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1.
Prostate ; 80(1): 99-108, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31742767

RESUMO

BACKGROUND: Prostate-specific membrane antigen (PSMA) is a well-established therapeutic and diagnostic target overexpressed in both primary and metastatic prostate cancers. PSMA antibody-drug conjugate (PSMA ADC) is a fully human immunoglobulin G1 anti-PSMA monoclonal antibody conjugated to monomethylauristatin E, which binds to PSMA-positive cells and induces cytotoxicity. In a phase 1 study, PSMA ADC was well tolerated and demonstrated activity as measured by reductions in serum prostate-specific antigen (PSA) and circulating tumor cells (CTCs). To further assess PSMA ADC, we conducted a phase 2 trial in metastatic castration-resistant prostate cancer (mCRPC) subjects who progressed following abiraterone/enzalutamide (abi/enz) therapy. METHODS: A total of 119 (84 chemotherapy-experienced and 35 chemotherapy-naïve) subjects were administered PSMA ADC 2.5 or 2.3 mg/kg IV q3w for up to eight cycles. Antitumor activity (best percentage declines in PSA and CTCs from baseline and tumor responses through radiological imaging), exploratory biomarkers, and safety (monitoring of adverse events [AEs], clinical laboratory tests, and Eastern Cooperative Oncology Group performance status) were assessed. RESULTS: PSA declines ≥50% occurred in 14% of all treated (n = 113) and 21% of chemotherapy-naïve subjects (n = 34). CTC declines ≥50% were seen in 78% of all treated (n = 77; number of subjects with ≥5 CTCs at baseline and a posttreatment result) and 89% of chemotherapy-naïve subjects (n = 19); 47% of all treated and 53% of chemotherapy-naïve subjects had a transition from ≥5 to less than 5 CTCs/7.5 mL blood at some point during the study. PSA and CTC reductions were associated with high PSMA expression (CTCs or tumor tissue) and low neuroendocrine serum markers. In the chemotherapy-experienced group, the best overall radiologic response to PSMA ADC treatment was stable disease in 51 (60.7%) subjects; 5.7% of subjects in the chemotherapy-naïve group had partial responses. The most common treatment-related AEs ≥Common Terminology Criteria for AE (CTCAE) grade 3 were neutropenia, fatigue, electrolyte imbalance, anemia, and neuropathy. The most common serious AEs were dehydration, hyponatremia, febrile neutropenia, and constipation. Two subjects who received 2.5 mg/kg died of sepsis. CONCLUSIONS: PSMA ADC demonstrated some activity with respect to PSA declines, CTC conversions/reductions, and radiologic assessments in abi/enz treated mCRPC subjects. Clinically significant treatment-related AEs included neutropenia and neuropathy.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Androstenos/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Benzamidas , Biomarcadores Tumorais/sangue , Resistencia a Medicamentos Antineoplásicos , Humanos , Imunotoxinas/efeitos adversos , Imunotoxinas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Nitrilas , Feniltioidantoína/administração & dosagem , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Taxa de Sobrevida , Resultado do Tratamento
2.
Prostate ; 79(6): 604-613, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30663074

RESUMO

BACKGROUND: Prostate-specific membrane antigen (PSMA) is a well-characterized target that is overexpressed selectively on prostate cancer cells. PSMA antibody-drug conjugate (ADC) is a fully human IgG1 monoclonal antibody conjugated to the microtubule disrupting agent monomethyl auristatin E (MMAE), which is designed to specifically bind PSMA-positive cells, internalize, and then release its cytotoxic payload into the cells. PSMA ADC has demonstrated potent and selective antitumor activity in preclinical models of advanced prostate cancer. A Phase 1 study was conducted to assess the safety, pharmacokinetics, and preliminary antitumor effects of PSMA ADC in subjects with treatment-refractory prostate cancer. METHODS: In this first-in-man dose-escalation study, PSMA ADC was administered by intravenous infusion every three weeks to subjects with progressive metastatic castration-resistant prostate cancer (mCRPC) who were previously treated with docetaxel chemotherapy. The primary endpoint was to establish a maximum tolerated dose (MTD). The study also examined the pharmacokinetics of the study drug, total antibody, and free MMAE. Antitumor effects were assessed by measuring changes in serum prostate-specific antigen (PSA), circulating tumor cells (CTCs), and radiologic imaging. RESULTS: Fifty-two subjects were administered doses ranging from 0.4 to 2.8 mg/kg. Subjects had a median of two prior chemotherapy regimens and prior treatment with abiraterone and/or enzalutamide. Neutropenia and peripheral neuropathy were identified as important first-cycle and late dose-limiting toxicities, respectively. The dose of 2.5 mg/kg was determined to be the MTD. Pharmacokinetics were approximately dose-proportional with minimal drug accumulation. Reductions in PSA and CTCs in subjects treated with doses of ≥1.8 mg/kg were durable and often concurrent. CONCLUSIONS: In an extensively pretreated mCRPC population, PSMA ADC demonstrated acceptable toxicity. Antitumor activity was observed over dose ranges up to and including 2.5 mg/kg. The observed anti-tumor activity supported further evaluation of this novel agent for the treatment of advanced metastatic prostate cancer.


Assuntos
Anticorpos Monoclonais , Neoplasias da Próstata , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Imunoglobulinas Intravenosas/farmacocinética , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Células Neoplásicas Circulantes/patologia , Oligopeptídeos/metabolismo , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
3.
J Transl Med ; 17(1): 271, 2019 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-31426803

RESUMO

BACKGROUND: ACAM2000, a thymidine kinase (TK)-positive strain of vaccinia virus, is the current smallpox vaccine in the US. Preclinical testing demonstrated potent oncolytic activity of ACAM2000 against several tumor types. This Phase I clinical trial of ACAM2000 delivered by autologous adipose stromal vascular fraction (SVF) cells was conducted to determine the safety and feasibility of such a treatment in patients with advanced solid tumors or acute myeloid leukemia (AML). METHODS: Twenty-four patients with solid tumors and two patients with AML participated in this open-label, non-randomized dose-escalation trial. All patients were treated with SVF derived from autologous fat and incubated for 15 min to 1 h with ACAM2000 before application. Six patients received systemic intravenous application only, one patient received intra-tumoral application only, 15 patients received combination intravenous with intra-tumoral deployment, 3 patients received intravenous and intra-peritoneal injection and 1 patient received intravenous, intra-tumoral and intra-peritoneal injections. Safety at each dose level of ACAM2000 (1.4 × 106 plaque-forming units (PFU) to 1.8 × 107 PFU) was evaluated. Blood samples for PK assessments, flow cytometry and cytokine analysis were collected at baseline and 1 min, 1 h, 1 day, 1 week, 1 month, 3 months and 6 months following treatment. RESULTS: No serious toxicities (> grade 2) were reported. Seven patients reported an adverse event (AE) in this study: self-limiting skin rashes, lasting 7 to 18 days-an expected adverse reaction to ACAM2000. No AEs leading to study discontinuation were reported. Viral DNA was detected in all patients' blood samples immediately following treatment. Interestingly, in 8 patients viral DNA disappeared 1 day and re-appeared 1 week post treatment, suggesting active viral replication at tumor sites, and correlating with longer survival of these patients. No major increase in cytokine levels or correlation between cytokine levels and skin rashes was noted. We were able to assess some initial efficacy signals, especially when the ACAM2000/SVF treatment was combined with checkpoint inhibition. CONCLUSIONS: Treatment with ACAM2000/SVF in patients with advanced solid tumors or AML is safe and well tolerated, and several patients had signals of an anticancer effect. These promising initial clinical results merit further investigation of therapeutic utility. Trial registration Retrospectively registered (ISRCTN#10201650) on October 22, 2018.


Assuntos
Tecido Adiposo/irrigação sanguínea , Tecido Adiposo/citologia , Vírus Oncolíticos/fisiologia , Timidina Quinase/metabolismo , Vaccinia virus/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , DNA Viral/sangue , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Terapia Viral Oncolítica/efeitos adversos , Células Estromais/metabolismo , Resultado do Tratamento , Adulto Jovem
4.
Phys Biol ; 12(1): 016008, 2015 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-25574741

RESUMO

Purpose. Circulating melanoma cells (CMCs) constitute a potentially important representation of time-resolved tumor biology in patients. To date, genomic characterization of CMCs has been limited due to the lack of a robust methodology capable of identifying them in a format suitable for downstream characterization. Here, we have developed a methodology to detect intact CMCs that enables phenotypic, morphometric and genomic analysis at the single cell level. Experimental design. Blood samples from 40 metastatic melanoma patients and 10 normal blood donors were prospectively collected. A panel of 7 chondroitin sulfate proteoglycan 4 (CSPG4)-specific monoclonal antibodies (mAbs) was used to immunocytochemically label CMCs. Detection was performed by automated digital fluorescence microscopy and multi-parametric computational analysis. Individual CMCs were captured by micromanipulation for whole genome amplification and copy number variation (CNV) analysis. Results. Based on CSPG4 expression and nuclear size, 1-250 CMCs were detected in 22 (55%) of 40 metastatic melanoma patients (0.5-371.5 CMCs ml(-1)). Morphometric analysis revealed that CMCs have a broad spectrum of morphologies and sizes but exhibit a relatively homogeneous nuclear size that was on average 1.5-fold larger than that of surrounding PBMCs. CNV analysis of single CMCs identified deletions of CDKN2A and PTEN, and amplification(s) of TERT, BRAF, KRAS and MDM2. Furthermore, novel chromosomal amplifications in chr12, 17 and 19 were also found. Conclusions. Our findings show that CSPG4 expressing CMCs can be found in the majority of advanced melanoma patients. High content analysis of this cell population may contribute to the design of effective personalized therapies in patients with melanoma.


Assuntos
Genoma Humano/genética , Melanoma/genética , Melanoma/patologia , Células Neoplásicas Circulantes/patologia , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Feminino , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias
5.
CNS Oncol ; 12(3): CNS102, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37462385

RESUMO

Aim: The EMulate Therapeutics Voyager™ is a simple, wearable, home-use device that uses an alternating electromagnetic field to alter biologic signaling within cells. Objective: To assess the safety/feasibility of the Voyager in the treatment of recurrent glioblastoma (rGBM). Methods: In this study, patients with rGBM were treated with Voyager as monotherapy or in combination with standard chemotherapy at the Investigator's discretion. Safety was assessed by incidence of adverse events associated with the Voyager. Patients were followed until death. Results: A total of 75 patients were enrolled and treated for at least one day with the Voyager (safety population). Device-related adverse events were uncommon and generally did not result in interruption or withdrawal from treatment. There were no serious adverse events associated with Voyager. A total of 60 patients were treated for at least one month (clinical utility population). The median progression-free survival (PFS) was 17 weeks (4.3 months) in the Voyager only group (n = 24) and 21 weeks (5.3 months) in the Voyager + concurrent therapy group (n = 36). The median overall survival (OS) was 7 months in the Voyager only group and 9 months in the Voyager + concurrent therapy group. In patients treated with Voyager + concurrent therapy, the median OS for patients enrolled with their 1st or 2nd recurrence (n = 26) was 10 months, while in patients enrolled with their 3rd or 4th recurrence (n = 10) OS was 7 months. Conclusion: The data support the safety and feasibility of the Voyager for the treatment of rGBM. Further prospective study of the device is warranted. Trial Registration Number: NCT02296580 (ClinicalTrials.gov).


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Neoplasias Encefálicas/tratamento farmacológico , Estudos de Viabilidade , Glioblastoma/tratamento farmacológico , Recidiva Local de Neoplasia , Estudos Prospectivos
6.
J Immunother Cancer ; 8(2)2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32641320

RESUMO

BACKGROUND: We report the clinical activity and safety of bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the transforming growth factor ß (TGF-ß)RII receptor (a TGF-ß 'trap') fused to a human IgG1 monoclonal antibody blocking programmed death-ligand 1 (PD-L1), in patients with heavily pretreated squamous cell carcinoma of the head and neck (SCCHN). METHODS: In this phase I dose-expansion cohort, patients with advanced SCCHN not amenable to curative therapy that progressed/recurred after platinum therapy in the recurrent/metastatic setting, or <6 months after platinum therapy in the locally advanced setting, received bintrafusp alfa 1200 mg intravenously every 2 weeks. The primary endpoint was confirmed best overall response (BOR; Response Evaluation Criteria for Solid Tumors (RECIST) 1.1) per independent review committee (IRC); other endpoints included BOR per investigator and safety. RESULTS: As of August 24, 2018, 32 patients had received bintrafusp alfa (median follow-up 86.4 weeks; range 2-97). Per IRC, the confirmed objective response rate (ORR) was 13% (95% CI 4% to 29%; 4 partial responses (PR)); 4 patients had stable disease (SD) (disease control rate 34%; 95% CI 12% to 43%). Per investigator, there were 5 PRs (ORR, 16%), including 2 patients who developed delayed PRs after initial disease increase (total clinical response rate 22%). Responses (ORRs) were observed in patients with PD-L1-positive (12%), PD-L1-negative (17%; 73-10 antibody for immunohistochemistry), human papillomavirus (HPV)-positive (33%) and HPV-negative tumors (5%). Grade 3 treatment-related adverse events (TRAEs) were reported in 11 patients (34%), with no grade 4 TRAEs or treatment-related deaths. CONCLUSIONS: Bintrafusp alfa showed clinical activity across subgroups of PD-L1 expression and in HPV-positive tumors and had a manageable safety profile in patients with heavily pretreated advanced SCCHN. Activity in HPV-positive tumors is favorable compared with historical data from PD-L1 inhibitors and is being further investigated in an ongoing study of HPV-associated tumors. TRIAL REGISTRATION NUMBER: NCT02517398.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Fator de Crescimento Transformador beta/efeitos dos fármacos , Idoso , Antineoplásicos Imunológicos/farmacologia , Feminino , Humanos , Masculino
7.
J Immunother Cancer ; 8(2)2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32907924

RESUMO

INTRODUCTION: Avelumab, an antiprogrammed death ligand-1 antibody, is approved as a monotherapy for treatment of metastatic Merkel cell carcinoma and advanced urothelial carcinoma, and in combination with axitinib for advanced renal cell carcinoma. We report the efficacy and safety of first-line avelumab in advanced non-small cell lung cancer (NSCLC). METHODS: In a phase I expansion cohort of the JAVELIN Solid Tumor trial, patients with treatment-naive, metastatic, or recurrent NSCLC received 10 mg/kg avelumab intravenously every 2 weeks. Endpoints included best overall response, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Overall, 156 patients were enrolled and treated. Median duration of follow-up was 18.6 months (range, 15 to 23 months). The objective response rate was 19.9% (95% CI, 13.9 to 27.0), including complete response in 3 (1.9%) and partial response in 28 (17.9%). Median DOR was 12.0 months (95% CI, 6.9 to not estimable). Median PFS was 4.0 months (95% CI, 2.7 to 5.4) and the 6-month PFS rate was 38.5% (95% CI, 30.7 to 46.3). Median OS was 14.1 months (95% CI, 11.3 to 16.9) and the 12-month OS rate was 56.6% (95% CI, 48.2 to 64.1). Treatment-related adverse events (TRAEs) occurred in 107 patients (68.6%), including grade ≥3 TRAEs in 19 (12.2%). Immune-related adverse events and infusion-related reactions occurred in 31 (19.9%) and 40 patients (25.6%), respectively. No treatment-related deaths occurred. CONCLUSION: Avelumab showed antitumor activity with a tolerable safety profile as a first-line treatment in patients with advanced NSCLC. These data support further investigation of avelumab in the phase III JAVELIN Lung 100 study. TRIAL REGISTRATION DETAILS: ClinicalTrials.gov NCT01772004; registered January 21, 2013.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos Imunológicos/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
8.
J Immunother Cancer ; 8(2)2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33323462

RESUMO

BACKGROUND: Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor (TGF)-ßRII (a TGF-ß 'trap') fused to a human IgG1 mAb blocking programmed cell death ligand 1. This is the largest analysis of patients with advanced, pretreated human papillomavirus (HPV)-associated malignancies treated with bintrafusp alfa. METHODS: In these phase 1 (NCT02517398) and phase 2 trials (NCT03427411), 59 patients with advanced, pretreated, checkpoint inhibitor-naive HPV-associated cancers received bintrafusp alfa intravenously every 2 weeks until progressive disease, unacceptable toxicity, or withdrawal. Primary endpoint was best overall response per Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1; other endpoints included safety. RESULTS: As of April 17, 2019 (phase 1), and October 4, 2019 (phase 2), the confirmed objective response rate per RECIST V.1.1 in the checkpoint inhibitor-naive, full-analysis population was 30.5% (95% CI, 19.2% to 43.9%; five complete responses); eight patients had stable disease (disease control rate, 44.1% (95% CI, 31.2% to 57.6%)). In addition, three patients experienced a delayed partial response after initial disease progression, for a total clinical response rate of 35.6% (95% CI, 23.6% to 49.1%). An additional patient with vulvar cancer had an unconfirmed response. Forty-nine patients (83.1%) experienced treatment-related adverse events, which were grade 3/4 in 16 patients (27.1%). No treatment-related deaths occurred. CONCLUSION: Bintrafusp alfa showed clinical activity and manageable safety and is a promising treatment in HPV-associated cancers. These findings support further investigation of bintrafusp alfa in patients with advanced, pretreated HPV-associated cancers.


Assuntos
Antígeno B7-H1/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Papillomaviridae/efeitos dos fármacos , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/tratamento farmacológico , Fator de Crescimento Transformador beta/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/virologia , Infecções por Papillomavirus/patologia
9.
Melanoma Manag ; 6(2): MMT20, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31406564

RESUMO

AIM: Metastatic melanoma patients were treated with patient-specific vaccines consisting of autologous dendritic cells loaded with antigens from irradiated cells from short-term autologous tumor cell lines. PATIENTS & METHODS: A total of 72 patients were enrolled in a single-arm Phase I/II (NCT00948480) trial or a randomized Phase II (NCT00436930). RESULTS: Toxicity was minimal. Median overall survival (OS) was 49.4 months; 5-year OS 46%. A 5-year OS was 72% for 18 recurrent stage 3 without measurable disease when treated and 53% for 30 stage 4 without measurable disease when treated. A total of 24 patients with measurable stage 4 when treated (median of four prior therapies) had an 18.5 months median OS and 46% 2-year OS. CONCLUSION: This dendritic cell vaccine was associated with encouraging survival in all three clinical subsets. Clinicaltrial.gov NCT00436930 and NCT00948480.

10.
CNS Oncol ; 8(1): CNS30, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30547676

RESUMO

AIM: Evaluation of the Nativis Voyager® device in patients with recurrent glioblastoma (rGBM). MATERIALS & METHODS: Voyager is a noninvasive, nonthermal, nonionizing and portable investigational device which delivers ultra-low radio frequency energy (ulRFE®) that uses a magnetic field to penetrate tissues to alter specific biologic functions within cells. Patients with rGBM were treated with Voyager alone (V) or Voyager in combination with standard of care (V + SoC). Safety and clinical utility were assessed every 2-4 months. RESULTS: Data from the first 11 patients treated are reported here. Median progression-free survival was 10 weeks in the V arm and 16 weeks in the V + SoC arm. Median overall survival was 16 months in V arm and 11 months in the V + SoC arm. No serious adverse events associated with the device were reported. CONCLUSION: These data suggest that the Voyager is safe and feasible for the treatment of rGBM.


Assuntos
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Magnetoterapia , Recidiva Local de Neoplasia/terapia , Adulto , Encéfalo/diagnóstico por imagem , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/mortalidade , Estudos de Coortes , Estudos de Viabilidade , Feminino , Glioblastoma/diagnóstico por imagem , Glioblastoma/mortalidade , Humanos , Magnetoterapia/instrumentação , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/mortalidade , Análise de Sobrevida , Resultado do Tratamento , Estados Unidos
11.
Lung Cancer ; 62(1): 92-8, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18367288

RESUMO

PURPOSE: Retrospective data suggests prolonging the time to complete thoracic radiotherapy (TRT) may negatively impact tumor control and survival in limited stage small cell lung cancer (LSCLC). We examined the association between TRT duration and outcomes on a prospective phase III study. MATERIAL AND METHODS: This review included 267 patients who received protocol TRT on a phase III CALGB LSCLC study assessing the addition of tamoxifen to standard chemo-radiotherapy. TRT, to a planned dose of 50Gy in 2Gy daily fractions, was initiated with the fourth chemotherapy cycle. TRT interruptions were mandated for hematologic toxicity (granulocytes<1000/mm3 or platelets<75,000/mm3) and esophageal toxicity (dysphagia necessitating intravenous hydration). RESULTS: TRT interruptions > or =3 days occurred in 115 patients (43%), most frequently during the 4th week of TRT, and did not differ between treatment arms. Hematologic toxicity and esophageal toxicity were the most frequent indications for interrupting TRT. Variables including advanced age (>70 years), gender, race, or radiotherapy treatment volume did not predict for TRT interruptions. Overall survival (OS) and local tumor control did not correlate with the administration of TRT interruptions or with TRT duration. CONCLUSION: Toxicity mandated interruptions of conventional dose, once-daily, TRT may not adversely affect outcomes for patients receiving TRT concurrent with chemotherapy (cycle 4) for LSCLC. The implications for accelerated or high dose TRT regimens are not clear.


Assuntos
Neoplasias Pulmonares/radioterapia , Radioterapia/efeitos adversos , Radioterapia/métodos , Carcinoma de Pequenas Células do Pulmão/radioterapia , Antineoplásicos/administração & dosagem , Terapia Combinada , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/mortalidade , Tamoxifeno/administração & dosagem , Resultado do Tratamento
12.
J Immunother Cancer ; 6(1): 19, 2018 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-29510745

RESUMO

BACKGROUND: Despite improved survival following checkpoint inhibitors, there is still a potential role for anti-cancer therapeutic vaccines. Because of biological heterogeneity and neoantigens resulting from each patient's mutanome, autologous tumor may be the best source of tumor-associated antigens (TAA) for vaccines. Ex vivo loading of autologous dendritic cells with TAA may be associated with superior clinical outcome compared to injecting irradiated autologous tumor cells. We conducted a randomized phase II trial to compare autologous tumor cell vaccines (TCV) and autologous dendritic cell vaccines (DCV) loaded with autologous TAA. METHODS: Short-term autologous tumor cell lines were established from metastatic tumor. Vaccines were admixed with 500 micrograms of GM-CSF and injected weekly for 3 weeks, then at weeks 8, 12,16, 20, and 24. The primary endpoint was overall survival. Secondary objectives were identification of adverse events, and results of delayed type hypersensitivity (DTH) reactions to intradermal tumor cell injections. RESULTS: Forty-two patients were randomized. All were followed from randomization until death or for five years; none were lost to follow-up. DCV was associated with longer survival: median 43.4 versus 20.5 months (95% CI, 18.6 to > 60 versus 9.3 to 32.3 months) and a 70% reduction in the risk of death (hazard ratio = 0.304, p = 0.0053, 95% CI, 0.131 to 0.702). Tumor DTH reactions were neither prognostic nor predictive. The most common treatment-related adverse events were mild to moderate local injection site reactions and flu-like symptoms; but grade 2 treatment-related adverse events were more frequent with TCV. Serum marker analyses at week-0 and week-4 showed that serum markers were similar at baseline in each arm, but differed after vaccination. CONCLUSIONS: This is the only human clinical trial comparing DCV and TCV as platforms for autologous TAA presentation. DCV was associated with minimal toxicity and long-term survival in patients with metastatic melanoma. DTH to autologous tumor cells was neither prognostic for survival nor predictive of benefit for either vaccine. TRIAL REGISTRATION: Clinical trials.gov NCT00948480 retrospectively registered 28 July 2009.


Assuntos
Vacinas Anticâncer/uso terapêutico , Células Dendríticas/transplante , Melanoma/terapia , Citocinas/sangue , Feminino , Humanos , Hipersensibilidade Tardia , Masculino , Melanoma/sangue , Pessoa de Meia-Idade , Análise de Sobrevida , Transplante Autólogo/efeitos adversos
13.
Med Oncol ; 24(2): 147-53, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17848737

RESUMO

A phase I/II trial was conducted to determine the toxicities and efficacy (overall response, overall survival, and progression-free survival) of the combination of topotecan and whole brain radiation therapy (XRT) in patients with brain metastases. Patients received 30 Gy XRT given in 10 fractions to the whole brain. In phase I, patients were treated in groups of three at each topotecan dose level; dose escalation proceeded until the maximum tolerated dose (MTD) was identified. The dose-limiting toxicity proved to be grade IV neutropenia at 0.6 mg/m2/d, resulting in an MTD of 0.5 mg/m2/d. One of nine patients showed a response to treatment, and that was partial (OR 11%). Three had stable disease (33%), and four experienced progressive disease (44%). Median progression-free survival was 60 d; median overall survival was 102 d. Intravenous topotecan at 0.5 mg/m2/d concomitant to XRT with 30 Gy in 3-Gy fractions is tolerable in patients with brain metastases. This regimen has the additional advantage of providing systemic treatment to patients with metastases in other locations while whole brain radiation is in progress. Although response and survival outcomes in this small study do not appear higher than expected from historical controls, these were not primary end points, and larger studies on this topic would be useful to elucidate the efficacy of this combination treatment regimen.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Topotecan/uso terapêutico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Dosagem Radioterapêutica , Topotecan/administração & dosagem , Topotecan/efeitos adversos , Resultado do Tratamento
14.
Cancer Chemother Pharmacol ; 79(4): 681-688, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28289865

RESUMO

PURPOSE: A phase I two-period two sequence cross-over study compared the bioavailability of two pimasertib (MSC1936369B/AS703026) formulations (capsule versus tablet) in advanced cancer patients. METHODS: Patients with advanced solid tumors were randomized to one of two treatment sequences utilizing pimasertib tablet (test; 3 × 20 mg, PO QD) and capsule (standard; 2 × 30 mg, PO QD). The trial comprised a screening and baseline period, two time periods or parts A and B, and a trial extension phase. RESULTS: N = 38 patients were randomized to two treatment sequences S1 and S2. PK parameters t 1/2, CL/f, and V z/f were within the same range for the two formulations. Tablet had bioavailability comparable to capsule based on the analysis of AUC0-t, however, tablet administration resulted in an increase of ~25% in C max versus capsule. Common predicted adverse events of pimasertib included ocular events, diarrhea and creatine phosphokinase elevation. Disease control rate was ~29% with 1 partial response and 4 of 10 patients with stable disease >4 months. CONCLUSIONS: Pimasertib tablet was overall well tolerated, had a similar safety and efficacy profile to standard capsule formulation and had bioavailability comparable to capsule.


Assuntos
Antineoplásicos/farmacocinética , Neoplasias/metabolismo , Niacinamida/análogos & derivados , Inibidores de Proteínas Quinases/farmacocinética , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Área Sob a Curva , Disponibilidade Biológica , Cápsulas , Estudos Cross-Over , Composição de Medicamentos , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Niacinamida/administração & dosagem , Niacinamida/farmacocinética , Niacinamida/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Comprimidos , Resultado do Tratamento
15.
Cancer Biother Radiopharm ; 30(5): 187-94, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26083950

RESUMO

In patients with metastatic melanoma, sequential single-arm and randomized phase II trials with a therapeutic vaccine consisting of autologous dendritic cells (DCs) loaded with antigens from self-renewing, proliferating, irradiated autologous tumor cells (DC-TC) showed superior survival compared with similar patients immunized with irradiated tumor cells (TC). We wished to determine whether this difference was evident in cohorts who at the time of treatment had (1) no evidence of disease (NED) or (2) had detectable disease. Eligibility criteria and treatment schedules were the same for all three trials. Pooled data confirmed that overall survival (OS) was longer in 72 patients treated with DC-TC compared with 71 patients treated with TC (median OS 60 versus 22 months; 5-year OS 51% versus 32%, p=0.004). Treatment with DC-TC was associated with longer OS in both cohorts. Among 70 patients who were NED at the time that treatment was started, OS was better for DC-TC: 5-year OS 73% versus 43% (p=0.015). Among 73 patients who had detectable metastases, OS was better for DC-TC: median 38.8 months versus 14.7 months, 5-year OS 33% versus 20% (p=0.025). This approach is promising as an adjunct to other therapies in patients who have had metastatic melanoma.


Assuntos
Vacinas Anticâncer/uso terapêutico , Células Dendríticas/transplante , Imunoterapia/métodos , Melanoma/terapia , Células-Tronco Neoplásicas/transplante , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Carga Tumoral , Apresentação de Antígeno , Células Dendríticas/imunologia , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Humanos , Interferon gama/administração & dosagem , Masculino , Melanoma/imunologia , Melanoma/secundário , Antígenos Específicos de Melanoma/imunologia , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/imunologia , Neoplasias Cutâneas/imunologia , Taxa de Sobrevida , Células Tumorais Cultivadas/imunologia
16.
Semin Oncol ; 29(4): 389-99, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12170442

RESUMO

The role of adjuvant therapy in the treatment of patients with high-risk malignant melanoma remains an area of intense investigation. The initial enthusiasm for high-dose interferon has been tempered by the results of more recent studies that allow for conflicting interpretations. Vaccine therapy trials have failed to clearly demonstrate a survival benefit, although several trials are currently ongoing. Recent studies of the role of chemotherapy suggest there may be combinations that have a survival benefit which deserve further study. This article will address patient selection and staging workup, and review options for treatment.


Assuntos
Melanoma/terapia , Terapia Neoadjuvante , Neoplasias Cutâneas/terapia , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Quimioterapia Adjuvante , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Humanos , Interferons/administração & dosagem , Interferons/uso terapêutico , Melanoma/patologia , Melanoma/secundário , Estadiamento de Neoplasias , Seleção de Pacientes , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Biópsia de Linfonodo Sentinela , Neoplasias Cutâneas/patologia , Taxa de Sobrevida , Tomografia Computadorizada de Emissão , Tomografia Computadorizada por Raios X
17.
Semin Oncol ; 29(5): 413-26, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12407507

RESUMO

The role of systemic chemotherapy in the treatment of patients with metastatic melanoma remains of questionable benefit. Despite encouraging phase II data from multiple institutions that suggested an improved overall response rate for patients treated with the Dartmouth regimen, recently completed phase III trials have failed to demonstrate a significant benefit in survival. Of concern is the fact that there have been relatively few new chemotherapeutic agents in the past several years that have demonstrated any activity in this disease. More recently there has been a shift away from combination chemotherapy to biochemotherapy. However, this approach has yet to be clearly defined as superior. The basis for optimism in the future in this field resides in the realm of molecular oncology. As mechanisms of resistance are identified, new molecules such as antisense oligonucleotides may provide the basis for increasing the sensitivity of melanoma to chemotherapeutic and/or immunotherapeutic treatments.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dacarbazina/análogos & derivados , Melanoma/tratamento farmacológico , Melanoma/secundário , Taxoides , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Carmustina/administração & dosagem , Carmustina/uso terapêutico , Cisplatino/administração & dosagem , Ensaios Clínicos como Assunto , Dacarbazina/administração & dosagem , Dacarbazina/uso terapêutico , Humanos , Compostos de Nitrosoureia/uso terapêutico , Paclitaxel/uso terapêutico , Tamoxifeno/administração & dosagem , Temozolomida
19.
Cancer Biother Radiopharm ; 19(5): 658-65, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15650459

RESUMO

AIM: The aim of this study was to investigate the feasibility, safety, and clinical efficacy of patient-specific dendritic cell vaccines in patients with metastatic melanoma. A planned interim analysis was conducted on the first 20 patients. METHODS: Tumor cell lines were established from metastatic tumor, expanded to 200 million cells, and then incubated with interferon-gamma for patients who were candidates for therapy. Cells were irradiated and cryopreserved. Patients underwent leukapheresis to obtain mononuclear cells that were cultured in the presence of IL-4 and GM-CSF to produce dendritic cells, which were incubated with cryopreserved, irradiated tumor cells, and then stored in aliquots of about 20 million cells for subcutaneous (s.c.) injections with GM-CSF once a week for 3 weeks, then once a month for 5 months. RESULTS: The first 20 eligible patients included 10 men and 10 women, with a median age of 48 years (range, 16-79 years). Three (3) patients had brain metastases, and 13 patients had experienced disease progression after biochemotherapy. At the time of vaccine treatment, 6 patients had evaluable metastatic disease, while 14 patients lacked measurable disease. Vaccine therapy was well tolerated, except for what appeared to be GM-CSF-related allergic reactions in 2 patients. Delayed-type hypersensitivity (DTH) tests to irradiated tumor cells were positive in 0 of 20 patients tested at baseline, but converted to positive in 8 patients (40%). At a median follow-up of 13.8 months, there is a 95% overall survival and a 48% progression-free survival. Four (4) patients have already survived more than 3.0 years since starting the vaccine. CONCLUSION: Based on tolerability, rate of tumor DTH conversion, and encouraging survival, the trial will continue accrual to at least 19 patients with measurable disease and 40 patients who lack measurable disease at the time of treatment.


Assuntos
Vacinas Anticâncer , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Melanoma/tratamento farmacológico , Antígeno Nuclear de Célula em Proliferação/metabolismo , Adolescente , Adulto , Idoso , Linhagem Celular Tumoral , Criopreservação , Células Dendríticas/citologia , Progressão da Doença , Intervalo Livre de Doença , Feminino , Seguimentos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Hipersensibilidade Tardia , Interferon gama/metabolismo , Interleucina-4/metabolismo , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Transplante de Neoplasias , Neoplasias/metabolismo , Antígeno Nuclear de Célula em Proliferação/farmacologia , Recidiva , Fatores de Tempo , Resultado do Tratamento
20.
J Immunother ; 35(8): 641-9, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22996370

RESUMO

Only 10% of metastatic melanoma patients survive 5 years, even though many can achieve substantial tumor reduction by surgical resection and/or radiation therapy and/or systemic therapy. An effective, nontoxic, consolidation immunotherapy could benefit such patients. We initiated a randomized trial to compare 2 promising patient-specific immunotherapy cell products. Patients had to have a diagnosis of metastatic melanoma and availability of an autologous melanoma cell line. Patients were stratified by whether their most advanced stage had been regional or distant metastases, and by whether they had measurable disease at the time of treatment, then they were randomized to receive irradiated autologous proliferating tumor cells or autologous dendritic cells (DC) loaded with antigens from such cells. Both products were injected subcutaneously in 500 µg of granulocyte-macrophage colony stimulating factor, weekly for 3 weeks and then monthly for 5 months. Patients in the 2 arms did not differ in baseline characteristics. All patients received prescribed therapy. Treatment was well tolerated. At the time of initial analysis, with no patients lost to follow-up, 50% of patients deceased, and all surviving patients followed for at least 6 months after randomization, survival is superior in the DC arm (hazard ratio, 0.27; 95% confidence interval, 0.098-0.729) with median survival not reached versus 15.9 months, and 2-year survival rates of 72% versus 31% (P=0.007). This trial provides evidence that a DC vaccine is associated with longer survival compared with a tumor cell vaccine, and is consistent with previous data suggesting a survival benefit from this patient-specific immunotherapy.


Assuntos
Vacinas Anticâncer/uso terapêutico , Células Dendríticas/transplante , Imunoterapia/métodos , Melanoma/terapia , Células-Tronco Neoplásicas/transplante , Neoplasias Cutâneas/terapia , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Seguimentos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Humanos , Masculino , Melanoma/imunologia , Melanoma/secundário , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/imunologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Análise de Sobrevida
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