Phase I/IIa study of concomitant radiotherapy with olaparib and temozolomide in unresectable or partially resectable glioblastoma: OLA-TMZ-RTE-01 trial protocol

Lesueur, Paul; Lequesne, Justine; Grellard, Jean‐Michel; Dugué, Audrey Emmanuelle; Coquan, Elodie; Brachet, Pierre-Emmanuel; Geffrelot, Julien; Kao, William; Emery, Évelyne; Berro, David Hassanein; Castéra, Laurent; Goardon, Nicolas; Lacroix, Joëlle; Lange, Marie; Capel, Aurélie; Leconte, Alexandra; Bleich, André; Léger, Angélique; Lelaidier, Anaïs; Clarisse, Bénédicte; Stefan, Dinu

doi:10.1186/s12885-019-5413-y

Cited by 91 publications

(71 citation statements)

References 22 publications

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“…ARID1A-defective tumors may also be particularly good candidates for immune checkpoint blockade due to the potentially large number of immune-activating neoepitopes generated by MMR deficiency [27]. The PARP inhibitors olaparib and BGB-290, among others, are currently being evaluated as radio-and chemosensitizers in both IDH-wildtype and IDH-mutant GBM in early phase clinical trials, but no molecular biomarkers for response have so far emerged [29][30][31].…”

Section: Discussionmentioning

confidence: 99%

Widely metastatic glioblastoma with BRCA1 and ARID1A mutations: a case report

et al. 2020

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Background: Glioblastoma (GBM) is a highly malignant brain neoplasm with poor survival. Despite its aggressive nature, metastatic spread of GBM is identified only rarely. While the molecular alterations associated with GBM and its subtypes are well-described, there remains a gap in understanding which alterations may predispose towards metastasis. In this report, we present a case of GBM with multi-organ metastases and discuss its genomic alterations. Case presentation: A 74-year-old woman was diagnosed with left occipital glioblastoma (IDH-wildtype, MGMTunmethylated), for which she underwent resection, standard chemoradiation, and then stereotactic radiosurgery (SRS) for local recurrence. One month after SRS, work-up for a pathologic hip fracture revealed a left breast mass, lytic lesions involving pelvic bones, and multiple pulmonary and hepatic lesions. Biopsies of the breast and bone lesions both demonstrated metastatic IDH-wildtype GBM. For worsening neurologic symptoms, the patient underwent debulking of a large right temporal lobe recurrence and expired shortly thereafter. Autopsy confirmed metastatic GBM in multiple systemic sites, including bilateral lungs, heart, liver, thyroid, left breast, small bowel, omentum, peritoneal surfaces, visceral surfaces, left pelvic bone, and hilar lymph nodes. Targeted sequencing was performed on tissue samples obtained pre-and postmortem, as well as on cell cultures and an orthotopic mouse xenograft derived from premortem surgical specimens. A BRCA1 mutation (p.I571T) was the only variant found in common among the primary, recurrence, and metastatic specimens, suggesting its likely status as an early driver mutation. Multiple subclonal ARID1A mutations, which promote genomic instability through impairment of DNA mismatch repair, were identified only in the recurrence. Mutational spectrum analysis demonstrated a high percentage of C:G to T:A transitions in the post-treatment samples but not in the primary tumor. Conclusion: This case report examines a rare case of widely metastatic IDH-wildtype GBM with a clonal somatic mutation in BRCA1. Post-treatment recurrent tumor in the brain and in multiple systemic organs exhibited evidence of acquired DNA mismatch repair deficiency, which may be explained by functional loss of ARID1A. We identify a potential role for immune checkpoint and PARP inhibitors in the treatment of metastatic GBM.

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Section: Discussionmentioning

confidence: 99%

Widely metastatic glioblastoma with BRCA1 and ARID1A mutations: a case report

et al. 2020

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“…For the "TCL1 MBEN" cohort (Online Resource Supplementary Fig. 8), molecular targeted therapy with inhibitors of ZNF217 and/or PARP4 may be effective, as it has been reported recently for CNS and non-CNS cancers (glioblastoma, breast carcinoma, ovarian cancers) [7,21,24]. Further investigation of the clinical and therapeutic relevance of transcriptionally defined MBEN subsets is warranted.…”

Section: Discussionmentioning

confidence: 88%

Transcriptional profiling of medulloblastoma with extensive nodularity (MBEN) reveals two clinically relevant tumor subsets with VSNL1 as potent prognostic marker

et al. 2019

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Medulloblastoma with extensive nodularity (MBEN) is one of the few central nervous system (CNS) tumor entities occurring in infants which is traditionally associated with good to excellent prognosis. Some MBEN, however, have been reported with an unfavorable clinical course. We performed an integrated DNA/RNA-based molecular analysis of a multi-institutional MBEN cohort (n = 41) to identify molecular events which might be responsible for variability in patients' clinical outcomes. RNA sequencing analysis of this MBEN cohort disclosed two clear transcriptome clusters (TCL) of these CNS tumors: "TCL1 MBEN" and "TCL2 MBEN" which were associated with various gene expression signatures, mutational landscapes and, importantly, prognosis. Thus, the clinically unfavorable "TCL1 MBEN" subset revealed transcriptome signatures composed of cancer-associated signaling pathways and disclosed a high frequency of clinically relevant germline PTCH1/SUFU alterations. In contrast, gene expression profiles of tumors from the clinically favorable "TCL2 MBEN" subgroup were associated with activation of various neurometabolic and neurotransmission signaling pathways, and germline SHH-pathway gene mutations were extremely rare in this transcriptome cluster. "TCL2 MBEN" also revealed strong and ubiquitous expression of VSNL1 (visinin-like protein 1) both at the mRNA and protein level, which was correlated with a favorable clinical course. Thus, combining mutational and epigenetic profiling with transcriptome analysis including VSNL1 immunohistochemistry, MBEN patients could be stratified into clinical risk groups of potential value for subsequent treatment planning.

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“…This project comes within a large scientific program of our Institution that aims at assessing various treatment approaches in primary and secondary brain tumours [29].…”

Section: Discussionmentioning

confidence: 99%

Stereotactic radiotherapy on brain metastases with recent hemorrhagic signal: STEREO-HBM, a two-step phase 2 trial

et al. 2020

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Background: Brain metastases often occur in cancer evolution. They are not only responsible for death but also for disorders affecting the quality of life and the cognitive functions. Management of brain metastases usually consists in multi-modality treatments, including neurosurgery, whole brain radiotherapy (WBRT), and more recently radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT), systemic treatment (chemotherapy or targeted therapy), combined or not with corticosteroids. Almost 20% of brain metastases can present recent (within 15 days) bleeding signs on neuro-imagery. In these conditions, WBRT is the usual treatment. Yet, patients may benefit from a more aggressive strategy with SRT or FSRT. However, these options were suspected to possibly major the risk of brain haemorrhage, although no scientifically proven. Radiation oncologists therefore usually remain reluctant to deliver SRS/FSRT for bleeding brain metastases. It is therefore challenging to establish a standard of care for the treatment of bleeding brain metastases. We propose a phase II trial to simultaneously assess safety and efficacy of FSRT to manage brain metastases with hemorrhagic signal. Methods: The STEREO-HBM study is a multicenter two-step non-randomised phase II trial addressing patients with at least one bleeding brain metastasis out of a maximum of 3 brain metastases. Each brain metastasis will be treated with 30 Gy in 3 fractions for 1 week. The main endpoint is based on both safety and efficacy endpoints as proposed by Bryant and Day's design. Safety endpoint is defined as the rate of bleeding complications 4 months post-FSRT while efficacy endpoint is defined as the 6-month local control rate. Multi-modal MRI will be used to assess intra-tumoral hemorrhagic events before and after treatment. Patients' quality of life will also be assessed. Discussion: Management of bleeding brain metastases is still debated and poorly explored in clinical trials. There is sparse and weak data on the signification of pretreatment intra-tumour haemorrhagic signs or on the risk of brain bleeding complications after FSRT. We expect this first prospective phase 2 trial in this particular setting will allow to clarify the place of FSRT to optimally manage bleeding brain metastases.

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Phase I/IIa study of concomitant radiotherapy with olaparib and temozolomide in unresectable or partially resectable glioblastoma: OLA-TMZ-RTE-01 trial protocol

Cited by 91 publications

References 22 publications

Widely metastatic glioblastoma with BRCA1 and ARID1A mutations: a case report

Widely metastatic glioblastoma with BRCA1 and ARID1A mutations: a case report

Transcriptional profiling of medulloblastoma with extensive nodularity (MBEN) reveals two clinically relevant tumor subsets with VSNL1 as potent prognostic marker

Stereotactic radiotherapy on brain metastases with recent hemorrhagic signal: STEREO-HBM, a two-step phase 2 trial

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