RESUMO
BACKGROUND: Multiple myeloma (MM) is a plasma cell tumour with an approximate annual incidence of 4500 in the UK. Therapeutic options for patients with MM have changed in the last decade with the arrival of proteasome inhibitors and immunomodulatory drugs. Despite these options, almost all patients will relapse post first-line autologous stem cell transplantation (ASCT). First relapse management (second-line treatment) has evolved in recent years with an expanding portfolio of novel agents, driving response rates influencing the durability of response. A second ASCT, as part of relapsed disease management (salvage ASCT), has been shown to prolong the progression-free survival and overall survival following a proteasome inhibitor-containing re-induction regimen, in the Cancer Research UK-funded National Cancer Research Institute Myeloma X (Intensive) study. It is now recommended that salvage ASCT be considered for suitable patients by the International Myeloma Working Group and the National Institute for Health and Care Excellence NG35 guidance. METHODS/DESIGN: ACCoRd (Myeloma XII) is a UK-nationwide, individually randomised, multi-centre, multiple randomisation, open-label phase III trial with an initial single intervention registration phase aimed at relapsing MM patients who have received ASCT in first-line treatment. We will register 406 participants into the trial to allow 284 and 248 participants to be randomised at the first and second randomisations, respectively. All participants will receive re-induction therapy until maximal response (four to six cycles of ixazomib, thalidomide and dexamethasone). Participants who achieve at least stable disease will be randomised (1:1) to receive either ASCTCon, using high-dose melphalan, or ASCTAug, using high-dose melphalan with ixazomib. All participants achieving or maintaining a minimal response or better, following salvage ASCT, will undergo a second randomisation (1:1) to consolidation and maintenance or observation. Participants randomised to consolidation and maintenance will receive consolidation with two cycles of ixazomib, thalidomide and dexamethasone, and maintenance with ixazomib until disease progression. DISCUSSION: The question of how best to maximise the durability of response to salvage ASCT warrants clinical investigation. Given the expanding scope of oral therapeutic agents, patient engagement with long-term maintenance strategies is a real opportunity. This study will provide evidence to better define post-relapse treatment in MM. TRIAL REGISTRATION: ISRCTN, ISRCTN10038996 . Registered on 15 December 2016.
Assuntos
Antineoplásicos/administração & dosagem , Compostos de Boro/administração & dosagem , Glicina/análogos & derivados , Quimioterapia de Manutenção/métodos , Mieloma Múltiplo/terapia , Inibidores de Proteassoma/administração & dosagem , Transplante de Células-Tronco/métodos , Condicionamento Pré-Transplante/métodos , Antineoplásicos/efeitos adversos , Compostos de Boro/efeitos adversos , Ensaios Clínicos Fase III como Assunto , Esquema de Medicação , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Humanos , Quimioterapia de Manutenção/efeitos adversos , Quimioterapia de Manutenção/mortalidade , Masculino , Estudos Multicêntricos como Assunto , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Neoplasia Residual , Intervalo Livre de Progressão , Inibidores de Proteassoma/efeitos adversos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Terapia de Salvação , Transplante de Células-Tronco/efeitos adversos , Transplante de Células-Tronco/mortalidade , Fatores de Tempo , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/mortalidade , Transplante Autólogo , Resultado do Tratamento , Reino UnidoRESUMO
BACKGROUND: The present review is part of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Infections in Compromised Hosts (ESGICH) consensus document on the safety of targeted and biological therapies. AIMS: To review, from an infectious diseases perspective, the safety profile of immune checkpoint inhibitors, LFA-3-targeted agents, cell adhesion inhibitors, sphingosine-1-phosphate receptor modulators and proteasome inhibitors, and to suggest preventive recommendations. SOURCES: Computer-based Medline searches with MeSH terms pertaining to each agent or therapeutic family. CONTENT: T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death (PD)-1/PD-1 ligand 1 (PD-L1)-targeted agents do not appear to intrinsically increase the risk of infection but can induce immune-related adverse effects requiring additional immunosuppression. Although CD4+ T-cell lymphopenia is associated with alefacept, no opportunistic infections have been observed. Progressive multifocal leukoencephalopathy (PML) may occur during therapy with natalizumab (anti-α4-integrin monoclonal antibody (mAb)) and efalizumab (anti-CD11a mAb), but no cases have been reported to date with vedolizumab (anti-α4ß7 mAb). In patients at high risk for PML (positive anti-JC polyomavirus serology with serum antibody index >1.5 and duration of therapy ≥48 months), the benefit-risk ratio of continuing natalizumab should be carefully considered. Fingolimod induces profound peripheral blood lymphopenia and increases the risk of varicella zoster virus (VZV) infection. Prophylaxis with (val)acyclovir and VZV vaccination should be considered. Proteasome inhibitors also increase the risk of VZV infection, and antiviral prophylaxis with (val)acyclovir is recommended. Anti-Pneumocystis prophylaxis may be considered in myeloma multiple patients with additional risk factors (i.e. high-dose corticosteroids). IMPLICATIONS: Clinicians should be aware of the risk of immune-related adverse effects and PML in patients receiving immune checkpoint and cell adhesion inhibitors respectively.
Assuntos
Terapia Biológica/efeitos adversos , Adesão Celular/efeitos dos fármacos , Doenças Transmissíveis/terapia , Genes cdc/efeitos dos fármacos , Terapia de Alvo Molecular/efeitos adversos , Inibidores de Proteassoma/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Terapia Biológica/métodos , Antígeno CTLA-4/antagonistas & inibidores , Ensaios Clínicos como Assunto , Consenso , Humanos , Hospedeiro Imunocomprometido , Leucoencefalopatia Multifocal Progressiva/terapia , Terapia de Alvo Molecular/métodos , Natalizumab/efeitos adversos , Natalizumab/uso terapêutico , Inibidores de Proteassoma/uso terapêutico , Receptores de Lisoesfingolipídeo/efeitos dos fármacosRESUMO
Carfilzomib, a second-generation proteasome inhibitor, has been increasingly used in relapsed/refractory multiple myeloma (MM) since its approval by the American food and drug administration (FDA) in the summer of 2012. The drug is active as a single agent and in combination with other antimyeloma agents. As a result of its efficacy and safety in the relapsed/refractory setting, carfilzomib is being evaluated in patients with newly diagnosed MM as well as in high-risk smoldering MM. This review will give a comprehensive summary of the drug, including its mechanism of action, the evaluated doses and schedules as well as a summary of the main clinical trials in the relapsed/refractory and newly diagnosed settings. A focus will be placed upon certain subgroups of interest as well as a description of the toxicity associated with carfilzomib use and a clinical perspective on toxicity management.
Assuntos
Antineoplásicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Oligopeptídeos/uso terapêutico , Inibidores de Proteassoma/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Comorbidade , Avaliação Pré-Clínica de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Mieloma Múltiplo/complicações , Mieloma Múltiplo/patologia , Oligopeptídeos/administração & dosagem , Oligopeptídeos/efeitos adversos , Oligopeptídeos/farmacocinética , Inibidores de Proteassoma/administração & dosagem , Inibidores de Proteassoma/efeitos adversos , Inibidores de Proteassoma/farmacocinética , Recidiva , Resultado do TratamentoRESUMO
Ixazomib (Ninlaro(®)) is an orally bioavailable, reversible proteasome inhibitor developed by Millennium Pharmaceuticals, Inc. (now Takeda Oncology). Ixazomib acts by binding to and inhibiting the ß5 subunit of the 20S proteasome. In November 2015, the US FDA approved ixazomib for use in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. Ixazomib is under regulatory review for this indication in the EU. Phase III development of ixazomib is underway worldwide for newly-diagnosed multiple myeloma (in patients who are not eligible for stem cell transplant, or as maintenance therapy) and for relapsed or refractory systemic light chain (AL) amyloidosis. Ixazomib is also under phase I-II development for the treatment of several other haematological and non-haematological malignancies, graft-versus-host disease and lupus nephritis. This article summarizes the milestones in the development of ixazomib leading to this first approval for multiple myeloma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos de Boro/uso terapêutico , Aprovação de Drogas , Glicina/análogos & derivados , Mieloma Múltiplo/tratamento farmacológico , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/uso terapêutico , Administração Oral , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Compostos de Boro/administração & dosagem , Compostos de Boro/efeitos adversos , Compostos de Boro/farmacocinética , Ensaios Clínicos como Assunto , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/farmacocinética , Glicina/uso terapêutico , Humanos , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/mortalidade , Inibidores de Proteassoma/administração & dosagem , Inibidores de Proteassoma/efeitos adversos , Inibidores de Proteassoma/farmacocinética , Ligação ProteicaRESUMO
Ixazomib is an investigational, reversible 20S proteasome inhibitor. It is the first oral proteasome inhibitor under clinical investigation in multiple myeloma (MM). Under physiological conditions, the stable citrate ester drug substance, ixazomib citrate (MLN9708), rapidly hydrolyzes to the biologically active boronic acid, ixazomib (MLN2238). Preclinical studies have demonstrated antitumor activity in MM cell lines and xenograft models. In Phase I/II clinical studies ixazomib has had generally manageable toxicities, with limited peripheral neuropathy observed to date. Preliminary data from these studies indicate ixazomib is active as a single agent in relapsed/refractory MM and as part of combination regimens in newly diagnosed patients. Phase III studies in combination with lenalidomide-dexamethasone are ongoing.
Assuntos
Compostos de Boro/uso terapêutico , Drogas em Investigação/uso terapêutico , Glicina/análogos & derivados , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteassoma/uso terapêutico , Animais , Compostos de Boro/efeitos adversos , Avaliação Pré-Clínica de Medicamentos , Drogas em Investigação/efeitos adversos , Glicina/efeitos adversos , Glicina/uso terapêutico , Humanos , Inibidores de Proteassoma/efeitos adversosRESUMO
CONTEXT: For its variety of biological activities, Tamarix aucheriana (Decne.) Baum. (Tamaricaceae) has an extensive history as a traditional Arab medicine. OBJECTIVES: Antimitogenic and chemo-sensitizing activities of syringic acid (SA) were studied against human colorectal cancer. MATERIALS AND METHODS: Chromatographic and spectral data were used for the isolation and identification of SA. MTT, flow cytometry, in vitro invasion and angiogenesis assays, fluoremetry, ELISA and Real Time qPCR were used to test antimitogenic and chemo-sensitizing activities of SA, cell cycle, apoptosis, proteasome and NFκB-DNA-binding activities, cancer cell invasion and angiogenesis, and expression of cell cycle/apoptosis-related genes. RESULTS: SA showed a time- and dose-dependent (IC50 = 0.95-1.2 mg mL⻹) antimitogenic effect against cancer cells with little cytotoxicity on normal fibroblasts (≤20%). SA-altered cell cycle (S/G2-M or G1/G2-M phases) in a time-dependent manner, induced apoptosis, inhibited DNA-binding activity of NFκB (p ≤ 0.0001), chymotrypsin-like/PGPH (peptidyl-glutamyl peptide-hydrolyzing) (p ≤ 0.0001) and the trypsin-like (p ≤ 0.002) activities of 26S proteasome and angiogenesis. SA also differentially sensitized cancer cells to standard chemotherapies with a marked increase in their sensitivity to camptothecin (500-fold), 5FU (20,000-fold), doxorubicin (210-fold), taxol (3134-fold), vinblastine (1000-fold), vincristine (130-fold) and amsacrine (107-fold) compared to standard drugs alone. DISCUSSION: SA exerted its chemotherapeutic and chemo-sensitizing effects through an array of mechanisms including cell-cycle arrest, apoptosis induction, inhibition of cell proliferation, cell migration, angiogenesis, NFκB DNA-binding and proteasome activities. CONCLUSION: These results demonstrate the potential of SA as an antimitogenic and chemo-sensitizing agent for human colorectal cancer.
Assuntos
Antimitóticos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ácido Gálico/análogos & derivados , Mitose/efeitos dos fármacos , Componentes Aéreos da Planta/química , Tamaricaceae/química , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/isolamento & purificação , Inibidores da Angiogênese/farmacologia , Antimitóticos/efeitos adversos , Antimitóticos/isolamento & purificação , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/metabolismo , Etnofarmacologia , Ácido Gálico/efeitos adversos , Ácido Gálico/isolamento & purificação , Ácido Gálico/farmacologia , Humanos , Concentração Inibidora 50 , Kuweit , Medicina Tradicional , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Complexo de Endopeptidases do Proteassoma/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/efeitos adversos , Inibidores de Proteassoma/isolamento & purificação , Inibidores de Proteassoma/farmacologia , Fator de Transcrição RelA/antagonistas & inibidores , Fator de Transcrição RelA/metabolismoRESUMO
BACKGROUND: In vitro studies in mantle cell lymphoma (MCL) cell lines and patient-derived cells have demonstrated synergistic apoptosis with combined rituximab and bortezomib (R-bortezomib) compared with single-agent bortezomib. Therefore, the authors of this report evaluated R-bortezomib in a preclinical model and in a phase 2 clinical trial. METHODS: A Hu-MCL-severe combined immunodeficiency (SCID) model engrafted with the Jeko cell line was treated with R-bortezomib, bortezomib, or rituximab. Twenty-five patients with relapsed follicular lymphoma (n = 11) and MCL (n = 14) received 375 mg/m(2) rituximab on Days 1 and 8 and 1.3 to 1.5 mg/m(2) bortezomib on Days 1, 4, 8, and 11 every 21 days for a median of 3 cycles (range, 1-5 cycles). RESULTS: R-bortezomib resulted in a statistically significant improvement in overall survival in Hu-MCL-SCID mice. In the clinical trial, the overall response rate was 40% in all 25 patients, 55% in patients with follicular lymphoma, and 29% in patients with MCL. The estimated 2-year progression-free survival (PFS) rate was 24% (95% confidence interval [CI], 10%-53%) in all patients and 60% (95% CI, 20%-85%) in responding patients. Thirteen patients (52%) developed grade 3 neurotoxicity, which consisted of constipation/ileus, sensory or motor neuropathy, or orthostatic hypotension. Patients who were heterozygous for the CD32a (Fcγ receptor IIa) 131 histidine (H) to arginine (R) polymorphism had a significantly decreased PFS (P = .009) after R-bortezomib compared with HH and RR homozygotes. CONCLUSIONS: R-bortezomib had significant activity in patients with relapsed or refractory follicular lymphoma and MCL, although an unexpectedly high incidence of grade 3 neurologic toxicity was a potential limiting factor with this combination.