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1.
NPJ Syst Biol Appl ; 6(1): 28, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32859946

RESUMO

Mosunetuzumab, a T-cell dependent bispecific antibody that binds CD3 and CD20 to drive T-cell mediated B-cell killing, is currently being tested in non-Hodgkin lymphoma. However, potent immune stimulation with T-cell directed therapies poses the risk of cytokine release syndrome, potentially limiting dose and utility. To understand mechanisms behind safety and efficacy and explore safety mitigation strategies, we developed a novel mechanistic model of immune and antitumor responses to the T-cell bispecifics (mosunetuzumab and blinatumomab), including the dynamics of B- and T-lymphocytes in circulation, lymphoid tissues, and tumor. The model was developed and validated using mosunetuzumab nonclinical and blinatumomab clinical data. Simulations delineated mechanisms contributing to observed cell and cytokine (IL6) dynamics and predicted that initial step-fractionated dosing limits systemic T-cell activation and cytokine release without compromising tumor response. These results supported a change to a step-fractionated treatment schedule of mosunetuzumab in the ongoing Phase I clinical trial, enabling safer administration of higher doses.


Assuntos
Especificidade de Anticorpos , Antígenos CD20/imunologia , Complexo CD3/imunologia , Ensaios Clínicos Fase I como Assunto , Síndrome da Liberação de Citocina/induzido quimicamente , Linfoma não Hodgkin/tratamento farmacológico , Modelos Biológicos , Síndrome da Liberação de Citocina/imunologia , Humanos , Linfoma não Hodgkin/imunologia , Risco , Pesquisa Translacional Biomédica
2.
Lancet Haematol ; 6(5): e254-e265, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30935953

RESUMO

BACKGROUND: Antibody-drug conjugates (ADCs) polatuzumab vedotin (pola) and pinatuzumab vedotin (pina) showed clinical activity and tolerability in phase 1 trials. The aim of this multicentre, open-label, phase 2 study was to compare rituximab plus pola (R-pola) or pina (R-pina) in patients with relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma. METHODS: In this phase 2 randomised study at 39 investigational sites in six countries, patients were randomly assigned (1:1), by use of a dynamic hierarchical randomisation scheme, to receive R-pola or R-pina (375 mg/m2 rituximab plus 2·4 mg/kg ADCs) every 21 days until disease progression or unacceptable toxicity up to 1 year. Treatment allocations were not masked to the investigator, patients or sponsor after the patients were enrolled and randomly assigned. The primary objectives were safety and tolerability, and antitumour response. The study is registered with ClinicalTrials.gov, number NCT01691898, and is closed to accrual. FINDINGS: 81 patients with diffuse large B-cell lymphoma and 42 with follicular lymphoma were recruited between Sept 27, 2012, and Oct 10, 2013, and were assigned to treatment. 81 patients with diffuse large B-cell lymphoma and 41 patients with follicular lymphoma were eligible for analysis. Of the 42 patients with diffuse large B-cell lymphoma who received R-pina, 25 (60%, 95% CI 43-74) achieved an objective response and 11 (26%, 95% CI 14-42) achieved a complete response. Of the 39 patients in this cohort who received R-pola, 21 (54%, 95% CI 37-70) achieved an objective response, and eight (21%, 95% CI 9-36) achieved a complete response. Of the 21 patients in the follicular lymphoma cohort who received R-pina, 13 (62%, 95% CI 38-82) achieved an objective response, and one (5%, 95% CI 0·1-24) achieved a complete response. Of the 20 patients in this cohort who received R-pola, 14 (70%, 95% CI 46-88) achieved an objective response, and nine (45%, 95% CI 23-68) achieved a complete response. In the diffuse large B-cell lymphoma cohort, grade 3-5 adverse events occurred in 33 (79%) of 42 patients receiving R-pina (most common were neutropenia [29%] and hyperglycaemia [10%]; nine [21%] grade 5 adverse events, five of which were infection-related), and in 30 (77%) of 39 patients receiving R-pola (most common were neutropenia [23%], anaemia [8%] and diarrhoea [8%]; no grade 5 adverse events). In the follicular lymphoma cohort, grade 3-5 adverse events occurred in 13 (62%) of 21 patients receiving R-pina (most common were neutropenia [29%] and hyperglycaemia [14%]; no grade 5 adverse events) and in ten (50%) of 20 patients receiving R-pola (most common were neutropenia [15%] and diarrhoea [10%]; one grade 5 adverse event). INTERPRETATION: R-pina and R-pola are potential treatment options in patients with relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma. Pola was selected by the study funder for further development in non-Hodgkin lymphoma, partly because of longer durations of response than pina, and an overall benefit-risk favouring R-pola. FUNDING: F Hoffmann-La Roche.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/patologia , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Imunoconjugados/administração & dosagem , Estimativa de Kaplan-Meier , Linfoma não Hodgkin/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Rituximab/administração & dosagem , Resultado do Tratamento
3.
AAPS J ; 19(3): 669-681, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28224402

RESUMO

Correlations between early and late efficacy endpoints were assessed to identify potential surrogate endpoints for overall survival (OS) or progression-free survival (PFS) with clinical trial-level data in three non-Hodgkin lymphoma (NHL) subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). One hundred and eight phase II-III trials (129 trial arms) in DLBCL, FL, and MCL were identified and included in the database. Correlations between efficacy endpoints were analyzed using weighted linear regression and Pearson's coefficient of determination (R 2). In newly diagnosed DLBCL, 6-month PFS was strongly correlated with 2-year OS (R 2 = 0.81, 95% confidence interval [CI] 0.51-0.96). Six-month PFS was strongly correlated with 3-year PFS (R 2 = 0.89, 95% CI 0.62-0.96) in FL and was moderately correlated with 2-year OS (R 2 = 0.69, 95% CI 0.40-0.91) in MCL trials. Linear regression determined that a 10% increase in 6-month PFS would yield a 13% ± 1.2% increase in 2-year OS in DLBCL, a 23% ± 1.1% increase in 3-year PFS in FL, or a 6.7% ± 1.0% increase in 2-year OS in MCL. Both 6-month PFS and complete response (CR) rate were moderately correlated with median PFS in FL trials with R 2 = 0.66 (95% CI 0.52-0.98) and R 2 = 0.69 (95% CI 0.22-0.89), respectively. Six-month PFS is a potential surrogate endpoint for 2-year OS in newly diagnosed DLBCL and MCL and for 3-year PFS in FL. Both 6-month PFS and CR rate are potential surrogate endpoints for median PFS in FL patients. Confirmation and validation of these correlations may facilitate early interpretation of NHL trials.


Assuntos
Antineoplásicos/uso terapêutico , Intervalo Livre de Doença , Linfoma não Hodgkin/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos
4.
Blood ; 129(5): 609-618, 2017 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-27908880

RESUMO

Acute myeloid leukemia (AML) is a major unmet medical need. Most patients have poor long-term survival, and treatment has not significantly changed in 40 years. Recently, bispecific antibodies that redirect the cytotoxic activity of effector T cells by binding to CD3, the signaling component of the T-cell receptor, and a tumor target have shown clinical activity. Notably, blinatumomab is approved to treat relapsed/refractory acute lymphoid leukemia. Here we describe the design, discovery, pharmacologic activity, pharmacokinetics, and safety of a CD3 T cell-dependent bispecific (TDB) full-length human IgG1 therapeutic antibody targeting CLL-1 that could potentially be used in humans to treat AML. CLL-1 is prevalent in AML and, unlike other targets such as CD33 and CD123, is not expressed on hematopoietic stem cells providing potential hematopoietic recovery. We selected a high-affinity monkey cross-reactive anti-CLL-1 arm and tested several anti-CD3 arms that varied in affinity, and determined that the high-affinity CD3 arms were up to 100-fold more potent in vitro. However, in mouse models, the efficacy differences were less pronounced, probably because of prolonged exposure to TDB found with lower-affinity CD3 TDBs. In monkeys, assessment of safety and target cell depletion by the high- and low-affinity TDBs revealed that only the low-affinity CD3/CLL1 TDB was well tolerated and able to deplete target cells. Our data suggest that an appropriately engineered CLL-1 TDB could be effective in the treatment of AML.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Antineoplásicos/uso terapêutico , Lectinas Tipo C/imunologia , Leucemia Mieloide Aguda/tratamento farmacológico , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Animais , Anticorpos Biespecíficos/efeitos adversos , Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/farmacocinética , Antineoplásicos/efeitos adversos , Antineoplásicos/imunologia , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Humanos , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/patologia , Macaca fascicularis , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
5.
Clin Cancer Res ; 23(5): 1167-1176, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-27601593

RESUMO

Purpose: Pinatuzumab vedotin is an antibody-drug conjugate with the potent antimicrotubule agent monomethyl auristatin E (MMAE) conjugated to an anti-CD22 antibody via a protease-cleavable linker. This phase I study determined its recommended phase II dose (RP2D) and evaluated its safety, tolerability, and antitumor activity alone and with rituximab in relapsed/refractory (r/r) non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL).Experimental Design: Patients received escalating doses of pinatuzumab vedotin every 21 days. Clinical activity at the RP2D alone or with rituximab was evaluated in r/r diffuse large B-cell lymphoma (DLBCL) and r/r indolent NHL (iNHL) patients.Results: Seventy-five patients received single-agent pinatuzumab vedotin. The RP2D was 2.4 mg/kg, based on dose-limiting toxicities (DLT) of grade 4 neutropenia >7 days in 1 of 3 patients and grade 4 neutropenia <7 days in 2 of 3 patients treated at 3.2 mg/kg (maximum assessed dose). No DLTs occurred at 2.4 mg/kg. At the RP2D, neutropenia was the most common grade ≥3 adverse event. Peripheral neuropathy-related grade ≥2 adverse events most frequently resulted in treatment discontinuation. Rituximab cotreatment did not impact safety, tolerability, or pharmacokinetics of pinatuzumab vedotin. Unconjugated MMAE exposure was much lower than antibody-conjugated MMAE exposure, without accumulation with repeat dosing. At the RP2D, objective responses were observed in DLBCL (9/25) and iNHL (7/14) patients; 2 of 8 patients treated with pinatuzumab vedotin (RP2D) and rituximab had complete responses. CLL patients showed no objective responses.Conclusions: The RP2D of pinatuzumab vedotin alone and with rituximab was 2.4 mg/kg, which was well tolerated, with encouraging clinical activity in r/r NHL. Clin Cancer Res; 23(5); 1167-76. ©2016 AACR.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Imunoconjugados/administração & dosagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Rituximab/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminobenzoatos/administração & dosagem , Anticorpos Anti-Idiotípicos/administração & dosagem , Anticorpos Anti-Idiotípicos/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Feminino , Humanos , Imunoconjugados/efeitos adversos , Imunoconjugados/imunologia , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/patologia , Linfoma não Hodgkin/imunologia , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/administração & dosagem , Rituximab/efeitos adversos , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia
6.
Lancet Oncol ; 16(6): 704-15, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25925619

RESUMO

BACKGROUND: Patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) have an unfavourable prognosis with few treatment options. Polatuzumab vedotin is an antibody-drug conjugate containing an anti-CD79B monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the safety and clinical activity of polatuzumab vedotin in relapsed or refractory B-cell NHL and chronic lymphocytic leukaemia (CLL). METHODS: In this phase 1, multicentre, open-label study, we enrolled patients with documented NHL or CLL expected to express CD79B (confirmation of CD79B expression was not required) and for whom no suitable therapy of curative intent or higher priority existed from 13 centres. The primary endpoints of the study were to assess safety and tolerability, determine the maximum tolerated dose, and identify the recommended phase 2 dose of polatuzumab vedotin as a single agent and in combination with rituximab. A 3 + 3 dose-escalation design was used in which we treated patients with polatuzumab vedotin (0·1-2·4 mg/kg every 21 days) in separate dose-escalation cohorts for NHL and CLL. After determination of the recommended phase 2 dose, we enrolled patients with relapsed or refractory diffuse large B-cell lymphoma and relapsed or refractory indolent NHL into indication-specific cohorts. We also enrolled patients with relapsed or refractory NHL into an additional cohort to assess the feasibility of the combination of polatuzumab vedotin and rituximab 375 mg/m(2). Patients who received any dose of polatuzumab vedotin were available for safety analyses. This study is registered with ClinicalTrials.gov, number NCT01290549. FINDINGS: Between March 21, 2011, and Nov 30, 2012, we enrolled 95 patients (34 to the NHL dose-escalation cohort, 18 to the CLL dose-escalation cohort, 34 with NHL to the expansion cohort at the recommended phase 2 dose, and nine with NHL to the rituximab combination cohort; no expansion cohort of CLL was started due to lack of activity in the dose-escalation cohort). The recommended phase 2 dose in NHL was 2·4 mg/kg as a single agent and in combination with rituximab; the maximum tolerated dose in CLL was 1·0 mg/kg as a result of dose-limiting toxic effects reported in two of five patients given 1·8 mg/kg. Grade 3-4 adverse events were reported in 26 (58%) of 45 patients with NHL treated at the single-agent recommended phase 2 dose, and the most common grade 3-4 adverse events were neutropenia (18 [40%] of 45), anaemia (five [11%]), and peripheral sensory neuropathy (four [9%]). Serious adverse events were reported in 17 (38%) of 45 patients, and included diarrhoea (two patients), lung infection (two patients), disease progression (two patients), and lung disorder (two patients). Seven (77%) of nine patients in the rituximab combination cohort had a grade 3-4 adverse event, with neutropenia (five [56%]), anaemia (two [22%]), and febrile neutropenia (two [22%]) reported in more than one patient. 11 (12%) of 95 patients died during the study: eight with relapsed or refractory diffuse large B-cell lymphoma (due to progressive disease in four patients, infections in three patients [two treatment related], and treatment-related worsening ascites in one patient) and three with relapsed or refractory CLL (due to progressive disease, pulmonary infection, and pneumonia; none thought to be treatment-related). At the recommended phase 2 dose, objective responses were noted in 23 of 42 activity-evaluable patients with NHL given single-agent polatuzumab vedotin (14 of 25 with diffuse large B-cell lymphoma, seven of 15 with indolent NHL, and two with mantle-cell lymphoma) and seven of nine patients treated with polatuzumab vedotin combined with rituximab. No objective responses were observed in patients with CLL. INTERPRETATION: Polatuzumab vedotin has an acceptable safety and tolerability profile in patients with NHL but not in those with CLL. Its clinical activity should be further assessed in NHL. FUNDING: Genentech.


Assuntos
Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Antígenos CD79/imunologia , Imunoconjugados/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Antígenos CD79/biossíntese , Esquema de Medicação , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma não Hodgkin/imunologia , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Rituximab
7.
Sci Transl Med ; 7(287): 287ra70, 2015 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-25972002

RESUMO

Bispecific antibodies and antibody fragments in various formats have been explored as a means to recruit cytolytic T cells to kill tumor cells. Encouraging clinical data have been reported with molecules such as the anti-CD19/CD3 bispecific T cell engager (BiTE) blinatumomab. However, the clinical use of many reported T cell-recruiting bispecific modalities is limited by liabilities including unfavorable pharmacokinetics, potential immunogenicity, and manufacturing challenges. We describe a B cell-targeting anti-CD20/CD3 T cell-dependent bispecific antibody (CD20-TDB), which is a full-length, humanized immunoglobulin G1 molecule with near-native antibody architecture constructed using "knobs-into-holes" technology. CD20-TDB is highly active in killing CD20-expressing B cells, including primary patient leukemia and lymphoma cells both in vitro and in vivo. In cynomolgus monkeys, CD20-TDB potently depletes B cells in peripheral blood and lymphoid tissues at a single dose of 1 mg/kg while demonstrating pharmacokinetic properties similar to those of conventional monoclonal antibodies. CD20-TDB also exhibits activity in vitro and in vivo in the presence of competing CD20-targeting antibodies. These data provide rationale for the clinical testing of CD20-TDB for the treatment of CD20-expressing B cell malignancies.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Antígenos CD20/imunologia , Complexo CD3/imunologia , Leucemia de Células B/terapia , Linfócitos T/imunologia , Animais , Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/farmacocinética , Humanos , Leucemia de Células B/imunologia , Macaca fascicularis , Camundongos , Camundongos Transgênicos
8.
Mol Cancer Ther ; 12(7): 1255-65, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23598530

RESUMO

Antibody-drug conjugates (ADC), potent cytotoxic drugs linked to antibodies via chemical linkers, allow specific targeting of drugs to neoplastic cells. We have used this technology to develop the ADC DCDT2980S that targets CD22, an antigen with expression limited to B cells and the vast majority of non-Hodgkin lymphomas (NHL). DCDT2980S consists of a humanized anti-CD22 monoclonal IgG1 antibody with a potent microtubule-disrupting agent, monomethyl auristatin E (MMAE), linked to the reduced cysteines of the antibody via a protease cleavable linker, maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl (MC-vc-PAB). We describe the efficacy, safety, and pharmacokinetics of DCDT2980S in animal models to assess its potential as a therapeutic for the treatment of B-cell malignancies. We did not find a strong correlation between in vitro or in vivo efficacy and CD22 surface expression, nor a correlation of sensitivity to free drug and in vitro potency. We show that DCDT2980S was capable of inducing complete tumor regression in xenograft mouse models of NHL and can be more effective than rituximab plus combination chemotherapy at drug exposures that were well tolerated in cynomolgus monkeys. These results suggest that DCDT2980S has an efficacy, safety, and pharmacokinetics profile that support potential treatment of NHL.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Imunoconjugados/farmacologia , Linfoma de Células B/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Oligopeptídeos/farmacologia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Animais , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados/farmacocinética , Feminino , Humanos , Imunoconjugados/farmacocinética , Linfoma de Células B/imunologia , Linfoma de Células B/metabolismo , Macaca fascicularis , Camundongos , Camundongos Endogâmicos ICR , Camundongos SCID , Distribuição Aleatória , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Future Oncol ; 9(3): 355-68, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23469971

RESUMO

Antibody-drug conjugates (ADCs) are a broad class of molecules comprising of a potent cytotoxic agent conjugated with a monoclonal antibody using a chemically stable linker. By selecting a monoclonal antibody directed against a tumor-specific or tumor-associated antigen, ADCs allow the targeted delivery of highly potent cytotoxic agents that result in unacceptable toxicity when administered as free agents. ADCs are currently being developed for the treatment of a wide variety of tumors. In this review, the current clinical and preclinical status of ADCs for the treatment of B-cell non-Hodgkin's lymphoma and B-cell leukemia will be discussed. ADCs have the potential to alter treatment paradigms for these diseases by providing both increased efficacy and improved safety and tolerability over current chemotherapy-based regimens.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Leucemia/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacocinética , Antígenos CD/imunologia , Antígenos CD/metabolismo , Antineoplásicos/farmacocinética , Ensaios Clínicos como Assunto , Portadores de Fármacos , Humanos , Imunotoxinas/farmacocinética , Imunotoxinas/uso terapêutico , Inotuzumab Ozogamicina , Leucemia/metabolismo , Linfoma de Células B/metabolismo , Maitansina/análogos & derivados , Maitansina/uso terapêutico
10.
J Clin Oncol ; 31(9): 1157-63, 2013 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-23382472

RESUMO

PURPOSE: Trastuzumab emtansine (T-DM1), an antibody-drug conjugate composed of the cytotoxic agent DM1 conjugated to trastuzumab via a stable thioether linker, has shown clinical activity in single-arm studies enrolling patients with human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (MBC) whose disease had progressed on HER2-targeted therapy in the metastatic setting. PATIENTS AND METHODS: Patients (N = 137) with HER2-positive MBC or recurrent locally advanced breast cancer were randomly assigned to trastuzumab plus docetaxel (HT; n = 70) or T-DM1 (n = 67) as first-line treatment until disease progression or unacceptable toxicity. Primary end points were investigator-assessed progression-free survival (PFS) and safety. Key secondary end points included overall survival (OS), objective response rate (ORR), duration of objective response, clinical benefit rate, and quality of life. RESULTS: Median PFS was 9.2 months with HT and 14.2 months with T-DM1 (hazard ratio, 0.59; 95% CI, 0.36 to 0.97); median follow-up was approximately 14 months in both arms. ORR was 58.0% (95% CI, 45.5% to 69.2%) with HT and 64.2% (95% CI, 51.8% to 74.8%) with T-DM1. T-DM1 had a favorable safety profile versus HT, with fewer grade ≥ 3 adverse events (AEs; 46.4% v 90.9%), AEs leading to treatment discontinuations (7.2% v 34.8%), [corrected] and serious AEs (20.3% v 25.8%). Preliminary OS results were similar between treatment arms; median follow-up was approximately 23 months in both arms. CONCLUSION: In this randomized phase II study, first-line treatment with T-DM1 for patients with HER2-positive MBC provided a significant improvement in PFS, with a favorable safety profile, versus HT.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Maitansina/análogos & derivados , Receptor ErbB-2/análise , Taxoides/administração & dosagem , Ado-Trastuzumab Emtansina , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Docetaxel , Feminino , Humanos , Maitansina/administração & dosagem , Maitansina/uso terapêutico , Pessoa de Meia-Idade , Metástase Neoplásica , Trastuzumab , Resultado do Tratamento
11.
Clin Pharmacol Drug Dev ; 2(1): 11-24, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27121556

RESUMO

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate in development for human epidermal growth factor receptor 2 (HER2)-positive cancer. Drugs in development are generally tested for their effects on QT interval, prolongation of which is associated with the potentially fatal arrhythmia torsades de pointes. In addition, an association between left ventricular dysfunction and other HER2-directed agents has been documented. This multicenter, phase 2 study, TDM4688g, assessed the safety and pharmacokinetic characteristics of T-DM1 (3.6 mg/kg every 3 weeks) in patients with previously treated HER2-positive metastatic breast cancer, and the safety of pertuzumab plus T-DM1, an anti-HER2 extracellular domain antibody, in patients with early disease progression on T-DM1 alone. The primary end point was the change in QTc interval from baseline to each postbaseline time point, adjusted for heart rate using Fridericia's correction. T-DM1 had no clinically relevant effect on QTc interval. The observed upper limit of the one-sided 95% confidence interval was below the 10-millisecond threshold of safety concern. The safety and efficacy of single-agent T-DM1 was consistent with that observed in previous studies. Pertuzumab plus T-DM1 was generally well tolerated with no new safety signals. These results support further investigation of T-DM1 as a single agent and with pertuzumab.

12.
Cancer Chemother Pharmacol ; 70(4): 591-601, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22886072

RESUMO

PURPOSE: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate in the development for the treatment of human epidermal growth factor receptor 2-positive cancers. Thrombocytopenia (TCP) is the dose-limiting toxicity of T-DM1. A semimechanistic population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to characterize the effect of T-DM1 on patient platelet counts. METHODS: A PK/PD model with transit compartments that mimic platelet development and circulation was fit to concentration-platelet-time course data from two T-DM1 single-agent studies (TDM3569g; N = 52 and TDM4258g; N = 112). NONMEM(®) 7 software was used for model development. Data from a separate phase II study (TDM4374g; N = 110) were used for model evaluation. Patient baseline characteristics were evaluated as covariates of model PD parameters. RESULTS: The model described the platelet data well and predicted the incidence of grade ≥3 TCP. The model predicted that with T-DM1 3.6 mg/kg given every 3 weeks (q3w), the lowest platelet nadir would occur after the first dose. Also predicted was a patient subgroup (46 %) having variable degrees of downward drifting platelet-time profiles, which were predicted to stabilize by the eighth treatment cycle to platelet counts above grade 3 TCP. Baseline characteristics were not significant covariates of PD parameters in the model. CONCLUSIONS: This semimechanistic PK/PD model accurately captures the cycle 1 platelet nadir, the downward drift noted in some patient platelet-time profiles, and the ~8 % incidence of grade ≥3 TCP with T-DM1 3.6 mg/kg q3w. This model supports T-DM1 3.6 mg/kg q3w as a well-tolerated dose with minimal dose delays or reductions for TCP.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Imunotoxinas/efeitos adversos , Maitansina/análogos & derivados , Receptor ErbB-2/análise , Trombocitopenia/induzido quimicamente , Ado-Trastuzumab Emtansina , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/farmacologia , Neoplasias da Mama/química , Feminino , Humanos , Maitansina/efeitos adversos , Maitansina/farmacocinética , Maitansina/farmacologia , Modelos Biológicos , Contagem de Plaquetas , Trastuzumab
13.
Curr Drug Metab ; 13(7): 911-22, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22475266

RESUMO

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprised of trastuzumab and the cytotoxic agent DM1 (derivative of maytansine) linked by a stable linker N-succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC). T-DM1 targets an epitope located at subdomain IV of human epidermal growth factor receptor 2 (HER2). Pertuzumab is a monoclonal antibody that targets an epitope located at subdomain II of HER2, distinct from the epitope recognized by T-DM1. The pharmacokinetics (PK), safety, and efficacy of T-DM1 combined with pertuzumab were studied in a phase 1b/2 trial in 67 patients with HER2-positive, locally advanced or metastatic breast cancer (MBC). The therapeutic protein-drug interaction (TP-DI) potential of T-DM1 plus pertuzumab was evaluated. The PK of T-DM1-related analytes and pertuzumab were compared with historical PK data. The results show that the exposure of T-DM1 and DM1, as estimated by noncompartmental analyses, was comparable with that reported by historical single-agent studies in patients with HER2-positive MBC. T-DM1 clearance and volume of distribution in the central compartment, as estimated by population PK analysis, were also comparable between this study and historical single-agent studies in patients with HER2-positive MBC. Summary statistics of pertuzumab trough and maximal exposure (concentrations at predose and 15-30 minutes after the end of infusion at cycle 1 and at steady state) were similar with those observed in a representative historical single-agent study with the same dosing regimen. The visual predictive check plot by population simulation further confirmed that T-DM1 did not alter pertuzumab PK. Based on these data and the PK and pharmacodynamic properties of T-DM1 and pertuzumab, the risk of TP-DI appears to be low when T-DM1 and pertuzumab are given together.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Interações Medicamentosas/fisiologia , Receptor ErbB-2/biossíntese , Ado-Trastuzumab Emtansina , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Masculino , Maitansina/administração & dosagem , Maitansina/análogos & derivados , Maitansina/metabolismo , Pessoa de Meia-Idade , Metástase Neoplásica , Trastuzumab
14.
Curr Drug Metab ; 13(7): 901-10, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22475269

RESUMO

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate in clinical development for the treatment of human epidermal growth factor receptor 2 (HER2)-positive cancers. Herein, we describe a series of studies to assess T-DM1 absorption, distribution, metabolism, and excretion (ADME) in rats as well as to assess human exposure to T-DM1 catabolites. Following administration of unlabeled and radiolabeled T-DM1 in female Sprague Dawley rats as a single dose, plasma, urine, bile and feces were assessed for mass balance, profiling and identification of catabolites. In rats, the major circulating species in plasma was T-DM1, while DM1 concentrations were low (1.08 to 15.6 ng/mL). The major catabolites found circulating in rat plasma were DM1, [N-maleimidomethyl] cyclohexane-1- carboxylate-DM1 (MCC-DM1), and Lysine-MCC-DM1. These catabolites identified in rats were also detected in plasma samples from patients with HER2-positive metastatic breast cancer who received single-agent T-DM1 (3.6 mg/kg every 3 weeks) in a phase 2 clinical study. There was no evidence of tissue accumulation in rats or catabolite accumulation in human plasma following multiple dosing. In rats, T-DM1 was distributed nonspecifically to the organs without accumulation. The major pathway of DM1-containing catabolite elimination in rats was the fecal/biliary route, with up to 80% of radioactivity recovered in the feces and 50% in the bile. The rat T-DM1 ADME profile is likely similar to the human profile, although there may be differences since trastuzumab does not bind the rat HER2- like receptor. Further research is necessary to more fully understand the T-DM1 ADME profile in humans.


Assuntos
Anticorpos Monoclonais Humanizados/química , Anticorpos Monoclonais Humanizados/farmacocinética , Maitansina/análogos & derivados , Ado-Trastuzumab Emtansina , Animais , Anticorpos Monoclonais Humanizados/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Maitansina/química , Maitansina/metabolismo , Maitansina/farmacocinética , Metabolismo/efeitos dos fármacos , Metabolismo/fisiologia , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual/efeitos dos fármacos , Distribuição Tecidual/fisiologia , Trastuzumab
15.
Cancer Chemother Pharmacol ; 69(5): 1229-40, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22271209

RESUMO

PURPOSE: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprising trastuzumab and DM1, a microtubule polymerization inhibitor, covalently bound via a stable thioether linker. To characterize the pharmacokinetics (PK) of T-DM1 in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, data from four studies (TDM3569g, TDM4258g, TDM4374g, and TDM4688g) of single-agent T-DM1 administered at 3.6 mg/kg every 3 weeks (q3w) were assessed in aggregate. METHODS: Multiple analytes-T-DM1, total trastuzumab (TT), DM1, and key metabolites-were quantified using enzyme-linked immunosorbent assays or liquid chromatography tandem mass spectrometry. PK parameters of T-DM1, TT, and DM1 exposure were calculated using standard noncompartmental approaches and correlated to efficacy (objective response rate) and safety (platelet counts, hepatic transaminase concentrations). Immunogenicity was evaluated by measuring anti-therapeutic antibodies (ATA) to T-DM1 after repeated dosing using validated bridging antibody electrochemiluminescence or enzyme-linked immunosorbent assays. RESULTS: PK parameters for T-DM1, TT, and DM1 were consistent across studies at cycle 1 and steady state. T-DM1 PK was not affected by residual trastuzumab from prior therapy or circulating extracellular domain of HER2. No significant correlations were observed between T-DM1 exposure and efficacy, thrombocytopenia, or increased concentrations of transaminases. Across the studies, ATA formation was detected in 4.5% (13/286) of evaluable patients receiving T-DM1 q3w. CONCLUSIONS: The PK profile of single-agent T-DM1 (3.6 mg/kg q3w) is predictable, well characterized, and unaffected by circulating levels of HER2 extracellular domain or residual trastuzumab. T-DM1 exposure does not correlate with clinical responses or key adverse events.


Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Neoplasias da Mama/tratamento farmacológico , Maitansina/análogos & derivados , Receptor ErbB-2/metabolismo , Ado-Trastuzumab Emtansina , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/patologia , Cromatografia Líquida , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Maitansina/farmacocinética , Maitansina/farmacologia , Maitansina/uso terapêutico , Pessoa de Meia-Idade , Espectrometria de Massas em Tandem , Trastuzumab , Resultado do Tratamento
16.
J Clin Pharmacol ; 52(5): 691-703, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-21953571

RESUMO

Trastuzumab emtansine (T-DM1) is a HER2-targeted antibody-drug conjugate in development for treatment of HER2-positive cancers. T-DM1 has been tested as a single agent in a phase I and 2 phase II studies of patients with heavily pretreated metastatic breast cancer (MBC), with the maximum tolerated dose established at 3.6 mg/kg intravenously for every-3-week dosing. The authors present results from the population pharmacokinetics analysis for T-DM1. Population pharmacokinetics for T-DM1 were characterized using a clinical database of 273 patients from the 3 studies. Pharmacokinetics was best described by a linear 2-compartment model. Population estimates (interindividual variability [IIV]) for pharmacokinetic parameters were clearance, 0.7 L/d (21.0%); central compartment volume (V(c)), 3.33 L (13.2%); peripheral compartment volume (V(p)), 0.89 L (50.4%); and intercompartmental clearance, 0.78 L/d. Body weight, albumin, tumor burden, and aspartate aminotransferase levels were identified as statistically significant covariates accounting for interindividual variability in T-DM1 pharmacokinetics, with body weight having a greater effect on IIV of clearance and V(c) than other covariates. T-DM1 exposure was relatively consistent across the weight range following body weight-based dosing. This analysis suggests no further T-DM1 dose adjustments are necessary in heavily pretreated patients with MBC.


Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Imunotoxinas/farmacocinética , Maitansina/análogos & derivados , Receptor ErbB-2/metabolismo , Moduladores de Tubulina/farmacocinética , Ado-Trastuzumab Emtansina , Adulto , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Aspartato Aminotransferases/sangue , Biomarcadores Tumorais/imunologia , Peso Corporal , Neoplasias da Mama/sangue , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Imunotoxinas/administração & dosagem , Imunotoxinas/efeitos adversos , Infusões Intravenosas , Modelos Lineares , Dose Máxima Tolerável , Maitansina/administração & dosagem , Maitansina/efeitos adversos , Maitansina/farmacocinética , Pessoa de Meia-Idade , Modelos Biológicos , Ligação Proteica , Receptor ErbB-2/imunologia , Albumina Sérica/metabolismo , Trastuzumab , Resultado do Tratamento , Moduladores de Tubulina/administração & dosagem , Moduladores de Tubulina/efeitos adversos , Carga Tumoral
17.
J Clin Oncol ; 29(4): 398-405, 2011 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-21172893

RESUMO

PURPOSE: The antibody-drug conjugate trastuzumab-DM1 (T-DM1) combines the biologic activity of trastuzumab with targeted delivery of a potent antimicrotubule agent, DM1, to human epidermal growth factor receptor 2 (HER2)-overexpressing cancer cells. Based on results from a phase I study that showed T-DM1 was well tolerated at the maximum-tolerated dose of 3.6 mg/kg every 3 weeks, with evidence of efficacy, in patients with HER2-positive metastatic breast cancer (MBC) who were previously treated with trastuzumab, we conducted a phase II study to further define the safety and efficacy of T-DM1 in this patient population. PATIENTS AND METHODS: This report describes a single-arm phase II study (TDM4258g) that assessed efficacy and safety of intravenous T-DM1 (3.6 mg/kg every 3 weeks) in patients with HER2-positive MBC who had tumor progression after prior treatment with HER2-directed therapy and who had received prior chemotherapy. RESULTS: With a follow-up of ≥ 12 months among 112 treated patients, the objective response rate by independent assessment was 25.9% (95% CI, 18.4% to 34.4%). Median duration of response was not reached as a result of insufficient events (lower limit of 95% CI, 6.2 months), and median progression-free survival time was 4.6 months (95% CI, 3.9 to 8.6 months). The response rates were higher among patients with confirmed HER2-positive tumors (immunohistochemistry 3+ or fluorescent in situ hybridization positive) by retrospective central testing (n = 74). Higher response rates were also observed in patients whose tumors expressed ≥ median HER2 levels by quantitative reverse transcriptase polymerase chain reaction for HER2 expression, compared with patients who had less than median HER2 levels. T-DM1 was well tolerated with no dose-limiting cardiotoxicity. Most adverse events (AEs) were grade 1 or 2; the most frequent grade ≥ 3 AEs were hypokalemia (8.9%), thrombocytopenia (8.0%), and fatigue (4.5%). CONCLUSION: T-DM1 has robust single-agent activity in patients with heavily pretreated, HER2-positive MBC and is well tolerated at the recommended phase II dose.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Imunotoxinas/uso terapêutico , Maitansina/análogos & derivados , Receptor ErbB-2/antagonistas & inibidores , Ado-Trastuzumab Emtansina , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Imunotoxinas/efeitos adversos , Imunotoxinas/farmacocinética , Estimativa de Kaplan-Meier , Maitansina/efeitos adversos , Maitansina/farmacocinética , Maitansina/uso terapêutico , Pessoa de Meia-Idade , RNA Mensageiro/análise , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Fatores de Tempo , Trastuzumab , Resultado do Tratamento , Estados Unidos
18.
Blood ; 112(8): 3255-63, 2008 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-18694999

RESUMO

Although studies have demonstrated that androgen withdrawal increases thymic size, molecular mechanisms underlying this expansion remain largely unknown. We show that decreased androgen signaling leads to enhanced immigration of bone marrow T-cell precursors, as manifested by both an early increase of early thymic progenitors (ETP) and improved uptake of adoptively transferred quantified precursors into congenic castrated hosts. We provide evidence that the ETP niche is enhanced after androgen withdrawal by proliferation of UEA(+) thymic epithelial cells (TEC) and increased TEC production of CCL25, a ligand critical for ETP entry. Moreover, the greatest increase in CCL25 production is by UEA(+) TEC, linking function of this subset with the increase in ETP immigration. Furthermore, blockade of CCL25 abrogated the effects of castration by impairing ETP entry, retarding immature thymocyte development, limiting increase of thymic size, and impairing increase of thymopoiesis. Taken together, these findings describe a cohesive mechanism underlying increased thymic productivity after androgen withdrawal.


Assuntos
Androgênios/metabolismo , Quimiocinas CC/metabolismo , Timo/metabolismo , Animais , Movimento Celular , Proliferação de Células , Separação Celular , Estudos de Coortes , Células Epiteliais/metabolismo , Masculino , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Ligação Proteica , Timo/citologia
19.
Blood ; 112(7): 2836-46, 2008 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-18658030

RESUMO

Insulin-like growth factor 1 (IGF-1) enhances thymopoiesis but given the broad distribution of IGF-1 receptors (IGF-1Rs), its mechanism of action has remained unclear. To identify points of thymic regulation by IGF-1, we examined its effects on T-cell precursors, thymocytes, and thymic epithelial cells (TECs) in normal and genetically altered mice. In thymus-intact but not thymectomized mice, IGF-1 administration increased peripheral naive and recent thymic emigrant (RTE) populations, demonstrating its effect on T-cell production, not peripheral expansion. IGF-1 administration increased bone marrow LSK (lineage(-), Sca-1(+), c-kit(+)) precursor proliferation and peripheral LSK populations, increased thymocyte populations in a sequential wave of expansion, and proportionately expanded TEC subpopulations and enhanced their chemokine expression. To separate IGF-1's effects on thymocytes and TECs, we generated mice lacking IGF-1R on thymocytes and T cells. Thymocyte and RTE numbers were decreased in these mice, but IGF-1 treatment produced comparable thymocyte numbers to similarly treated wild-type mice. We additionally separated thymic- from LSK-specific effects by demonstrating that IGF-1 increased thymocyte numbers despite impaired early thymic progenitor (ETP) importation in PSGL-1KO mice. These results indicate the critical point thymic function regulation by IGF-1 involves TEC expansion regulating thymocyte precursor entry and facilitating thymocyte development.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/farmacologia , Timo/citologia , Timo/efeitos dos fármacos , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Contagem de Células , Ciclo Celular/efeitos dos fármacos , Linhagem da Célula/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quimiocinas/metabolismo , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Fator de Crescimento Insulin-Like I/administração & dosagem , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos
20.
Biol Blood Marrow Transplant ; 14(4): 365-78, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18342778

RESUMO

Chronic graft-versus-host-disease (cGVHD) is a major barrier to successful allogeneic hematopoietic stem cell transplantation (allo-HSCT), with highly variable clinical presentations. The pathophysiology of cGVHD remains relatively poorly understood. The utilization of murine models to study cGVHD encompasses experimental challenges distinct from those that have been successfully used to study acute GVHD (aGVHD). Nevertheless, despite these challenges, murine models of cGVHD have contributed to the understanding of cGVHD, and highlight its mechanistic complexity. In this article, insights into the pathophysiology of cGVHD obtained from murine studies are summarized in the context of their relevancy to clinical cGVHD. Despite experimental limitations, current and future models of murine cGVHD will continue to provide insights into the understanding of clinical cGVHD and provide information for new therapeutic interventions.


Assuntos
Doença Enxerto-Hospedeiro/fisiopatologia , Animais , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Doença Crônica , Modelos Animais de Doenças , Doença Enxerto-Hospedeiro/imunologia , Lúpus Eritematoso Sistêmico , Camundongos , Camundongos Endogâmicos , Timo/imunologia , Transplante Homólogo/imunologia
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