RESUMO
PURPOSE: Treatment options are limited in patients with metastatic neuroendocrine neoplasms (NEN). We present the results for a phase II trial of combination nivolumab and temozolomide in patients with advanced NEN along with results of immune changes in peripheral blood. PATIENTS AND METHODS: NCT03728361 is a nonrandomized, phase II study of nivolumab and temozolomide in patients with NEN. The primary endpoint was response rate using RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Immune profiling was performed by mass cytometry to evaluate the effect on peripheral blood immune cell subsets. RESULTS: Among all 28 patients with NEN, the confirmed response rate was 9/28 [32.1%, 95% confidence interval (CI): 15.9-52.4]. Of 11 patients with lung NEN, the response rate was 64% (n = 7); there was a significant difference in responses by primary tumor location (lung vs. others, P = 0.020). The median PFS was 8.8 months (95% CI: 3.9-11.1 months), and median OS was 32.3 months (95% CI: 20.7-not reached months). Exploratory blood immune cell profiling revealed an increase in circulating CD8+ T cells (27.9% ± 13.4% vs. 31.7% ± 14.6%, P = 0.03) and a decrease in CD4+ T cells (59.6% ± 13.1% vs. 56.5% ± 13.0%, P = 0.001) after 2 weeks of treatment. LAG-3-expressing total T cells were lower in patients experiencing a partial response (0.18% ± 0.24% vs. 0.83% ± 0.55%, P = 0.028). Myeloid-derived suppressor cell levels increased during the study and did not correlate with response. CONCLUSIONS: Combination nivolumab and temozolomide demonstrated promising activity in NEN. See related commentary by Velez and Garon, p. 691.
Assuntos
Neoplasias Pulmonares , Tumores Neuroendócrinos , Humanos , Nivolumabe/uso terapêutico , Temozolomida/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Tumores Neuroendócrinos/tratamento farmacológico , Intervalo Livre de ProgressãoRESUMO
PURPOSE: Nuclear factor-kappaB (NF-kappaB) activation induces resistance to irinotecan. Preclinically, thalidomide and COX-2 inhibitors reduce NF-kappaB activation. We tested the feasibility of combining irinotecan with thalidomide and thalidomide/celecoxib in patients with refractory malignancies. PATIENTS/METHODS: The study was conducted in two parts. First, the optimal dose of thalidomide (400 or 200 mg daily) in combination with irinotecan 125 mg/m(2) days 1 and 8 every 3 weeks was determined. In the second part, celecoxib 400 mg twice-daily was added to irinotecan/thalidomide. Pharmacokinetics of irinotecan and thalidomide alone or concurrently were evaluated. Tumor necrosis factor alpha, beta-fibroblast growth factor, and NF-kappaB activation were measured in blood mononuclear cells (PBMC). No CYP450 enzyme inducers/inhibitors were allowed. RESULTS: Thirty-six patients were enrolled: Eleven received thalidomide 400 mg, 13 thalidomide 200 mg and 12 thalidomide 400 mg and celecoxib, with irinotecan. For the two-drug combination, there was a higher rate of moderate/severe diarrhea/myelosuppression with thalidomide 200 mg. Thus thalidomide 400 mg was combined with celecoxib. The triple combination resulted in similar toxicity as the doublet with the lower thalidomide dose. Concurrent administration of irinotecan/thalidomide did not influence pharmacokinetics. Anti-tumor responses occurred in two patients and prolonged stabilization in eight others. NF-kappaB activation increased over time. Patients experiencing tumor response or prolonged stabilization had lower NF-kappaB activation, albeit not statistically significant (P = 0.124). CONCLUSIONS: The combination of thalidomide/irinotecan is safe and devoid of PK interactions. Thalidomide 400 mg appeared more suitable for combination, whereas the addition of celecoxib did not improve tolerability. Tumor-specific studies in patients with lesser prior treatment will be necessary to establish the therapeutic impact of the combinations.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Camptotecina/análogos & derivados , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Neoplasias/tratamento farmacológico , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Talidomida/uso terapêutico , Adulto , Idoso , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Área Sob a Curva , Camptotecina/administração & dosagem , Camptotecina/farmacocinética , Camptotecina/uso terapêutico , Celecoxib , Quimioterapia Adjuvante , Cromatografia Líquida de Alta Pressão , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Fator 2 de Crescimento de Fibroblastos/metabolismo , Seguimentos , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , NF-kappa B/antagonistas & inibidores , Neoplasias/patologia , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Talidomida/administração & dosagem , Talidomida/farmacocinética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
PURPOSE: This phase II study was undertaken to assess objective response, toxicity, tumor marker response, and pharmacodynamics of bortezomib in patients with metastatic neuroendocrine (carcinoid and islet cell) tumors. EXPERIMENTAL DESIGN: A total of 16 patients with measurable metastatic carcinoid (n=12) or islet cell (n=4) tumors received i.v. bolus of single agent bortezomib at a dose of 1.5 mg/m2 on days 1, 4, 8, and 11 every 21 days. Tumor response was assessed at 12-week intervals using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. All patients were chemotherapy naïve and had Eastern Cooperative Oncology Group performance status of 0 to 1. RESULTS: No patient achieved a partial or a complete remission. The patients received total of 264 doses of therapy with a median of 15 doses per patient. Grade 4 toxicities were not observed. The most common grade 3 adverse events included peripheral sensory neuropathy (37%), diarrhea (25%), vomiting (18%), and ileus (18%). Six of 10 patients who experienced grade 2 to 3 peripheral sensory neuropathy also had grade 2 to 3 dizziness (n=2), orthostatic hypotension (n=2), syncope (n=1), ileus (n=2), or abdominal cramps (n=1). Changes in tumor marker levels did not correlate with tumor response. The mean percentage of 20S proteasome inhibition achieved in whole blood at 1 and 24 hours after bortezomib administration was 68 and 30%, respectively. CONCLUSIONS: Despite achieving the surrogate biologic end point, single-agent bortezomib did not induce any objective responses in patients with metastatic carcinoid or islet cell tumors. Additional investigation is warranted to clarify the possible association of autonomic neuropathy with bortezomib.
Assuntos
Antineoplásicos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Tumor Carcinoide/tratamento farmacológico , Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Inibidores de Proteases/uso terapêutico , Pirazinas/uso terapêutico , Adulto , Idoso , Biomarcadores Tumorais , Bortezomib , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Metástase Neoplásica , Inibidores de Proteassoma , Fatores de Tempo , Resultado do TratamentoRESUMO
Paclitaxel and carboplatin upregulate thymidine phosphorylase and thus may provide synergistic antitumor activity in combination with capecitabine (CTX). We, therefore, performed a phase I/II study of CTX. In the phase I study, patients with advanced solid tumors received carboplatin on day 1, paclitaxel on days 1, 8, 15 and capecitabine orally twice a day on days 8-21, every 4 weeks. Phase II patients with advanced adenocarcinoma of unknown primary (ACUP) were treated at the maximal tolerable dose. The phase I study enrolled 29 patients evaluable for dose limiting toxicity. The recommended phase II dose was capecitabine 750 mg/m(2) bid, paclitaxel 60 mg/m(2)/week and carboplatin AUC of 6. There were 9 confirmed responses, 5 partial responses and disease stabilization >3 months in 14 patients. The phase II study was prematurely terminated at 25 patients due to cessation of funding. The objective response rate was 32 % (95 % CI 0.15-0.54), the median progression-free survival 5.5 months (95 % CI 2.8-10.8 months) and the median overall survival 10.8 months (95 % CI 6.0-32.0 months). CTX demonstrated acceptable tolerability and antitumor activity. At the recommended dose level in patients with ACUP, this regimen showed encouraging preliminary activity.