RESUMEN
BACKGROUND: Pancreatic ductal adenocarcinoma is characterised by low immunogenicity and an immunosuppressive tumour microenvironment. LOAd703, an oncolytic adenovirus with transgenes encoding TMZ-CD40L and 4-1BBL, lyses cancer cells selectively, activates cytotoxic T cells, and induces tumour regression in preclinical models. The aim of this study was to evaluate the safety and feasibility of combining LOAd703 with chemotherapy for advanced pancreatic ductal adenocarcinoma. METHODS: LOKON001 was a non-randomised, phase 1/2 study conducted at the Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA, and consisted of two arms conducted sequentially; the results of arm 1 are presented here. In arm 1, patients 18 years or older with previously treated or treatment-naive unresectable or metastatic pancreatic ductal adenocarcinoma were treated with standard 28-day cycles of intravenous nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 (up to 12 cycles) and intratumoural injections of LOAd703 every 2 weeks. Patients were assigned using Bayesian optimal interval design to receive 500 µL of LOAd703 at 5 × 1010 (dose 1), 1 × 1011 (dose 2), or 5 × 1011 (dose 3) viral particles per injection, injected endoscopically or percutaneously into the pancreatic tumour or a metastasis for six injections. The primary endpoints were safety and treatment-emergent immune response in patients who received at least one dose of LOAd703, and antitumour activity was a secondary endpoint. This study was registered with ClinicalTrials.gov, NCT02705196, arm 2 is ongoing and open to new participants. FINDINGS: Between Dec 2, 2016, and Oct 17, 2019, 23 patients were assessed for eligibility, leading to 22 patients being enrolled. One patient withdrew consent, resulting in 21 patients (13 [62%] men and eight [38%] women) assigned to a dose group (three to dose 1, four to dose 2, and 14 to dose 3). 21 patients were evaluable for safety. Median follow-up time was 6 months (IQR 4-10), and data cutoff was Jan 5, 2023. The most common treatment-emergent adverse events overall were anaemia (96 [8%] of 1237 events), lymphopenia (86 [7%] events), hyperglycaemia (70 [6%] events), leukopenia (63 [5%] events), hypertension (62 [5%] events), and hypoalbuminaemia (61 [5%] events). The most common adverse events attributed to LOAd703 were fever (14 [67%] of 21 patients), fatigue (eight [38%]), chills (seven [33%]), and elevated liver enzymes (alanine aminotransferase in five [24%], alkaline phosphatase in four [19%], and aspartate aminotransferase in four [19%]), all of which were grade 1-2, except for a transient grade 3 aminotransferase elevation occurring at dose 3. A maximum tolerated dose was not reached, thereby establishing dose 3 as the highest-evaluated safe dose when combined with nab-paclitaxel plus gemcitabine. Proportions of CD8+ effector memory cells and adenovirus-specific T cells increased after LOAd703 injections in 15 (94%) of 16 patients for whom T-cell assays could be performed. Eight (44%, 95% CI 25-66) of 18 patients evaluable for activity had an objective response. INTERPRETATION: Combining LOAd703 with nab-paclitaxel plus gemcitabine in patients with advanced pancreatic ductal adenocarcinoma was feasible and safe. To build upon this novel chemoimmunotherapeutic approach, arm 2 of LOKON001, which combines LOAd703, nab-paclitaxel plus gemcitabine, and atezolizumab, is ongoing. FUNDING: Lokon Pharma, the Swedish Cancer Society, and the Swedish Research Council.
Asunto(s)
Adenocarcinoma , Anemia , Virus Oncolíticos , Neoplasias Pancreáticas , Trombocitopenia , Masculino , Humanos , Femenino , Gemcitabina , Virus Oncolíticos/genética , Teorema de Bayes , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/tratamiento farmacológico , Paclitaxel , Anemia/inducido químicamente , Trombocitopenia/inducido químicamente , Adenocarcinoma/terapia , Adenocarcinoma/tratamiento farmacológico , Albúminas , Terapia Genética/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Microambiente TumoralRESUMEN
This phase 1 study sought to characterize the safety, tolerability, and pharmacokinetic behavior of VLX1570, a small molecule inhibitor of the deubiquitinases (DUBs) that remove sterically bulky ubiquitin chains from proteins during processing in the19S regulatory subunit of the proteasome, in patients with relapsed and refractory multiple myeloma (MM). Fourteen patients were treated with escalating doses of VLX1570 ranging from 0.05 to 1.2 mg/kg as a brief intravenous (IV) infusion on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Due to its poor aqueous solubility, VLX1570 was formulated in polyethylene glycol, polyoxyethylated castor oil, and polysorbate 80 and administered as a brief intravenous (IV) infusion via a central venous catheter. Anti-myeloma effects were noted at doses at or above 0.6 mg/kg, however, two patients treated at the 1.2 mg/kg dose level experienced severe, abrupt, and progressive respiratory insufficiency, which was associated with diffuse pulmonary infiltrates on imaging studies, similar to those rarely noted with bortezomib and other inhibitors of the 20S proteasome, culminating in death. Although the contribution of VLX1570's formulation to the pulmonary toxicity could not be ruled out, the severity and precipitous nature of the toxicity and the steep relationship between dose and toxicity, the study was discontinued. Despite the severe pulmonary toxicity noted with VLX1570, efforts directed at identifying DUB inhibitors with greater therapeutic indices appear warranted based on the unique mechanism of action, robustness of preclinical antitumor activity, and activity of the DUB inhibitors in MM resistant to PIs targeting the 20S proteasome subunit.
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Antineoplásicos/administración & dosificación , Azepinas/administración & dosificación , Compuestos de Bencilideno/administración & dosificación , Enzimas Desubicuitinizantes/antagonistas & inhibidores , Mieloma Múltiple/tratamiento farmacológico , Insuficiencia Respiratoria/inducido químicamente , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Azepinas/efectos adversos , Azepinas/farmacocinética , Compuestos de Bencilideno/efectos adversos , Compuestos de Bencilideno/farmacocinética , Resistencia a Antineoplásicos , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Mieloma Múltiple/metabolismo , Mieloma Múltiple/mortalidad , Recurrencia , Insuficiencia Respiratoria/mortalidadRESUMEN
Blastic plasmacytoid dendritic cell neoplasm is an aggressive malignancy derived from plasmacytoid dendritic cells. There is currently no accepted standard of care for treating this neoplasm, and therapeutic strategies have never been prospectively evaluated. Since blastic plasmacytoid dendritic cell neoplasm cells express high levels of interleukin-3 receptor α chain (IL3-Rα or CD123), antitumor effects of the interleukin-3 receptor-targeted drug SL-401 against blastic plasmacytoid dendritic cell neoplasm were evaluated in vitro and in vivo. The cytotoxicity of SL-401 was assessed in patient-derived blastic plasmacytoid dendritic cell neoplasm cell lines (CAL-1 and GEN2.2) and in primary blastic plasmacytoid dendritic cell neoplasm cells isolated from 12 patients using flow cytometry and an in vitro cytotoxicity assay. The cytotoxic effects of SL-401 were compared to those of several relevant cytotoxic agents. SL-401 exhibited a robust cytotoxicity against blastic plasmacytoid dendritic cell neoplasm cells in a dose-dependent manner. Additionally, the cytotoxic effects of SL-401 were observed at substantially lower concentrations than those achieved in clinical trials to date. Survival of mice inoculated with a blastic plasmacytoid dendritic cell neoplasm cell line and treated with a single cycle of SL-401 was significantly longer than that of untreated controls (median survival, 58 versus 17 days, P<0.001). These findings indicate that blastic plasmacytoid dendritic cell neoplasm cells are highly sensitive to SL-401, and support further evaluation of SL-401 in patients suffering from blastic plasmacytoid dendritic cell neoplasm.
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Biomarcadores de Tumor/metabolismo , Células Dendríticas/patología , Neoplasias Hematológicas/patología , Subunidad alfa del Receptor de Interleucina-3/antagonistas & inhibidores , Trastornos Mieloproliferativos/patología , Plasmacitoma/patología , Proteínas Recombinantes de Fusión/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Animales , Apoptosis , Biomarcadores de Tumor/genética , Western Blotting , Proliferación Celular , Células Dendríticas/metabolismo , Femenino , Citometría de Flujo , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/terapia , Humanos , Técnicas In Vitro , Subunidad alfa del Receptor de Interleucina-3/genética , Subunidad alfa del Receptor de Interleucina-3/metabolismo , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Trastornos Mieloproliferativos/metabolismo , Trastornos Mieloproliferativos/terapia , Plasmacitoma/metabolismo , Plasmacitoma/terapia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
While imatinib and other tyrosine kinase inhibitors (TKIs) are highly efficacious in the treatment of chronic myeloid leukaemia (CML), some patients become refractory to these therapies. After confirming that interleukin-3 receptor (IL3R, CD123) is highly expressed on CD34(+) /CD38(-) BCR-ABL1(+) CML stem cells, we investigated whether targeting IL3R with diphtheria toxin (DT)-IL3 fusion proteins SL-401 (DT388 -IL3) and SL-501 (DT388 -IL3[K116W]) could eradicate these stem cells. SL-401 and SL-501 inhibited cell growth and induced apoptosis in the KBM5 cell line and its TKI-resistant KBM5-STI subline. Combinations of imatinib with these agents increased apoptosis in KBM5 and in primary CML cells. In six primary CML samples, including CML cells harbouring the ABL1 T315I mutation, SL-401 and SL-501 decreased the absolute numbers of viable CD34(+) /CD38(-) /CD123(+) CML progenitor cells by inducing apoptosis. IL3-targeting agents reduced clonogenic growth and diminished the fraction of primitive long-term culture-initiating cells in samples from patients with advanced phase CML that were resistant to TKIs or harboured an ABL1 mutation. Survival was also extended in a mouse model of primary TKI-resistant CML blast crisis. These data suggest that the DT-IL3 fusion proteins, SL-401 and SL-501, deplete CML stem cells and may increase the effectiveness of current CML treatment, which principally targets tumour bulk.
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Antineoplásicos/farmacología , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Receptores de Interleucina-3/efectos de los fármacos , Proteínas Recombinantes de Fusión/farmacología , Animales , Apoptosis/efectos de los fármacos , Benzamidas/farmacología , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos , Mesilato de Imatinib , Subunidad alfa del Receptor de Interleucina-3/metabolismo , Leucemia Mieloide de Fase Crónica/patología , Ratones Endogámicos NOD , Ratones SCID , Trasplante de Neoplasias , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Piperazinas/farmacología , Pirimidinas/farmacología , Trasplante Heterólogo , Células Tumorales CultivadasRESUMEN
The purpose of this study was to assess the efficacy and safety of bevacizumab plus cetuximab with or without gemcitabine in patients with advanced pancreatic adenocarcinoma. Patients with locally advanced or metastatic pancreatic adenocarcinoma, previously untreated, were randomized to bevacizumab (10 mg/kg q2w) plus cetuximab (400/250 mg/m(2) initial/weekly), either with (Arm A) or without (Arm B) gemcitabine (1000 mg/m(2) weekly × 3 of 4 weeks). Tumor assessments were performed q8w. Primary study endpoint was progression-free survival (PFS). Sixty-one patients were randomized to Arm A (n = 30) or Arm B (n = 31). Median treatment duration was 9 weeks in Arm A and 8 weeks in Arm B (range, 2.0-40.4). Patients in Arm A had median PFS and overall survival values of 3.55 months and 5.41 months, respectively, compared to 1.91 months and 4.17 months in Arm B. The study closed early due to lack of sufficient efficacy in both treatment arms. Although both regimens were well tolerated, patients treated with gemcitabine experienced more grade 3-4 toxicities, including proteinuria and thromboembolic events. The combination of cetuximab and bevacizumab did not result in promising activity with or without gemcitabine, suggesting that a strategy of dual EGFR/VEGF inhibition in pancreatic cancer does not warrant further development. To our knowledge, this is one of the first trials to evaluate a completely noncytotoxic regimen in the first-line treatment of advanced pancreatic cancer. (ClinicalTrials.gov number, NCT00326911).
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamiento farmacológico , Adenocarcinoma/complicaciones , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab , Cetuximab , Desoxicitidina/efectos adversos , Desoxicitidina/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Dolor/complicaciones , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/patología , Calidad de Vida , Resultado del Tratamiento , GemcitabinaRESUMEN
BACKGROUND: TAS-106 is a novel nucleoside analog that inhibits RNA polymerases I, II and II and has demonstrated robust antitumor activity in a wide range of models of human cancer in preclinical studies. This study was performed to principally evaluate the feasibility of administering TAS-106 as a bolus intravenous (IV) infusion every 3 weeks. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of TAS-106 as a single bolus IV infusion every 3 weeks. Plasma and urine sampling were performed during the first course to characterize the pharmacokinetic profile of TAS-106 and assess pharmacodynamic relationships. RESULTS: Thirty patients were treated with 66 courses of TAS-106 at eight dose levels ranging from 0.67-9.46 mg/m(2). A cumulative sensory peripheral neuropathy was the principal dose-limiting toxicity (DLT) of TAS-106 at the 6.31 mg/m(2) dose level, which was determined to be the maximum tolerated dose (MTD). Other mild-moderate drug-related toxicities include asthenia, anorexia, nausea, vomiting, myelosuppression, and dermatologic effects. Major objective antitumor responses were not observed. The pharmacokinetics of TAS-106 were dose-proportional. The terminal elimination half-life (t(1/2)) averaged 11.3 ± 3.3 h. Approximately 71% of TAS-106 was excreted in the urine as unchanged drug. Pharmacodynamic relationships were observed between neuropathy and: C(5min;) AUC(0-inf;) and dermatologic toxicity. CONCLUSIONS: The recommended phase II dose of TAS-106 is 4.21 mg/m(2). However, due to a cumulative drug-related peripheral sensory neuropathy that proved to be dose-limiting, further evaluation of this bolus every 21 day infusion schedule will not be pursued and instead, an alternate dosing schedule of TAS-106 administered as a continuous 24-hour infusion will be explored to decrease C(max) in efforts to minimize peripheral neuropathy and maximize antitumor activity.
Asunto(s)
Antineoplásicos/administración & dosificación , Citidina/análogos & derivados , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Neoplasias/tratamiento farmacológico , ARN Polimerasa III/antagonistas & inhibidores , ARN Polimerasa II/antagonistas & inhibidores , ARN Polimerasa I/antagonistas & inhibidores , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Área Bajo la Curva , Biotransformación , Citidina/administración & dosificación , Citidina/efectos adversos , Citidina/farmacocinética , Esquema de Medicación , Inhibidores Enzimáticos/efectos adversos , Estudios de Factibilidad , Femenino , Semivida , Humanos , Infusiones Intravenosas , Estimación de Kaplan-Meier , Masculino , Dosis Máxima Tolerada , Tasa de Depuración Metabólica , Persona de Mediana Edad , Neoplasias/enzimología , Neoplasias/genética , Neoplasias/patología , ARN Polimerasa I/metabolismo , ARN Polimerasa II/metabolismo , ARN Polimerasa III/metabolismo , Texas , Resultado del TratamientoRESUMEN
PURPOSE: Preclinical data suggest that the synthetic retinoid bexarotene may be an effective chemopreventive agent and that it may act synergistically in combination with platinum-based chemotherapy. The primary objective of this study was to determine whether repeated doses of bexarotene capsules affect pharmacokinetic parameters of paclitaxel or carboplatin in patients with advanced non-small cell lung cancer. METHODS: Patients received treatment with paclitaxel (200 mg/m(2)) and carboplatin to provide a target AUC of 6 mg min/mL (day 1) every 3 weeks. Continuous oral bexarotene therapy (400 mg/m(2)/day) was initiated on Day 4, and patients started lipid-lowering therapy prior to beginning chemotherapy. Blood sampling to characterize the pharmacokinetic profiles of the chemotherapeutic agents with or without bexarotene was performed during cycle 1 (without concomitant bexarotene) and during cycle 2 (with concomitant bexarotene). RESULTS: An analysis of drug concentration data from 16 patients indicated that bexarotene did not affect the pharmacokinetics of paclitaxel, free carboplatin, or total carboplatin concentrations. However, both maximal plasma concentrations and total exposure of bexarotene increased by 80% in the presence of paclitaxel-carboplatin by an, as of yet, unexplained mechanism. The toxicities observed resembled those of either the chemotherapy regimen or bexarotene alone, and there was no evidence for an enhancement of any drug-related toxicity with the combined treatment. CONCLUSIONS: The administration of bexarotene, paclitaxel, and carboplatin is feasible and safe; however, the increased bexarotene plasma concentrations and exposure warrant further investigation if this combination is to be utilized clinically.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Administración Oral , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bexaroteno , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Carboplatino/farmacocinética , Carboplatino/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Interacciones Farmacológicas , Femenino , Humanos , Hipolipemiantes/administración & dosificación , Hipolipemiantes/uso terapéutico , Infusiones Intravenosas , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Paclitaxel/farmacocinética , Paclitaxel/uso terapéutico , Receptores X Retinoide/agonistas , Tetrahidronaftalenos/administración & dosificación , Tetrahidronaftalenos/efectos adversos , Tetrahidronaftalenos/farmacocinética , Tetrahidronaftalenos/uso terapéuticoRESUMEN
PURPOSE: Bexarotene (Targretin(®) capsules) is a retinoid-X-receptor agonist and an inducer of CYP3A4-mediated metabolism. This phase I trial evaluated the pharmacokinetic (PK) and drug-drug interactions of bexarotene with chemotherapy and a lipid-lowering agent (atorvastatin or fenofibrate). This trial was run in parallel with phase III trials of the combinations to determine whether repeated doses of bexarotene capsules affect the pharmacokinetics (PK) of the chemotherapeutic or the lipid-lowering agents. METHODS: Patients (n = 48) with advanced non-small cell lung cancer were treated with repetitive cycles of either paclitaxel/carboplatin or cisplatin/vinorelbine chemotherapy, bexarotene (400 mg/m(2)/day) administered continuously starting on day 4 of chemotherapy, and a lipid-lowering drug, either atorvastatin or fenofibrate, starting at least 5 days before chemotherapy due to hypertriglyceridemia induced by bexarotene. Extensive plasma sampling to characterize the PK profiles of the lipid-lowering drugs, relevant chemotherapy agents was performed on day 1 (without bexarotene) and during chemotherapy cycles 2 or 3 (with bexarotene). RESULTS: Here, we report the drug-drug interactions between the lipid-lowering agents and bexarotene. Mean atorvastatin clearance and dose-corrected AUC values were reduced by nearly 50% with the addition of concomitant bexarotene. As fenofibrate was less effective at controlling hypertriglyceridemia, too few patients received this agent to make any meaningful conclusions about drug-drug interactions. CONCLUSIONS: A drug-drug interaction was seen in this trial with bexarotene co-administration leading to a significant reduction in the AUC of atorvastatin. The likely mechanism for this interaction is through induction of CYP3A4 by bexarotene given the role of this enzyme in the metabolism of atorvastatin. Knowledge of this interaction is important for optimizing lipid management with atorvastatin for patients receiving bexarotene.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/metabolismo , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Área Bajo la Curva , Atorvastatina , Bexaroteno , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Esquema de Medicación , Interacciones Farmacológicas , Femenino , Ácidos Heptanoicos/administración & dosificación , Ácidos Heptanoicos/efectos adversos , Ácidos Heptanoicos/farmacocinética , Humanos , Hipercolesterolemia/inducido químicamente , Hipertrigliceridemia/inducido químicamente , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Pirroles/administración & dosificación , Pirroles/efectos adversos , Pirroles/farmacocinética , Tetrahidronaftalenos/administración & dosificación , Tetrahidronaftalenos/efectos adversos , Tetrahidronaftalenos/farmacocinética , Resultado del TratamientoRESUMEN
Insulin-like growth factor type-1 receptor (IGF-1R) plays a central role in cell proliferation and survival and is overexpressed in many tumor types. Notably, IGF-1R-mediated signaling confers resistance to diverse cytotoxic, hormonal, and biologic agents, suggesting that therapies targeting IGF-1R may be effective against a broad range of human malignancies. Cixutumumab (IMC-A12; ImClone Systems) is a fully human immunoglobulin G1 (IgG1) monoclonal antibody that specifically inhibits IGF-1R signaling. Binding of cixutumumab to IGF-1R results in receptor internalization and degradation. Because cixutumumab is an IgG1 monoclonal antibody, it may induce additional cytotoxicity via immune effector mechanisms such as antibody-dependent cellular cytotoxicity. In preclinical studies, cixutumumab monotherapy resulted in growth inhibition of multiple experimental cancers. Moreover, cixutumumab safely enhanced the tumor growth inhibitory and cytotoxic effects of a broad range of chemotherapeutics, and modulated the action of agents that target hormone receptors and signal transduction, which may have implications for cancer therapy. Herein, we review published preclinical and clinical data for cixutumumab and provide a comprehensive overview of selected clinical studies.
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Anticuerpos Monoclonales/farmacología , Neoplasias/tratamiento farmacológico , Receptor IGF Tipo 1/antagonistas & inhibidores , Animales , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Resistencia a Antineoplásicos , Humanos , Factor I del Crecimiento Similar a la Insulina/fisiologíaRESUMEN
PURPOSE: This phase I study was conducted to characterize the safety profile, pharmacokinetics, pharmacodynamics, dose-limiting toxicity (DLT), and the maximum-tolerated dose of E7820, a novel oral sulfonamide derivative with antiangiogenic properties, when administered to patients with advanced solid malignancies. PATIENTS AND METHODS: Patients received single daily doses of E7820 orally for 28 days in cycle 1, followed by a 7-day no-treatment period, after which time-uninterrupted daily dosing ensued. The starting dose of E7820 was 10 mg/d, which was increased to 20, 40, 70, 100, and 200 mg/d in cohorts of new patients. RESULTS: Thirty-seven patients [21 male; median age 65 (40-82] were enrolled. At 100 mg/d, 1 patient experienced a DLT consisting of grade 3 neutropenia, thrombocytopenia, and elevated liver enzymes. At the 200-mg dose level, 2 patients experienced grade 4 thrombocytopenia and neutropenia. No partial or complete responses were observed; 8 patients had stable disease (≥ 4 months), including 5 patients with protracted stable disease exceeding 6 months. Mean time to maximum plasma concentration values ranged from 1 to 12 hours, whereas mean terminal half-life values ranged from 5.6 to 8.6 hours. Flow cytometric analysis of platelet integrin α-2 expression showed a sustained greater than 50% decrease beyond day 28 in 3 of 4 patients at 200 mg, whereas moderate (<30%) decreases were observed at 70- and 100-mg dose levels. CONCLUSIONS: The recommended phase II dose of E7820 is 100 mg/d, based on a fasting schedule. E7820 downregulates integrin α-2 expression in surrogate tissues (platelets) and is associated with stable disease in a wide variety of heavily pretreated malignancies.
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Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/farmacología , Indoles/farmacología , Indoles/uso terapéutico , Integrina alfa2/genética , Neoplasias/tratamiento farmacológico , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Indoles/administración & dosificación , Indoles/efectos adversos , Integrina alfa2/biosíntesis , Integrina alfa2/sangre , Integrina alfa2/metabolismo , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias/genética , Neoplasias/metabolismo , Neutropenia/tratamiento farmacológico , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Trombocitopenia/tratamiento farmacológico , Resultado del TratamientoRESUMEN
PURPOSE: To evaluate the antitumor activity of SP1049C, a novel P-glycoprotein targeting micellar formulation of doxorubicin, consisting of doxorubicin and two non-ionic block copolymers (pluronics), in patients with advanced adenocarcinoma of the esophagus and gastroesophageal junction (GEJ). PATIENTS AND METHODS: Patients with metastatic or locally advanced unresectable adenocarcinoma of the esophagus or GEJ who had not previously received systemic chemotherapy and had measurable disease were treated with SP1049C 75 mg/m(2) (doxorubicin equivalents) as a brief intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate in patients who had received a least one course of SP1049C and had undergone tumor assessment, whereas, secondary endpoints included the objective response rate, progression-free survival (PFS), overall survival, and safety in the intent-to-treat (ITT) population. A review of scans was also conducted post-hoc by a blinded panel of radiologists. RESULTS: Twenty-one patients, of which 19 were evaluable for response, were treated with at least one dose of SP1049C. Nine patients had a partial response (PR) and eight patients had either a minor response or stable disease as their best response. The objective response rate was 47% (95% CI: 24.4-71) in the evaluable patient population, whereas the objective response rate was 43% (95% CI: 21.8-65.9) in the ITT population. The post-hoc radiological review confirmed that all nine responders had a PR; seven of the nine had a PR that was confirmed by a subsequent scan, whilst two patients had unconfirmed PRs. The median overall survival and PFS were 10.0 months (95%CI: 4.8-11.2) and 6.6 months (95% CI: 4.5-7.6), respectively. Neutropenia was the principal toxicity of SP1049C. Four patients developed an absolute percentage decrement of at least 15% in their left ventricular ejection fraction, none of which decreased to below 45% nor were symptomatic. CONCLUSION: SP1049C has a notable single-agent activity in patients with adenocarcinoma of the esophagus and GEJ, as well as an acceptable safety profile. These results, in addition to the results of preclinical studies demonstrating superior antitumor activity of SP1049C compared with doxorubicin in a standard formulation, indicate that further evaluations of SP1049C alone or combined with other relevant therapeutics in this disease setting are warranted.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Adenocarcinoma/tratamiento farmacológico , Doxorrubicina/análogos & derivados , Doxorrubicina/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Unión Esofagogástrica/patología , Poloxámero/análogos & derivados , Poloxámero/uso terapéutico , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Adenocarcinoma/patología , Adenocarcinoma/fisiopatología , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Doxorrubicina/efectos adversos , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/fisiopatología , Unión Esofagogástrica/fisiopatología , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Estadificación de Neoplasias , Poloxámero/efectos adversos , Volumen SistólicoRESUMEN
PURPOSE: To determine antitumor activity of cetuximab monotherapy in patients with refractory metastatic colorectal carcinoma (mCRC) with lack of specific membrane immunostaining for the epidermal growth factor receptor (EGFR). PATIENTS AND METHODS: Patients had immunohistochemical (IHC)-determined mCRC with absent EGFR immunostaining that progressed after receiving at least one standard, fluoropyrimidine-containing chemotherapeutic regimen. Absent EGFR immunostaining was defined as the IHC absence of specific membrane staining in ≥500 cancer cells examined in well-preserved tissue. The study was performed prior to results of studies linking cetuximab sensitivity to K-ras mutation status. Patients received 400 mg/m(2) of intravenous (i.v.) cetuximab followed by once-weekly i.v. cetuximab 250 mg/m(2) until disease progression or unacceptable toxicity. Patients were evaluated for objective response at least every 6 weeks. Kaplan-Meier estimates were calculated for duration of response, time to progression (TTP), and overall survival (OS). RESULTS: Seven (8.2%) of 85 mCRC patients whose tumors lacked EGFR immunostaining had major responses following cetuximab treatment. The median duration of response was 5.1 months. Median TTP and OS were 2.5 months and 10.0 months, respectively; the 1-year survival rate was 39.6%. The most frequently reported cetuximab-related adverse events were acneiform dermatitis, fatigue, headache, and dry skin. CONCLUSION: Cetuximab monotherapy produces objective antitumor activity in patients with mCRC that does not express EGFR as determined by IHC. The activity and safety profiles of cetuximab monotherapy in mCRC lacking EGFR immunostaining are similar to previous observations in EGFR IHC-positive disease that was not selected based on K-ras mutation status.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Resistencia a Antineoplásicos , Receptores ErbB/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Antineoplásicos/efectos adversos , Cetuximab , Neoplasias Colorrectales/enzimología , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Factores de Tiempo , Resultado del TratamientoRESUMEN
AIM: Phase II multi-disease randomized discontinuation trial to assess the safety and efficacy of sorafenib including patients with advanced soft tissue sarcoma (STS). METHODS: Sorafenib (400 mg twice daily) was initially administered for 12 weeks. Patients with: ≥25% tumour shrinkage continued sorafenib; ≥25% tumour growth discontinued; other patients were randomized and received sorafenib or placebo. RESULTS: Twenty-six patients (median age 55 years) were enrolled. Common drug-related adverse events, including fatigue, hand-foot skin reaction, rash or gastrointestinal disturbances, were manageable, reversible and generally low grade. Fatigue, skin toxicity, nausea, diarrhoea and hypertension occurred at grade ≥3 in 19% of patients. After 12 weeks eight (31%) patients had not progressed. Three patients who experienced tumour shrinkage and continued on sorafenib, and five (19%) were randomized either to continue sorafenib or to receive placebo. Of the three patients randomized to sorafenib, one achieved a partial response and two had SD. Overall one patient achieved a partial response and three further patients achieved minor responses. CONCLUSIONS: There was evidence of disease activity in STS as defined by tumor regressions including one objective partial response. Further investigation in STS is warranted.
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Bencenosulfonatos/uso terapéutico , Piridinas/uso terapéutico , Sarcoma/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Bencenosulfonatos/efectos adversos , Demografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piridinas/efectos adversos , Sarcoma/diagnóstico por imagen , Neoplasias de los Tejidos Blandos/diagnóstico por imagen , Sorafenib , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: The insulin-like growth factor 1 (IGF1) signaling pathway is an important growth-regulatory pathway, which plays a crucial role in colorectal cancer (CRC) proliferation, differentiation, migration, angiogenesis, and apoptosis. Previous studies showed that hyperactivation of the IGF1 receptor (IGF1R) may result in resistance to anti-epidermal growth factor receptor-targeted treatment. We tested whether germline variations within the IGF1 pathway are associated with clinical outcome in wild-type (wt) KRAS drug-refractory metastatic CRC (mCRC) patients who were treated with cetuximab monotherapy (IMC-0144). EXPERIMENTAL DESIGN: Formalin-fixed, paraffin-embedded (FFPE) tissue samples of 130 drug-refractory mCRC patients enrolled in IMC-0144, a phase II clinical trial of cetuximab monotherapy, were analyzed. gDNA was extracted from dissected FFPE tumor tissue, and KRAS mutation status and six potentially functional IGF1 and IGF1R polymorphisms were analyzed using direct DNA sequencing or PCR-RFLP. Tumor response analysis was based on recursive partitioning, and survival analyses were based on univariate and multivariate hazard regression models. RESULTS: In univariate and multivariate analyses, five IGF pathway single-nucleotide polymorphisms were significantly associated with progression-free survival (PFS) and/or overall survival (OS). In multivariate combined risk allele analysis, the additive model for PFS and OS was significantly associated with the number of risk alleles in wt KRAS patients (P = 0.001 and P = 0.02, respectively). In addition, wt KRAS patients harboring IGF1 rs2946834 A/A genotype had a 50% objective response rate compared with 0% for A/G genotype. CONCLUSIONS: These results indicate that IGF1 pathway polymorphisms are potential predictive/prognostic molecular markers for cetuximab efficacy in wt KRAS mCRC patients. Prospective biomarker-embedded clinical trials are warranted to validate our findings. Clin Cancer Res; 16(22); 5591-602. ©2010 AACR.
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Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Polimorfismo de Nucleótido Simple/genética , Proteínas Proto-Oncogénicas , Transducción de Señal/genética , Proteínas ras , Anciano , Anticuerpos Monoclonales Humanizados , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Cetuximab , Neoplasias Colorrectales/patología , Pruebas Genéticas , Mutación de Línea Germinal/genética , Humanos , Persona de Mediana Edad , Análisis Multivariante , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas p21(ras) , Proteínas ras/genéticaRESUMEN
INTRODUCTION: EGFR inhibitors (EGFRIs) have been shown to be clinically effective in various cancers. Unique skin toxicity is commonly observed with EGFRIs and a correlation between the clinical benefit of EGFRIs and this characteristic rash has been reported. Erlotinib is a potent EGFRI approved for treatment of non-small cell lung cancer (NSCLC) and pancreatic cancer. METHODS: This is the first time in which patients were given increasing doses of an EGFRI to induce a mechanistic rash and study its associated pathology in skin. Biopsies were collected during treatment from both rash-affected and unaffected skin of 23 NSCLC patients and compared with pre-treatment biopsies. RESULTS: Altered differentiation of appendegeal epithelium (hair follicles and sebaceous glands) was remarkable in both affected and unaffected skin, although epidermal growth was not significantly reduced. A predominantly mononuclear leucocyte infiltrate was detected in the interfollicular dermis or around skin appendages. This infiltrate included TRAIL-positive cells with a dendritic cell (DC) morphology, although T-cells, antigen-presenting DCs and macrophages were also evident. This is the first report showing the involvement of a dendritic cell subtype with EGFRI skin toxicity. CONCLUSIONS: Altered differentiation of pilosebaceous epithelium is evident in both rash-affected and unaffected skin and constitutes the primary process of EGFRI in human skin. We propose that this eventually triggers inflammation and the EGFRI rash. TRAIL-positive inflammatory cells could link rash development and immune-triggered apoptosis of epithelial cells, including those of underlying carcinomas.
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Antineoplásicos/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Erupciones por Medicamentos/patología , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/efectos adversos , Piel/patología , Adulto , Anciano , Antineoplásicos/administración & dosificación , Apoptosis , Biopsia con Aguja , Dendritas/patología , Relación Dosis-Respuesta a Droga , Erupciones por Medicamentos/etiología , Clorhidrato de Erlotinib , Exantema/inducido químicamente , Exantema/patología , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Quinazolinas/administración & dosificaciónRESUMEN
PURPOSE: This phase I study evaluated the feasibility, safety, pharmacokinetics (PK), and preliminary evidence of anticancer activity of the sequential administration of paclitaxel and trabectedin on an every-2-week schedule in patients with refractory solid malignancies. The study also sought to determine the maximum tolerated dose (MTD) level on this schedule, as well as to recommend doses for disease-directed studies. EXPERIMENTAL DESIGN: Twenty-seven patients were treated with paclitaxel (80-120 mg/m(2); 1-hour i.v. infusion, day 1) and trabectedin (0.525-0.775 mg/m(2); 3-hour i.v. infusion, day 2) with doses increased in successive cohorts. Blood sampling for PK and drug-drug interaction studies was done. RESULTS: Neutropenia, which resulted in treatment delay exceeding 1 week, was the principal dose-limiting toxicity for this paclitaxel-trabectedin regimen and precluded dose escalation above 120 mg/m(2) paclitaxel and 0.650 mg/m(2) trabectedin. At the MTD (120 mg/m(2) paclitaxel and 0.650 mg/m(2) trabectedin), the safety profile was favorable in patients receiving cumulative treatment. Relevant drug-drug PK interactions between paclitaxel and trabectedin were not identified. A patient with soft tissue sarcoma had a complete response and several patients with various refractory solid malignancies showed protracted stable disease as their best response. CONCLUSIONS: The MTD level of sequential paclitaxel 1-hour infusion (day 1) and trabectedin 3-hour infusion (day 2) administered every 2 weeks is 120 and 0.650 mg/m(2), respectively. The manageable toxicities at the MTD, preliminary evidence of antitumor activity, and lack of notable PK drug-drug interactions warrant further disease-directed studies of this regimen in relevant tumor types and settings.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anemia/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Bajo la Curva , Dioxoles/administración & dosificación , Dioxoles/efectos adversos , Dioxoles/farmacocinética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Resistencia a Antineoplásicos , Fatiga/inducido químicamente , Estudios de Factibilidad , Femenino , Humanos , Infusiones Intravenosas , Leucopenia/inducido químicamente , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Neoplasias/metabolismo , Neoplasias/patología , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Paclitaxel/farmacocinética , Tetrahidroisoquinolinas/administración & dosificación , Tetrahidroisoquinolinas/efectos adversos , Tetrahidroisoquinolinas/farmacocinética , Trabectedina , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: This study aimed to determine a maximum tolerated dose (MTD) and recommended dose for disease-directed studies of necitumumab (IMC-11F8), a fully human IgG(1) monoclonal antibody directed at the epidermal growth factor receptor, and to characterize the safety profile, pharmacokinetics, preliminary antitumor activity, and immunogenicity of necitumumab. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were treated with 100 to 1,000 mg (flat dosing) necitumumab followed by a 2-week pharmacokinetics sampling period, before beginning 6-week cycles of therapy. RESULTS: Sixty patients received necitumumab weekly (29 patients) or every other week (31 patients). Two patients receiving 1,000 mg every 2 weeks experienced dose-limiting toxicities (DLT; grade 3 headache), accompanied by grade 3 nausea and vomiting in one patient. Occurring hours after the initial dose, these DLTs established 800 mg as the MTD. Mild dose-related skin toxicity was the most common drug-related toxicity (80%). One patient in each arm experienced grade 3 acneform rash, which responded to oral antibiotics and topical therapy. Toxicity was similar on both schedules. Necitumumab exhibited saturable elimination and nonlinear pharmacokinetics. At 800 mg (both arms), its half-life was approximately 7 days. All patients treated with >or=600 mg necitumumab achieved target trough concentrations (>or=40 microg/mL). Antibodies against necitumumab were not detected. Partial response and stable disease were experienced by 2 and 16 patients, respectively. CONCLUSION: Well tolerated, necitumumab is associated with preliminary evidence of antitumor activity, and achieves biologically relevant concentrations throughout the dosing period. The recommended dose of necitumumab for further clinical development is 800 mg (flat dose) weekly or every 2 weeks based on the clinical setting.
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Anticuerpos Monoclonales/uso terapéutico , Receptores ErbB/inmunología , Neoplasias/inmunología , Neoplasias/terapia , Adulto , Anciano , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales Humanizados , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/patología , Tasa de Supervivencia , Distribución Tisular , Resultado del TratamientoRESUMEN
A large body of evidence suggests that the platelet-derived growth factor (PDGF) family and associated receptors are potential targets in oncology therapeutic development because of their critical roles in the proliferation and survival of various cancers and in the regulation and growth of the tumor stroma and blood vessels. Several small molecules that nonspecifically target the PDGF signaling axis are in current use or development as anticancer therapies. However, for the majority of these agents, PDGF and its receptors are neither the primary targets nor the principal mediators of anticancer activity. IMC-3G3, a fully human monoclonal antibody of the immunoglobulin G subclass 1, specifically binds to the human PDGF receptor alpha (PDGFRalpha) with high affinity and blocks PDGF ligand binding and PDGFRalpha activation. The results of preclinical studies and the frequent expression of PDGFRalpha in many types of cancer and in cancer-associated stroma support a rationale for the clinical development of IMC-3G3. Currently, IMC-3G3 is being evaluated in early clinical development for patients with several types of solid malignancies.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Animales , Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Humanos , Inmunoglobulina G/uso terapéutico , Ratones , Neovascularización Patológica/tratamiento farmacológico , Receptores del Factor de Crecimiento Derivado de Plaquetas/inmunología , Receptores del Factor de Crecimiento Derivado de Plaquetas/fisiologíaRESUMEN
FMS-related tyrosine kinase receptor 3 (FLT3) is a class III receptor tyrosine kinase that holds considerable promise as a therapeutic target in hematologic malignancies. Current efforts directed toward the development of small-molecule tyrosine kinase inhibitors of FLT3 may be limited by off-target toxicities and the development of drug resistance. Target-specific antibodies could overcome these hurdles and provide additional mechanisms to enhance the antitumor efficacy of FLT3 inhibitors. IMC-EB10 is a novel antibody directed against FLT3. The binding of IMC-EB10 to FLT3 results in antiproliferative effects in vitro and in mouse models engrafted with human leukemia cells that harbor wild-type or constitutively activated FLT3. Future clinical trials will test these notions formally and will identify the most appropriate opportunities for this member of a new generation of antileukemic therapies.