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1.
Invest New Drugs ; 37(1): 76-86, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-29667134

RESUMEN

Purpose DFP-10917 is a novel deoxycytidine analog with a unique mechanism of action. Brief exposure to high concentrations of DFP-10917 inhibits DNA polymerase resulting in S-phase arrest, while prolonged exposure to DFP-10917 at low concentration causes DNA fragmentation, G2/M-phase arrest, and apoptosis. DFP-10917 demonstrated activity in tumor xenografts resistant to other deoxycytidine analogs. Experimental design Two phase I studies assessed the safety, pharmacokinetic, pharmacodynamic and preliminary efficacy of DFP-10917. Patients with refractory solid tumors received DFP-10917 continuous infusion 14-day on/7-day off and 7-day on/7-day off. Enrollment required age > 18 years, ECOG Performance Status 0-2 and adequate organ function. Results 29 patients were dosed in both studies. In 14-day infusion, dose-limiting toxicities (DLT) consisting of febrile neutropenia and thrombocytopenia occurred at 4.0 mg/m2/day. At 3.0 mg/m2/day, 3 patients experienced neutropenia in cycle 2. The dose of 2.0 mg/m2/day was well tolerated in 6 patients. In 7-day infusion, grade 4 neutropenia was DLT at 4.0 mg/m2/day. The maximum tolerated dose was 3 mg/m2/day. Other toxicities included nausea, vomiting, diarrhea, neutropenia, and alopecia. Eight patients had stable disease for >12 weeks. Paired comet assays performed for 7 patients showed an increase in DNA strand breaks at day 8. Pharmacokinetic data showed dose-proportionality for steady-state concentration and AUC of DFP-10917 and its primary metabolite. Conclusion Continuous infusion of DFP-10917 is feasible and well tolerated with myelosuppression as main DLT. The recommended doses are 2.0 mg/m2/day and 3.0 mg/m2/day on the 14-day and 7-day continuous infusion schedules, respectively. Preliminary activity was suggested. Pharmacodynamic data demonstrate biological activity at the tested doses.


Asunto(s)
Antineoplásicos/farmacología , Antineoplásicos/farmacocinética , Desoxicitidina/análogos & derivados , Isoflurofato/química , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/farmacocinética , Desoxicitidina/farmacología , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Infusiones Intravenosas , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/patología , Pronóstico , Distribución Tisular
2.
Cancer ; 121(4): 570-9, 2015 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-25312684

RESUMEN

BACKGROUND: Aldoxorubicin, a prodrug of doxorubicin, covalently binds to serum albumin, allowing for the administration of much higher doses of doxorubicin in a previous clinical study. The current phase 1B/2 study evaluated the safety of aldoxorubicin, including preliminary efficacy and safety of its maximum tolerated dose (MTD). METHODS: Patients aged 18 to 70 years with recurrent/refractory malignant solid tumors received aldoxorubicin at a dose of 230 mg/m(2) , 350 mg/m(2) , or 450 mg/m(2) (170 mg/m(2) , 260 mg/m(2) , or 335 mg/m(2) doxorubicin equivalents, respectively) by intravenous infusion once every 21 days for up to 8 consecutive cycles. RESULTS: A total of 25 patients were enrolled, including 17 patients (68%) with advanced soft tissue sarcoma (STS). The MTD of aldoxorubicin was 350 mg/m(2) ; dose-limiting toxicities included grade 4 neutropenia and grade 3 febrile neutropenia (NCI CTCAE v4.0). Drug-related adverse events included myelosuppression, nausea, fatigue, alopecia, stomatitis, vomiting, and oropharyngeal pain. No clinically significant cardiac toxicities were reported. Seven patients (28%) had elevated serum troponin levels while taking part in the study, but these elevations were not clinically significant or associated with cardiac findings. A partial response was achieved in 20% of patients, and stable disease was reported in 40% of patients. The median progression-free survival was 4.80 months, and the median overall survival was 11.25 months. Among patients with STS who were treated at the MTD (13 patients), a partial response was achieved in 38% and stable disease in 46%; the median progression-free survival was 11.25 months and the median overall survival was 21.71 months. CONCLUSIONS: Aldoxorubicin at a dose of 350 mg/m(2) administered once every 21 days for up to 8 cycles was found to be acceptably safe and demonstrated preliminary efficacy in patients with advanced solid tumors, including STS. Further investigation of aldoxorubicin is ongoing.


Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/efectos adversos , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Sarcoma/tratamiento farmacológico , Adulto , Anciano , Alopecia/inducido químicamente , Médula Ósea/efectos de los fármacos , Esquema de Medicación , Neutropenia Febril/inducido químicamente , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Náusea/inducido químicamente , Estadificación de Neoplasias , Neutropenia/inducido químicamente , Profármacos , Sarcoma/patología , Índice de Severidad de la Enfermedad , Estomatitis/inducido químicamente , Resultado del Tratamiento , Vómitos/inducido químicamente
3.
Clin Cancer Res ; 30(2): 323-333, 2024 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-38047868

RESUMEN

PURPOSE: Chordomas are ultrarare tumors of the axial spine and skull-base without approved systemic therapy. Most chordomas have negative expression of thymidylate synthase (TS), suggesting a potential for responding to the antifolate agent pemetrexed, which inhibits TS and other enzymes involved in nucleotide biosynthesis. We evaluated the therapeutic activity and safety of high-dose pemetrexed in progressive chordoma. PATIENTS AND METHODS: Adult patients with previously treated, progressive chordoma participated in an open-label, single-institution, single-arm, pilot clinical trial of intravenous pemetrexed 900 mg/m2 every 3 weeks and supportive medications of folic acid, vitamin B12, and dexamethasone. The primary endpoint was objective response rate according to RECIST v1.1. Secondary endpoints included adverse events, progression-free survival (PFS), tumor molecular profiles, and alterations in tissue and blood-based biomarkers. RESULTS: Fifteen patients were enrolled and the median number of doses administered was 15 (range, 4-31). One patient discontinued treatment due to psychosocial issues after four cycles and one contracted COVID-19 after 13 cycles. Of the 14 response-evaluable patients, 2 (14%) achieved a partial response and 10 (71%) demonstrated stable disease. Median PFS was 10.5 months (95% confidence interval: 9 months-undetermined) and 6-month PFS was 67%. Adverse events were expected and relatively mild, with one grade 3 creatinine increased, and one each of grade 3 and 4 lymphopenia. No grade 5 adverse events, unexpected toxicities, or dose-limiting toxicities were observed. Several patients reported clinical improvement in disease-related symptoms. CONCLUSIONS: High-dose pemetrexed appears tolerable and shows objective antitumor activity in patients with chordoma. Phase II studies of high-dose pemetrexed are warranted.


Asunto(s)
Cordoma , Neoplasias Pulmonares , Adulto , Humanos , Pemetrexed/efectos adversos , Cordoma/patología , Proyectos Piloto , Glutamatos/efectos adversos , Guanina/uso terapéutico , Estadificación de Neoplasias , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resultado del Tratamiento , Neoplasias Pulmonares/tratamiento farmacológico
4.
Int Med Case Rep J ; 15: 7-14, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35079224

RESUMEN

PURPOSE: To report a case of combined central retinal vein and artery occlusion that evolved into ischemic optic neuropathy following the Pfizer COVID-19 vaccination. METHODS: Patient was followed with optical coherence tomography (OCT), fluorescein angiography, and Humphrey visual field. RESULTS: Patient was able to recover vision from count fingers to 20/30 on a combination of aflibercept, steroidal and non-steroidal anti-inflammatories, a diuretic (acetazolamide), antiplatelet agents (aspirin and pentoxifylline), and an anticoagulant (apixaban). CONCLUSION: COVID-19 vaccination may be associated with a myriad of sight-threatening ocular thrombotic conditions, which may respond to a combination of anti-inflammatory and anticoagulant therapies.

5.
Clin Cancer Res ; 27(10): 2723-2733, 2021 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-33622704

RESUMEN

PURPOSE: BAY1436032, an inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), was active against multiple IDH1-R132X solid tumors in preclinical models. This first-in-human study was designed to determine the safety and pharmacokinetics of BAY1436032, and to evaluate its potential pharmacodynamics and antitumor effects. PATIENTS AND METHODS: The study comprised of dose escalation and dose expansion cohorts. BAY1436032 tablets were orally administered twice daily on a continuous basis in subjects with mIDH1 solid tumors. RESULTS: In dose escalation, 29 subjects with various tumor types were administered BAY1436032 across five doses (150-1,500 mg twice daily). BAY1432032 exhibited a relatively short half-life. Most evaluable subjects experienced target inhibition as indicated by a median maximal reduction of plasma R-2-hydroxyglutarate levels of 76%. BAY1436032 was well tolerated and an MTD was not identified. A dose of 1,500 mg twice daily was selected for dose expansion, where 52 subjects were treated in cohorts representing four different tumor types [lower grade glioma (LGG), glioblastoma, intrahepatic cholangiocarcinoma, and a basket cohort of other tumor types]. The best clinical outcomes were in subjects with LGG (n = 35), with an objective response rate of 11% (one complete response and three partial responses) and stable disease in 43%. As of August 2020, four of these subjects were in treatment for >2 years and still ongoing. Objective responses were observed only in LGG. CONCLUSIONS: BAY1436032 was well tolerated and showed evidence of target inhibition and durable objective responses in a small subset of subjects with LGG.


Asunto(s)
Compuestos de Anilina/uso terapéutico , Antineoplásicos/uso terapéutico , Bencimidazoles/uso terapéutico , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Isocitrato Deshidrogenasa/genética , Mutación , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Compuestos de Anilina/administración & dosificación , Compuestos de Anilina/efectos adversos , Compuestos de Anilina/farmacocinética , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Bencimidazoles/administración & dosificación , Bencimidazoles/efectos adversos , Bencimidazoles/farmacocinética , Biomarcadores de Tumor , Análisis Mutacional de ADN , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Femenino , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Neoplasias/diagnóstico , Neoplasias/mortalidad
6.
Oncoimmunology ; 9(1): 1847846, 2020 11 19.
Artículo en Inglés | MEDLINE | ID: mdl-33312760

RESUMEN

Preclinical data suggest that a "prime-boost" vaccine regimen using a target-expressing lentiviral vector for priming, followed by a recombinant protein boost, may be effective against cancer; however, this strategy has not been evaluated in a clinical setting. CMB305 is a prime-boost vaccine designed to induce a broad anti-NY-ESO-1 immune response. It is composed of LV305, which is an NY-ESO-1 expressing lentiviral vector, and G305, a recombinant adjuvanted NY-ESO-1 protein. This multicenter phase 1b, first-in-human trial evaluated CMB305 in patients with NY-ESO-1 expressing solid tumors. Safety was examined in a 3 + 3 dose-escalation design, followed by an expansion with CMB305 alone or in a combination with either oral metronomic cyclophosphamide or intratumoral injections of a toll-like receptor agonist (glucopyranosyl lipid A). Of the 79 patients who enrolled, 81.0% had sarcomas, 86.1% had metastatic disease, and 57.0% had progressive disease at study entry. The most common adverse events were fatigue (34.2%), nausea (26.6%), and injection-site pain (24.1%). In patients with soft tissue sarcomas, a disease control rate of 61.9% and an overall survival of 26.2 months (95% CI, 22.1-NA) were observed. CMB305 induced anti-NY-ESO-1 antibody and T-cell responses in 62.9% and 47.4% of patients, respectively. This is the first trial to test a prime-boost vaccine regimen in patients with advanced cancer. This approach is feasible, can be delivered safely, and with evidence of immune response as well as suggestion of clinical benefit.


Asunto(s)
Vacunas contra el Cáncer , Sarcoma , Adyuvantes Inmunológicos , Antígenos de Neoplasias/genética , Vacunas contra el Cáncer/efectos adversos , Humanos , Proteínas de la Membrana/genética
7.
Future Oncol ; 5(3): 291-303, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19374536

RESUMEN

The mammalian target of rapamycin (mTOR) is an intracellular protein with a key role in cellular protein synthesis and energy balance that influences many aspects of cell growth and proliferation, including differentiation, cell-cycle progression, angiogenesis, protein degradation and apoptosis. mTOR can be activated by numerous oncogenic signals, such as growth factor activation through the EGF, IGF and VEGF receptors, mutation and silencing of the PTEN tumor suppressor gene, activating mutations in the PI3K catalytic subunit, Akt amplification and the Ras-Raf-MEK pathway. Once activated, the cellular functions of mTOR are achieved through its downstream targets, 4E-BP1 and p70S6K1. The mTOR pathway can be further regulated through a negative feedback loop, which may lead to resistance to specific inhibitors of mTOR. This review will outline the mTOR signaling pathway, which is often activated in cancers and account for tumor proliferation and growth, highlight the rationale in targeting mTOR with a focus on the preclinical and clinical development of one of these inhibitors, deforolimus (AP23573, MK-8669), and discuss potential benefit and barriers to these agents being introduced in the clinic.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico , Proteínas Quinasas/metabolismo , Transducción de Señal/fisiología , Sirolimus/análogos & derivados , Animales , Ensayos Clínicos como Asunto , Humanos , Proteínas Quinasas/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Sirolimus/farmacología , Serina-Treonina Quinasas TOR
8.
Expert Opin Investig Drugs ; 26(4): 427-443, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28267385

RESUMEN

INTRODUCTION: Activating mutations in the genes encoding the tyrosine receptor kinases KIT and platelet-derived growth factor receptor occur in 85%-90% of patients with gastrointestinal stromal tumors (GIST). Although imatinib and other tyrosine kinase inhibitors have revolutionized the treatment of GIST, most patients progress within a few years. Areas covered: Monoclonal antibodies and small-molecule inhibitors targeting specific signaling pathways or proteins associated with resistance to existing treatments are being explored as alternative treatment approaches for GIST. Other alternative approaches include inhibiting more general regulators of protein folding, chromatin packaging, and cell-cycle regulation; nontargeted approaches are also being evaluated in select patient populations. This review summarizes preclinical and clinical data from agents using these accessory pathways. Expert opinion: As we learn more about GIST biology, it is becoming clear that treatment strategies will become more personalized, as reflected by the fact that several trials are enrolling specific subpopulations of patients with GIST. Going forward, researchers should evaluate these new drugs alone or in combination with other types of drugs to better meet patient needs.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Gastrointestinales/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/farmacología , Diseño de Fármacos , Neoplasias Gastrointestinales/etiología , Neoplasias Gastrointestinales/patología , Tumores del Estroma Gastrointestinal/genética , Tumores del Estroma Gastrointestinal/patología , Humanos , Terapia Molecular Dirigida , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-kit/genética , Receptores del Factor de Crecimiento Derivado de Plaquetas/genética
9.
JAMA Oncol ; 1(9): 1272-80, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26378637

RESUMEN

IMPORTANCE: Standard therapy for advanced soft-tissue sarcoma has not changed substantially in decades, and patient prognosis remains poor. Aldoxorubicin, a novel albumin-binding prodrug of doxorubicin, showed clinical activity against advanced soft-tissue sarcoma in phase 1 studies. OBJECTIVE: To evaluate efficacy and safety of aldoxorubicin vs doxorubicin in patients with advanced soft-tissue sarcoma. DESIGN, SETTING, AND PARTICIPANTS: International, multicenter, phase 2b, open-label, randomized study at general community practices, private practices, or institutional practices. Between August 2012 and December 2013, 140 patients with previously untreated locally advanced, unresectable, or metastatic soft-tissue sarcoma were screened. INTERVENTIONS: Randomization (2:1) to aldoxorubicin 350 mg/m2 (dose equivalent to doxorubicin 260 mg/m2) or doxorubicin 75 mg/m2, administered once every 3 weeks for up to 6 cycles. MAIN OUTCOMES AND MEASURES: Primary end point was progression-free survival. Secondary end points were 6-month progression-free survival, overall survival, tumor response rate, and safety. All efficacy end points were evaluated by independent and local review. RESULTS: A total of 126 patients were randomized, and 123 received aldoxorubicin (n = 83) or doxorubicin (n = 40). Median (range) patient age was 54.0 (21-77 years); 42 (34%) had leiomyosarcoma. By independent review, median progression-free survival was significantly improved (5.6 [95% CI, 3.0-8.1] vs 2.7 [95% CI, 1.6-4.3] months; P = .02) with aldoxorubicin compared with doxorubicin, as was the rate of 6-month progression-free survival (46% and 23%; P = .02). Median overall survival was 15.8 (95% CI, 13.0 to not available) months with aldoxorubicin and 14.3 (95% CI, 8.6-20.6) months with doxorubicin (P = .21). Overall tumor response rate (by Response Evaluation Criteria in Solid Tumors, version 1.1) by independent review was higher with aldoxorubicin than with doxorubicin (25% [20 patients, all partial response] vs 0%). Grade 3 or 4 neutropenia was more frequent with aldoxorubicin than with doxorubicin (24 [29%] vs 5 [12%]), but not grade 3 or 4 febrile neutropenia (12 [14%] vs 7 [18%]). No acute cardiotoxic effects were observed with either treatment, although left ventricular ejection fraction less than 50% occurred in 3 of 40 patients receiving doxorubicin. CONCLUSIONS AND RELEVANCE: Single-agent aldoxorubicin therapy showed superior efficacy over doxorubicin by prolonging progression-free survival and improving rates of 6-month progression-free survival and tumor response. Aldoxorubicin therapy exhibited manageable adverse effects, without unexpected events, and without evidence of acute cardiotoxicity. Further investigation of aldoxorubicin therapy in advanced soft-tissue sarcoma is warranted. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01514188.


Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Doxorrubicina/administración & dosificación , Profármacos/administración & dosificación , Sarcoma/tratamiento farmacológico , Adulto , Anciano , Antibióticos Antineoplásicos/efectos adversos , Doxorrubicina/efectos adversos , Doxorrubicina/análogos & derivados , Esquema de Medicación , Métodos Epidemiológicos , Femenino , Humanos , Hidrazonas/administración & dosificación , Hidrazonas/efectos adversos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Profármacos/efectos adversos , Resultado del Tratamiento , Adulto Joven
11.
Cancer Chemother Pharmacol ; 74(1): 77-84, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24817603

RESUMEN

PURPOSE: Melanomas are vascular tumors with a high incidence of BRAF mutations driving tumor proliferation. Complete inhibition of vascular endothelial growth factor (VEGF) signaling has potential for enhanced antitumor efficacy. METHODS: Patients with advanced melanoma and adequate organ function were eligible. Sorafenib was given orally at 200 mg BiD for 5 days every week; bevacizumab was administered 5 mg/kg intravenously every 14 days. The primary objective was to determine clinical biological activity. The secondary objectives were safety, tolerability, and time to progression (TTP). Pharmacodynamic analysis included serum VEGF and soluble VEGF receptor-1 and VEGF receptor-2 performed at baseline, C1D15 and C2D1. The study was terminated during the first stage of a Simon two-stage design, after 14 of planned 21 subjects were enrolled. RESULTS: Of the 14 patients who received treatment, no objective tumor responses were observed. Stable disease (SD) ≥16 weeks was observed in 57 % patients, including three patients with SD lasting ≥1 year. Median TTP was 32 weeks. The most frequently reported drug-related adverse events (AEs) were hand-foot syndrome (57.1 %), fatigue (57.1 %), hypertension (64.3 %), and proteinuria (35.7). Grade 3/4 drug-related AEs were hypertension (14.2 %), hand-foot syndrome, proteinuria, and thrombocytopenia (7 % each). Patients with low VEGF (<300 pg/ml) experienced longer TTP than those with high VEGF [median 50 vs. 15 weeks, p = 0.02). A similar pattern was seen for VEGFR1 and VEGFR2, although it did not reach statistical significance. CONCLUSIONS: Combined VEGF/VEGFR blockade using bevacizumab with sorafenib shows clinical activity. The linkage between VEGF levels and time to tumor progression needs further exploration.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Melanoma/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab , Biomarcadores/sangre , Progresión de la Enfermedad , Monitoreo de Drogas , Terminación Anticipada de los Ensayos Clínicos , Estudios de Factibilidad , Femenino , Síndrome Mano-Pie/fisiopatología , Humanos , Hipertensión/inducido químicamente , Hipertensión/fisiopatología , Cinética , Masculino , Melanoma/sangre , Melanoma/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Niacinamida/administración & dosificación , Niacinamida/efectos adversos , Niacinamida/uso terapéutico , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Receptores de Factores de Crecimiento Endotelial Vascular/sangre , Receptores de Factores de Crecimiento Endotelial Vascular/química , Índice de Severidad de la Enfermedad , Sorafenib , Factores de Crecimiento Endotelial Vascular/sangre , Factores de Crecimiento Endotelial Vascular/química
12.
Clin Breast Cancer ; 14(3): 169-76, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24393852

RESUMEN

INTRODUCTION: Effective therapies after failure of treatment with anthracyclines and taxanes are needed for patients with metastatic breast cancer. Dinaciclib (MK-7965, formerly SCH727965), a small-molecule cyclin-dependent kinase inhibitor, has demonstrated antitumor activity in phase I studies with solid-tumor patients. This phase II trial was designed to assess the efficacy and safety of dinaciclib compared with that of capecitabine in women with previously treated advanced breast cancer. PATIENTS AND METHODS: Patients were randomized to receive either dinaciclib at 50 mg/m(2), administered as a 2-hour infusion every 21 days, or 1250 mg/m(2) capecitabine, administered orally twice daily in 21-day cycles. RESULTS: An unplanned interim analysis showed that the time to disease progression was inferior with dinaciclib treatment compared with capecitabine treatment; therefore, the trial was stopped after 30 patients were randomized. Dinaciclib treatment demonstrated antitumor activity in 2 of 7 patients with estrogen receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (1 confirmed and 1 unconfirmed partial response), as well as acceptable safety and tolerability. Grade 3 or 4 treatment-related adverse events were common and included neutropenia, leukopenia, increase in aspartate aminotransferase, and febrile neutropenia. Population pharmacokinetic model-predicted mean dinaciclib exposure (area under the concentration-time curve extrapolated to infinity [AUC[I]]) at 50 mg/m(2) was similar to that observed in a previous phase I trial, and no drug accumulation was observed after multiple-dose administration. CONCLUSION: Although dinaciclib monotherapy demonstrated some antitumor activity and was generally tolerated, efficacy was not superior to capecitabine. Future studies may be considered to evaluate dinaciclib in select patient populations with metastatic breast cancer and in combination with other agents.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Desoxicitidina/análogos & derivados , Fluorouracilo/análogos & derivados , Compuestos de Piridinio/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacocinética , Neoplasias de la Mama/mortalidad , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Capecitabina , Óxidos N-Cíclicos , Desoxicitidina/farmacocinética , Desoxicitidina/uso terapéutico , Femenino , Fluorouracilo/farmacocinética , Fluorouracilo/uso terapéutico , Humanos , Indolizinas , Estimación de Kaplan-Meier , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Compuestos de Piridinio/farmacocinética
13.
Cancer Chemother Pharmacol ; 74(6): 1241-50, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25304209

RESUMEN

PURPOSE: ATI-1123 is a liposomal formulation of docetaxel and may be administered without the premedications and hypersensitivity reactions. This Phase I study examines the safety, tolerability, pharmacokinetics (PKs), and antitumor activity of ATI-1123. METHODS: Patients with advanced solid malignancies received escalating doses of ATI-1123 intravenously over 1-h every 3 weeks. The dosing commenced using an accelerated titration design and was followed by a modified 3 + 3 Fibonacci schema to determine maximally tolerated dose (MTD). Plasma was analyzed for encapsulated/non-encapsulated docetaxel; PK analyses were performed using model independent method. Response was assessed using RECIST criteria. RESULTS: In total, 29 patients received doses ranging from 15 to 110 mg/m(2). At 110 mg/m(2), two of six patients experienced dose-limiting toxicities including grade 3 stomatitis and febrile neutropenia. The 90 mg/m(2) cohort was expanded to ten patients and identified as the MTD. The most common adverse events were fatigue, nausea, neutropenia, anemia, anorexia, and diarrhea. ATI-1123 exhibited linear and dose proportional PKs. One patient with lung cancer had confirmed partial response, and stable disease was observed in 75 % patients. CONCLUSIONS: ATI-1123 demonstrated an acceptable tolerability and favorable PK profile in patients with solid tumors. Our results provide support for Phase II trials to determine the antitumor activity of this drug.


Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias/tratamiento farmacológico , Taxoides/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Docetaxel , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Infusiones Intravenosas , Liposomas , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/patología , Taxoides/efectos adversos , Taxoides/farmacocinética , Resultado del Tratamiento
14.
Mol Cancer Ther ; 11(2): 308-16, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22203732

RESUMEN

GRN1005 is a novel peptide-drug conjugate composed of paclitaxel covalently linked to a peptide, angiopep-2, that targets the low-density lipoprotein receptor-related protein 1. This first-in-human study evaluated the safety, tolerability, pharmacokinetics, and efficacy of GRN1005 in patients with advanced solid tumors. Patients in sequential cohorts (one patient per cohort until grade 2 toxicity, then 3 + 3 design) received intravenous GRN1005 at escalating doses between 30 and 700 mg/m(2) once in every 21 days. In the maximum tolerated dose (MTD) expansion group, patients were required to have brain metastases. Fifty-six patients received GRN1005, including 41 with brain metastases (median number of prior therapies = 4). MTD was 650 mg/m(2); the main dose-limiting toxicity was myelosuppression. Sixteen of 20 patients dosed at the MTD had brain metastases. Pharmacokinetics was dose linear and the mean terminal-phase elimination half-life was 3.6 hours. No evidence of accumulation was observed after repeat dosing. No anti-GRN1005 antibodies were detected. Five of the 20 patients (25%) dosed at 650 mg/m(2) (MTD), three of whom had previous taxane therapy, achieved an overall partial response (breast, n = 2; non-small cell lung cancer, n = 2; and ovarian cancer, n = 1); responses in all five patients were also accompanied by shrinkage of brain lesions (-17% to -50%). In addition, six patients (11%; doses 30-700 mg/m(2)) experienced stable disease that lasted 4 months or more. GRN1005 was well tolerated and showed activity in heavily pretreated patients with advanced solid tumors, including those who had brain metastases and/or failed prior taxane therapy.


Asunto(s)
Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Paclitaxel/farmacocinética , Paclitaxel/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Alopecia/inducido químicamente , Antineoplásicos Fitogénicos/efectos adversos , Antineoplásicos Fitogénicos/farmacocinética , Antineoplásicos Fitogénicos/uso terapéutico , Área Bajo la Curva , Encéfalo/metabolismo , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Fatiga/inducido químicamente , Femenino , Humanos , Infusiones Intravenosas , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Neoplasias/patología , Neutropenia/inducido químicamente , Paclitaxel/efectos adversos , Péptidos , Resultado del Tratamiento , Adulto Joven
15.
J Clin Oncol ; 30(1): 78-84, 2012 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-22067397

RESUMEN

PURPOSE: Ridaforolimus is an inhibitor of mammalian target of rapamycin, an integral component of the phosphatidyl 3-kinase/AKT signaling pathway, with early evidence of activity in sarcomas. This multicenter, open-label, single-arm, phase II trial was conducted to assess the antitumor activity of ridaforolimus in patients with distinct subtypes of advanced sarcomas. PATIENTS AND METHODS: Patients with metastatic or unresectable soft tissue or bone sarcomas received ridaforolimus 12.5 mg administered as a 30-minute intravenous infusion once daily for 5 days every 2 weeks. The primary end point was clinical benefit response (CBR) rate (complete response or partial response [PR] or stable disease ≥ 16 weeks). Safety, progression-free survival (PFS), overall survival (OS), time to progression, and duration of response were also evaluated. RESULTS: A total of 212 patients were treated in four separate histologic cohorts. In this heavily pretreated population, 61 patients (28.8%) achieved CBR. Median PFS was 15.3 weeks; median OS was 40 weeks. Response Evaluation Criteria in Solid Tumors (RECIST) confirmed response rate was 1.9%, with four patients achieving confirmed PR (two with osteosarcoma, one with spindle cell sarcoma, and one with malignant fibrous histiocytoma). Archival tumor protein markers analyzed were not correlated with CBR. Related adverse events were generally mild or moderate and consisted primarily of stomatitis, mucosal inflammation, mouth ulceration, rash, and fatigue. CONCLUSION: Single-agent ridaforolimus in patients with advanced and pretreated sarcomas led to PFS results that compare favorably with historical metrics. A phase III trial based on these data will further define ridaforolimus activity in sarcomas.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Sarcoma/tratamiento farmacológico , Sirolimus/análogos & derivados , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Biomarcadores de Tumor/sangre , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Sarcoma/metabolismo , Sarcoma/patología , Factores Sexuales , Sirolimus/administración & dosificación , Sirolimus/efectos adversos , Sirolimus/uso terapéutico , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/sangre
16.
Curr Drug Targets ; 12(14): 2001-8, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21777196

RESUMEN

Heat shock proteins (Hsp) are highly conserved proteins and their expression is dependent on the level of various cellular stresses. Hsp work as a molecular chaperon for several cellular proteins and have cytoprotective roles. Their function is essential for normal cell viability and growth. Hsp90 interacts with proteins mediating cell signaling involved in essential processes such as proliferation, cell cycle control, angiogenesis and apoptosis. The naturally occurring Hsp90 inhibitor geldanamycin (GA) was the first to demonstrate anticancer activity but its significant toxicity profile in pre-clinical models precluded its clinical development. Subsequent, several Hsp90 inhibitors have been developed and underwent clinical development with favorable safety profiles. Several initial clinical studies have shown promising anticancer activity of Hsp90 inhibitors mainly in breast cancer, non small cell lung carcinoma (NSCLC), gastrointestinal stromal tumors (GIST) and various hematological malignancies. The universal involvement of Hsp90 in multiple oncogenic processes makes Hsp90 inhibitors ideal compounds to be explored as a single agent or in combination with other anticancer therapies.


Asunto(s)
Antineoplásicos/farmacología , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Proteínas HSP90 de Choque Térmico/química , Proteínas HSP90 de Choque Térmico/fisiología , Humanos , Invasividad Neoplásica , Neoplasias/irrigación sanguínea , Neoplasias/tratamiento farmacológico , Neoplasias/etiología
17.
Target Oncol ; 6(1): 29-39, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21533543

RESUMEN

The mammalian target of rapamycin (mTOR) is a protein kinase that functions as a key regulator of cell growth, proliferation and differentiation, cell-cycle progression, angiogenesis, protein degradation, and apoptosis. Following activation by a number of oncogenic signals such as growth factors, energy and nutrients, mTOR stimulates several downstream effectors including the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 4 E binding protein-1 (4 EBP-1), as well as a complex network of regulatory loops. Activation of the mTOR pathway plays a critical role in the development of many tumor types, including renal cell and breast carcinomas, neuroendocrine tumors, and sarcomas. Bone and soft tissue sarcomas are rare, heterogeneous tumors that are curable by local treatments if diagnosed at early stages; however advanced or metastatic sarcomas are rarely curable and very few drugs are efficacious in this setting. Several disruptions in phosphatidylinositol-3 kinase (PI3K)-Akt-mTOR signaling are associated with malignant transformation or progression in various sarcoma sub-types. The PI3K-Akt-mTOR pathway is therefore an exciting target for therapy of sarcomas, and its blockade represents an opportunity to improve outcomes in this poor-prognosis disease. Early studies with mTOR inhibitors have demonstrated promising antitumor activity in patients with metastatic sarcoma who have failed standard treatments. This article discusses the mTOR signaling pathway and summarizes the clinical experience with mTOR inhibitors in patients with advanced or metastatic sarcoma.


Asunto(s)
Antibióticos Antineoplásicos/uso terapéutico , Sarcoma/tratamiento farmacológico , Sirolimus/análogos & derivados , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Animales , Antibióticos Antineoplásicos/farmacología , Humanos , Terapia Molecular Dirigida , Transducción de Señal , Sirolimus/farmacología , Sirolimus/uso terapéutico
18.
Clin Cancer Res ; 17(2): 363-71, 2011 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-21224368

RESUMEN

PURPOSE: To determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity of CT-322 (BMS-844203), a VEGFR-2 inhibitor and the first human fibronectin domain-based targeted biologic (Adnectin) to enter clinical studies. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were treated with escalating doses of CT-322 intravenously (i.v.) weekly (qw), or biweekly (q2w). Plasma samples were assayed for CT-322 concentrations, plasma VEGF-A concentrations, and antidrug antibodies. RESULTS: Thirty-nine patients completed 105 cycles of 0.1 to 3.0 mg/kg CT-322 i.v. either qw or q2w. The most common treatment-emergent grade 1/2 toxicities were fatigue, nausea, proteinuria, vomiting, anorexia, and hypertension. Grade 3/4 toxicities were rare. Reversible proteinuria, retinal artery, and vein thrombosis, left ventricular dysfunction, and reversible posterior leukoencephalopathy syndrome were dose limiting at 3.0 mg/kg. The MTD was 2 mg/kg qw or q2w. CT-322 plasma concentrations increased dose proportionally. Plasma VEGF-A levels increased with dose and plateaued at 2 mg/kg qw. Anti-CT-322 antibodies developed without effects on pharmacokinetics, VEGF-A levels, or safety. Minor decreases in tumor measurements occurred in 4 of 34 evaluable patients and 24 patients had stable disease. CONCLUSIONS: CT-322 can be safely administered at 2 mg/kg i.v. qw or q2w and exhibits promising antitumor activity in patients with advanced solid tumors. The absence of severe toxicities at the MTD, demonstration of plasma drug concentrations active in preclinical models, and clinical pharmacodynamic evidence of VEGFR-2 inhibition warrant further development of CT-322 and suggest strong potential for Adnectin-based targeted biologics.


Asunto(s)
Antineoplásicos/uso terapéutico , Fibronectinas/uso terapéutico , Neoplasias/tratamiento farmacológico , Fragmentos de Péptidos/uso terapéutico , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Adulto , Anciano , Formación de Anticuerpos , Antineoplásicos/efectos adversos , Antineoplásicos/inmunología , Antineoplásicos/farmacocinética , Femenino , Fibronectinas/efectos adversos , Fibronectinas/inmunología , Fibronectinas/farmacocinética , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Terapia Molecular Dirigida , Fragmentos de Péptidos/efectos adversos , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/farmacocinética
19.
Clin Cancer Res ; 16(11): 3044-56, 2010 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-20501621

RESUMEN

PURPOSE: To evaluate the safety, pharmacokinetics, and antitumor activity of AMG 386, an investigational selective angiopoietin 1/2-neutralizing peptibody, in combination with FOLFOX-4 (F), carboplatin/paclitaxel (C/P), or docetaxel (D), in adult patients with advanced solid tumors. EXPERIMENTAL DESIGN: Three cohorts of patients (F, n = 6; C/P, n = 8; D, n = 12) received one full cycle of chemotherapy alone during the pretreatment phase, followed by administration of AMG 386 10 mg/kg i.v. weekly in combination with chemotherapy until disease progression or intolerance. Safety and tolerability, tumor response, pharmacokinetic profiles, and biomarkers were assessed. RESULTS: Twenty-six patients were enrolled; 22 received treatment with AMG 386. No dose-limiting toxicities or grade 3 or 4 adverse events related to AMG 386 were reported. The most common adverse events were diarrhea and hypomagnesemia (n = 3 each). One patient developed grade 2 hypertension and one had grade 1 subconjunctival eye hemorrhage. No neutralizing antibodies to AMG 386 were detected. There were no pharmacokinetic interactions between AMG 386 and F, C/P, or D. One patient receiving AMG 386 plus C/P for bladder cancer refractory to gemcitabine/cisplatin had a complete response at week 8. The remaining best tumor responses were partial response (n = 3, one from each cohort), stable disease > or =8 weeks (n = 13), and progressive disease (n = 1). CONCLUSIONS: Weekly administration of AMG 386 in combination with three common chemotherapy regimens was well tolerated in patients with advanced solid tumors. No pharmacokinetic interactions between AMG 386 and any of the tested chemotherapy regimens were noted. Promising antitumor activity was observed with all three treatment combinations.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/tratamiento farmacológico , Proteínas Recombinantes de Fusión/uso terapéutico , Adulto , Angiopoyetina 1/antagonistas & inhibidores , Angiopoyetina 2/antagonistas & inhibidores , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Esquema de Medicación , Drogas en Investigación/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes/administración & dosificación
20.
Expert Rev Hematol ; 2(4): 399-414, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21082945

RESUMEN

Despite significant advances in the treatment of hematological malignancies over the last decade, morbidity and mortality from these disorders remain high. New discoveries in the pathogenesis of these malignancies have led to better understanding of these diseases and new thinking in drug development. mTOR is a downstream effector of the PI3K/Akt (protein kinase B) signaling pathway that mediates cell survival and proliferation and is known to be deregulated in many cancers. Preclinical activity of mTOR inhibitors has been very promising in various hematological malignancies. Rapamycin analogs with relatively favorable pharmaceutical properties, including temsirolimus (CCI-779), everolimus (RAD001) and deforolimus (AP23573), are under clinical evaluations in patients with hematologic malignancies. They have shown encouraging results thus far and a favorable toxicity profile. Their utility, mainly as cytostatic agents, needs to be further explored in combination with pre-existing chemotherapeutic agents for various hematological malignancies.


Asunto(s)
Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/enzimología , Inhibidores de Proteínas Quinasas/uso terapéutico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Humanos , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo
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