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  • Oxford University Press (OUP)  (9)
  • Cerretti, Giulia  (9)
  • 1
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii72-vii72
    Abstract: The poor prognosis of patients affected by glioblastoma (GBM) prompts the search for new and more effective therapies, particularly for GBMs with unmethylated MGMT. In this regard, drug repurposing, can represent a safe and inexpensive way to bring novel pharmacological approaches from bench to bedside. Chlorpromazine, a medication in use since six decades for the therapy of psychiatric disorders, shows in vitro features that make it eligible for repositioning in GBM therapy. In our experimentation on six GBM cell lines, chlorpromazine inhibited cell viability in an apoptosis-independent way, induced polyploidy, reduced cloning efficiency as well as neurosphere formation and downregulated the expression of stemness genes. Notably, we found that chlorpromazine synergized with temozolomide, in reducing cell viability and strongly cooperated in reducing cloning efficiency and inducing cell death in vitro for all the GBM cell lines assayed. With these assumptions, we started a multicentric Phase II clinical trial on newly diagnosed GBM patients with unmethylated MGMT by adding chlorpromazine to temozolomide in the adjuvant phase of the standard first-line therapeutic protocol. The experimental procedure involves the combination of CPZ with standard treatment with TMZ in the adjuvant phase of the Stupp protocol. CPZ is administered orally at a dose of 50 mg/day – GG 1-28 – of every cycle of the adjuvant treatment with TMZ. At present, 53 patients out of 60 patients planned have been enrolled, without relevant toxicity.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 2
    Online Resource
    Online Resource
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi71-vi71
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi71-vi71
    Abstract: Regorafenib (REG), an oral multikinase inhibitor, showed benefit in recurrent GBM (recGBM) patients in the REGOMA trial. We investigated the clinical outcome and safety of REG in a real-life population of recGBM patients treated at Veneto Institute of Oncology as off-label use. MATERIAL AND METHODS Patients receiving REG were entered prospectively on a clinical database. Data were retrospectively analyzed. The primary endpoints were overall survival (OS) and safety. The major inclusion criteria were: histologically confirmed diagnosis of GBM, disease progression by RANO criteria after Stupp protocol, ECOG PS ≤ 2. Patients received REG 160 mg per day for the first 3 weeks in a 4-week cycle. Kaplan-Meier method was used to estimate the survival, RANO criteria for radiological assessment, CTCAE v5.0 for drug related adverse events. RESULTS 54 patients were enrolled: median age was 56, ECOG PS 0-1 in 91%, MGMTmet in 53%, second surgery at the time of relapse in 30%. Median follow-up was 11.1ms, 30 PTS (56%) had died and 50 PTS (93%) had progressed. MedianOS was 10.2 ms (95%CI, 6.4-13.9), 12m-OS was 43%; medianPFS was 2.3 ms (95%CI, 1.3-3.3) and 6m-PFS was 18%. Disease control rate (DCR) was 46.3%; stable disease was reported in 38.8% and partial response in 7.4%. Age, MGMT and corticosteroid use at baseline were not statistically significant on multivariate analysis for OS. Grade 3 drug-related adverse events (AEs) occurred in 10 patients (18%) and the most frequent were hand-foot skin reaction, asthenia and increased lipase and transaminases; 1 PT(2%) reported a grade 4 AE (rash maculo-papular). AEs led to REG dose reductions in 37% of patients and, it was permanently discontinued in 5%. CONCLUSIONS We reported a “real-world” experience of REG in recGBM patients. Results are close to those reported in REGOMA trial; we showed a longer OS. Toxicity was manageable. Encouraging clinical benefits of REG in recGBM population were confirmed.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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  • 3
    In: Neuro-Oncology Advances, Oxford University Press (OUP), Vol. 5, No. Supplement_3 ( 2023-08-04), p. iii31-iii32
    Abstract: We retrospectively analyzed 34 patients (pts) [19 males, 15 females, median age 54] with recurrent IDH wildtype glioblastoma treated with target therapy (TT) based on their next-generation sequencing (NGS) profile, between March2020 and December2022 at Veneto Institute of Oncology, Padua (Italy). ECOG PS was 0-1 in 29 pts. All pts received previous radiotherapy and temozolomide. NGS was obtained with FoundationOne®CDx on formalin-fixed paraffin-embedded samples. We identified 6 druggable genomic alterations, classified according to ESCAT (ESMO Scale for Clinical Actionability of molecular Targets): BRAFV600E mutation (IB), NTRK1-2-3 fusions (IC), FGFR1-2-3 alterations (IIB), ROS1 fusions (IIIA), PIK3CA mutations (IIIA) and PTEN loss/mutations (IIIA). The median line of therapy with TT was 3 (range 2-7). TT was dabrafenib/trametinib (9 pts), larotrectinib (2 pts), erdafitinib (4 pts), entrectinib (1 pt), alpelisib (6 pts), ipatasertib+/-atezolizumab (12 pts). At data cut-off (March2023), 19 patients had died. In the entire cohort, median overall survival and progression-free survival (PFS) after starting TT was 8.72 and 2.14 months, respectively. The dabrafenib/trametinib subgroup had the longest median PFS (5.23 months), a disease control rate (DCR) of 77%, an objective response rate of 22%, and a median duration of response of 22.5 months. 7/9 pt had died and 2 pts are continuing dabrafenib/trametinib. The pt with ROS1-GOCP fusion maintained a complete response for 12 months with entrectinib. Among the others, no complete/partial responses were detected. DCR due to stable disease was 50% in larotrectinib and erdafitinib subgroups and 8.3% in ipatasertib+/-atezolizumab subgroup. No toxicities were reported in dabrafenib/trametinib subgroup. Among all patients, no grade 4 drug-related adverse events were observed and in any case TT was interrupted for toxicity. Our results confirm the activity of dabrafenib/trametinib in BRAFV600E mutant glioblastoma pts and might suggest further explorations in targeting ROS1 and FGFR.
    Type of Medium: Online Resource
    ISSN: 2632-2498
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 4
    Online Resource
    Online Resource
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii3-vii3
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii3-vii3
    Abstract: the current standard to treat meningiomas can include surgical resection and radiotherapy. Despite the high rate of relapse no systemic treatment is indicated. Few data are available regarding the effectiveness of bevacizumab (BEV) in this setting. We performed a retrospective analysis investigating the efficacy and safety of BEV in meningioma patients relapsed after receiving surgery and radiotherapy. Gene mutations were also collected. Material and METHODS we analyzed pts treated with off-label BEV from Jul 2019 to Feb 2022. Inclusion criteria were diagnosis of grade 2-3 meningioma, previous treatment with surgery and radiotherapy, no indication to further surgery or reirradiation, absence of contraindications to the use of BEV. Data were estrapolated from clinical records. RESULTS Median follow up was 13 months (3-30 range). 26 pts were enrolled. Median age was 68 ys (29-84); male pts were 16 (61%);61% (16 pts) with atypical meningioma, 38.5% (10 pts) with anaplastic meningioma; 27% (7 pts) underwent 2 or more surgeries; 58% had 2 or more RT treatments; 96.1% (25 pts) received & lt; 2 previous lines of systemic treatment. 61% of patients (16 pts) had NGS analyses available; 62% (10 pts) had NF2 mutations (1 pt had a confirmed diagnosis of neurofibromatosis type 2), 23% (6 pts) CDKN2A/2B deletion, 11% (3 pts) PTEN mutation. OS rate was 82% and 62% at 6 and 12 months respectively; 6 months PFS rate was 83%. The DCR was 71% and the ORR was 19%. Median PFS and OS weren't reached. 19% (5 pts) experienced CTCAE grade 1 or 2 toxicity, mainly hypertension. CONCLUSION BEV showed very promising activity in recurrent grade 2-3 meningioma. The treatment was well tolerated. BEV should be considered an optimal therapeutic option in this setting of meningioma patients. The NGS results might be useful in identifying targetable mutations in case of further recurrence.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 5
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii8-vii8
    Abstract: panels allow the identification of alterations within hundreds of cancer-related genes and can guide a personalized strategy in glioma treatment. METHODS From Nov 2019 to Jan 2022 at Veneto Institute of Oncology, Padua, Italy, a large cohort of IDHwt-GBM tissues was analyzed by NGS (FoundationOne®CDx). We identified all potential actionable molecular alterations at diagnosis and/or at recurrence. High tumor mutational burden (TMB) was defined as ≥10 mutations/megabase. RESULTS We analyzed 429 IDHwt-GBM samples: NGS profile was available for 419 samples (97.7%); sample failures in 10 cases (2.3%). 351 (84%) and 68 (16%) GBM samples derived from surgery at diagnosis and recurrence, respectively. All patients received radiotherapy and/or temozolomide as first line therapy. Among all the analyzed samples, the most frequent actionable molecular alterations were: CDKN2A (57%), CDKN2B (53%), EGFR amplification (39%), EGFR mutation (24%), PTEN loss (27%), RB1 (23%), NF1 (18%), PIK3CA (18%), CDK4 (15%), MDM2 (10%), PDGFRA (8%), BRCA1-2 (7%), FGFR1-3 (7%), Myc (6%), JAK (6%), ROS1 (5%), METmut (2%), METampl (2%), BRAF V600E (2%). No NTRK1/2/3 druggable alterations were observed. High TMB was found in 18 samples. The incidence of alteration of EGFR (ampl/mut), RB1, PIK3CA was statistically different between the two subgroups of newly diagnosed and recurrent GBM samples (Fisher test). To date, 10% of patients received a personalized treatment as compassionate use, off-label use or in clinical trials (9 Dabrafenib/Trametinib, 8 Alpelisib, 3 Erdafitinib, 2 Ipatasertib, 1 Alectinib, 1 Capmatinib, 1 Palbociclib, 1 Entrectinib, 1 Pamiparib). Activity analysis is still ongoing. CONCLUSIONNGS is feasible in GBM samples. Potentially, a high rate of patients could receive a personalized treatment. The activity analysis is ongoing. However, the incidence of actionable molecular alterations may differ between diagnosis and recurrent GBM samples.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 6
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi15-vi15
    Abstract: the significance of TERT promoter mutations, telomere length and their interactions with MGMT methylation status in patients with IDH-wildtype GBM patients remain unclear. We performed a monoinstitutional study to better investigate their impact and their interaction on clinical outcomes. METHODS TERTmutations (C228T and C250T), relative telomere length (RTL) and MGMT methylation were assessed in 278 newly-diagnosed and in 65 recurrent IDH-wildtype GBM PTS which were treated from Dec2016 to Jan2020. We explored association between gene characteristics and neuroradiological response, PFS, OS. Telomere length was measured by monochrome multiplex PCR and RTL values were calculated as a telomere/single-copy gene ratio. RESULTS characteristics of newly diagnosed GBM PTS were: median age 63 ys, ECOG PS0-1 in 71% of PTS, radical surgery in 38%, 78% received radiation therapy plus TMZ, MGMTmet in 53%, TERT promoter was mutated in 80% (75% C228T, 25% C250T), median RTL was 1.57 (range 0.4-11.37). ORR was reported in 15% of PTS, medianOS was 15 ms (95% CI 13-18 ms), medianPFS was 8 ms (95% CI 7-9 ms). At multivariable analysis, TERT mutations and RTL were not associated with clinical outcomes; about OS, TERT mutations and RTL reported a HR of 1.05 (95% CI 0.64-1.64) and 0.99 (95% CI 0.89-1.10), respectively; MGMTmet tumors showed significant improved PFS and OS with a HR of 0.54(95% CI 0.40-0.71) and 0.47 (95% CI 0.34-0.64), respectively. All interactions among MGMT-status, TERT-mutation status and RTL were not statistically significant. Characteristics of recurrent GBM PTS were: median age 55 ys, ECOG PS0-1 in 60% of PTS, MGMTmet in 37%, TERT mutations in 75% (75% C228T, 25% C250T), RTL was 1.67 (range 0.68-8.87). At multivariable analysis, only MGMTmet tumors resulted significantly associated to prolonged OS(HR0.16;95%CI0.07-0.40). No gene interaction was significant. CONCLUSIONS we analyzed the impact of TERT mutations, RTL and MGMT in newly diagnosed and recurrent IDH-wildtype GBM PTS. TERT status and RTL were not associated with clinical outcomes. MGMT was the only prognostic factor. No significant interaction was demonstrated between TERT mutations, RTL and MGMT
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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  • 7
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi66-vi67
    Abstract: Despite advances in surgical and first-line treatment, all glioblastoma pts relapse. The aim of this study is to evaluate the benefit of metronomic temozolomide (mTMZ) for recurrent glioblastoma. METHODS 120 pts treated at Veneto Institute of Oncology from September 2013 to March 2021 were retrospectively reviewed. Major inclusion criteria were: first-line therapy with Stupp protocol, relapse after first or subsequent line of therapy, treatment with mTMZ schedule (50mg/m2 continuously), hystologically confirmed diagnosis. RESULTS mFollow-up was 15.6ms, mAge 59ys (range 18-81), ECOG PS 0-2 in 107pts (89%) and 3 in 11 (9%). MGMT was methylated in 66 of 105 (62%) evaluable pts, IDH mutated in 9 of 106 (8%). mNumber of prior lines of treatment was 2 (range 1-7); 41% of pts received mTMZ beyond the third line. mTime between last standard TMZ (sTMZ) cycle and mTMZ administration was 6ms (range 1-50); 40% of pts started mTMZ after 3ms from sTMZ. All pts were evaluable for response: 3 (2%) and 48 (40%) showed PR and SD. mOS from the start of mTMZ was 5.4ms (95% CI 4.3-6.4), mPFS 2.6ms (95% CI 2.3-2.8). On univariate analysis, MGMTmet and MGMTunmet pts had a mOS of 5.6 and 4.4ms (p= 0.03); mOS for pts with ECOG PS & gt; or ≤ 2 was 2.3 and 6.0ms (p & lt; 0.001). On multivariate analysis, MGMTmet status (HR= 2.3, 95% CI, p= 0.004) and ECOG PS (HR= 0.5, 95% CI, p= 0.017) remained significant for PFS; ECOG PS (HR= 0.4, 95% CI, p= 0.001) was the only factor significantly associated with OS. The most common grade 3-4 hematologic toxicities were lymphopenia (10%) and thrombocytopenia (3%). Grade 3-4 nonhematologic toxicities were uncommon. CONCLUSIONS Rechallenge with mTMZ can be a well tolerated treatment option for recurrent glioblastoma, even in heavily pretreated pts. Pts with MGMTmet and good ECOG PS might report the major benefit.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2094060-9
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  • 8
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi61-vi61
    Abstract: The poor prognosis of patients affected by glioblastoma (GBM) prompts the search for new and more effective therapies, particularly for GBMs with unmethylated MGMT. In this regard, drug repurposing, can represent a safe and inexpensive way to bring novel pharmacological approaches from bench to bedside. Chlorpromazine, a medication in use since six decades for the therapy of psychiatric disorders, shows in vitro features that make it eligible for repositioning in GBM therapy. In our experimentation on six GBM cell lines, chlorpromazine inhibited cell viability in an apoptosis-independent way, induced polyploidy, reduced cloning efficiency as well as neurosphere formation and downregulated the expression of stemness genes. Notably, we found that chlorpromazine synergized with temozolomide, in reducing cell viability and strongly cooperated in reducing cloning efficiency and inducing cell death in vitro for all the GBM cell lines assayed. With these assumptions, we started a multicentric Phase II clinical trial on newly diagnosed GBM patients with unmethylated MGMT by adding chlorpromazine to temozolomide in the adjuvant phase of the standard first-line therapeutic protocol. The experimental procedure involves the combination of CPZ with standard treatment with TMZ in the adjuvant phase of the Stupp protocol. CPZ is administered orally at a dose of 50 mg/day – GG 1-28 – of every cycle of the adjuvant treatment with TMZ. At present, 28 patients out of 41 patients planned have been enrolled, without relevant toxicity.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2094060-9
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  • 9
    In: Neuro-Oncology Advances, Oxford University Press (OUP)
    Abstract: Data on the use of targeted therapies in glioma are still limited and the identification of useful targetable mutations is still under investigation. Among all the relevant alterations identified through next generation sequencing (NGS) tests, ROS1 alterations can rarely be found in gliomas, and the most common of them is GOPC::ROS1 fusion. Targeted therapies, such as entrectinib, are available for such alterations. Hereby, the case of a patient affected by GOPC::ROS1 fused glioblastoma and treated with entrectinib is presented; this patient achieved a complete and prolonged response with no relevant toxicities from the treatment.
    Type of Medium: Online Resource
    ISSN: 2632-2498
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2024
    detail.hit.zdb_id: 3009682-0
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