RESUMEN
Vascular inflammation, infusion reactions, glomerulopathies, and other potentially adverse effects may be observed in laboratory animals, including monkeys, on toxicity studies of therapeutic monoclonal antibodies and recombinant human protein drugs. Histopathologic and immunohistochemical (IHC) evaluation suggests these effects may be mediated by deposition of immune complexes (ICs) containing the drug, endogenous immunoglobulin, and/or complement components in the affected tissues. ICs may be observed in glomerulus, blood vessels, synovium, lung, liver, skin, eye, choroid plexus, or other tissues or bound to neutrophils, monocytes/macrophages, or platelets. IC deposition may activate complement, kinin, and/or coagulation/fibrinolytic pathways and result in a systemic proinflammatory response. IC clearance is biphasic in humans and monkeys (first from plasma to liver and/or spleen, second from liver or spleen). IC deposition/clearance is affected by IC composition, immunomodulation, and/or complement activation. Case studies are presented from toxicity study monkeys or rats and indicate IHC-IC deposition patterns similar to those predicted by experimental studies of IC-mediated reactions to heterologous protein administration to monkeys and other species. The IHC-staining patterns are consistent with findings associated with generalized and localized IC-associated pathology in humans. However, manifestations of immunogenicity in preclinical species are generally not considered predictive to humans.
Asunto(s)
Complejo Antígeno-Anticuerpo/metabolismo , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Enfermedades Vasculares/patología , Animales , Anticuerpos Monoclonales/farmacología , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Complemento C3/metabolismo , Complejo de Ataque a Membrana del Sistema Complemento/metabolismo , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Femenino , Haplorrinos , Humanos , Inmunoglobulina G/metabolismo , Inmunoglobulina M/metabolismo , Inmunohistoquímica , Masculino , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Fagocitosis/efectos de los fármacos , Ratas , Enfermedades Vasculares/inducido químicamenteRESUMEN
Data from a clinical study of 86 pancreatic cancer patients with involuntary, significant weight loss (cachexia) were used to explore the relationship between patient-reported outcomes (PROs) and survival. In all, 28 pancreatic cancer patients with cachexia were given gemcitabine (Gemzar) plus 3 mg/kg of infliximab (Remicade), 28 were given gemcitabine plus 5 mg/kg of infliximab, and 30 were given gemcitabine plus placebo in a double-blinded, phase II, multicenter trial. PRO endpoints included scores from the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Functional Assessment of Anorexia/ Cachexia Therapy (FAACT), Brief Pain Inventory (BPI), and the Short-Form 36 general health survey (SF-36). Population mean scores at baseline indicated fatigue problems (FACIT-F), nutritional health issues (FAACT), and mild-to-moderate pain (BPI "worst pain" score). Baseline normalized SF-36 values for physical functioning, vitality, and mental health indicated substantial impairment. Baseline fatigue and physical-functioning scores predicted survival as well as, or better than, baseline Karnofsky Performance Status or hemoglobin level. A cut-point in the FACIT-F score (median < or = 30) strongly predicted mortality; patients with greater fatigue had a lower median overall survival than did those with less fatigue. These findings supported several features of an a priori clinical-benefit model. Patient-reported fatigue provided powerful prognostic information; tracking of this symptom may be useful for treatment planning and medical monitoring of advanced-stage pancreatic cancer patients with cachexia. These results must be confirmed by larger trials.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Caquexia/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/complicaciones , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Antimetabolitos Antineoplásicos/uso terapéutico , Apetito , Caquexia/etiología , Caquexia/mortalidad , Desoxicitidina/uso terapéutico , Método Doble Ciego , Fatiga/etiología , Fatiga/mortalidad , Femenino , Humanos , Infliximab , Estado de Ejecución de Karnofsky , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Neoplasias Pancreáticas/mortalidad , Pronóstico , Encuestas y Cuestionarios , Análisis de Supervivencia , Pérdida de Peso , GemcitabinaRESUMEN
To evaluate the safety and efficacy of infliximab administered with gemcitabine to treat cancer cachexia and to explore a functional measure of clinical benefit, investigators involved in this multicenter, phase II, placebo-controlled study randomized 89 patients with stage II-IV pancreatic cancer and cachexia to receive either placebo or 3 mg/ kg or 5 mg/kg of infliximab at weeks 0, 2, and 4 and then every 4 weeks to week 24; patients also received 1,000 mg/m2 of gemcitabine weekly from weeks 0-6 and then for 3 of every 4 weeks until their disease progressed. The primary endpoint was change in lean body mass (LBM) at 8 weeks from baseline; major secondary endpoints included overall survival, progression-free survival, Karnofsky performance status, and 6-minute walk test distance. In addition, quality of life was measured. The mean change in LBM at 8 weeks was +0.4 kg for patients receiving placebo, +0.3 kg for those receiving 3 mg/kg of infliximab, and +1.7 kg for those receiving 5 mg/kg of infliximab. No statistically significant differences in LBM or secondary endpoints were observed among the groups. Safety findings were similar in all groups. Adding infliximab to gemcitabine to treat cachexia in advanced pancreatic cancer patients was not associated with statistically significant differences in safety or efficacy when compared with placebo.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Caquexia/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/secundario , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Método Doble Ciego , Femenino , Humanos , Infliximab , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Masculino , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/patología , Placebos , Pronóstico , Tasa de Supervivencia , GemcitabinaRESUMEN
A new paradigm is becoming widely accepted, that chronic inflammation, driven in part by chemokines and cytokines at the site of a tumour, may facilitate tumour progression instead of promoting anti-tumour immunity. Tumours and activated stromal cells secrete pro-inflammatory chemokines and cytokines that act either directly or indirectly through stimulation of the vascular endothelium to recruit leukocytes to the tumour. After activation, these tumour-associated leukocytes release angiogenic factors, mitogens, proteolytic enzymes, and chemotactic factors, recruiting more inflammatory cells and stimulating angiogenesis to sustain tumour growth and facilitate tumour metastasis. Breaking this cycle by inhibiting targets such as cytokines, chemokines and other inflammatory mediators, either alone, or more realistically, in combination with other therapies, such as anti-angiogenic or cytotoxic agents, may provide highly efficacious therapeutic regimens for the treatment of malignancies. This article reviews anti-cytokine and anti-chemokine therapies being pursued in cancer, and discusses in more detail anti-tumour necrosis factor-alpha (TNF) approaches.
Asunto(s)
Quimiocinas/antagonistas & inhibidores , Citocinas/antagonistas & inhibidores , Neoplasias/terapia , Progresión de la Enfermedad , Humanos , Inflamación/fisiopatología , Factores de RiesgoRESUMEN
PURPOSE: To determine the maximum tolerated dose and pharmacokinetics of cantuzumab mertansine, an immunoconjugate of the potent maytansine derivative (DM1) and the humanized monoclonal antibody (huC242) directed to CanAg, intravenously (i.v.) once every 3 weeks and to seek evidence of antitumor activity. PATIENTS AND METHODS: Patients with CanAg-expressing solid malignancies were treated with escalating doses of cantuzumab mertansine administered i.v. every 3 weeks. The pharmacokinetic parameters of cantuzumab mertansine, the presence of plasma-shed CanAg, and the development of both human antihuman and human anti-DM1 conjugate antibodies also were characterized. RESULTS: Thirty-seven patients received 110 courses of cantuzumab mertansine at doses ranging from 22 to 295 mg/m2. Acute, transient, and reversible elevations of hepatic transaminases were the principal toxic effects. Nausea, vomiting, fatigue, and diarrhea were common but rarely severe at the highest dose levels. Dose, peak concentration, and area under the concentration-time curve correlated with the severity of transaminase elevation. The mean (+/- SD) clearance and terminal elimination half-life values for cantuzumab mertansine averaged 39.5 (+/-13.1) mL/h/m2 and 41.1 (+/-16.1) hours, respectively. Strong expression (3+) of CanAg was documented in 68% of patients. Two patients with chemotherapy-refractory colorectal carcinoma had minor regressions, and four patients had persistently stable disease for more than six courses. CONCLUSION: The recommended dose for cantuzumab mertansine is 235 mg/m2 i.v. every 3 weeks. The absence of severe hematologic toxic effects, preliminary evidence of cantuzumab mertansine tumor localization, and encouraging biologic activity in chemotherapy-refractory patients warrant further broad clinical development of this immunoconjugate in CanAg-expressing tumors.
Asunto(s)
Antineoplásicos Fitogénicos/farmacocinética , Maitansina/farmacocinética , Neoplasias/metabolismo , Adulto , Anciano , Anticuerpos Monoclonales , Antineoplásicos Fitogénicos/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Semivida , Humanos , Inmunoconjugados , Infusiones Intravenosas , Masculino , Dosis Máxima Tolerada , Maitansina/farmacología , Persona de Mediana Edad , Mucina-1/inmunologíaRESUMEN
PURPOSE: The purpose is to determine the maximum-tolerated dose, assess the toxicities, characterize the pharmacokinetic behavior, and seek preliminary evidence of biological activity of cantuzumab mertansine when administered as a weekly i.v. infusion without interruption. EXPERIMENTAL DESIGN: Patients with incurable solid tumors that expressed the target antigen for cantuzumab mertansine, CanAg, were treated with doses of cantuzumab mertansine ranging from 40 to 138 mg/m(2). The maximum-tolerated dose was defined as the highest dose at which no more than 1 of 6 patients experienced dose-limiting toxicity. Plasma concentrations of cantuzumab mertansine and total humanized antibody were determined, and area under the plasma concentration-time curve (to the last measured concentration) was calculated. RESULTS: Thirty-nine patients received a total of 280 weekly doses of cantuzumab mertansine. Acute, transient elevation of the hepatic transaminases and reversible fatigue were identified as the dose-limiting toxicities at the highest dose level. The maximum-tolerated dose was determined to be 115 mg/m(2)/week. Evidence of clinical activity was noted in 3 patients. Pharmacokinetic analyses revealed that the pharmacokinetic variability was moderate, without evidence of dose dependency. Furthermore, the drug had a long terminal half-life ( approximately 40 h). CONCLUSIONS: This study identified a safe and tolerable dose of the novel immunoconjugate prodrug cantuzumab mertansine. The evidence of antitumor activity suggests that additional clinical development is warranted, with a focus on tumors that express high levels of CanAg and which are known to be sensitive to antimicrotubule agents.
Asunto(s)
Antineoplásicos/uso terapéutico , Maitansina/análogos & derivados , Maitansina/administración & dosificación , Maitansina/uso terapéutico , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Hígado/enzimología , Masculino , Dosis Máxima Tolerada , Microtúbulos/metabolismo , Persona de Mediana Edad , Profármacos , Factores de Tiempo , Transaminasas/metabolismoRESUMEN
The critical pathogenic role of tumor necrosis factor (TNF)alpha in inflammatory disorders such as rheumatoid arthritis and inflammatory bowel disease is well established. The role played by TNFalpha in both the treatment and pathogenesis of cancer remains less understood. Recent advances help to create a framework for understanding seemingly paradoxical effects of TNFalpha as both an anti-tumour agent and a mediator of tumour growth. High pharmacological doses of TNFalpha combined with chemotherapy can regress otherwise intractable tumours, and efforts continue to optimize delivery to avoid severe toxicities. Mounting evidence demonstrates that pathophysiological concentrations of endogenous TNFalpha act to promote tumour genesis and growth. The cellular and molecular pathways mediating these phenomena are starting to be clarified. Current data support the continued development of both TNFalpha and anti-TNFalpha therapy for clinical treatment of cancers in distinct settings.
Asunto(s)
Neoplasias/etiología , Factor de Necrosis Tumoral alfa/fisiología , Animales , Humanos , Neoplasias/terapia , Transducción de Señal , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/uso terapéuticoRESUMEN
Acute myeloid leukemia (AML) blasts express high levels of interlekin-3 (IL-3) receptor-α (CD123). CSL360 is a recombinant, chimeric immunoglobulin G1 (IgG1), anti-CD123 monoclonal antibody (MoAb) that neutralizes IL-3 and demonstrates anti-leukemic activity in vitro. This phase 1 study assessed safety, pharmacokinetics and bioactivity of weekly intravenous CSL360 for 12 weeks in 40 patients with advanced AML across five dose levels (0.1-10.0 mg/kg). Other than mild infusion reactions, CSL360 was well tolerated. The maximal tolerated dose was not reached. The half-life was 4.9 days, and the area under the curve (AUC) and maximum concentration (Cmax) increased proportionally with dose. Doses ≥ 3.0 mg/kg resulted in complete saturation and down-regulation of CD123 and abolition of ex vivo proliferative responsiveness to IL-3, indicating adequate blockade of IL-3 signaling. Two patients responded, with one remaining in complete remission after 17 doses. CSL360 bound CD123 specifically, but did not induce anti-leukemic activity in most patients. While safe, MoAb blockade of CD123 function is insufficient as a therapeutic strategy.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Proliferación Celular/efectos de los fármacos , Femenino , Regulación Leucémica de la Expresión Génica , Humanos , Interleucina-3/metabolismo , Subunidad alfa del Receptor de Interleucina-3/antagonistas & inhibidores , Subunidad alfa del Receptor de Interleucina-3/genética , Subunidad alfa del Receptor de Interleucina-3/metabolismo , Masculino , Persona de Mediana Edad , Recurrencia , Resultado del Tratamiento , Adulto JovenRESUMEN
GOALS OF WORK: The objective of this study was to determine the effect of infliximab, an antitumor necrosis factor alpha (TNFalpha) antibody, on fatigue in patients with advanced cancer. MATERIALS AND METHODS: This was a pilot study undertaken in a specialist palliative care unit. Seventeen eligible outpatients were enrolled in this study. Infliximab 5 mg/kg was administered intravenously at baseline and if there was observable clinical benefit, every 4 weeks thereafter until clinical benefit was lost. The primary outcome measure assessing subjective functional improvement was the change in fatigue severity scale (FSS) score at 4 weeks following an infliximab infusion. Secondary outcome measures of subjective functional improvement that were assessed 4 weeks after each infliximab infusion included changes in Karnofsky performance status (KPS), hospital anxiety and depression scale (HADS) score, anxiety and depression subscores, and appetite visual analogue scale. Clinical laboratory assessments were C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), TNFalpha, interleukin-6, and leptin concentrations. MAIN RESULTS: At week 4, 9 of 14 patients improved in FSS, 3 of 15 improved in KPS, 7 of 15 improved in total HADS and the majority had modest improvements in serum CRP, ESR, or leptin concentrations. Case studies of six patients with overall improvement are described in detail. Five serious adverse events occurred; two were serious infections possibly related to treatment. CONCLUSIONS: A subgroup of patients in this small pilot study demonstrated uniform subjective/clinical benefit. We were not able to identify any predictors of this response; a larger, controlled study may reveal more information.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Fatiga/tratamiento farmacológico , Fatiga/fisiopatología , Neoplasias/fisiopatología , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Femenino , Hospitales para Enfermos Terminales , Humanos , Infliximab , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Cuidados Paliativos , Proyectos Piloto , Estudios Prospectivos , Resultado del TratamientoRESUMEN
PURPOSE: Tumor necrosis factor alpha (TNF-alpha) may play a role in renal cell carcinoma (RCC). We performed two sequential phase II studies of infliximab, an anti-TNF-alpha monoclonal antibody, in patients with immunotherapy-resistant or refractory RCC. PATIENTS AND METHODS: Patients progressing after cytokine therapy were treated with intravenous infliximab as follows: study 1 (19 patients), 5 mg/kg at weeks 0, 2, and 6, and then every 8 weeks; study 2 (18 patients), 10 mg/kg at weeks 0, 2, and 6, and then every 4 weeks. Treatment continued until disease progression (PD). Response was assessed according to Response Evaluation Criteria in Solid Tumors. Plasma levels of TNF-alpha, CCL2, and interleukin-6 (IL-6) were measured before and during treatment. RESULTS: TNF-alpha and its receptors were detected in malignant cells in RCC biopsies. In study 1, three patients (16%) achieved partial response (PR) and three patients (16%) achieved stable disease (SD). Median duration of response (PR + SD) was 7.7 months (range, 5.0 to 40.5+ months). In study 2, 11 patients (61%) achieved SD. Median duration of response was 6.2 months (range, 3.5 to 24+ months). One patient developed grade 3 hypersensitivity and another died as a result of pulmonary infection/sepsis. Enzyme-linked immunosorbent assay analysis of plasma revealed that higher levels of TNF-alpha at baseline and higher levels of CCL2 during treatment were associated with PD. There were also correlations between higher levels of TNF-alpha, IL-6, and CCL2 and poor survival (< 12 months). CONCLUSION: This is the first direct clinical evidence suggesting that TNF-alpha may be a therapeutic target in RCC. Plasma levels of TNF-alpha, IL-6, and CCL2 may have predictive and prognostic significance.