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1.
Ophthalmic Res ; 66(1): 1030-1043, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37257422

RESUMO

INTRODUCTION: The Understanding New Interventions with GBM ThErapy (UNITE) study was designed to assess the effect of prophylaxis for ocular side effects (OSEs) in patients with glioblastoma receiving the antibody-drug conjugate (ADC) depatuxizumab mafodotin. UNITE (NCT03419403) was a phase 3b, open-label, randomized, exploratory study performed at 18 research sites in 5 countries. METHODS: The study enrolled adult patients with epidermal growth factor receptor-amplified, histologically confirmed, newly diagnosed supratentorial glioblastoma or grade IV gliosarcoma, and a Karnofsky Performance Status ≥70, receiving depatuxizumab mafodotin. All patients were administered depatuxizumab mafodotin during concurrent radiotherapy and temozolomide and with adjuvant temozolomide. Ninety patients were to be randomized (1:1:1) to OSE prophylactic treatments with each depatuxizumab mafodotin infusion: (a) standard steroid eye drops, (b) standard steroid eye drops plus vasoconstrictor eye drops and cold compress, or (c) enhanced steroids plus vasoconstrictor eye drops and cold compress. A Corneal Epitheliopathy Adverse Event (CEAE) scale was devised to capture symptoms, grade OSEs (scale of 0-5), and inform ADC dose modifications. The primary endpoint was the frequency of a required change in OSE management due to inadequate control of OSEs, defined as decline from baseline in visual acuity (using logarithm of the minimum angle of resolution [LogMAR] scale) or a Grade ≥3 CEAE event, in the worst eye in the first 8 weeks of treatment; unless otherwise specified, the treatment period refers to both the chemoradiation and adjuvant phases. RESULTS: The UNITE study was stopped early after interim analysis of separate phase III trial showed no difference in survival from depatuxizumab mafodotin. Forty patients were randomized (38 received depatuxizumab mafodotin). Overall, 23 patients experienced inadequate control of OSEs that required change in OSE management within 8 weeks of treatment, with 21 (70.0%) experiencing ≥+0.3 change on LogMAR scale in baseline-adjusted visual acuity and 12 reporting a grade ≥3 CEAE. There were no definitive differences among prophylactic treatments. CONCLUSIONS: The premature cessation of the study precludes definitive conclusions regarding the OSE prophylaxis strategies. No new clinically significant safety findings were noted. Despite these limitations, this study highlights the need for novel assessment tools to better understand and mitigate OSEs associated with ADCs.


Assuntos
Glioblastoma , Adulto , Humanos , Receptores ErbB/metabolismo , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patologia , Soluções Oftálmicas/uso terapêutico , Esteroides/uso terapêutico , Temozolomida/uso terapêutico , Vasoconstritores/uso terapêutico
2.
Gynecol Oncol ; 165(2): 385-392, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35277279

RESUMO

Tisotumab vedotin is a tissue factor-directed antibody-drug conjugate developed for treatment of recurrent or metastatic cervical cancer (r/mCC). In the pivotal phase 2 study innovaTV 204, 101 r/mCC patients received tisotumab vedotin. 138 ocular treatment-related AEs (TRAEs), predominantly Grade 1 or 2, were observed in 54 (53%) patients. The most common ocular TRAEs were conjunctivitis (26 patients [26%]), dry eye (23 patients [23%]), and keratitis (11 patients [11%]). Observed ocular TRAEs are hypothesized to be conjunctival and inflammatory in nature, resulting in signs and symptoms readily recognizable by patients and healthcare providers. Generally, ocular TRAEs were manageable with ophthalmic care (prophylactic and symptom management) and dose modifications. Of 138 ocular TRAEs, 118 (86%) resolved within 30 days after last dose of tisotumab vedotin. Median time to resolution was 0.7 months (interquartile range: 0.3-1.6). To help reduce the risk of ocular AEs, an eye care plan based on clinical trial experience was developed. This encompasses an oncology care team partnering with an eye care provider, incorporates eye exams at baseline (per trial mitigation measures) and prior to each dose, includes eye drops and cold packs, avoids contact lens use, and advises prompt referral for new or worsening ocular signs and symptoms. Moreover, dose modification guidelines have been developed to manage potential ocular AEs. Ocular AEs will require patient management strategies that may be new to oncology teams. Oncologists should become familiar with symptoms that typically arise, and eye care providers should be an integral part of the comprehensive care team treating patients receiving tisotumab vedotin. With diligent monitoring for early signs and symptoms, careful adherence to required eye care, pharmacologic intervention when ocular AEs arise, and dose modifications when needed, ocular AEs can be detected early and symptoms can be alleviated before any impact on vision, to ultimately help patients stay on therapy.


Assuntos
Imunoconjugados , Neoplasias do Colo do Útero , Anticorpos Monoclonais Humanizados/uso terapêutico , Feminino , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Oligopeptídeos , Neoplasias do Colo do Útero/patologia
3.
Phys Rev Lett ; 117(3): 037207, 2016 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-27472137

RESUMO

The temperature-pressure phase diagram of the ferromagnet LaCrGe_{3} is determined for the first time from a combination of magnetization, muon-spin-rotation, and electrical resistivity measurements. The ferromagnetic phase is suppressed near 2.1 GPa, but quantum criticality is avoided by the appearance of a magnetic phase, likely modulated, AFM_{Q}. Our density functional theory total energy calculations suggest a near degeneracy of antiferromagnetic states with small magnetic wave vectors Q allowing for the potential of an ordering wave vector evolving from Q=0 to finite Q, as expected from the most recent theories on ferromagnetic quantum criticality. Our findings show that LaCrGe_{3} is a very simple example to study this scenario of avoided ferromagnetic quantum criticality and will inspire further study on this material and other itinerant ferromagnets.

4.
Invest New Drugs ; 32(6): 1246-57, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25142258

RESUMO

PURPOSE: This first-in-human study evaluated the CD70-targeted antibody-drug conjugate SGN-75 in patients with relapsed or refractory CD70-positive non-Hodgkin lymphoma (NHL) or metastatic renal cell carcinoma (RCC). Methods SGN-75 was administered intravenously to 58 patients (39 RCC, 19 NHL) every 3 weeks (Q3Wk; doses escalated from 0.3 to 4.5 mg/kg) or on Days 1, 8, and 15 of 28-day cycles (weekly; doses of 0.3 or 0.6 mg/kg). Dose-limiting toxicities were evaluated during Cycle 1; treatment response was monitored every 2 cycles. RESULTS: The maximum tolerated dose of SGN-75 in RCC patients was 3 mg/kg Q3Wk. Due to toxicity concerns (idiopathic thrombocytopenic purpura in 2 NHL patients treated weekly), dose escalation in the weekly schedule was terminated; no regimen was recommended for NHL patients. The most common adverse events reported in patients treated Q3Wk (N = 47) were fatigue (40%), dry eye (32%), nausea (30%), and thrombocytopenia (26%). The nadir for thrombocytopenia typically occurred during Cycle 1. Ocular adverse events (e.g., corneal epitheliopathy, dry eye) were reported for 57% of patients treated Q3Wk and were generally reversible. Antitumor activity in patients treated Q3Wk included 1 complete response, 2 partial responses, and 20 stable disease. SGN-75 exposures were approximately dose proportional, with a mean terminal half-life of 10 days. Substantial depletions of CD70-positive peripheral blood lymphocytes were observed after SGN-75 treatment. CONCLUSIONS: Modest single-agent activity and generally manageable adverse events were observed in heavily pretreated RCC and NHL patients. Administration Q3Wk was better tolerated than weekly dosing. Targeted ablation of CD70-positive lymphocytes was demonstrated.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Imunoconjugados/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Oligopeptídeos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Ligante CD27/metabolismo , Carcinoma de Células Renais/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Imunoconjugados/efeitos adversos , Imunoconjugados/farmacocinética , Imunoconjugados/farmacologia , Neoplasias Renais/metabolismo , Linfoma não Hodgkin/metabolismo , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Oligopeptídeos/efeitos adversos , Oligopeptídeos/farmacocinética , Oligopeptídeos/farmacologia , Critérios de Avaliação de Resposta em Tumores Sólidos
5.
J Biol Chem ; 287(31): 25964-74, 2012 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-22689578

RESUMO

CLECSF8 is a poorly characterized member of the "Dectin-2 cluster" of C-type lectin receptors and was originally thought to be expressed exclusively by macrophages. We show here that CLECSF8 is primarily expressed by peripheral blood neutrophils and monocytes and weakly by several subsets of peripheral blood dendritic cells. However, expression of this receptor is lost upon in vitro differentiation of monocytes into dendritic cells or macrophages. Like the other members of the Dectin-2 family, which require association of their transmembrane domains with signaling adaptors for surface expression, CLECSF8 is retained intracellularly when expressed in non-myeloid cells. However, we demonstrate that CLECSF8 does not associate with any known signaling adaptor molecule, including DAP10, DAP12, or the FcRγ chain, and we found that the C-type lectin domain of CLECSF8 was responsible for its intracellular retention. Although CLECSF8 does not contain a signaling motif in its cytoplasmic domain, we show that this receptor is capable of inducing signaling via Syk kinase in myeloid cells and that it can induce phagocytosis, proinflammatory cytokine production, and the respiratory burst. These data therefore indicate that CLECSF8 functions as an activation receptor on myeloid cells and associates with a novel adaptor molecule. Characterization of the CLECSF8-deficient mice and screening for ligands using oligosaccharide microarrays did not provide further insights into the physiological function of this receptor.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lectinas Tipo C/metabolismo , Células Mieloides/metabolismo , Proteínas Tirosina Quinases/metabolismo , Receptores Imunológicos/metabolismo , Animais , Diferenciação Celular , Células Cultivadas , Expressão Gênica , Regulação da Expressão Gênica , Humanos , Lectinas Tipo C/química , Camundongos , Células Mieloides/enzimologia , Células Mieloides/fisiologia , Especificidade de Órgãos , Fagocitose , Cultura Primária de Células , Estrutura Terciária de Proteína , Transporte Proteico , Receptores Imunológicos/química , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , Explosão Respiratória , Transdução de Sinais , Quinase Syk , Fator de Necrose Tumoral alfa/metabolismo
6.
Clin Cancer Res ; 28(10): 2020-2029, 2022 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-35165101

RESUMO

PURPOSE: Praluzatamab ravtansine (CX-2009) is a conditionally activated Probody drug conjugate (PDC) comprising an anti-CD166 mAb conjugated to DM4, with a protease-cleavable linker and a peptide mask that limits target engagement in normal tissue and circulation. The tumor microenvironment is enriched for proteases capable of cleaving the linker, thereby releasing the mask, allowing for localized binding of CX-2009 to CD166. CX-2009 was evaluated in a phase I/II clinical trial for patients with advanced solid tumors. PATIENTS AND METHODS: Eligible patients had metastatic cancer receiving ≥2 prior treatments. CX-2009 was administered at escalating doses every 3 weeks (0.25-10 mg/kg) or every 2 weeks (4-6 mg/kg). Primary objective was to determine the safety profile and recommended phase II dose (RP2D). RESULTS: Of 99 patients enrolled, the most prevalent subtype was breast cancer (n = 45). Median number of prior therapies was 5 (range, 1-19). Dose-limiting toxicities were observed at 8 mg/kg every 3 weeks and 6 mg/kg every 2 weeks. On the basis of tolerability, the RP2D was 7 mg/kg every 3 weeks. Tumor regressions were observed at doses ≥4 mg/kg. In the hormone receptor-positive/HER2-nonamplified breast cancer subset (n = 22), 2 patients (9%) had confirmed partial responses, and 10 patients (45%) had stable disease. Imaging with zirconium-labeled CX-2009 confirmed uptake in tumor lesions and shielding of major organs. Activated, unmasked CX-2009 was measurable in 18 of 22 posttreatment biopsies. CONCLUSIONS: CD166 is a novel, ubiquitously expressed target. CX-2009 is the first conditionally activated antibody-drug conjugate to CD166 to demonstrate both translational and clinical activity in a variety of tumor types.


Assuntos
Antineoplásicos , Neoplasias da Mama , Imunoconjugados , Maitansina , Neoplasias , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Imunoconjugados/efeitos adversos , Maitansina/uso terapêutico , Neoplasias/patologia , Microambiente Tumoral
7.
J Clin Oncol ; 38(16): 1824-1835, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32213105

RESUMO

PURPOSE: This phase I study, which to our knowledge is the first-in-human study of this kind, investigates the safety, tolerability, pharmacokinetics, and clinical activity of anetumab ravtansine, an antibody-drug conjugate of anti-mesothelin antibody linked to maytansinoid DM4, in patients with advanced, metastatic, or recurrent solid tumors known to express the tumor-differentiation antigen mesothelin. PATIENTS AND METHODS: This phase I, open-label, multicenter, dose-escalation and dose-expansion study of anetumab ravtansine enrolled 148 adult patients with multiple solid tumor types. Ten dose-escalation cohorts of patients with advanced or metastatic solid tumors (0.15-7.5 mg/kg) received anetumab ravtansine once every 3 weeks, and 6 expansion cohorts of patients with advanced, recurrent ovarian cancer or malignant mesothelioma received anetumab ravtansine at the maximum tolerated dose once every 3 weeks, 1.8 mg/kg once per week, and 2.2 mg/kg once per week. RESULTS: Forty-five patients were enrolled across the 10 dose-escalation cohorts. The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg once every 3 weeks or 2.2 mg/kg once per week. Thirty-two patients were enrolled in the 6.5 mg/kg once-every-3-weeks, 35 in the 1.8 mg/kg once-per-week, and 36 in the 2.2 mg/kg once-per-week expansion cohorts. The most common drug-related adverse events were fatigue, nausea, diarrhea, anorexia, vomiting, peripheral sensory neuropathy, and keratitis/keratopathy. There were no drug-related deaths. Anetumab ravtansine pharmacokinetics were dose proportional; the average half-life was 5.5 days. Among 148 patients with mesothelioma or ovarian, pancreatic, non-small-cell lung, and breast cancers, 1 had a complete response, 11 had partial responses, and 66 had stable disease. High levels of tumor mesothelin expression were detected in patients with clinical activity. CONCLUSION: Anetumab ravtansine exhibited a manageable safety and favorable pharmacokinetic profile with encouraging preliminary antitumor activity in heavily pretreated patients with mesothelin-expressing solid tumors. The results allowed for the determination of recommended doses, schedules, and patient populations for anetumab ravtansine in phase II studies.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Proteínas Ligadas por GPI/antagonistas & inibidores , Imunoconjugados/administração & dosagem , Maitansina/análogos & derivados , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacocinética , Feminino , Proteínas Ligadas por GPI/imunologia , Humanos , Imunoconjugados/efeitos adversos , Imunoconjugados/farmacocinética , Masculino , Dose Máxima Tolerável , Maitansina/administração & dosagem , Maitansina/efeitos adversos , Maitansina/farmacocinética , Mesotelina , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia , Neoplasias/imunologia , Neoplasias/mortalidade , Neoplasias/patologia , Intervalo Livre de Progressão
8.
Clin Cancer Res ; 25(6): 1727-1736, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30413525

RESUMO

PURPOSE: Reversible, low-grade ocular adverse events (AE) are associated with administration of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeted antibody-drug conjugate undergoing phase III clinical evaluation in platinum-resistant ovarian cancer. This study investigated the underlying mechanisms of ocular toxicity and evaluated primary prophylactic use of corticosteroid eye drops in patients receiving mirvetuximab soravtansine. PATIENTS AND METHODS: Target expression in the human eye was determined by IHC. The ocular toxicity profile of mirvetuximab soravtansine was assessed preclinically using Dutch-Belted rabbits. In a phase I clinical study, patients with ovarian cancer were treated with 6 mg/kg mirvetuximab soravtansine intravenously once every 3 weeks, including one expansion cohort with corticosteroid eye drops administered daily for the first 10 days of each treatment cycle. RESULTS: FRα expression was absent from human corneal tissues. Ocular abnormalities in the rabbit eye appeared phenotypically consistent with off-target effects on the cornea. Forty patients were enrolled in the expansion cohort. Reversible grade 1 or 2 blurred vision and keratopathy occurred in 16 (40%) and 12 (30%) patients, respectively; no grade 3/4 ocular events were observed. Compared with those patients who did not receive primary prophylaxis, corticosteroid eye drop use resulted in fewer dose reductions (5% vs. 15%) and none discontinued due to ocular AEs. CONCLUSIONS: Preclinical modeling was predictive of the corneal-related symptoms seen in some patients dosed with mirvetuximab soravtansine. Primary prophylactic use of topical corticosteroid eye drops resulted in a trend toward symptomatic improvement and a reduction in ocular AE-related dose modifications in patients treated with mirvetuximab soravtansine.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Doenças da Córnea/prevenção & controle , Glucocorticoides/administração & dosagem , Imunoconjugados/efeitos adversos , Maitansina/análogos & derivados , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Córnea/efeitos dos fármacos , Córnea/patologia , Doenças da Córnea/induzido quimicamente , Doenças da Córnea/patologia , Esquema de Medicação , Avaliação Pré-Clínica de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Receptor 1 de Folato/antagonistas & inibidores , Receptor 1 de Folato/metabolismo , Humanos , Imunoconjugados/administração & dosagem , Infusões Intravenosas , Masculino , Maitansina/administração & dosagem , Maitansina/efeitos adversos , Pessoa de Meia-Idade , Soluções Oftálmicas/administração & dosagem , Neoplasias Ovarianas/patologia , Coelhos , Testes de Toxicidade Subaguda , Resultado do Tratamento
9.
Ophthalmology ; 115(3): 483-7, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18201764

RESUMO

PURPOSE: Perifosine is a novel alkylphospholipid with antiproliferative properties attributed to protein kinase B inhibition. The authors describe a form of ulcerative keratitis in 5 patients with advanced gastrointestinal stromal tumor (GIST) enrolled in a phase I/II trial of perifosine in combination with imatinib. DESIGN: Interventional case series. PARTICIPANTS: Five patients (1 man, 4 women) with imatinib-resistant metastatic GIST who received a combination of imatinib and perifosine orally. METHODS: The medical records were reviewed retrospectively. MAIN OUTCOME MEASURES: Ocular toxicity and ulcerative keratitis associated with perifosine. RESULTS: The ocular symptoms included redness, irritation, tearing, photophobia, and a gradual decrease in vision. Slit-lamp biomicroscopy in each case revealed a peripheral, paralimbal, ring-shaped, superficial corneal stromal infiltration and ulcerative keratitis, reminiscent of the autoimmune keratitis in conditions such as rheumatoid arthritis. The ulcerative keratitis was unilateral in 3 and bilateral in 2 patients; it was National Cancer Institute grade II (symptoms interfering with function but not interfering with activities of daily living) in all patients. All 5 patients had imatinib-resistant metastatic GIST and had continued on the highest dose of imatinib tolerated and initiated therapy with perifosine 100 mg daily or 900 mg weekly. A combination of topical steroids, topical antibiotics, and lubricating drops were used to manage ulcerative keratitis. In the first 3 patients, ulcerative keratitis initially was treated with topical antibiotics without improvement, but subsequently they improved significantly after topical steroids were added. CONCLUSIONS: A vision-threatening form of ulcerative keratitis may occur in patients taking perifosine. It is possible that imatinib in combination with perifosine contributes to this corneal toxicity; however, the authors are unaware of this ocular toxicity having been reported for imatinib when used without perifosine. The visual loss associated with perifosine may be reversible if detected and treated early and with judicious early use of topical steroids, topical antibiotic coverage, and lubrication.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Úlcera da Córnea/induzido quimicamente , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Neoplasias Intestinais/tratamento farmacológico , Fosforilcolina/análogos & derivados , Administração Oral , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Benzamidas , Úlcera da Córnea/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Feminino , Glucocorticoides/uso terapêutico , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Fosforilcolina/administração & dosagem , Fosforilcolina/efeitos adversos , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Prednisolona/análogos & derivados , Prednisolona/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-kit , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Estudos Retrospectivos
10.
Clin Cancer Res ; 24(18): 4399-4406, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-29848572

RESUMO

Purpose: To determine the safety, pharmacokinetics, and recommended phase II dose of an antibody-drug conjugate (ADC) targeting ectonucleotide phosphodiesterases-pyrophosphatase 3 (ENPP3) conjugated to monomethyl auristatin F (MMAF) in subjects with advanced metastatic renal cell carcinoma (mRCC).Patients and Methods: Two phase I studies were conducted sequentially with 2 ADCs considered equivalent, hybridoma-derived AGS-16M8F and Chinese hamster ovary-derived AGS-16C3F. AGS-16M8F was administered intravenously every 3 weeks at 5 dose levels ranging from 0.6 to 4.8 mg/kg until unacceptable toxicity or progression. The study was terminated before reaching the MTD. A second study with AGS-16C3F started with the AGS-16M8F bridging dose of 4.8 mg/kg given every 3 weeks.Results: The AGS-16M8F study (n = 26) closed before reaching the MTD. The median duration of treatment was 12 weeks (1.7-83 weeks). One subject had durable partial response (PR; 83 weeks) and 1 subject had prolonged stable disease (48 weeks). In the AGS-16C3F study (n = 34), the protocol-defined MTD was 3.6 mg/kg, but this was not tolerated in multiple doses. Reversible keratopathy was dose limiting and required multiple dose deescalations. The 1.8 mg/kg dose was determined to be safe and was associated with clinically relevant signs of antitumor response. Three of 13 subjects at 1.8 mg/kg had durable PRs (range, 100-143 weeks). Eight subjects at 2.7 mg/kg and 1.8 mg/kg had disease control >37 weeks (37.5-141 weeks).Conclusions: AGS-16C3F was tolerated and had durable antitumor activity at 1.8 mg/kg every 3 weeks. Clin Cancer Res; 24(18); 4399-406. ©2018 AACR.


Assuntos
Anticorpos Anti-Idiotípicos/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Imunoconjugados/administração & dosagem , Oligopeptídeos/administração & dosagem , Diester Fosfórico Hidrolases/genética , Pirofosfatases/genética , Idoso , Idoso de 80 Anos ou mais , Animais , Anticorpos Anti-Idiotípicos/efeitos adversos , Células CHO , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Cricetulus , Relação Dose-Resposta a Droga , Feminino , Humanos , Imunoconjugados/efeitos adversos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Metástase Neoplásica , Oligopeptídeos/efeitos adversos , Diester Fosfórico Hidrolases/imunologia , Pirofosfatases/imunologia
11.
Cornea ; 26(6): 756-8, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17592333

RESUMO

PURPOSE: To report the first case of bilateral marginal keratitis in the setting of engraftment syndrome in a patient who had undergone hematopoietic stem cell transplantation. METHODS: A 63-year-old man with a history of myelodysplastic syndrome presented with a 5-day history of red eyes. Two weeks before presentation, the patient had received a matched unrelated donor peripheral blood stem cell transplant and subsequently developed engraftment syndrome with a rapid white blood cell count recovery, noninfectious fever, skin rash, and shortness of breath. Ocular symptoms coincided with the timing of the white blood cell recovery. On examination, vision was 20/20 OU with +1 conjunctival injection with bilateral corneal subepithelial infiltrates in the periphery, particularly in areas of corneal pannus from previously existing contact lens-related neovascularization. There was no evidence of blepharitis, meibomian gland dysfunction, or uveitis. Ocular bacterial and viral cultures were negative, and a conjunctival biopsy was negative for viral inclusions or ocular graft-versus-host disease. RESULTS: The patient was initially treated with topical antibiotics for 2 days without any improvement and treated with topical corticosteroids 4 times daily. Examination 7 days after starting topical corticosteroids showed complete resolution of the marginal keratitis. CONCLUSIONS: Engraftment syndrome is notable for a rapid recovery of the white blood cell count after hematopoietic stem cell transplantation. Patients who present with presumed conjunctivitis in the setting of autologous and allogeneic stem cell transplantation should be evaluated for engraftment syndrome-related marginal keratitis.


Assuntos
Dispneia/etiologia , Exantema/etiologia , Febre/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Ceratite/etiologia , Administração Tópica , Glucocorticoides/uso terapêutico , Humanos , Ceratite/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/terapia , Prednisolona/análogos & derivados , Prednisolona/uso terapêutico , Síndrome
12.
Clin Lymphoma Myeloma Leuk ; 16(3): 139-45, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26775883

RESUMO

BACKGROUND: Long-term disease-free survival in adult patients with acute lymphoblastic leukemia (ALL) remains unsatisfactory, and the treatment options are limited for those patients with relapse or a failure to respond after initial therapy. We conducted a dose-escalation/expansion phase II, multicenter, single-arm study to determine the optimal dose of coltuximab ravtansine (SAR3419), an anti-CD19 antibody-drug conjugate, in this setting. PATIENTS AND METHODS: The dose-escalation part of the study determined the selected dose of coltuximab ravtansine for the evaluation of efficacy and safety in the dose-expansion phase. Patients received coltuximab ravtansine induction therapy (≤ 8 weekly doses). The responding patients were eligible for maintenance therapy (biweekly administration for ≤ 24 weeks). Three dose levels of coltuximab ravtansine were examined: 55, 70, and 90 mg/m(2). The primary endpoint was the objective response rate (ORR). The secondary endpoints included the duration of response (DOR) and safety. RESULTS: A total of 36 patients were treated: 19 during dose escalation and 17 during dose expansion. One dose-limiting toxicity was observed at 90 mg/m(2) (grade 3 peripheral motor neuropathy); therefore, 70 mg/m(2) was selected for the dose-expansion phase. Five patients discontinued therapy because of adverse events (AEs). The most common AEs were pyrexia, diarrhea, and nausea. Of the 17 evaluable patients treated at the selected dose, 4 had a disease response (estimated ORR using the Bayesian method: 25.5% (80% confidence interval, 14.2%-39.6%). The DOR was 1.9 months (range, 1-5.6 months). Because of these results, the study was prematurely discontinued. CONCLUSION: Coltuximab ravtansine was well tolerated but was associated with a low clinical response rate in patients with relapsed or refractory ALL.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Imunotoxinas/uso terapêutico , Maitansina/análogos & derivados , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Imunotoxinas/administração & dosagem , Imunotoxinas/efeitos adversos , Masculino , Maitansina/administração & dosagem , Maitansina/efeitos adversos , Maitansina/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Recidiva , Retratamento , Resultado do Tratamento
13.
Curr Oncol Rep ; 7(1): 74-9, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15610690

RESUMO

Primary intraocular lymphoma (PIOL) is a subset of primary central nervous system lymphoma (PCNSL) in which malignant lymphoid cells invade the retina, vitreous body, or optic nerve head. It is usually a large B-cell non-Hodgkin's lymphoma. PIOL typically presents as a vitritis that is unresponsive to corticosteroid therapy. Diagnosis of PIOL requires pathologic confirmation of malignant cells in specimens of the cerebrospinal fluid, vitreous, or chorioretinal biopsies. The optimal therapy for PIOL has yet to be determined. It is generally believed that PIOL should be treated with a combination of systemic chemotherapy, including high-dose methotrexate and radiotherapy. However, several new developments for PIOL with central nervous system involvement have been reported, including intrathecal therapy and autologous stem-cell transplantation. In addition, intravitreal methotrexate has been successful in the treatment of isolated recurrent ocular disease. This article provides an overview of treatment modalities for initial, recurrent, and relapsed PIOL.


Assuntos
Neoplasias Oculares/diagnóstico , Neoplasias Oculares/terapia , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/terapia , Oncologia/métodos , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Terapia Combinada/métodos , Humanos , Oncologia/tendências , Metotrexato/uso terapêutico , Radioterapia/métodos , Recidiva , Retina/patologia , Transplante de Células-Tronco , Resultado do Tratamento
14.
Ocul Surf ; 3(4 Suppl): S177-9, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17216114

RESUMO

Acute graft vs host disease (GVHD) is thought to be mainly a Th1 inflammatory-mediated process, whereas chronic GVHD involves primarily Th2 inflammation. To elucidate new strategies for the treatment and prevention of ocular GVHD, it is important to understand the pathophysiologic connection between systemic and organ-specific acute and chronic GVHD. The two types of inflammatory processes, however, represent only a part of a highly intricate, complex disorder. Studies to further understand the inflammatory profile of ocular GVHD are ongoing.

15.
Ocul Surf ; 3(4 Suppl): S131-8, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17216102

RESUMO

The goal of this symposium was to coalesce information presented by 22 investigators in the field of corneal and ocular surface inflammation into common pathways of inflammation. The perspective elucidated in this article defines the components of the normal ocular surface immune architecture and describes the consensus reached on the mechanisms/pathways involved in 1) acute inflammation; 2) late-stage (chronic) response; and 3) allergic disease. Seven diagrams didactically illustrate mechanisms. This paper is the introductory article in a supplement containing 18 articles by the symposium participants.

16.
Sci Rep ; 3: 3419, 2013 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-24305504

RESUMO

The International Chronic Ocular GVHD Consensus Group held 4 working meetings to define new diagnostic metrics for chronic ocular graft-versus-host disease (GVHD). After considering the factors currently used to diagnose chronic ocular GVHD, the Consensus Group identified 4 subjective and objective variables to measure in patients following allogeneic hematopoietic stem cell transplantation (HSCT): OSDI, Schirmer's score without anesthesia, corneal staining, and conjunctival injection. Each variable was scored 0-2 or 0-3, with a maximum composite score of 11. Consideration was also given to the presence or the absence of systemic GVHD. On the basis of their composite score and the presence or absence of systemic GVHD, patients were assigned to one of three diagnostic categories: NO, PROBABLE, or DEFINITE ocular GVHD. New diagnostic criteria for chronic ocular GVHD are presented by the Consensus Group. Validation studies are needed to identify the best combination of the proposed metrics to maximize diagnostic sensitivity and specificity.


Assuntos
Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/patologia , Adulto , Doença Crônica , Consenso , Olho/patologia , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Adulto Jovem
17.
Trans Am Ophthalmol Soc ; 110: 64-73, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23818735

RESUMO

PURPOSE: In conjunctival melanoma, tumor thickness and nonlimbal location are associated with poor prognosis. However, other established high-risk features for cutaneous melanoma, including ulceration, mitotic figures, epithelioid cell type, and lymphovascular invasion, have not previously been studied extensively for their prognostic value in conjunctival melanoma. We examined the hypothesis that these features also predict regional nodal metastasis and death in conjunctival melanoma. METHODS: The medical records of 44 of 46 consecutive conjunctival melanoma patients treated between June 2003 and December 2009 were retrospectively reviewed; tumor tissue was not available for the two excluded patients. Demographic and clinicopathologic features, including tumor location, tumor thickness, ulceration, mitotic rate, histology, lymphovascular invasion, and microsatellitosis, were reviewed. Outcome measures included regional nodal metastasis, distant metastasis, and death. RESULTS: Twenty-six women and 18 men had a median age of 62 years. Regional nodal metastasis occurred in 7 patients (16%) and distant metastasis in 9 (20%). Median follow-up was 40 months. At last follow-up, 10 patients (23%) had died of disease. Tumor thickness>2.0 mm, ulceration, and mitotic figure>1/mm2 predicted regional nodal metastasis and death from disease. In addition to these three histologic features, vascular invasion, epithelioid cell type, and microsatellitosis significantly predicted death from disease. Tumor location (bulbar vs nonbulbar) was not correlated with regional nodal metastasis or death. CONCLUSIONS: In conjunctival melanoma, as in cutaneous melanoma, thicker tumor, ulceration, and higher mitotic rate are correlated with regional nodal metastasis. In addition, lymphovascular invasion, epithelioid cell type, and microsatellitosis are correlated with melanoma-related death.


Assuntos
Neoplasias da Túnica Conjuntiva/patologia , Melanoma/patologia , Neoplasias da Túnica Conjuntiva/mortalidade , Feminino , Humanos , Metástase Linfática/patologia , Masculino , Melanoma/mortalidade , Melanoma/secundário , Pessoa de Meia-Idade , Invasividade Neoplásica , Estudos Retrospectivos
19.
Curr Opin Ophthalmol ; 17(4): 344-8, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16900025

RESUMO

PURPOSE OF REVIEW: To summarize recent findings regarding the clinical spectrum, pathophysiology, and treatment of ocular graft versus host disease. RECENT FINDINGS: Ocular graft versus host disease is a common sequela of allogeneic hematopoietic transplantation affecting up to 80% of chronic graft versus host disease patients. Clinical features of ocular graft versus host disease encompass all parts of the eye, from the lid to the choroids, although ocular graft versus host disease is most commonly viewed as a disease of the ocular surface, with the conjunctiva and lacrimal gland most commonly affected. Clinical features of ocular graft versus host disease (keratoconjunctivitis sicca, cicatricial conjunctivitis, scleritis, and others) mirror other inflammatory ocular conditions associated with autoimmune/collagen vascular diseases. Immunohistochemistry studies of lacrimal gland dysfunction and conjunctival inflammation in chronic ocular graft versus host disease are summarized. Current diagnosis and treatment of chronic graft versus host disease are outlined in the recent publications from the National Institute of Health Chronic graft versus host disease Consensus Workshops, and the information relevant to ocular graft versus host disease is delineated. SUMMARY: Ocular graft versus host disease evaluation, diagnosis, and management should be approached in a multidisciplinary fashion in the context of the patient's overall graft versus host disease status.


Assuntos
Oftalmopatias/etiologia , Doença Enxerto-Hospedeiro/complicações , Imunossupressores/uso terapêutico , Diagnóstico Diferencial , Oftalmopatias/diagnóstico , Oftalmopatias/tratamento farmacológico , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Resultado do Tratamento
20.
Biol Blood Marrow Transplant ; 12(1): 31-47, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16399567

RESUMO

This consensus document provides an update for pathologists and clinicians about the interpretation of biopsy results and use of this information in the management of hematopoietic cell transplantation patients. Optimal sampling and tissue preparation are discussed. Minimal criteria for the diagnosis of graft-versus-host disease (GVHD) are proposed, together with specific requirements for the diagnosis of chronic GVHD. Four final diagnostic categories (no GVHD, possible GVHD, consistent with GVHD, and definite GVHD) reflect the integration of histopathology with clinical, laboratory, and radiographic information. Finally, the Working Group developed a set of worksheets to facilitate communication of clinical information to the interpreting pathologist and to aid in clinicopathologic correlation studies. Forms are available at . The recommendations of the Working Group represent a consensus opinion supplemented by evaluation of available peer-reviewed literature. Consensus recommendations and suggested data-capture forms should be validated in prospective clinicopathologic studies.


Assuntos
Ensaios Clínicos como Assunto/normas , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Biópsia , Doença Crônica , Gerenciamento Clínico , Doença Enxerto-Hospedeiro/diagnóstico , Humanos , National Institutes of Health (U.S.) , Patologia/normas , Guias de Prática Clínica como Assunto , Estados Unidos
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