RESUMO
TriN 2755 is an alkylating antineoplastic agent for intravenous (IV) use, carrying the triazene group as the cytotoxic principal. Using a standard 3 + 3 design, a phase I study was performed in tumour bearing dogs to determine the maximum tolerated dose (MTD), the dose limiting toxicity (DLT), and pharmacokinetic (PK) profile of TriN 2755. Thirty dogs were included in the study. TriN 2755 was administered over 20 min on two consecutive weeks per month for a total of three cycles. The starting dose was 25 mg kg-1 and the MTD was 74.6 mg kg-1 . Three dogs experienced DLT, which was characterized by gastrointestinal adverse events. The PKs of TriN 2755 and its main metabolites in plasma and sputum are described in a two-compartment model. The response rate for 19 of 30 dogs was 47.3% (six partial remission, three stable disease) and the median progression-free interval (PFI) for the responders was 47 days (range: 21-450 days).
Assuntos
Antineoplásicos/farmacologia , Doenças do Cão/tratamento farmacológico , Neoplasias/veterinária , Triazenos/farmacologia , Animais , Cães , Relação Dose-Resposta a Droga , Feminino , Masculino , Dose Máxima Tolerável , Neoplasias/tratamento farmacológico , Prognóstico , Análise de Regressão , Suíça , Resultado do TratamentoRESUMO
BACKGROUND: Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure. PATIENTS AND METHODS: Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m(2) either with standard paclitaxel at 200 mg/m(2) (arm A) or PK-guided dosing of paclitaxel (arm B). In arm B, initial paclitaxel dose was adjusted to body surface area, age, sex, and subsequent doses were guided by neutropenia and previous-cycle paclitaxel exposure [time above a plasma concentration of 0.05 µM (Tc>0.05)] determined from a single blood sample on day 2. The primary end point was grade 4 neutropenia; secondary end points included neuropathy, radiological response, progression-free survival (PFS) and overall survival (OS). RESULTS: Among 365 patients randomly assigned, grade 4 neutropenia was similar in both arms (19% versus 16%; P = 0.10). Neuropathy grade ≥2 (38% versus 23%, P < 0.001) and grade ≥3 (9% versus 2%, P < 0.001) was significantly lower in arm B, independent of the platinum drug used. The median final paclitaxel dose was significantly lower in arm B (199 versus 150 mg/m(2), P < 0.001). Response rate was similar in arms A and B (31% versus 27%, P = 0.405), as was adjusted median PFS [5.5 versus 4.9 months, hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.91-1.49, P = 0.228] and OS (10.1 versus 9.5 months, HR 1.05, 95% CI 0.81-1.37, P = 0.682). CONCLUSION: PK-guided dosing of paclitaxel does not improve severe neutropenia, but reduces paclitaxel-associated neuropathy and thereby improves the benefit-risk profile in patients with advanced NSCLC. CLINICAL TRIAL INFORMATION: NCT01326767 (https://clinicaltrials.gov/ct2/show/NCT01326767).
Assuntos
Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/administração & dosagem , Paclitaxel/administração & dosagem , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carboplatina/efeitos adversos , Carboplatina/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/patologia , Cisplatino/efeitos adversos , Cisplatino/farmacocinética , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/efeitos adversos , Paclitaxel/farmacocinéticaRESUMO
BACKGROUND: Panobinostat, a pan-deacetylase inhibitor, overcomes imatinib resistance in preclinical models of gastrointestinal stromal tumours (GIST). Here we determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of panobinostat in combination with imatinib (IM) for treatment of patients with refractory GIST. METHODS: Following a 7-day run-in phase of IM (400 mg per day), escalating doses of panobinostat were added following a '3 plus 3' design. Twelve heavily pretreated GIST patients were enrolled in two dose levels. RESULTS: Most common adverse events were thrombocytopenia, anaemia, fatigue, creatinine elevation, nausea, emesis and diarrhoea. Twenty micrograms of panobinostat and 400 mg IM were declared the MTD. Pharmacologically active concentrations of panobinostat and IM were achieved as evidenced by histone H3 acetylation in blood mononuclear cells in vivo and inhibition of the IM-resistant KIT (D816) mutation in vitro. In FDG-PET-CT scans after IM run-in and following 3 weeks panobinostat treatment, 1 out of 11 evaluable patients showed a metabolic partial response, 7 patients were metabolically stable and 3 patients progressed. Longest treatment duration was 17 weeks (median 6). CONCLUSION: Panobinostat and IM can be administered at doses achieving target inhibition in vivo. Further clinical exploration of patients with treatment-refractory GIST is warranted. Correlative studies in this trial may help to optimise dosing schedules in GIST.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Feminino , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/efeitos adversos , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/efeitos adversos , Mesilato de Imatinib , Indóis/administração & dosagem , Indóis/efeitos adversos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Panobinostat , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversosRESUMO
Albeit platinum complexes are widely used in cancer chemotherapy, their cellular processing has not been completely elucidated so far. In this study the effects of modulating multidrug resistance-associated protein (MRP)-mediated efflux and glutathione (GSH) depletion on the cytotoxicity of oxaliplatin were assessed in a human ileocecal colorectal adenocarcinoma cell line and its oxaliplatin-resistant variant. Upon oxaliplatin exposure, DNA platination was elevated by co-incubation with Gü83, a MRP1 and MRP2 inhibitor, but cytotoxicity was not increased. Addition of oxaliplatin did not alter the cellular GSH content. Following GSH depletion, platinum accumulation was unchanged but cytotoxicity was increased in oxaliplatin-sensitive cells. In conclusion, modulation of MRP-mediated efflux did not affect oxaliplatin cytotoxicity in the investigated cell lines. Intracellular GSH depletion seems to sensitize the cells but does not overcome resistance.
Assuntos
Antineoplásicos/metabolismo , Glutationa/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Compostos Organoplatínicos/metabolismo , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Humanos , Inativação Metabólica , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Compostos Organoplatínicos/toxicidade , Oxaliplatina , Platina/metabolismoRESUMO
INTRODUCTION: Nimotuzumab is a humanized monoclonal antibody that binds to the EGFR. Based on phase I data, the recommended dose has been established at 200 mg weekly. This study was aimed at evaluating the safety and efficacy of nimotuzumab monotherapy in patients (pts) with locally advanced or metastatic pancreatic cancer. METHODS: Pts who failed first line standard chemotherapy for advanced disease and had at least one measurable lesion were eligible for the study. Nimotuzumab was given intravenously at 200 mg once weekly for 6 weeks (wks). Follow up by CT scan was performed after 8 weeks. Pts continued receiving treatment 3-weekly until disease progression or unacceptable toxicity occurred. Endpoints included tumor response (RECIST), progression-free survival (PFS), and safety. RESULTS: A total of 56 pts were enrolled for treatment (ECOG status of 1 [n = 41] or 0 [n = 15]), the majority (47 pts) had metastatic disease. Nearly half of the pts [n = 26] received ≥2 regimens. Pts evaluable for response: n = 36; CR: 0; PR: 0; SD: 6 pts. Median PFS for pts with SD was 19.2 weeks, for all pts 6.7 weeks (95% CI: 6.43-7.14 weeks). PFS after 1 year was 10.3% with a median overall survival of 18.1 weeks. Treatment-related adverse events were generally mild including rash grade 1 in 5 pts. After a single dose of 200 mg, the t(1/2) was calculated to 45 h. CONCLUSION: These data confirm that nimotuzumab is safe and very well tolerated. To improve efficacy, a randomized, placebo-controlled trial with Gem has been initiated.
Assuntos
Adenocarcinoma/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Receptores ErbB/imunologia , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Pancreáticas/patologiaAssuntos
Antineoplásicos/farmacologia , Neoplasias da Túnica Conjuntiva/tratamento farmacológico , Melanoma/tratamento farmacológico , Linhagem Celular Tumoral , Neoplasias da Túnica Conjuntiva/patologia , Humanos , Melanoma/patologia , Mitomicina/farmacologia , Compostos de Nitrosoureia/farmacologia , Compostos Organofosforados/farmacologia , Tretinoína/farmacologiaAssuntos
Anticorpos Monoclonais/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Neoplasias Pancreáticas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologiaAssuntos
Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Neoplasias Hematológicas/tratamento farmacológico , Antibióticos Antineoplásicos/metabolismo , Área Sob a Curva , Ensaios Clínicos como Assunto , Doxorrubicina/análogos & derivados , Doxorrubicina/sangue , Doxorrubicina/química , Doxorrubicina/metabolismo , Monitoramento de Medicamentos , Meia-Vida , Humanos , Infusões Intravenosas , Leucócitos/citologia , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Índice de Gravidade de DoençaAssuntos
Antineoplásicos/farmacocinética , Indazóis/farmacocinética , Neoplasias/metabolismo , Compostos de Rutênio/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Biomarcadores/sangue , Biomarcadores/química , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Adutos de DNA/sangue , Adutos de DNA/química , Relação Dose-Resposta a Droga , Meia-Vida , Humanos , Indazóis/administração & dosagem , Indazóis/química , Indazóis/uso terapêutico , Infusões Intravenosas , Leucócitos/química , Taxa de Depuração Metabólica , Neoplasias/tratamento farmacológico , Compostos Organometálicos , Compostos de Rutênio/administração & dosagem , Compostos de Rutênio/química , Compostos de Rutênio/uso terapêutico , Albumina Sérica/análise , Albumina Sérica/química , Albumina Sérica/metabolismo , Transferrina/análise , Transferrina/química , Transferrina/metabolismoAssuntos
Antineoplásicos/farmacocinética , Benzenossulfonatos/farmacocinética , Nefropatias/terapia , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/farmacocinética , Diálise Renal , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Benzenossulfonatos/metabolismo , Benzenossulfonatos/uso terapêutico , Coleta de Amostras Sanguíneas , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Esquema de Medicação , Humanos , Nefropatias/sangue , Nefropatias/fisiopatologia , Niacinamida/análogos & derivados , Compostos de Fenilureia , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/química , Piridinas/metabolismo , Piridinas/uso terapêutico , Sorafenibe , Fatores de TempoAssuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Ácido Oxônico/farmacocinética , Ácido Oxônico/uso terapêutico , Tegafur/farmacocinética , Tegafur/uso terapêutico , 2-Piridinilmetilsulfinilbenzimidazóis/administração & dosagem , Administração Oral , Antiulcerosos/administração & dosagem , Antimetabólitos Antineoplásicos/sangue , Antimetabólitos Antineoplásicos/farmacocinética , Área Sob a Curva , Disponibilidade Biológica , Ensaios Clínicos como Assunto , Di-Hidrouracila Desidrogenase (NADP)/sangue , Combinação de Medicamentos , Jejum , Fluoruracila/análogos & derivados , Fluoruracila/metabolismo , Alimentos , Determinação da Acidez Gástrica , Meia-Vida , Humanos , Concentração de Íons de Hidrogênio , Ácido Oxônico/sangue , Ácido Oxônico/metabolismo , Pantoprazol , Piridinas/metabolismo , Piridinas/farmacocinética , Piridinas/uso terapêutico , Tegafur/sangue , Tegafur/metabolismo , Triazinas/metabolismo , Uracila/análogos & derivados , Uracila/metabolismo , beta-Alanina/análogos & derivados , beta-Alanina/metabolismoRESUMO
Sorafenib, an oral multikinase inhibitor, shows efficacy in renal cell and hepatocellular carcinoma (HCC) and is well tolerated when combined with doxorubicin in other solid tumours. Eighteen patients with inoperable HCC received doxorubicin 60 mg/m(2) IV for up to six 3-week cycles. Sorafenib 400mg bid was administered continuously starting day 4. Patients discontinuing doxorubicin were eligible for sorafenib monotherapy. The most frequent grade 3-4 drug-related adverse events were neutropaenia (61%), leukopaenia (45%) and diarrhoea (17%, grade 3). Seven of eight patients who completed six cycles of doxorubicin continued treatment with sorafenib for at least 3 months. Doxorubicin moderately increased AUC (21%) and C(max) (33%) when administered with sorafenib. The disease control rate for 16 evaluable patients was 69%. Sorafenib plus doxorubicin appears to be well tolerated and more effective in the treatment of HCC than doxorubicin alone. Follow-up with single-agent sorafenib in these patients also appears to be well tolerated.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzenossulfonatos/administração & dosagem , Benzenossulfonatos/efeitos adversos , Benzenossulfonatos/sangue , Carcinoma Hepatocelular/sangue , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/sangue , Esquema de Medicação , Feminino , Humanos , Neoplasias Hepáticas/sangue , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/sangue , Sorafenibe , Resultado do TratamentoRESUMO
In this study, we investigated the kinetics of oxaliplatin-DNA adduct formation in white blood cells of cancer patients in relation to efficacy as well as oxaliplatin-associated neurotoxicity. Thirty-seven patients with various solid tumours received 130 mg m(-2) oxaliplatin as a 2-h infusion. Oxaliplatin-DNA adduct levels were measured in the first cycle using adsorptive stripping voltammetry. Platinum concentrations were measured in ultrafiltrate and plasma using a validated flameless atomic absorption spectrometry method. DNA adduct levels showed a characteristic time course, but were not correlated to platinum pharmacokinetics and varied considerably among individuals. In patients showing tumour response, adduct levels after 24 and 48 h were significantly higher than in nonresponders. Oxaliplatin-induced neurotoxicity was more pronounced but was not significantly different in patients with high adduct levels. The potential of oxaliplatin-DNA adduct measurements as pharmacodynamic end point should be further investigated in future trials.
Assuntos
Antineoplásicos/sangue , Adutos de DNA/sangue , Leucócitos/metabolismo , Neoplasias/sangue , Compostos Organoplatínicos/sangue , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Humanos , Compostos Organoplatínicos/efeitos adversos , Compostos Organoplatínicos/farmacologia , OxaliplatinaRESUMO
BACKGROUND: Sorafenib (BAY 43-9006), a novel, oral multi-kinase inhibitor, blocks serine/threonine and receptor tyrosine kinases in the tumor and vasculature. Sorafenib demonstrated single-agent activity in Phase I studies, and was tolerated and inhibited tumor growth in combination with doxorubicin in preclinical studies. This Phase I dose-escalation study determined the safety, pharmacokinetics and efficacy of sorafenib plus doxorubicin. PATIENTS AND METHODS: Thirty-four patients with refractory, solid tumors received doxorubicin 60 mg/m(2) on Day 1 of 3-week cycles, and oral sorafenib from Day 4 of Cycle 1 at 100, 200 or 400 mg bid. RESULTS: Common drug-related adverse events were neutropenia (56%), hand-foot skin reaction (44%), stomatitis (32%), and diarrhea (32%). The maximum tolerated dose was not reached. One patient with pleural mesothelioma achieved a partial response (modified WHO criteria) and remained on therapy for 39.7 weeks. Fifteen patients (48%) achieved stable disease for >/=12 weeks. Doxorubicin exposure increased moderately with sorafenib 400 mg bid. The pharmacokinetics of sorafenib and doxorubicinol were not affected. CONCLUSION: Sorafenib 400 mg bid plus doxorubicin 60 mg/m(2) was well tolerated. The increased doxorubicin exposure with sorafenib 400 mg bid did not result in significantly increased toxicity; low patient numbers make the clinical significance of this unclear. These promising efficacy results justify further clinical investigation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias/tratamento farmacológico , Adulto , Idoso , Benzenossulfonatos/administração & dosagem , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias/metabolismo , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/administração & dosagem , Terapia de Salvação , SorafenibeAssuntos
Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Neoplasias/metabolismo , Antibióticos Antineoplásicos/sangue , Preparações de Ação Retardada , Doxorrubicina/sangue , Humanos , Infusões Intravenosas , LipossomosRESUMO
Treosulphan has recently demonstrated antileukaemic activity and potent haematopoietic stem cell toxicity. Dose-escalated treosulphan (3 x 12 or 3 x 14 g/m2) combined with cyclophosphamide (Cy) was chosen for a new preparative regimen before allogeneic haematopoietic stem cell transplantation in 18 patients (median age 44, range 19-64 years) with haematological malignancies, considered ineligible for other myeloablative preparative regimens. Pharmacokinetic studies demonstrated rapid treosulphan plasma clearance and a dose-dependent increase of its maximum plasma concentrations and area under the concentration-time curves. Rapid and sustained white blood cell and platelet recovery and full donor chimerism was attained in all evaluable patients. Nonhaematological regimen-related CTC grades 3-4 adverse events were transient and predominantly consisted of cardiac (28%), gastrointestinal (39%), and hepatic (39%) toxicities. The 1-year nonrelapse mortality was 22%. Principal causes of transplant-related lethal events were infections in three of four affected patients. Only one patient died from regimen-related cardiac toxicity. The 1-year relapse estimate is 22%, overall and progression-free survival estimates are 67 and 56%, respectively. In conclusion, this new treosulphan and Cy combination is an effective, comparatively well-tolerated myeloablative preparative regimen even in patients with an increased risk for regimen-related toxic complications.