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Immune checkpoint inhibitors targeting PD-1/L1 have modest efficacy in hepatocellular carcinoma as single agents. Targeting membranous phosphatidylserine may induce pro-inflammatory and -immune stimulating effects that enhance immunotherapy activity. This hypothesis was tested in a single-arm phase 2 trial evaluating frontline bavituximab, a phosphatidylserine targeting antibody, plus pembrolizumab (anti-PD-1) in patients with unresectable hepatocellular carcinoma (NCT03519997). The primary endpoint was investigator-assessed objective response rate among evaluable patients, and secondary end points included progression-free survival, incidence of adverse events, overall survival, and duration of response. Among 28 evaluable patients, the confirmed response rate was 32.1%, which met the pre-specified endpoint, and the median progression-free survival was 6.3 months (95% CI, 1.3-11.3 months). Treatment related-adverse events of any grade occurred in 45.7% of patients, with grade 3 or greater adverse events in 14.3% of patients. Adverse events of any cause were observed in 33 patients (94.3%), with grade 3 or greater adverse events in 11 patients (31.4%). Prespecified exploratory analyses of baseline tumor specimens showed that a depletion of B cells, and the presence of fibrotic tissue and expression of immune checkpoints in stroma was associated with tumor response. These results suggest that targeting phosphatidylserine may lead to synergistic effects with PD-1 blockade without increasing toxicity rates, and future studies on this therapeutic strategy may be guided by biomarkers characterizing the pre-treatment tumor microenvironment.
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Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Fosfatidilserinas , Receptor de Muerte Celular Programada 1 , Neoplasias Hepáticas/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Microambiente TumoralRESUMEN
PURPOSE: This phase Ib study evaluated the safety and efficacy of paclitaxel plus navicixizumab, a bispecific antiangiogenic antibody to vascular endothelial growth factor and delta-like ligand 4, against platinum-resistant ovarian cancer. PATIENTS AND METHODS: This open-label, nonrandomized, dose-escalation and -expansion study included 44 patients with previously treated, recurrent, platinum-resistant grade 2/3 ovarian cancer. Treatment was intravenous navicixizumab (3 mg/kg or 4 mg/kg once every 2 weeks) plus paclitaxel (80 mg/m2 intravenously on days 0, 7, and 14 of 28-day cycles). The primary and secondary objectives were to evaluate the safety and efficacy of navicixizumab plus paclitaxel. An RNA-based diagnostic panel was retrospectively used to test the hypothesis that tumors with high angiogenesis or immune-suppressed tumor microenvironment (TME) subtypes (biomarker-positive) are more likely to respond to navicixizumab than those with immune-active/-desert TME subtypes (biomarker-negative). RNA expression was analyzed in available pretreatment tumor tissue to classify 33 patients' TME subtypes, and TME panel findings were correlated with tumor response. RESULTS: The dose-escalation cohorts enrolled patients at navicixizumab doses of 3 mg/kg once every 2 weeks (n = 3) and 4 mg/kg once every 2 weeks (n = 2); 3 mg/kg was selected for expansion (n = 39). No dose-limiting toxicities occurred. The most common grade 3/4 treatment-related adverse events were hypertension (40.9%), neutropenia (6.8%), and thrombocytopenia (4.5%). Pulmonary hypertension occurred in 18.2% (grade 1-2). The overall objective response rate was 43.2% (95% CI, 28.3 to 59.0): 33.3% (95% CI, 17.3 to 52.8) in patients previously treated with bevacizumab, 64.3% (95% CI, 35.1 to 87.2) in bevacizumab-naive patients, and 62% (95% CI, 31.6 to 86.1) in biomarker-positive patients. The median duration of response was 6 months (95% CI, 5.4 months to not estimable). CONCLUSION: Navicixizumab plus paclitaxel demonstrated promising clinical activity in bevacizumab-treated and -naive patients with platinum-resistant ovarian cancer, with manageable toxicity.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de las Trompas Uterinas , Neoplasias Ováricas , Anticuerpos Biespecíficos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/uso terapéutico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Neoplasias de las Trompas Uterinas/tratamiento farmacológico , Femenino , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Paclitaxel , Platino (Metal)/uso terapéutico , ARN/uso terapéutico , Estudios Retrospectivos , Microambiente Tumoral , Factor A de Crecimiento Endotelial VascularRESUMEN
PURPOSE: Although chemotherapy is standard of care for metastatic colorectal cancer (mCRC), immunotherapy has no role in microsatellite stable (MSS) mCRC, a "cold" tumor. PolyPEPI1018 is an off-the-shelf, multi-peptide vaccine derived from 7 tumor-associated antigens (TAA) frequently expressed in mCRC. This study assessed PolyPEPI1018 combined with first-line maintenance therapy in patients with MSS mCRC. PATIENTS AND METHODS: Eleven patients with MSS mCRC received PolyPEPI1018 and Montanide ISA51VG adjuvant subcutaneously, combined with fluoropyrimidine/biologic following first-line induction with chemotherapy and a biologic (NCT03391232). In Part A of the study, 5 patients received a single dose; in Part B, 6 patients received up to three doses of PolyPEPI1018 every 12 weeks. The primary objective was safety; secondary objectives were preliminary efficacy, immunogenicity at peripheral and tumor level, and immune correlates. RESULTS: PolyPEPI1018 vaccination was safe and well tolerated. No vaccine-related serious adverse event occurred. Eighty percent of patients had CD8+ T-cell responses against ≥3 TAAs. Increased density of tumor-infiltrating lymphocytes were detected post-treatment for 3 of 4 patients' liver biopsies, combined with increased expression of immune-related gene signatures. Three patients had objective response according to RECISTv1.1, and 2 patients qualified for curative surgery. Longer median progression-free survival for patients receiving multiple doses compared with a single dose (12.5 vs. 4.6 months; P = 0.017) suggested a dose-efficacy correlation. The host HLA genotype predicted multi-antigen-specific T-cell responses (P = 0.01) indicative of clinical outcome. CONCLUSIONS: PolyPEPI1018 added to maintenance chemotherapy for patients with unresectable, MSS mCRC was safe and associated with specific immune responses and antitumor activity warranting further confirmation in a randomized, controlled setting.
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Productos Biológicos , Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Productos Biológicos/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Humanos , Aceite Mineral , Neoplasias del Recto/etiología , Vacunas de SubunidadRESUMEN
PURPOSE: In the phase III DUO trial, duvelisib, an oral dual PI3K-δ,γ inhibitor, demonstrated significantly improved efficacy versus ofatumumab [median (m) progression-free survival (PFS), 13.3 vs. 9.9 months (HR, 0.52; P < 0.0001); overall response rate [ORR], 74% vs. 45% (P < 0.0001)], with a manageable safety profile in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). We report results from patients with progressive disease (PD) after ofatumumab who crossed over to duvelisib in the DUO trial. PATIENTS AND METHODS: Patients with radiographically confirmed PD after ofatumumab received duvelisib 25 mg twice daily in 28-day cycles until PD, intolerance, death, or study withdrawal. The primary endpoint was ORR per investigator. Secondary endpoints included duration of response (DOR), PFS, and safety. RESULTS: As of December 14, 2018, 90 ofatumumab-treated patients in the DUO trial prior to crossover had an ORR of 29%, mDOR of 10.4 months, and mPFS of 9.4 months. After crossover, 77% of patients (69/90) achieved a response, with an mDOR of 14.9 months and mPFS of 15.7 months. Patients with del(17p) and/or TP53 mutations had similar outcomes [ORR, 77% (20/26); mPFS, 14.7 months]. Notably, 73% of patients (47/64) with disease previously refractory to ofatumumab achieved a response. The most frequent any-grade/grade 3/4 treatment-emergent adverse events were diarrhea (47%/23%), neutropenia (26%/23%), pyrexia (24%/4%), cutaneous reactions (23%/4%), and thrombocytopenia (10%/6%). CONCLUSIONS: Duvelisib demonstrated high response rates with good durability and a manageable safety profile in patients with R/R CLL/SLL who progressed on ofatumumab, including patients with high-risk disease and disease previously refractory to ofatumumab.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Fosfatidilinositol 3-Quinasa Clase Ib/metabolismo , Estudios Cruzados , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Femenino , Humanos , Isoquinolinas/administración & dosificación , Isoquinolinas/efectos adversos , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Purinas/administración & dosificación , Purinas/efectos adversos , Terapia Recuperativa , Tasa de SupervivenciaRESUMEN
Importance: Preferential delivery of docetaxel to tumors by prostate-specific membrane antigen (PSMA)-targeted nanoparticles is clinically effective, and the selective reduction of PSMA-positive circulating tumor cells (CTCs) after treatment has implications for patient selection and disease monitoring. Objective: To determine the safety and efficacy of BIND-014, a PSMA-directed docetaxel-containing nanoparticle, in patients with metastatic castration-resistant prostate cancer (mCRPC). Design, Setting, and Participants: A multicenter open-label, phase 2 clinical trial of 42 chemotherapy-naive patients with progressing mCRPC after treatment with abiraterone acetate and/or enzalutamide was conducted from June 24, 2013, to June 10, 2016. Intervention: Treatment with BIND-014 at a dosage of 60 mg/m2 was given intravenously on day 1 of 21-day cycles in combination with prednisone until disease progression or unacceptable toxic effects occurred. Main Outcomes and Measures: The primary end point was radiographic progression-free survival according to Prostate Cancer Working Group 2 recommendations and Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included prostate-specific antigen (PSA) response (≥50% reduction from baseline) and changes in CTC number (from ≥5 to <5 cells per 7.5 mL of blood) (CellSearch). Changes in CTC number based on PSMA expression levels on CTCs were also evaluated (Epic Sciences). Results: Among the 42 patients (81% white), the median age was 66 (range, 50-85) years, and median number of doses received was 6 (range, 1-21). A PSA response was observed in 12 of 40 patients (30%; 95% CI, 18%-45%), measurable disease response in 6 of 19 (32% [95% CI, 15%-54%]), and CTC conversions in 13 of 26 (50%; 95% CI, 32%-68%). Median radiographic progression-free survival was 9.9 (95% CI, 7.1-12.6) months. With use of the Epic Sciences non-EPCAM-based CTC detection platform, CTCs were detected in 16 of 18 patients (89%); 11 of 18 (61%) had CTCs with PSMA expression above the analytical threshold level (PSMA positive) at baseline (range, 0.4-72.4 CTCs/mL). After treatment, PSMA-positive CTCs were preferentially reduced. Treatment-related adverse events included grade 1 or 2 fatigue (29 of 42 patients [69%]), nausea (23 [55%]), neuropathy (14 [33%]), and neutropenic fever (1 [2%]). Conclusions and Relevance: These findings suggest that treatment with BIND-014 is active and well tolerated in patients with chemotherapy-naive mCRPC. Antitumor activity may be related to PSMA expression levels on CTCs, which suggests that patients who are likely to benefit from this treatment can be identified before treatment is initiated. Trial Registration: ClinicalTrials.gov Identifier: NCT01812746.
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Docetaxel/uso terapéutico , Nanopartículas/uso terapéutico , Antígeno Prostático Específico/antagonistas & inhibidores , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Diarrea/inducido químicamente , Supervivencia sin Enfermedad , Docetaxel/efectos adversos , Fatiga/inducido químicamente , Humanos , Masculino , Persona de Mediana Edad , Nanopartículas/efectos adversos , Náusea/inducido químicamente , Metástasis de la Neoplasia , Antígeno Prostático Específico/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Resultado del TratamientoRESUMEN
Advancing nanomedicines from concept to clinic requires integration of new science with traditional pharmaceutical development. The medical and commercial success of nanomedicines is greatly facilitated when those charged with developing nanomedicines are cognizant of the unique opportunities and technical challenges that these products present. These individuals must also be knowledgeable about the processes of clinical and product development, including regulatory considerations, to maximize the odds for successful product registration. This article outlines these topics with a goal to accelerate the combination of academic innovation with collaborative industrial scientists who understand pharmaceutical development and regulatory approval requirements-only together can they realize the full potential of nanomedicines for patients.
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Productos Biológicos , Aprobación de Drogas , Nanomedicina/tendencias , Nanopartículas , Animales , Productos Biológicos/uso terapéutico , Sistemas de Liberación de Medicamentos/tendencias , Industria Farmacéutica/legislación & jurisprudencia , Industria Farmacéutica/tendencias , Humanos , Nanomedicina/legislación & jurisprudencia , Nanopartículas/administración & dosificaciónRESUMEN
PURPOSE: First-in-human phase I trial to determine the safety, pharmacokinetics, and antitumor activity of BIND-014, a novel, tumor prostate-specific membrane antigen (PSMA)-targeted nanoparticle, containing docetaxel. EXPERIMENTAL DESIGN: Patients with advanced solid tumors received BIND-014 every three weeks (n = 28) or weekly (n = 27), with dose levels ranging from 3.5 to 75 mg/m(2) and 15 to 45 mg/m(2), respectively. RESULTS: BIND-014 was generally well tolerated, with no unexpected toxicities. The most common drug-related toxicities (>20% of patients) on either schedule included neutropenia, fatigue, anemia, alopecia, and diarrhea. BIND-014 demonstrated a dose-linear pharmacokinetic profile, distinct from docetaxel, with prolonged persistence of docetaxel-encapsulated circulating nanoparticles. Of the 52 patients evaluable for response, one had a complete response (cervical cancer on the every three week schedule) and five had partial responses (ampullary adenocarcinoma, non-small cell lung, and prostate cancers on the every-three-week schedule, and breast and gastroesophageal cancers on the weekly schedule). Responses were noted in both PSMA-detectable and -undetectable tumors. CONCLUSIONS: BIND-014 was generally well tolerated, with predictable and manageable toxicity and a unique pharmacokinetic profile compared with conventional docetaxel. Clinical activity was noted in multiple tumor types. The recommended phase II dose of BIND-014 is 60 mg/m(2) every three weeks or 40 mg/m(2) weekly. Clin Cancer Res; 22(13); 3157-63. ©2016 AACR.
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Portadores de Fármacos/farmacocinética , Portadores de Fármacos/uso terapéutico , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Nanopartículas/uso terapéutico , Neoplasias/tratamiento farmacológico , Taxoides/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antígenos de Superficie , Docetaxel , Esquema de Medicación , Portadores de Fármacos/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nanopartículas/efectos adversos , Neoplasias/patologíaRESUMEN
PURPOSE: This phase II trial evaluated the efficacy and safety of cixutumumab, a human anti-insulin-like growth factor receptor 1 (IGF-1R) monoclonal IgG1 antibody, and explored potential biomarkers in postmenopausal women with hormone receptor-positive breast cancer. EXPERIMENTAL DESIGN: Patients with hormone receptor-positive breast cancer that progressed on antiestrogen therapy received (2:1 randomization) cixutumumab 10 mg/kg and the same antiestrogen (arm A) or cixutumumab alone (arm B) every 2 weeks (q2w). Primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS) and safety. Correlative analyses of IGF-1R, total insulin receptor (IR), and IR isoforms A (IR-A) and B (IR-B) expression in tumor tissue were explored. RESULTS: Ninety-three patients were randomized (arm A, n = 62; arm B, n = 31). Median PFS was 2.0 and 3.1 months for arm A and arm B, respectively. Secondary efficacy measures were similar between the arms. Overall, cixutumumab was well tolerated. IGF-1R expression was not associated with clinical outcomes. Regardless of the treatment, lower IR-A, IR-B, and total IR mRNA expression in tumor tissue was significantly associated with longer PFS [IR-A: HR, 2.62 (P = 0.0062); IR-B: HR, 2.21 (P = 0.0202); and total IR: HR, 2.18 (P = 0.0230)] and OS [IR-A: HR, 2.94 (P = 0.0156); IR-B: HR, 2.69 (P = 0.0245); and total IR: HR, 2.72 (P = 0.0231)]. CONCLUSIONS: Cixutumumab (10 mg/kg) with or without antiestrogen q2w had an acceptable safety profile, but no significant clinical efficacy. Patients with low total IR, IR-A, and IR-B mRNA expression levels had significantly longer PFS and OS, independent of the treatment. The prognostic or predictive value of IR as a biomarker for IGF-1R-targeted therapies requires further validation.
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Anticuerpos Monoclonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Moduladores de los Receptores de Estrógeno/uso terapéutico , Receptor IGF Tipo 1/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Posmenopausia/efectos de los fármacos , Posmenopausia/metabolismo , Pronóstico , ARN Mensajero/metabolismoRESUMEN
UNLABELLED: Radioactive ligands for the prostate-specific membrane antigen (PSMA) are under development for therapy of metastasized prostate cancer. Since PSMA expression is also found in the kidneys, renal tracer uptake can be dose-limiting. Because kidney kinetics differ from tumor kinetics, serial application of PSMA inhibitors such as 2-(phosphonomethyl)pentanedioic acid (PMPA) may improve the kidney-to-tumor ratio. In this study, we evaluated the effect of PMPA on the biodistribution of 2 promising PSMA ligands. METHODS: Human prostate cancer xenografts (LNCaP) were transplanted subcutaneously into mice. After injection of (125)I-MIP1095, a 16-h latency period was allowed for tracer clearance from the blood and renal calices. After baseline scintigraphy, PMPA was injected in doses of 0.2-50 mg/kg (n = 3 per dose, 5 controls), followed by scans at 2, 4, 6, and 24 h after PMPA injection. Kidney and tumor displacement was determined as a percentage of baseline. A shortened but similar design was used to evaluate the PSMA ligand MIP1404, which contains a chelate for (99m)Tc/rhenium. RESULTS: PMPA injection 16 h after MIP1095 translated into a rapid and quantitative relevant displacement of renal activity. Tumor uptake was reduced to a significantly lesser extent in a dose-dependent manner. PMPA doses of 0.2-1 mg/kg appear optimal for sustaining nearly complete tumor uptake while simultaneously achieving near-total blocking of specific renal PSMA binding. The effect was successfully validated with the PSMA ligand MIP1404. CONCLUSION: PSMA-targeted radionuclide therapy can benefit from serial PMPA comedication by reducing off-target radiation to the kidneys. These data will be used for a first approximation in clinical translation, although in patients an optimization of the dose and time schedule may be necessary.
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Antígenos de Superficie/metabolismo , Glutamato Carboxipeptidasa II/metabolismo , Compuestos Organofosforados/química , Animales , Glutamatos , Humanos , Riñón/diagnóstico por imagen , Ligandos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante de Neoplasias , Compuestos Organofosforados/farmacocinética , Compuestos de Organotecnecio/química , Cintigrafía , Tecnecio/química , Factores de Tiempo , Urea/análogos & derivadosRESUMEN
Prostate cancer is the leading cause of cancer-related death in men in the United States. A major cause of drug resistance in prostate and other epithelial tumors may be due to the presence of a fraction of tumor cells that retain the ability to initiate tumors and hence are termed tumor-initiating cells (TIC) or cancer stem cells. Here, we report that darinaparsin, an organic derivative of arsenic trioxide, is cytotoxic to prostate cancer cell lines as well as fresh prostate cancer cells from patients at low micromolar concentrations, and importantly inhibits the TIC subpopulations. It also inhibits growth of the castrate-resistant Du145 prostate tumor propagated as xenograft in mice and inhibits the tumor-initiating potential of prostate cancer cells. Although the mechanism by which darinaparsin acts is not completely known, we show that it kills prostate cancer cells by blocking cells in the G2-M phase of the cell cycle and inhibits Hedgehog signaling by downregulating Gli-2 transcriptional activity. These data provide a rationale for evaluating darinaparsin in patients with castrate-resistant prostate cancer.
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Antineoplásicos/administración & dosificación , Arsenicales/administración & dosificación , Glutatión/análogos & derivados , Factores de Transcripción de Tipo Kruppel/genética , Células Madre Neoplásicas/efectos de los fármacos , Proteínas Nucleares/genética , Neoplasias de la Próstata/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Animales , Antineoplásicos/farmacología , Arsenicales/farmacología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Docetaxel , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glutatión/administración & dosificación , Glutatión/farmacología , Proteínas Hedgehog/metabolismo , Humanos , Masculino , Ratones , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Taxoides/administración & dosificación , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína Gli2 con Dedos de ZincRESUMEN
PURPOSE: The platelet-derived growth factor receptor (PDGFR) has an important role in tumorigenesis and tumor progression. Olaratumab (IMC-3G3) is a fully human monoclonal antibody that selectively binds human PDGFRα and blocks ligand binding. This phase I study assessed the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), pharmacokinetics, and preliminary antitumor activity of olaratumab in patients with advanced solid tumors. METHODS: Patients were enrolled into five dose-escalating cohorts of 3-6 patients each. Olaratumab was administered intravenously weekly at 4, 8, or 16 mg/kg (cohorts 1-3) or once every other week at 15 or 20 mg/kg (cohorts 4-5), with 4 weeks/cycle. RESULTS: Nineteen patients were treated in five cohorts. There were no dose-limiting toxicities; the MTD was not identified with the doses studied. The most common olaratumab-related adverse events (AE) were fatigue and infusion reactions (10.5 % each). With the exception of 1 patient (20 mg/kg) experiencing two grade 3 drug-related AEs after the dose-limiting toxicity assessment period, all drug-related AEs were grade 1 or 2. The trough concentrations (C min) for 16 mg/kg weekly and 20 mg/kg biweekly were higher than 155 µg/mL, and the concentration found to be efficacious in preclinical xenograft models. Twelve patients (63.2 %) had a best response of stable disease [median duration of 3.9 months (95 % CI 2.3-8.7)]. CONCLUSIONS: Olaratumab was well tolerated and showed preliminary antitumor activity. RP2Ds are 16 mg/kg weekly and 20 mg/kg biweekly. Phase II studies of olaratumab as monotherapy and in combination are ongoing in several tumor types.
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Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/metabolismo , Neoplasias/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/metabolismo , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/inmunología , Resultado del TratamientoRESUMEN
BACKGROUND: IMC-18F1 (icrucumab), a human monoclonal antibody against vascular endothelial growth factor receptor-1 (VEGFR-1), potently inhibits ligand-dependent phosphorylation of VEGFR-1 and downstream signaling, making icrucumab an attractive candidate for antitumor activity. OBJECTIVES: The primary objective was to determine the safety profile and maximum tolerated dose of icrucumab in patients with advanced solid tumors that were previously unresponsive to standard therapy or for which no standard therapy was available. METHODS: In this open-label, dose-escalation, Phase 1 study, patients received icrucumab intravenously weekly at 2, 3, 6, and 12 mg/kg (Cohorts 1-4), every other week (q2w) at 15 mg/kg (Cohort 5), or every third week at 20 mg/kg (Cohort 6). Patients received icrucumab until evidence of progressive disease or other withdrawal criteria were met. RESULTS: Twenty-six patients received icrucumab. The most common adverse events were fatigue, nausea, peripheral edema, anemia, dyspnea, and vomiting. No dose-limiting toxicities (DLTs) were observed in Cohorts 1-5. Two DLTs were observed in Cohort 6 (anemia and hyponatremia), and enrollment was stopped. No patient demonstrated an immunogenic response. Overall, icrucumab exhibited nonlinear pharmacokinetics at doses >6 mg/kg. Six patients (23.1 %) achieved stable disease with median duration of 11.1 weeks (range = 10.3-18.7 weeks); tumor types were thyroid, melanoma, colorectal (3 patients), and small-cell lung cancers. CONCLUSIONS: Icrucumab was safely administered weekly at doses of 2-12 mg/kg and q2w at a dose of 15 mg/kg with no DLTs. Based on achievement of stable disease, icrucumab has potential for antitumor activity against advanced solid tumors.
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Anticuerpos Monoclonales/administración & dosificación , Antineoplásicos/administración & dosificación , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/metabolismo , Receptor 1 de Factores de Crecimiento Endotelial Vascular/inmunologíaRESUMEN
Despite significant advances in understanding of molecular pathobiology, the adoption of this knowledge and its application to drug development is sporadic. Consequently, the drug development process has remained intrinsically laborious and inefficient. Translational research seeks to improve this process by integrating scientific advances into well-defined clinical challenges and opportunities. The focus of this article is on cancer therapeutics, specifically, 2 biotechnology organizations' advances in oncology: (1) optimizing the safety and efficacy of a novel DNA cross-linking small molecule, palifosfamide, and (2) bringing synthetic biology into clinical practice using a controllable gene therapy strategy with intratumorally injected interleukin-12 DNA, a potent cytokine.
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Biotecnología , Terapia Molecular Dirigida , Neoplasias/terapia , Investigación Biomédica Traslacional , Animales , HumanosRESUMEN
INTRODUCTION: We conducted a phase II study of dual-agent monoclonal antibody therapy consisting of cetuximab and bevacizumab in combination with paclitaxel and carboplatin chemotherapy in non-small-cell lung cancer. METHODS: Patients with stage IIIB/IV nonsquamous non-small-cell lung cancer randomly received cetuximab (400 mg/m initially, 250 mg/m weekly thereafter) plus bevacizumab (15 mg/kg) for six cycles combined with paclitaxel (200 mg/m) and carboplatin (area under the curve 6) for either six cycles (six-cycle arm) or the first three cycles (three-cycle arm) (one cycle = 3 weeks). The primary objective was progression-free survival (PFS), estimated separately for each treatment arm. RESULTS: In 121 patients, the median PFS was 6.05 months (95% confidence interval [CI]: 5.65, 7.03) in the six-cycle arm and 4.50 months (95% CI: 4.01, 5.42) in the three-cycle arm. Respective median overall survival times were 12.06 months (95% CI: 9.40, 19.25) and 11.63 months (95% CI: 6.64, 17.61). The tumor response rate was 51.7% (95% CI: 39.0%, 64.3%) and 44.3% (95% CI: 31.8%, 56.7%) in the six-cycle and three-cycle arms, respectively, with corresponding median response durations of 4.86 months (95% CI: 4.30, 7.16) and 3.94 months (95% CI: 2.92, 4.47). Quality of life was consistent across arms. Cetuximab-related grade 3/4 events in greater than 5% of patients (six-cycle arm, three-cycle arm) were dermatitis acneiform (6.9%; 8.6%) and fatigue (13.8%; 5.2%). Three patients died during the study from drug-related adverse events (one in the six-cycle arm and two in the three-cycle arm). CONCLUSIONS: Both the regimens showed expected PFS and numerically comparable overall survival. Quality of life was similar in the two arms, and both the regimens were well tolerated.
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Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Grandes/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Bevacizumab , Carboplatino/administración & dosificación , Carcinoma de Células Grandes/mortalidad , Carcinoma de Células Grandes/patología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Cetuximab , Ensayos Clínicos Fase III como Asunto , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Pronóstico , Tasa de SupervivenciaRESUMEN
INTRODUCTION: This phase I/II study evaluated the safety and antitumor effect of the combination of erlotinib with cixutumumab, a recombinant fully humanized anti-insulin-like growth factor-1 receptor IgG1 monoclonal antibody, in advanced non-small cell lung cancer (NSCLC). METHODS: Patients with advanced NSCLC were treated in an initial safety-lead and drop-down cohorts using erlotinib 150 mg/d with cixutumumab 6 or 5 mg/kg on days 1, 8, 15, and 22 in 28-day cycles (cohorts 1 and 2). Emerging pharmacokinetic data led to an additional cohort (3 + 3 design) with cixutumumab at 15 mg/kg on day 1 in 21-day cycles (cohort 3). RESULTS: Eighteen patients entered the study (6 at 6 mg/kg, 8 at 5 mg/kg, and 4 at 15 mg/kg), with median age of 65 years. Four of six patients at 6 mg/kg experienced dose-limiting toxicities (DLTs), whereas at 5 mg/kg, one of eight patients experienced DLT but three of eight patients still required a dose delay during cycle 1. At 15 mg/kg every 21 days, two of four patients experienced DLTs. In all cohorts, DLTs were either G3 rash or fatigue. Five patients had stable disease as best response and 14 patients had progressive disease. The median progression-free survival was 39 days (range 21-432+ days). Biomarkers analyses showed a trend toward better progression-free survival seen with higher free baseline insulin-like growth factor-1 levels as seen with other insulin-like growth factor-1R inhibitors. CONCLUSIONS: The combinations of cixutumumab at 6 mg/kg every 7 days and 15 mg/kg every 21 days and full-dose erlotinib are not tolerable in unselected patients with NSCLC, as measured by DLT. Cixutumumab at 5 mg/kg every 7 days was tolerable per DLT, but dose delays were common. Efficacy in unselected patients with NSCLC seems to be low.
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Anticuerpos Monoclonales/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/uso terapéutico , Receptor IGF Tipo 1/antagonistas & inhibidores , Anciano , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Pulmón de Células no Pequeñas/secundario , Receptores ErbB/antagonistas & inhibidores , Clorhidrato de Erlotinib , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/uso terapéutico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
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).
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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
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
The benefits of inhibiting vascular endothelial growth factor (VEGF) signaling in cancer patients are predominantly attributed to effects on tumor endothelial cells. Targeting non-endothelial stromal cells to further impact tumor cell growth and survival is being pursued through the inhibition of additional growth factor pathways important for the survival and/or proliferation of these cells. However, recent data suggest that VEGF receptor (VEGFR)-specific inhibitors may target lymphatic vessels and pericytes in addition to blood vessels. Here, in fact, we demonstrate that DC101 (40 mg/kg, thrice a week), an antibody specific to murine VEGFR2, significantly reduces all three of these stromal components in subcutaneous (SKRC-29) and orthotopic (786-O-LP) models of renal cell carcinoma (RCC) established in nu/nu athymic mice. Sunitinib (40 mg/kg, once daily), a receptor tyrosine kinase inhibitor of VEGFR2 and other growth factor receptors, also caused significant loss of tumor blood vessels in RCC models but had weaker effects than DC101 on pericytes and lymphatic vessels. In combination, sunitinib did not significantly add to the effects of DC101 on tumor blood vessels, lymphatic vessels, or pericytes. Nevertheless, sunitinib increased the effect of DC101 on tumor burden in the SKRC-29 model, perhaps related to its broader specificity. Our data have important implications for combination therapy design, supporting the conclusion that targeting VEGFR2 alone in RCC has the potential to have pleiotropic effects on tumor stroma.
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Anticuerpos Monoclonales/farmacología , Antineoplásicos/farmacología , Carcinoma de Células Renales/tratamiento farmacológico , Indoles/farmacología , Neoplasias Renales/tratamiento farmacológico , Pirroles/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/irrigación sanguínea , Carcinoma de Células Renales/patología , Modelos Animales de Enfermedad , Interacciones Farmacológicas , Femenino , Humanos , Factor 1 Inducible por Hipoxia/biosíntesis , Indoles/uso terapéutico , Neoplasias Renales/irrigación sanguínea , Neoplasias Renales/patología , Vasos Linfáticos/efectos de los fármacos , Vasos Linfáticos/patología , Ratones , Ratones Desnudos , Mutación , Trasplante de Neoplasias , Neovascularización Patológica , Pericitos/efectos de los fármacos , Pericitos/patología , Pirroles/uso terapéutico , Células del Estroma/efectos de los fármacos , Células del Estroma/patología , Sunitinib , Carga Tumoral , Células Tumorales Cultivadas , Receptor 2 de Factores de Crecimiento Endotelial Vascular/inmunología , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genéticaRESUMEN
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
The Targeted Cancer Therapies World Congress, held in Zurich, included topics covering new developments in the field of cancer therapy. This conference report highlights selected presentations on the global market for targeted cancer therapies, understanding European regulatory evaluation strategies and meeting the requirements for acceptable reimbursement.