Author
Marcelo Capra
Bio: Marcelo Capra is an academic researcher from Universidade Federal do Rio Grande do Sul. The author has contributed to research in topics: Population & Therapeutic drug monitoring. The author has an hindex of 11, co-authored 22 publications receiving 226 citations.
Papers
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National and Kapodistrian University of Athens1, City of Hope National Medical Center2, University College Hospital3, University of Ostrava4, Charles University in Prague5, Murdoch University6, Samsung Medical Center7, University of São Paulo8, French Institute of Health and Medical Research9, Seoul National University Hospital10, University of California, San Francisco11
TL;DR: In this article, the authors compared the efficacy of isatuximab plus carfilzomib-dexamethasone versus CARF-DEXAMETHASONE in patients with relapsed or refractory multiple myeloma.
131 citations
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Memorial Sloan Kettering Cancer Center1, Ankara University2, Fudan University3, Jilin University4, University of La Frontera5, Medical University Plovdiv6, Sun Yat-sen University7, Zhejiang University8, Memorial Hospital of South Bend9, Hollywood Private Hospital10, Harbin Medical University11, Sigmund Freud University Vienna12, Ege University13, University of Pécs14, Bayer HealthCare Pharmaceuticals15, Bayer16, Peking Union Medical College17, University of Bologna18
TL;DR: In this article, copanlisib was combined with rituximab to improve progression-free survival in patients with relapsed indolent non-Hodgkin lymphoma.
Abstract: Summary Background Copanlisib, an intravenous pan-class I PI3K inhibitor, showed efficacy and safety as monotherapy in patients with relapsed or refractory indolent non-Hodgkin lymphoma who had received at least two therapies. The CHRONOS-3 study aimed to assess the efficacy and safety of copanlisib plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma. Methods CHRONOS-3 was a multicentre, double-blind, randomised, placebo-controlled, phase 3 study in 186 academic medical centres across Asia, Australia, Europe, New Zealand, North America, Russia, South Africa, and South America. Patients aged 18 years and older with an Eastern Cooperative Oncology Group performance status of no more than 2 and histologically confirmed CD20-positive indolent B-cell lymphoma relapsed after the last anti-CD20 monoclonal antibody-containing therapy and progression-free and treatment-free for at least 12 months, or at least 6 months for patients unwilling or unfit to receive chemotherapy, were randomly assigned (2:1) with an interactive voice-web response system via block randomisation (block size of six) to copanlisib (60 mg given as a 1-h intravenous infusion on an intermittent schedule on days 1, 8, and 15 [28-day cycle]) plus rituximab (375 mg/m2 given intravenously weekly on days 1, 8, 15, and 22 during cycle 1 and day 1 of cycles 3, 5, 7, and 9) or placebo plus rituximab, stratified on the basis of histology, progression-free and treatment-free interval, presence of bulky disease, and previous treatment with PI3K inhibitors. The primary outcome was progression-free survival in the full analysis set (all randomised patients) by masked central review. Safety was assessed in all patients who received at least one dose of any study drug. This study is registered with ClinicalTrials.gov , NCT02367040 and is ongoing. Findings Between Aug 3, 2015, and Dec 17, 2019, 652 patients were screened for eligibility. 307 of 458 patients were randomly assigned to copanlisib plus rituximab and 151 patients were randomly assigned to placebo plus rituximab. With a median follow-up of 19·2 months (IQR 7·4–28·8) and 205 total events, copanlisib plus rituximab showed a statistically and clinically significant improvement in progression-free survival versus placebo plus rituximab; median progression-free survival 21·5 months (95% CI 17·8–33·0) versus 13·8 months (10·2–17·5; hazard ratio 0·52 [95% CI 0·39–0·69]; p Interpretation Copanlisib plus rituximab improved progression-free survival in patients with relapsed indolent non-Hodgkin lymphoma compared with placebo plus rituximab. To our knowledge, copanlisib is the first PI3K inhibitor to be safely combined with rituximab and the first to show broad and superior efficacy in combination with rituximab in patients with relapsed indolent non-Hodgkin lymphoma. Funding Bayer.
55 citations
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TL;DR: Adding dexamethasone to isatuximab increased response rates and survival outcomes with no detrimental effect on safety in relapsed/refractory multiple myeloma.
35 citations
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TL;DR: IM can be measured in DBS using UHPLC-MS/MS with results comparable to those obtained in blood plasma, and is stable at DBS maintained at 40°C for 36 days.
Abstract: Background: Imatinib (IM) is widely used in treatment of chronic myeloid leukemia with target trough plasma concentrations above 1000 ng ml-1. DBS can increase access to IM therapeutic drug monitoring. Results: IM was measured in the range 50–4000 ng ml-1 by UHPLC–MS/MS using one 6 mm DBS in a fully validated method. IM was stable at DBS maintained at 40°C for 36 days. Plasma and DBS concentrations were highly correlated (r > 0.96). The use of a IM concentration target of 765 ng ml-1 in DBS identified 93% of patients with plasma concentration below 1000 ng ml-1. Conclusion: IM can be measured in DBS using UHPLC–MS/MS with results comparable to those obtained in blood plasma.
32 citations
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University of Hamburg1, Monash University2, Columbia University3, University of Colorado Boulder4, Charles University in Prague5, Semmelweis University6, Albert Schweitzer Hospital7, University of Florence8, University of Bologna9, Chonnam National University10, Emory University11, St. Vincent's Health System12, University of Mainz13, Royal Adelaide Hospital14, University of São Paulo15, University of Milan16, St Mary's Hospital17, Mayo Clinic18, Ankara University19, Pusan National University20, Erasmus University Rotterdam21, Janssen Pharmaceutica22, Spanish National Research Council23
TL;DR: New data reinforce the effectiveness and tolerability of daratumumab-based regimens for RRMM, regardless of cytogenetic risk status, as well as the safety profile of CASTOR.
Abstract: Multiple myeloma (MM) patients with high cytogenetic risk have poor outcomes In CASTOR, daratumumab plus bortezomib/dexamethasone (D-Vd) prolonged progression-free survival (PFS) versus bortezomib/dexamethasone (Vd) alone and exhibited tolerability in patients with relapsed or refractory MM (RRMM) This subgroup analysis evaluated D-Vd versus Vd in CASTOR based on cytogenetic risk, determined using fluorescence in situ hybridization and/or karyotype testing performed locally High-risk patients had t(4;14), t(14;16), and/or del17p abnormalities Minimal residual disease (MRD; 10−5 sensitivity threshold) was assessed via the clonoSEQ® assay V20 Of the 498 patients randomized, 40 (16%) in the D-Vd group and 35 (14%) in the Vd group were categorized as high risk After a median follow-up of 400 months, D-Vd prolonged median PFS versus Vd in patients with standard (166 vs 66 months; HR, 026; 95% CI, 019-037; P < 00001) and high (126 vs 62 months; HR, 041; 95% CI, 021–083; P = 00106) cytogenetic risk D-Vd achieved deep responses, including higher rates of MRD negativity and sustained MRD negativity versus Vd, regardless of cytogenetic risk The safety profile was consistent with the overall population of CASTOR These updated data reinforce the effectiveness and tolerability of daratumumab-based regimens for RRMM, regardless of cytogenetic risk status ClinicalTrialsgov,
NCT02136134
Registered 12 May 2014
31 citations
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TL;DR: Curative therapies, including intensive chemotherapy and allogeneic stem cell transplantation, are generally applicable to a minority of patients who are younger and fit, while most older individuals exhibit poor prognosis and survival.
401 citations
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TL;DR: The context dependency of aneuploidy in cancer is explained and its clinical potential is discussed, which may have clinical relevance as a prognostic marker and as a potential therapeutic target.
Abstract: Cancer is driven by multiple types of genetic alterations, which range in size from point mutations to whole-chromosome gains and losses, known as aneuploidy. Chromosome instability, the process that gives rise to aneuploidy, can promote tumorigenesis by increasing genetic heterogeneity and promoting tumour evolution. However, much less is known about how aneuploidy itself contributes to tumour formation and progression. Unlike some pan-cancer oncogenes and tumour suppressor genes that drive transformation in virtually all cell types and cellular contexts, aneuploidy is not a universal promoter of tumorigenesis. Instead, recent studies suggest that aneuploidy is a context-dependent, cancer-type-specific oncogenic event that may have clinical relevance as a prognostic marker and as a potential therapeutic target. Aneuploidy contributes to tumorigenesis, but the underlying processes are not well understood. This Review explains the context dependency of aneuploidy in cancer and discusses its clinical potential as a prognostic marker and a therapeutic target.
344 citations
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Harvard University1, Mayo Clinic2, University of Navarra3, Ankara University4, First Faculty of Medicine, Charles University in Prague5, Oslo University Hospital6, University of Oslo7, National and Kapodistrian University of Athens8, National Taiwan University9, Palacký University, Olomouc10, University of Bologna11, University of Melbourne12, Genzyme13
TL;DR: The aim of this study was to determine the progression-free survival benefit of isatuximab plus pomalidomide and dexamethasone compared with pomidine and dexAMethas one in patients with relapsed and refractory multiple myeloma.
328 citations
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University of Texas MD Anderson Cancer Center1, University of Rochester Medical Center2, Medical University of Łódź3, Tom Baker Cancer Centre4, Vita-Salute San Raffaele University5, Rabin Medical Center6, University of Leeds7, Stanford University8, King's College9, North Shore Hospital10, Ghent University Hospital11, Autonomous University of Barcelona12, University of California, San Diego13
TL;DR: Ibrutinib benefit was consistent in patients with high prognostic risk ( TP53 mutation, 11q deletion, and/or unmutated IGHV ) and increased depth of response over time and sustained PFS and OS benefit versus chlorambucil.
Abstract: RESONATE-2 is a phase 3 study of first-line ibrutinib versus chlorambucil in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Patients aged ≥65 years (n = 269) were randomized 1:1 to once-daily ibrutinib 420 mg continuously or chlorambucil 0.5–0.8 mg/kg for ≤12 cycles. With a median (range) follow-up of 60 months (0.1–66), progression-free survival (PFS) and overall survival (OS) benefits for ibrutinib versus chlorambucil were sustained (PFS estimates at 5 years: 70% vs 12%; HR [95% CI]: 0.146 [0.098–0.218]; OS estimates at 5 years: 83% vs 68%; HR [95% CI]: 0.450 [0.266–0.761]). Ibrutinib benefit was also consistent in patients with high prognostic risk (TP53 mutation, 11q deletion, and/or unmutated IGHV) (PFS: HR [95% CI]: 0.083 [0.047–0.145]; OS: HR [95% CI]: 0.366 [0.181–0.736]). Investigator-assessed overall response rate was 92% with ibrutinib (complete response, 30%; 11% at primary analysis). Common grade ≥3 adverse events (AEs) included neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), and hyponatremia (6%); occurrence of most events as well as discontinuations due to AEs decreased over time. Fifty-eight percent of patients continue to receive ibrutinib. Single-agent ibrutinib demonstrated sustained PFS and OS benefit versus chlorambucil and increased depth of response over time.
279 citations