VALERIA BUCCHERI

(Fonte: Lattes)
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Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/31 - Laboratório de Genética e Hematologia Molecular, Hospital das Clínicas, Faculdade de Medicina

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Colaboração internacional: Canadá ×

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  • conferenceObject
    Subcutaneous Rituximab in Combination with Fludarabine and Cyclophosphamide for Patients with CLL: Initial Results of a Phase Ib Study (SAWYER [BO25341]) Show Non-Inferior Pharmacokinetics and Comparable Safety to That of Intravenous Rituximab
    (2012) ASSOULINE, Sarit; BUCCHERI, Valeria; DELMER, Alain; DOELKEN, Gottfried; GAIDANO, Gianluca; MCINTYRE, Christine; BREWSTER, Mike; HOURCADE-POTELLERET, Florence; SAYYED, Pakeeza; BADOUX, Xavier
    Rituximab in combination with fludarabine and cyclophosphamide (FC) is recommended as the standard treatment for patients (pts) with chronic lymphocytic leukemia (CLL) where the goal of therapy is to achieve complete remission (ESMO Clinical Practice Guidelines, Ann Oncol 2011). Rituximab is currently administered intravenously (IV) where infusions may take several hours. A subcutaneous (SC) formulation of rituximab has been developed which could significantly shorten administration times, increasing patient convenience and potentially improving tolerability. Here we report part 1 data of a two part, randomized, open-label Phase Ib study of rituximab SC + FC vs rituximab IV + FC in previously untreated pts with CLL (SAWYER [BO25341]). The part 1 objectives were to ensure that the SC dose predicted from the BP22333 study (Salar et al. EHA 2012; ASH 2010) would result in comparable trough serum rituximab concentration (Ctrough) to IV in the CLL setting, and to assess safety and tolerability. Pts (≥18 years old) were enrolled in the study at any point during their initial standard treatment with rituximab IV + FC x 6, prior to commencement of Cycle 5. In Cycle 5, pts received rituximab at 500mg/m2 IV + FC and in Cycle 6 rituximab IV was replaced with rituximab SC at 1400 mg, 1600 mg or 1870 mg. Rituximab PK was evaluated on an ongoing basis throughout Cycles 5 and 6 and integrated into a population PK model using nonlinear mixed effects modeling. Model-based simulations were performed to predict serum Ctrough and AUC for various rituximab SC fixed doses (1400–1650 mg). A total of 64 pts were enrolled in part 1 of the study, 55 of these received rituximab SC + FC at doses of either 1400 mg (n=16), 1600 mg (n=17) or 1870 mg (n=22). Eight pts discontinued treatment prior to Cycle 6 and one pt enrolled to receive 1870 mg rituximab SC at Cycle 6 received a lower dose in error. The median age of pts was 60 years and pts were classified as Binet stage A (27%), B (55%), or C (19%). At Cycle 6, predicted mean Ctrough values for a fixed dose of 1600 mg rituximab SC were 75.2 μg/ml (90% CI: 60.1–90.1 μg/ml) compared with 62.5 μg/ml (90% CI: 49.4–73.6 μg/ml) for a 500 mg/m2 dose of rituximab IV. Furthermore, AUC values for 1600 mg rituximab SC were 3760 μg/ml (90% CI: 3250–4240 μg/ml) compared with 3470 μg/ml (90% CI: 3100–3820 μg/ml) for 500 mg/m2 rituximab IV, suggesting that a rituximab SC dose of 1600 mg would result in a Ctrough and AUC non-inferior to that of the approved IV regimen, independent of pt body surface area. The majority of adverse events (AEs) reported over the course of Cycles 5 plus 6 were grade 1 or 2 in intensity with 10/16 (63%) pts in the 1400 mg group, 11/17 (65%) pts in the 1600 mg group and 20/22 (91%) pts in the 1870 mg group reporting at least one AE. More pts experienced at least one grade ≥3 AE during Cycle 5 (19 pts following rituximab IV) than Cycle 6 (11 pts following rituximab SC) with the most common grade ≥3 AE reported being neutropenia. Two serious AEs occurred in Cycle 5 and two in Cycle 6. There were no deaths and no withdrawals from treatment due to AEs during Cycles 5 and 6. AEs that occurred during or within 24 h of the administration and were assessed by the investigator as related to rituximab IV/SC were defined as administration-related reactions (ARRs). Two pts reported ARRs at Cycle 5 compared with 12 pts at Cycle 6, with the majority of the Cycle 6 ARRs being related to local injection site reactions. After Cycle, 6 pts and nurses were asked if they preferred SC or IV administration. Of the 56 questionnaires completed, over 90% of pts and their treating nurses preferred the SC route of administration. In conclusion, results of the population PK analysis propose the selection of a 1600 mg rituximab SC fixed dose for pts with CLL to be administered in part 2 of the study. Safety profiles for rituximab SC were comparable with rituximab IV. A greater number of ARRs were observed after treatment with rituximab SC, these were mainly transient injection site pain and erythema. Questionnaire results after one cycle of rituximab SC indicated clearly that the preferred route of administration, for both nurses and pts was SC. In this study FC could be administered IV or orally; the opportunity to administer FC orally permits the possibility of a chemoimmunotherapy free from IV infusions. The study is ongoing to establish non-inferiority in observed Ctrough levels between the confirmed rituximab SC dose and the reference rituximab IV dose. Disclosures: Assouline: Roche: Honoraria. Off Label Use: Subcutaneous rituximab in combination with fludarabine and cyclophosphamide for patients with CLL. Delmer: French Society of Hematology: Consultancy, Honoraria, Research Funding, participation in French advisory board Other. Gaidano: Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Participated in Advisory Boards Other; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Participated in Advisory Boards, Participated in Advisory Boards Other; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Participated in Advisory Boards, Participated in Advisory Boards Other; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Participated in Advisory Boards, Participated in Advisory Boards Other. McIntyre: Roche: Employment. Brewster: Roche: Employment, Equity Ownership. Hourcade-Potelleret: Roche: Employment. Sayyed: Roche: Employment.
  • conferenceObject
    Health-related quality of life (HRQoL) from KEYNOTE-204: A phase III, randomized, open-label study of pembrolizumab (pembro) vs brentuximab vedotin (BV) in relapsed or refractory classical Hodgkin lymphoma (R/R cHL)
    (2020) ZINZANI, P. L.; RAMCHANDREN, R.; SANTORO, A.; PASZKIEWICZ-KOZIK, E.; GASIOROWSKI, R.; JOHNSON, N. A.; OLIVEIRA, J. S. R. de; BUCCHERI, V.; PERINI, G. F.; DICKINSON, M.; MCDONALD, A.; OZCAN, M.; SEKIGUCHI, N.; RAUT, M.; ZHU, Y.; NAHAR, A.; MARINELLO, P.; KURUVILLA, J.
  • conferenceObject
  • article 8 Citação(ões) na Scopus
    Quality-of-life analysis of pembrolizumab vs brentuximab vedotin for relapsed/refractory classical Hodgkin lymphoma
    (2022) ZINZANI, Pier Luigi; RAMCHANDREN, Radhakrishnan; SANTORO, Armando; PASZKIEWICZ-KOZIK, Ewa; GASIOROWSKI, Robin; JOHNSON, Nathalie A.; OLIVEIRA, Jose S. R. de; BUCCHERI, Valeria; PERINI, Guilherme Fleury; DICKINSON, Michael; MCDONALD, Andrew; OZCAN, Muhit; SEKIGUCHI, Naohiro; ZHU, Ying; RAUT, Monika; SARETSKY, Todd L.; NAHAR, Akash; KURUVILLA, John
    KEYNOTE-204 (NCT02684292) demonstrated a progression-free survival advantage for pembrolizumab over brentuximab vedotin (BV) in patients who had relapsed or refractory classical Hodgkin lymphoma (R/R cHL) following, or who were ineligible for, autologous stem cell transplantation (ASCT). Health-related quality of life (HRQoL), measured by patient-reported outcomes (PROs) from KEYNOTE-204, are reported from patients who received >= 1 dose of study treatment and completed >= 1 PRO assessment. The EORTC QoL Questionnaire Core 30 (QLQ-C30) and EuroQoL EQ-5D were administered at baseline, every 6 weeks until week 24, and every 12 weeks thereafter. Prespecified end points included least squares mean (LSM) changes from baseline to week 24 and time to true deterioration (TTD; >= 10-point decline from baseline). Comparisons were evaluated using 2-sided P values uncontrolled for multiplicity. High compliance at baseline (>90%) and through week 24 (>80%) was demonstrated across treatment groups (PRO analysis set: pembrolizumab, n = 146; BV, n = 150). The EORTC QLQ-C30 global health status (GHS)/quality of life (QoL) score improved from baseline to week 24 on pembrolizumab and worsened on BV and demonstrated significant LSM differences at 24 weeks (GHS/QoL: 8.60 [95% confidence interval, 3.89-13.311; P = .0004). Significant improvements were observed in each QLQ-C30 domain except emotional and cognitive functioning. Compared with BV, pembrolizumab prolonged TTD for GHS/QoL (hazard ratio, 0.40 [95% CI, 0.22-0.741; P = .003) and each QLQ-C30 domain except cognitive functioning. In conclusion, pembrolizumab demonstrated overall improvements in PROs of HRQoL measures over BV in the KEYNOTE-204 study. These data and previously reported efficacy results support pembrolizumab as the preferred treatment option for patients with RJR cHL who are ineligible for or experience relapse after ASCT.
  • article 13 Citação(ões) na Scopus
    Primary prophylaxis with G-CSF may improve outcomes in patients with newly diagnosed stage III/IV Hodgkin lymphoma treated with brentuximab vedotin plus chemotherapy
    (2020) STRAUS, David; COLLINS, Graham; WALEWSKI, Jan; ZINZANI, Pier Luigi; GRIGG, Andrew; SUREDA, Anna; ILLES, Arpad; KIM, Tae Min; ALEKSEEV, Sergey; SPECHT, Lena; BUCCHERI, Valeria; YOUNES, Anas; CONNORS, Joseph; FORERO-TORRES, Andres; FENTON, Keenan; GAUTAM, Ashish; PUREVJAL, Indra; LIU, Rachael; GALLAMINI, Andrea
    We investigate the impact of granulocyte-colony stimulating factor (G-CSF) primary prophylaxis (G-PP,N = 83) versus no G-PP (N = 579) on safety and efficacy of brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A + AVD) in the ECHELON-1 study of previously untreated stage III/IV classical Hodgkin lymphoma. G-PP was associated with lower incidence of >= grade 3 neutropenia (29% versus 70%) and febrile neutropenia (11% versus 21%). Fewer dose delays (35% versus 49%), reductions (20% versus 26%), and hospitalizations (29% versus 38%) were observed. Seven neutropenia-associated deaths occurred in the A + AVD arm; none received G-PP. A + AVD with G-PP was associated with decreased risk of a modified progression-free survival event by 26% compared with A + AVD alone (95% CI: 0.40-1.37). G-PP reduced the rate and severity of adverse events, including febrile neutropenia, reduced treatment delays, dose reductions, and discontinuations, and may thus improve efficacy outcomes. These data support G-PP for all patients treated with A + AVD.
  • article 36 Citação(ões) na Scopus
    Pharmacokinetics, safety, and efficacy of subcutaneous versus intravenous rituximab plus chemotherapy as treatment for chronic lymphocytic leukaemia (SAWYER): a phase 1b, open-label, randomised controlled non-inferiority trial
    (2016) ASSOULINE, Sarit; BUCCHERI, Valeria; DELMER, Alain; GAIDANO, Gianluca; TRNENY, Marek; BERTHILLON, Natalia; BREWSTER, Michael; CATALANI, Olivier; LI, Sai; MCINTYRE, Christine; SAYYED, Pakeeza; BADOUX, Xavier
    Background Part one of the two-part SAWYER study predicted that subcutaneous rituximab 1600 mg would achieve trough serum concentrations that were non-inferior to those achieved with intravenous rituximab 500 mg/m(2) in patients with chronic lymphocytic leukaemia. In part two of the study, we aimed to confirm the pharmacokinetic non-inferiority of subcutaneous rituximab, and investigate its safety and efficacy. Methods We did this phase 1b, open-label, randomised controlled non-inferiority study at 68 centres in 19 countries in Europe, North America, South America, and Australasia. Patients aged 18 years or older with untreated chronic lymphocytic leukaemia were randomly assigned, via an interactive voice-response system with a permuted block randomisation scheme (block size of ten), to receive subcutaneous rituximab 1600 mg or intravenous rituximab 500 mg/m(2) plus fludarabine and cyclophosphamide every 4 weeks for up to six cycles. In cycle one, all patients received intravenous rituximab 375 mg/m(2). Randomisation was stratified by Binet stage and fludarabine and cyclophosphamide administration route (oral vs intravenous). Study investigators and patients were not masked to group allocation, but allocation was concealed from the statistician, clinical scientist, and clinical pharmacologist. The primary endpoint was trough serum concentration at cycle five, with a non-inferiority margin of 0.8 for the adjusted geometric mean ratio of the subcutaneous to the intravenous dose. We did the primary analysis in patients in the intention-to-treat population with complete pharmacokinetic data (pharmacokinetic population). This trial is registered with ClinicalTrials.gov, number NCT01292603, and is ongoing, although the treatment stage is now complete. Findings Between Aug 20, 2012, and June 17, 2013, we randomly assigned 176 patients to receive subcutaneous rituximab (n=88) or intravenous rituximab (n=88); 134 (76%) patients comprised the pharmacokinetic population. As of May 7, 2014, median follow-up was 13.9 months (IQR 11.9-16.0) for patients in the subcutaneous group and 14.1 months (11.6-16.5) for patients in the intravenous group. At cycle five, the geometric mean trough serum concentration in patients given subcutaneous rituximab was non-inferior to that in patients given intravenous rituximab (97.5 mu g/mL vs 61.5 mu g/mL), with an adjusted geometric mean ratio of 1.53 (90% CI 1.27-1.85). In the safety analysis, the proportion of patients reporting adverse events was similar between the subcutaneous and intravenous groups (all grades: 82 [96%] of 85 patients and 81 [91%] of 89 patients; serious adverse events: 25 [29%] and 29 [33%] patients; grade >= 3: 59 [69%] and 63 [71%] patients, respectively). The most common adverse event of grade 3 or higher was neutropenia (48 [56%] patients in the subcutaneous group and 46 [52%] patients in the intravenous group); the most common serious adverse event was febrile neutropenia (n=9 [11%] and n=4 [4%], respectively). We recorded administration-related reactions in 37 (44%) patients given subcutaneous rituximab and 40 (45%) patients given the intravenous dose, with differences between administration routes for injection-site erythema (n=10 [12%] and n=0, respectively) and nausea (n=2 [2%] and n=11 [12%], respectively). More patients reported local cutaneous reactions after subcutaneous rituximab (n=36 [42%]) than after intravenous rituximab (n=2 [2%]); most of these reactions were grade 1 or 2. Interpretation When combined with fludarabine and cyclophosphamide, subcutaneous rituximab 1600 mg achieved trough serum concentrations that were pharmacokinetically non-inferior to those achieved with intravenous rituximab 500 mg/m(2), with a similar safety and efficacy profile between the two groups. Treatment with subcutaneous rituximab should allow patients with chronic lymphocytic leukaemia to receive clinical benefit from the drug via a more convenient delivery method than the intravenous route, and might also be used in combination regimens with approved and emerging oral regimens.
  • article 33 Citação(ões) na Scopus
    Pharmacokinetics and safety of subcutaneous rituximab plus fludarabine and cyclophosphamide for patients with chronic lymphocytic leukaemia
    (2015) ASSOULINE, Sarit; BUCCHERI, Valeria; DELMER, Alain; GAIDANO, Gianluca; MCINTYRE, Christine; BREWSTER, Michael; CATALANI, Olivier; HOURCADE-POTELLERET, Florence; SAYYED, Pakeeza; BADOUX, Xavier
    AimsThe aim of the phase Ib, two part SAWYER study (BO25341; NCT01292603) was to investigate the pharmacokinetics and safety of subcutaneous (s.c.) rituximab compared with intravenous (i.v.) rituximab, both in combination with fludarabine and cyclophosphamide (FC), as first line treatment for patients with chronic lymphocytic leukaemia (CLL). MethodsDuring part 1 (dose-finding), CLL patients received rituximab i.v. followed by a single dose of rituximab s.c. at one of three fixed doses (1400, 1600 or 1870mg) in cycle 6. The primary objective was to identify a fixed s.c. dose that would achieve comparable rituximab serum trough concentrations (C-trough) to those achieved with the standard 4 weekly 500mgm(-2) rituximab i.v. dose. ResultsFifty-five patients received a fixed dose of rituximab s.c., 16 received 1400mg, 17 received 1600mg and 22 received 1870mg. The 1600mg dose was predicted to achieve non-inferior C-trough to standard rituximab i.v. treatment. The rituximab s.c. safety profile was comparable with rituximab i.v., except that local administration-related reactions, mainly mild/moderate injection site reactions, occurred more frequently with rituximab s.c., which was not unexpected. Subcutaneous administration was preferred to i.v. administration by >90% of patients and nurses (n=112). ConclusionsSAWYER part 1 data predict that rituximab s.c. 1600mg will achieve non-inferior C-trough concentrations to rituximab i.v. 500mgm(-2), administered 4 weekly. This fixed s.c. dose is currently undergoing formal non-inferiority assessment in SAWYER part 2. In future, CLL treatment regimens comprising rituximab s.c. and oral FC could substantially reduce i.v. chair time.