eyre TA

PROVIDER: S-EPMC4329650 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Single arm NCRI phase II study of CHOP in combination with Ofatumumab in induction and maintenance for patients with newly diagnosed Richter's syndrome.

Eyre Toby A TA Clifford Ruth R Roberts Corran C Boyle Lucy L Francis Anne A Schuh Anna A Dutton Susan J SJ

BMC cancer 20150213

<h4>Background</h4>Transformation of B-cell chronic lymphocytic leukaemia (B-CLL) to diffuse large B cell lymphoma (DLBCL) (Richter's syndrome (RS)) is a rare (2-15% of patients) but catastrophic complication of B-CLL. Dose-intense chemotherapy regimens investigated in small single institution trials, but with the exception of bone marrow transplantation for a minority of patients, little has improved the median overall survival of patients with RS beyond eight months. Patients are often elderly ...[more]

PMID: 25775024

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Project description:BackgroundTransformation 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.MethodsThe 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.DiscussionThe 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 registrationEudraCT: 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.

Project description:BackgroundThe impact of prolonging temozolomide (TMZ) maintenance beyond six cycles in newly diagnosed glioblastoma (GBM) remains a topic of discussion. We investigated the effects of prolonged TMZ maintenance on progression-free survival (PFS) and overall survival (OS).Patients and methodsIn this retrospective single-center cohort study, we included patients with GBM who were treated with radiation therapy with concomitant and adjuvant TMZ. For analysis, patients were considered who either completed six TMZ maintenance cycles (group B), continued with TMZ therapy beyond six cycles (group C), or stopped TMZ maintenance therapy within the first six cycles (group A). Patients with progression during the first six TMZ maintenance cycles were excluded.ResultsClinical data from 107 patients were included for Kaplan-Meier analyses and 102 for Cox regressions. Median PFS times were 8.1 months (95% confidence interval [CI] 6.1-12.4) in group A, 13.7 months (95% CI 10.6-17.5) in group B, and 20.9 months (95% CI 15.2-43.5) in group C. At first progression, response rates of TMZ/lomustine rechallenge were 47% in group B and 13% in group C. Median OS times were 12.7 months (95% CI 10.3-16.8) in group A, 25.2 months (95% CI 17.7-55.5) in group B, and 28.6 months (95% CI 24.4-open) in group C. Nevertheless, multivariate Cox regression for patients in group C compared with group B that accounted for imbalances of other risk factors showed no different relative risk (RR) for OS (RR 0.77, p = .46).ConclusionOur data do not support a general extension of TMZ maintenance therapy beyond six cycles. The Oncologist 2017;22:570-575 IMPLICATIONS FOR PRACTICE: Radiation therapy with concomitant and adjuvant temozolomide (TMZ) maintenance therapy is still the standard of care in patients below the age of 65 years in newly diagnosed glioblastoma. However, in clinical practice, many centers continue TMZ maintenance therapy beyond six cycles. The impact of this continuation is controversial and has not yet been addressed in prospective randomized clinical trials. We compared the effect of more than six cycles of TMZ in comparison with exactly six cycles on overall survival (OS) and progression-free survival (PFS) by multivariate analysis and found a benefit in PFS but not OS. Thus, our data do not suggest prolonging TMZ maintenance therapy beyond six cycles, which should be considered in neurooncological practice.

Project description:n the EMN01 trial, the addition of an alkylator (melphalan or cyclophosphamide) to lenalidomide-steroid induction therapy was prospectively evaluated in transplant-ineligible patients with multiple myeloma. After induction, patients were randomly assigned to maintenance treatment with lenalidomide alone or with prednisone continuously. The analysis presented here (median follow-up of 71 months) is focused on maintenance treatment and on subgroup analyses defined according to the International Myeloma Working Group Frailty Score. Of the 654 evaluable patients, 217 were in the lenalidomide-dexamethasone arm, 217 in the melphalan-prednisone-lenalidomide arm and 220 in the cyclophosphamide-prednisone-lenalidomide arm. With regards to the Frailty Score, 284 (43%) patients were fit, 205 (31%) were intermediate-fit and 165 (25%) were frail. After induction, 402 patients were eligible for maintenance therapy (lenalidomide arm, n=204; lenalidomide-prednisone arm, n=198). After a median duration of maintenance of 22.0 months, progression-free survival from the start of maintenance was 22.2 months with lenalidomide-prednisone vs 18.6 months with lenalidomide (hazard ratio 0.85, P=0.14), with no differences across frailty subgroups. The most frequent grade ≥3 toxicity was neutropenia (10% of lenalidomide-prednisone and 21% of lenalidomide patients; P=0.001). Grade ≥3 non-hematologic adverse events were rare (<15%). In fit patients, melphalan-prednisone-lenalidomide significantly prolonged progression-free survival compared to cyclophosphamide-prednisone-lenalidomide (hazard ratio 0.72, P=0.05) and lenalidomide-dexamethasone (hazard ratio 0.72, P=0.04). Likewise, a trend towards a better overall survival was noted for patients treated with melphalan-prednisone-lenalidomide or cyclophosphamide-prednisone-lenalidomide, as compared to lenalidomide-dexamethasone. No differences were observed in intermediate-fit and frail patients. This analysis showed positive outcomes of maintenance with lenalidomide-based regimens, with a good safety profile. For the first time, we showed that fit patients benefit from a full-dose triplet regimen, while intermediate-fit and frail patients benefit from gentler regimens. ClinicalTrials.gov registration number: NCT01093196.

Dataset Information

Single arm NCRI phase II study of CHOP in combination with Ofatumumab in induction and maintenance for patients with newly diagnosed Richter's syndrome.

Publications

Single arm NCRI phase II study of CHOP in combination with Ofatumumab in induction and maintenance for patients with newly diagnosed Richter's syndrome.

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