RESUMO
BACKGROUND: Rilotumumab, an investigational, monoclonal antibody, inhibits MET-mediated signalling. In a randomized phase 2 trial of rilotumumab±epirubicin/cisplatin/capecitabine in gastric or oesophagogastric junction cancer, patients receiving rilotumumab showed a trend towards improved survival, especially in MET-positive patients, but no clear dose-response relationship was observed. Exposure-response and biomarker analyses were used for dose selection and to differentiate patient subpopulations that may benefit most from treatment. Here, we analyse rilotumumab exposure-survival and exposure-safety and the impact of MET expression on these relationships. METHODS: Individual rilotumumab exposure parameters were generated using population pharmacokinetic modelling. Relationships among rilotumumab dose (7.5 and 15 mg kg(-1)), exposure, and clinical outcomes (progression-free survival (PFS) and overall survival (OS)) were evaluated with Cox regression models and Kaplan-Meier plots. MET status and other baseline covariates were evaluated in subgroup and multivariate analyses. Treatment-emergent adverse events were summarised by exposure. RESULTS: Among MET-positive patients, higher rilotumumab exposure, vs placebo and low exposure, was associated with improved median PFS (80% CI: 7.0 (5.7-9.7) vs 4.4 (2.9-4.9) and 5.5 (4.2-6.8) months) and OS (13.4 (10.6-18.6) vs 5.7 (4.7-10.2) and 8.1 (6.9-11.1) months) without increased toxicity. No rilotumumab benefit was seen among MET-negative patients. CONCLUSIONS: Rilotumumab had an exposure-dependent treatment effect in patients with MET-positive gastric or oesophagogastric junction cancer.
Assuntos
Adenocarcinoma/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacocinética , Proteínas Proto-Oncogênicas c-met/genética , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Relação Dose-Resposta a Droga , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Resultado do TratamentoRESUMO
BACKGROUND: We completed a phase I clinical trial to test the safety and toxicity of combined treatment with cixutumumab (anti-IGF-1R antibody) and selumetinib (MEK 1/2 inhibitor). METHODS: Patients with advanced solid tumours, refractory to standard therapy received selumetinib hydrogen sulphate capsules orally twice daily, and cixutumumab intravenously on days 1 and 15 of each 28-day cycle. The study used a 3+3 design, with a dose-finding cohort followed by an expansion cohort at the maximally tolerated dose that included pharmacokinetic and pharmacodynamic correlative studies. RESULTS: Thirty patients were enrolled, with 16 in the dose-finding cohort and 14 in the expansion cohort. Grade 3 or greater toxicities included nausea and vomiting, anaemia, CVA, hypertension, hyperglycaemia, and ophthalmic symptoms. The maximally tolerated combination dose was 50 mg twice daily of selumetinib and 12 mg kg(-1) every 2 weeks of cixutumumab. Two patients achieved a partial response (one unconfirmed), including a patient with BRAF wild-type thyroid carcinoma, and a patient with squamous cell carcinoma of the tongue, and six patients achieved time to progression of >6 months, including patients with thyroid carcinoma, colorectal carcinoma, and basal cell carcinoma. Comparison of pre- and on-treatment biopsies showed significant suppression of pERK and pS6 activity with treatment. CONCLUSIONS: Our study of anti-IGF-1R antibody cixutumumab and MEK 1/2 inhibitor selumetinib showed that the combination is safe and well-tolerated at these doses, with preliminary evidence of clinical benefit and pharmacodynamic evidence of target inhibition.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Humanos , MAP Quinase Quinase Quinases/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Receptor IGF Tipo 1/antagonistas & inibidores , Resultado do TratamentoRESUMO
The pupose of this study was to evaluate the activity of ON 01910.Na, a mitotic inhibitor, in in vitro and in vivo models of pancreatic cancer and to discover biomarkers predictive of efficacy. Successive in vitro and in vivo models were used; these included cell line-derived and patient-derived tumors from our PancXenoBank, a live collection of freshly generated pancreatic cancer xenografts. ON 01910.Na showed equivalent activity to gemcitabine against pancreatic cancer cell lines in vitro. The activity of the agent correlated with suppression of phospho-CDC25C and cyclin B1. These markers were optimized for a fine-needle aspirate ex vivo rapid assay. Cyclin B1 mRNA evaluation yielded the most optimal combination of accuracy and reproducibility. Next, nine patient-derived tumors from the PancXenoBank were profiled using the assay developed in cell lines and treated with ON01910.Na for 28 days. Two cases were cataloged as potential responders and seven as resistants. There was a correlation between the ex vivo assay and sensitivity to the tested agent, as the two cases prospectively identified as sensitive met prespecified criteria for response. Of the seven tumors of predictive resistant, only one was found to be sensitive to ON 01910.Na. In addition, there was a good correlation between cyclin B1 downregulation ex vivo and changes in cyclin B1 protein post-treatment. The novel mitotic inhibitor, ON 01910.Na, showed activity in preclinical model of pancreatic cancer. A rapid assay was rationally developed that not only identified cases sensitive to ON 01910.Na, but also anticipated the pharmacodynamic events occurring after in vivo exposure.
Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glicina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Sulfonas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Antimetabólitos Antineoplásicos/uso terapêutico , Biópsia por Agulha Fina , Linhagem Celular Tumoral , Ciclina B/metabolismo , Ciclina B1 , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Feminino , Glicina/farmacologia , Glicina/uso terapêutico , Humanos , Camundongos , Camundongos Nus , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Valor Preditivo dos Testes , Sulfonas/uso terapêutico , Fosfatases cdc25/metabolismo , GencitabinaRESUMO
BACKGROUND: Troxacitabine is a novel L-nucleoside analogue. Preclinical studies showed improved activity with infusions of at least 3 days compared with bolus regimens, especially at concentrations >20 ng/ml. This phase I study tested the feasibility of achieving a troxacitabine steady-state concentration of 20 ng/ml for at least 72 h in patients with solid tumors. PATIENTS AND METHODS: Patients with solid tumors received troxacitabine as a progressively longer infusion on days 1-4 of a 28-day cycle. The initial length of infusion and infusion rate were 48 h and 3 mg/m(2)/day. RESULTS: Twenty-one patients were treated at infusion lengths that increased from 48 to 72 h and then 96 h. The infusion rate was decreased from 3 to 1.88 mg/m(2)/day due to toxicity. Dose-limiting toxicities consisted of grade 4 neutropenia (three) and grade 3 constipation (one). The maximum tolerated dose of continuous infusion troxacitabine in patients with solid tumors is 7.5 mg/m(2) administered over 96 h. This dose level resulted in steady-state drug concentration of at least 20 ng/ml for 72 h. CONCLUSIONS: Administration of troxacitabine by continuous infusion achieved the prospectively defined target plasma concentration. Pharmacokinetics (PK) modeling coupled with real-time PK assessment was an efficient approach to conduct hypothesis-driven phase I trials.
Assuntos
Citosina/análogos & derivados , Dioxolanos/administração & dosagem , Dioxolanos/farmacocinética , Invasividade Neoplásica/patologia , Neoplasias/tratamento farmacológico , Adulto , Idoso , Citosina/administração & dosagem , Citosina/efeitos adversos , Citosina/farmacocinética , Dioxolanos/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Infusões Intravenosas , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/mortalidade , Neoplasias/patologia , Valor Preditivo dos Testes , Probabilidade , Medição de Risco , Análise de Sobrevida , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Flavopiridol, a synthetic flavone that inhibits cell cycle progression, has demonstrated activity in colon cancer in xenografts and in a phase I trial. We evaluated flavopiridol in a phase II trial in patients with previously untreated advanced colorectal cancer (ACRC). PATIENTS AND METHODS: Twenty chemotherapy-naïve patients with ACRC received flavopiridol at a dose of 50 mg/m(2)/day via a 72-h continuous infusion every 14 days. Response was assessed by computed tomography or magnetic resonance imaging every 8 weeks. RESULTS: Twenty patients were enrolled; 19 were evaluable for toxicity and 18 for response. There were no objective responses. Five patients had stable disease lasting a median of 7 weeks. The median time to progression was 8 weeks. Median survival was 65 weeks. The principal grade 3/4 toxicities were diarrhea, fatigue and hyperglycemia, occurring in 21%, 11% and 11% of patients, respectively. Other common toxicities included anemia, anorexia and nausea/vomiting. CONCLUSIONS: Flavopiridol in this dose and schedule does not have single-agent activity in patients with ACRC. Recent preclinical data suggest that flavopiridol enhances apoptosis when combined with chemotherapy. Trials that evaluate flavopiridol in combination with active cytotoxic drugs should help to define the role of this novel agent in ACRC.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Flavonoides/administração & dosagem , Invasividade Neoplásica/patologia , Piperidinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Neoplasias Colorretais/mortalidade , Intervalos de Confiança , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Flavonoides/efeitos adversos , Seguimentos , Humanos , Infusões Intravenosas , Imageamento por Ressonância Magnética , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Piperidinas/efeitos adversos , Probabilidade , Análise de Sobrevida , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
BACKGROUND: Hypermethylation and inactivation of tumor suppressor genes by the enzyme DNA methyltransferase may lead to neoplastic transformation. MG98, a phosphorothioate antisense oligodeoxynucleotide that is a specific inhibitor of mRNA for human DNA methyltransferase 1 (DNMT1), was evaluated in a phase I study. PATIENTS AND METHODS: MG98 was given as a 2 h i.v. infusion twice weekly three weeks out of every four to patients with solid tumors. Pharmacokinetic evaluation was performed on days 1 and 15 of cycle 1 and mRNA expression of DNMT1 was measured in peripheral blood mononuclear cells (PBMCs). RESULTS: Nineteen patients were entered onto the study. A total of 74 cycles (range 1-18 cycles) were administered at dose levels from 40 to 480 mg/m(2). Dose limiting toxicity was seen in two of three patients at 480 mg/m(2) and consisted of a constellation of fever, chills, fatigue and, in one case, confusion beginning within 6 h after the first infusion. Other toxic effects included fatigue, anorexia, nausea, vomiting and diarrhea, reversible elevations in transaminases and partial thromboplastin time. Pharmacokinetic evaluation showed C(max) and AUC to be dose proportional with low inter- and intra-patient variability. No consistent changes in DNMT1 mRNA expression were noted in PBMCs. One partial response was documented in a patient with renal cell carcinoma treated at 80 mg/m(2). CONCLUSIONS: The recommended dose of MG98 was 360 mg/m(2) given by 2 h infusion twice a week for three weeks out of every four. Phase II trials using this dose and schedule are underway.
Assuntos
DNA (Citosina-5-)-Metiltransferases/antagonistas & inibidores , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Oligonucleotídeos Antissenso/administração & dosagem , Oligonucleotídeos Antissenso/farmacocinética , Tionucleotídeos/administração & dosagem , Tionucleotídeos/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/metabolismo , Relação Dose-Resposta a Droga , Esquema de Medicação , Inibidores Enzimáticos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Oligonucleotídeos Antissenso/efeitos adversos , RNA Mensageiro/biossíntese , Tionucleotídeos/efeitos adversosRESUMO
1. TAS-103, a novel condensed quinoline derivative, has been developed as an anticancer drug targeting topoisomerases I and II. 2. The purpose of the present study was to characterize the metabolism and urinary excretion of TAS-103 after the intravenous infusion of a single dose to patients in Phase I clinical trials. 3. Five metabolites were detected using high-performance liquid chromatography (HPLC) photodiode array and a precursor scan by liquid chromatography mass spectrometry mass spectrometry (LC/MS/MS). 4. Structures of the five metabolites were determined using the results of enzymatic hydrolysis and the analysis of production mass spectra obtained by LC/MS/MS, and by comparing HPLC retention times and UV, mass and production mass spectra of authentic standards. 5. The metabolites were identified as demethyl-TAS-103 glucuronide (DM-TAS-103-G), TAS-103 glucuronide (TAS-103-G), TAS-103 glucuronide N-oxide (NO-TAS-103-G), demethyl-TAS-103 (DM-TAS-103) and TAS-103 N-oxide (NO-TAS-103). 6. The mean total amount of TAS-103 and TAS-103-G in urine was only 6.03% of the dose, suggesting that urine is not the main elimination route. TAS-103 was extensively metabolized, and a small percentage of the parent drug (0.41%) was found in urine.
Assuntos
Aminoquinolinas/metabolismo , Aminoquinolinas/urina , Antineoplásicos/metabolismo , Antineoplásicos/urina , Indenos/metabolismo , Indenos/urina , Aminoquinolinas/administração & dosagem , Aminoquinolinas/química , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Cromatografia Líquida de Alta Pressão , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/urina , Glucuronídeos/química , Glucuronídeos/metabolismo , Glucuronídeos/urina , Humanos , Indenos/administração & dosagem , Indenos/química , Infusões Intravenosas , Espectrometria de Massas , Estrutura Molecular , Espectrofotometria Ultravioleta , Inibidores da Topoisomerase I , Inibidores da Topoisomerase IIRESUMO
PURPOSE: Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that are believed to be involved in primary and metastatic tumor growth by degrading the basement membrane and changing the extracellular matrix to facilitate invasion of malignant cells and angiogenesis. Overexpression of MMPs has been documented in various solid tumors. BAY12-9566 is a selective inhibitor of MMPs, in particular MMP-2, -3. and -9. The purpose of this trial was to define the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety profile, pharmacokinetics and pharmacodynamics of orally administered BAY12-9566 in patients with incurable solid tumors. METHODS: The starting dose of BAY12-9566 for this single institution, outpatient phase I study was 100 mg/day orally. Patients were allowed to receive drug for up to 12 months. A total of 27 patients with various solid malignancies including colorectal, breast, lung, cervical and ovarian cancers were enrolled at doses from 100 to 1,600 mg/day. Patients were evaluated weekly while on treatment. Relevant radiologic examination was performed every 8 weeks to document and follow sites of measurable or evaluable disease. RESULTS: Toxicities from BAY12-9566 included liver injury test abnormalities, anemia, shoulder and back pain. thrombocytopenia, mild nausea and fatigue, diarrhea, rash and deep vein thrombosis. No toxicity greater than grade III was observed. As doses were increased from 100 to 400 to 1,600 mg/day, even in divided doses, less than proportional increases in AUC were observed. At the highest dose level of 1600 mg/day, the day 29 AUC (3778.00 mg x h/l) remained similar to the day 29 AUC (3312.60 mg x h/l) at the dose level of 1200 mg/day. No responses were seen, but 14 patients remained on study with stable disease for 4 to 26 months. CONCLUSIONS: BAY12-9566 was well tolerated at doses as high as 800 mg orally twice daily. Although mild alterations in liver injury tests, platelet count and hematocrit were noted, these were not dose-limiting. The drug was well absorbed. However, the absence of proportional increases in AUC with doses greater than 800 mg and the achievement of Css in the range associated with biologic activity in preclinical models led to the selection of 800 mg twice daily for further evaluation in phase III trials.
Assuntos
Antineoplásicos/efeitos adversos , Neoplasias/tratamento farmacológico , Compostos Orgânicos , Administração Oral , Adulto , Idoso , Anemia/induzido quimicamente , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Área Sob a Curva , Compostos de Bifenilo , Relação Dose-Resposta a Droga , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Pessoa de Meia-Idade , Fenilbutiratos , Trombocitopenia/induzido quimicamenteRESUMO
PURPOSE: Sodium phenylbutyrate (PB) demonstrates potent differentiating capacity in multiple hematopoietic and solid tumor cell lines. We conducted a Phase I and pharmacokinetic study of PB by continuous infusion to characterize the maximum tolerated dose, toxicities, pharmacokinetics, and antitumor effects in patients with refractory solid tumors. PATIENTS AND METHODS: Patients were treated with a 120-h PB infusion every 21 days. The dose was escalated from 150 to 515 mg/kg/day. Pharmacokinetics were performed during and after the first infusion period using a validated high-performance liquid chromatographic assay and single compartmental pharmacokinetic model for PB and its principal metabolite, phenylacetate. RESULTS: A total of 24 patients were enrolled on study, with hormone refractory prostate cancer being the predominant tumor type. All patients were evaluable for toxicity and response. A total of 89 cycles were administered. The dose-limiting toxicity (DLT) was neuro-cortical, exemplified by excessive somnolence and confusion and accompanied by clinically significant hypokalemia, hyponatremia, and hyperuricemia. One patient at 515 mg/kg/day and another at 345 mg/kg/day experienced this DLT. Toxicity resolved < or =12 h of discontinuing the infusion. Other toxicities were mild, including fatigue and nausea. The maximum tolerated dose was 410 mg/kg/day for 5 days. Pharmacokinetics demonstrated that plasma clearance of PB increased in a continuous fashion beginning 24 h into the infusion. In individuals whose V(max) for drug elimination was less than their drug-dosing rate, the active metabolite phenylacetate accumulated progressively. Plasma PB concentrations (at 410 mg/kg/day) remained above the targeted therapeutic threshold of 500 micromol/liter required for in vitro activity. CONCLUSION: The DLT in this Phase I study for infusional PB given for 5 days every 21 days is neuro-cortical in nature. The recommended Phase II dose is 410 mg/kg/day for 120 h.
Assuntos
Antineoplásicos/uso terapêutico , Glutamina/análogos & derivados , Neoplasias/tratamento farmacológico , Fenilbutiratos/uso terapêutico , Adulto , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Cromatografia Líquida de Alta Pressão , Distúrbios do Sono por Sonolência Excessiva/induzido quimicamente , Relação Dose-Resposta a Droga , Fadiga/induzido quimicamente , Feminino , Glutamina/sangue , Humanos , Hipopotassemia/induzido quimicamente , Infusões Intravenosas , Masculino , Taxa de Depuração Metabólica , Náusea/induzido quimicamente , Neutropenia/induzido quimicamente , Pacientes Desistentes do Tratamento , Fenilacetatos/sangue , Fenilbutiratos/efeitos adversos , Fenilbutiratos/farmacocinética , Antígeno Prostático Específico/sangue , Antígeno Prostático Específico/efeitos dos fármacos , Neoplasias da Próstata/sangue , Neoplasias da Próstata/tratamento farmacológico , Fatores de Tempo , Células Tumorais Cultivadas , Ácido Úrico/sangueRESUMO
PURPOSE: Oral administration of penclomedine was investigated based on preclinical studies indicating that an oral schedule of penclomedine treatment may prevent the neurotoxicity observed in phase I studies of an intravenous (i.v.) formulation, possibly by reducing maximum plasma concentrations (Cmax) of the neurotoxic parent species. METHODS: Penclomedine was administered i.v. (200 mg/m2) and orally (250 mg/m2) in alternate sequences to patients with solid tumor malignancies. Plasma concentrations of parent drug and the principal metabolite, 4-O-demethylpenclomedine, were determined by a reversed-phase HPLC assay. RESULTS: Penclomedine was detectable in the plasma of all patients within 1 h of oral penclomedine treatment and Cmax was reached within 1 to 4 h. Consistent with the hypothesis that an oral schedule of administration may circumvent neurotoxicity, a paired data analysis demonstrated a significant reduction in Cmax values following oral administration (P=0.017). However the magnitude of this reduction was highly variable. Similarly an extensive range in the relative exposure to both parent drug and metabolite were observed. The bioavailability of penclomedine ranged from 28% to 98% (median 73%). CONCLUSIONS: Oral penclomedine does produce systemic exposure, but substantial interpatient variability in absorption and systemic exposure is present which may limit the clinical role of the oral route of administration.
Assuntos
Antineoplásicos/farmacocinética , Neoplasias/metabolismo , Picolinas/farmacocinética , Administração Oral , Adulto , Idoso , Antineoplásicos/administração & dosagem , Área Sob a Curva , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Vias de Administração de Medicamentos , Esquema de Medicação , Humanos , Infusões Intravenosas , Dose Máxima Tolerável , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Picolinas/administração & dosagemRESUMO
Targeting an anti-cancer drug to tumors should increase the Area Under the drug concentration-time Curve (AUC) in tumors while decreasing the AUC in normal cells and should therefore increase the therapeutic index of that drug. Anti-tumor drugs typically have half-lives far shorter than the cell cycle transit times of most tumor cells. Tumor targeting, with concomitant long tumor exposure times, will increase the proportion of cells that move into cycle when the drug concentration is high, which should result in more tumor cell killing. In an effort to test that hypothesis, we conjugated a natural fatty acid, docosahexaenoic acid (DHA), through an ester bond to the paclitaxel 2'-oxygen. The resulting paclitaxel fatty acid conjugate (DHA-paclitaxel) does not assemble microtubules and is non-toxic. In the M109 mouse tumor model, DHA-paclitaxel is less toxic than paclitaxel and cures 10/10 tumored animals, whereas paclitaxel cures 0/10. One explanation for the conjugate's greater therapeutic index is that the fatty acid alters the pharmacokinetics of the drug to increase its AUC in tumors and decrease its AUC in normal cells. To test that possibility, we compared the pharmacokinetics of DHA-paclitaxel with paclitaxel in CD2F1 mice bearing approximately 125 mg sc M109 tumors. The mice were injected at zero time with a bolus of either DHA-paclitaxel or paclitaxel formulated in 10% cremophor/10% ethanol/80% saline. Animals were sacrificed as a function of time out to 14 days. Tumors and plasma were frozen and stored. The concentrations of paclitaxel and DHA-paclitaxel were analyzed by LC/MS/MS. The results show that DHA targets paclitaxel to tumors: tumor AUCs are 61-fold higher for DHA-paclitaxel than for paclitaxel at equitoxic doses and eight-fold higher at equimolar doses. Likewise, at equi-toxic doses, the tumor AUCs of paclitaxel derived from i.v. DHA-paclitaxel are 6.1-fold higher than for paclitaxel derived from i.v. paclitaxel. The tumor concentration of paclitaxel derived from i.v. paclitaxel drops rapidly, so that by 16 h it has fallen to the same concentration (2.8 microM) as after an equi-toxic concentration of DHA-paclitaxel. In plasma, paclitaxel AUC after an MTD dose of DHA-paclitaxel is approximately 0.5% of DHA-paclitaxel AUC. Thus, the increase in tumor AUC and the limited plasma AUC of paclitaxel following DHA-paclitaxel administration are consistent with the increase in therapeutic index of DHA-paclitaxel relative to paclitaxel in the M109 mouse tumor model. A phase I clinical study has been completed at The Johns Hopkins Hospital to evaluate the safety of DHA-paclitaxel in patients with a variety of solid tumors. Twenty-one patients have been treated to date. The recommended phase II dose is 1100 mg/m(2), which is equivalent to 4.6 times the maximum approved paclitaxel dose on a molar basis. No alopecia or significant peripheral neuropathy, nausea, or vomiting have been observed. Asymptomatic, transient neutropenia has been the primary side effect. Eleven of 22 evaluable phase I patients transitioned from progressive to stable disease, as assessed by follow-up CT. Significant quality of life improvements have been observed. Thus, DHA-paclitaxel is well tolerated in patients and cures tumors in mice by targeting drug to tumors.
Assuntos
Antineoplásicos Fitogênicos/química , Ácidos Docosa-Hexaenoicos/química , Neoplasias/tratamento farmacológico , Paclitaxel/análogos & derivados , Paclitaxel/química , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Área Sob a Curva , Sistemas de Liberação de Medicamentos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Transplante de Neoplasias , Paclitaxel/administração & dosagem , Paclitaxel/farmacocinética , Células Tumorais CultivadasRESUMO
PURPOSE: Phenylbutyrate (PB) is an aromatic fatty acid with multiple mechanisms of action including histone deacetylase inhibition. Preclinically, PB demonstrates both cytotoxic and differentiating effects at a concentration of 0.5 mM. We conducted a Phase I trial of p.o. PB patients with refractory solid tumor malignancies to evaluate toxicity, pharmacokinetic parameters, and feasibility of p.o. administration. EXPERIMENTAL DESIGN: Twenty-eight patients with refractory solid tumor malignancies were enrolled on this dose-escalation to maximally tolerated dose trial. Five dose levels of PB were studied: 9 g/day (n = 4), 18 g/day (n = 4), 27 g/day (n = 4), 36 g/day (n = 12), and 45 g/day (n = 4). Pharmacokinetic studies were performed and included an p.o. bioavailability determination. Compliance data were also collected. RESULTS: The recommended Phase II dose is 27 g/day. Overall the drug was well tolerated with the most common toxicities being grade 1-2 dyspepsia and fatigue. Nonoverlapping dose-limiting toxicities of nausea/vomiting and hypocalcemia were seen at 36 g/day. The p.o. bioavailability of PB was 78% for all dose levels, and the biologically active concentration of 0.5 mM was achieved at all dose levels. Compliance was excellent with 93.5% of all possible doses taken. No partial remission or complete remission was seen, but 7 patients had stable disease for more than 6 months while on the drug. CONCLUSIONS: PB (p.o.) is well tolerated and achieves the concentration in vivo that has been shown to have biological activity in vitro. PB may have a role as a cytostatic agent and should be additionally explored in combination with cytotoxics and other novel drugs.
Assuntos
Glutamina/análogos & derivados , Neoplasias/tratamento farmacológico , Fenilbutiratos/farmacocinética , Administração Oral , Adulto , Idoso , Área Sob a Curva , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Fadiga/induzido quimicamente , Feminino , Glutamina/sangue , Humanos , Hipocalcemia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Neoplasias/metabolismo , Doenças do Sistema Nervoso/induzido quimicamente , Fenilacetatos/sangue , Fenilbutiratos/administração & dosagem , Fenilbutiratos/efeitos adversos , Resultado do Tratamento , Vômito/induzido quimicamenteRESUMO
Sodium phenylbutyrate (PB) is an aromatic fatty acid with cytostatic and differentiating activity against malignant myeloid cells (ID(50), 1-2 mM). Higher doses induce apoptosis. Patients with myelodysplasia (n = 11) and acute myeloid leukemia (n = 16) were treated with PB as a 7-day continuous infusion repeated every 28 days in a Phase I dose escalation study. The maximum tolerated dose was 375 mg/kg/day; higher doses led to dose-limiting reversible neurocortical toxicity. At the maximum tolerated dose, PB was extremely well tolerated, with no significant toxicities; median steady-state plasma concentration at this dose was 0.29 +/- 0.16 mM. Although no patients achieved complete or partial remission, four patients achieved hematological improvement (neutrophils in three, platelet transfusion-independence in one). Other patients developed transient increases in neutrophils or platelets and decrements in circulating blasts. Monitoring of the percentage of clonal cells using centromere fluorescence in situ hybridization over the course of PB administration showed that hematopoiesis remained clonal. Hematological response was often associated with increases in both colony-forming units-granulocyte-macrophage and leukemic colony-forming units. PB administration was also associated with increases in fetal erythrocytes. These data document the safety of continuous infusion PB and provide preliminary evidence of clinical activity in patients with myeloid malignancies.
Assuntos
Leucemia Mieloide/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Fenilbutiratos/uso terapêutico , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Alopecia/induzido quimicamente , Antígenos CD34/análise , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Células Clonais , Diarreia/induzido quimicamente , Relação Dose-Resposta a Droga , Hemoglobina Fetal/efeitos dos fármacos , Hemoglobina Fetal/metabolismo , Citometria de Fluxo , Hemorragia/induzido quimicamente , Humanos , Pessoa de Meia-Idade , Mucosa Bucal/efeitos dos fármacos , Mucosa Bucal/patologia , Síndromes Mielodisplásicas/imunologia , Náusea/induzido quimicamente , Fenilbutiratos/efeitos adversos , Fenilbutiratos/farmacocinética , Estomatite/induzido quimicamente , Resultado do Tratamento , Vômito/induzido quimicamenteRESUMO
BACKGROUND/PURPOSE: 4-Ipomeanol (IPO; NSC 394438), a naturally occurring furan isolated from common sweet potatoes (Ipomoea batatas) infected with the fungus Fusarium solani was the first agent to be developed by the National Cancer Institute based on a biochemical-biological rationale as an anticancer agent targeted specifically against lung cancer. Prior to clinical development, IPO was shown to induce pulmonary toxicity in the lungs of several mammalian species because the agent is metabolized to a highly reactive furan epoxide by specific cytochrome P450 monooxygenases found in pulmonary Clara cells and type II pneumocytes, which share biochemical features with bronchogenic carcinoma. However, instead of inducing the anticipated lung toxicity in patients with lung cancer in disease-directed phase I studies, hepatotoxicity was the principal toxic effect of IPO in humans. Based on the presumption that IPO may be preferentially activated by cytochrome P450 monooxygenases in liver cells and biochemically-related hepatic malignancies, a phase II study was conducted to determine the activity and evaluate the toxicity of IPO in patients with advanced hepatocellular carcinoma. PATIENTS AND METHODS: Nineteen patients with advanced measurable hepatocellular carcinoma were enrolled on the phase II trial. All patients had an Eastern Cooperative Oncology Group performance status of at least two, no evidence of pulmonary dysfunction, and had either no prior treatment or minimal prior therapy. Patients were treated with IPO at a dose of either 1032 mg/m2, which was the maximum tolerated and recommended phase II dose previously derived for patients with normal hepatic function (15 patients) or 826 mg/m2 if they had serum bilirubin concentrations in the range of 2.0 to 3.0 mg/dL (four patients). Treatment was repeated every three weeks. Objective tumor response, the primary endpoint of the study, was assessed after every two courses of treatment, and both pulmonary function and lung density were rigorously monitored using successive pulmonary function testing and computerized tomography. RESULTS: All nineteen patients were evaluable for both response and toxicity. No major objective responses were observed. One patient had a minor, brief reduction in lung metastases. Although marker lesions and overall disease remained stable for at least 12 and 24 months in three and two patients, respectively, the median time to progression was three months and the median survival was five months for all patients. The principal toxicity was reversible elevations in hepatic transaminases, which occasionally resulted in dose reduction. No clinically-significant pulmonary toxicity was noted. CONCLUSION: IPO at a dose of either 826 or 1032 mg/m2 administered every three weeks did not demonstrate a relevant degree of clinical activity against advanced hepatocellular carcinoma. Further evaluations of TO is not recommended for this disease.
Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Terpenos/administração & dosagem , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Terpenos/efeitos adversos , Terpenos/uso terapêutico , Resultado do TratamentoRESUMO
PURPOSE: Allogeneic granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor vaccines can cure established tumors in the mouse, but their efficacy against human tumors is uncertain. We have developed a novel GM-CSF-secreting pancreatic tumor vaccine. To determine its safety and ability to induce antitumor immune responses, we conducted a phase I trial in patients with surgically resected adenocarcinoma of the pancreas. PATIENTS AND METHODS: Fourteen patients with stage 1, 2, or 3 pancreatic adenocarcinoma were enrolled. Eight weeks after pancreaticoduodenectomy, three patients received 1 x 10(7) vaccine cells, three patients received 5 x 10(7) vaccine cells, three patients received 10 x 10(7) vaccine cells, and five patients received 50 x 10(7) vaccine cells. Twelve of 14 patients then went on to receive a 6-month course of adjuvant radiation and chemotherapy. One month after completing adjuvant treatment, six patients still in remission received up to three additional monthly vaccinations with the same vaccine dose that they had received originally. RESULTS: No dose-limiting toxicities were encountered. Vaccination induced increased delayed-type hypersensitivity (DTH) responses to autologous tumor cells in three patients who had received >or= 10 x 10(7) vaccine cells. These three patients also seemed to have had an increased disease-free survival time, remaining disease-free at least 25 months after diagnosis. CONCLUSION: Allogeneic GM-CSF-secreting tumor vaccines are safe in patients with pancreatic adenocarcinoma. This vaccine approach seems to induce dose-dependent systemic antitumor immunity as measured by increased postvaccination DTH responses against autologous tumors. Further clinical evaluation of this approach in patients with pancreatic cancer is warranted.
Assuntos
Adenocarcinoma/terapia , Vacinas Anticâncer/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Neoplasias Pancreáticas/terapia , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Idoso , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/farmacocinética , Terapia Combinada , Qualidade de Produtos para o Consumidor , Intervalo Livre de Doença , Relação Dose-Resposta Imunológica , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacocinética , Humanos , Hipersensibilidade Tardia/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologiaRESUMO
PURPOSE: (1) To determine the toxicity of an intensified postoperative adjuvant regimen for periampullary adenocarcinoma (pancreatic and nonpancreatic) utilizing concurrent 5-fluorouracil (5-FU), leucovorin (LV), dipyridamole (DPM), and mitomycin-C (MMC) combined with split-course locoregional external beam radiotherapy (EBRT) to 50 Gy. This was followed by 4 cycles of the same chemotherapy as adjuvant therapy. (2) To determine preliminary estimates of the overall and disease-free survival associated with the use of this regimen. (3) To compare the toxicities and early survival results of patients treated with the current regimen to those of patients who completed our prior trial of concurrent chemoradiation infusion with 5-FU/LV chemotherapy and regional nodal and prophylactic hepatic irradiation. METHODS: Postpancreaticoduodenectomy, patients received every 4 weeks bolus administration of 5-FU, (400 mg/m(2)), and LV, (20 mg/m(2), Days l-3), DPM (75 mg p.o., 4 times per day, Days 0-3, and every 8 weeks), MMC, (10 mg/m(2); maximum of 20 mg, Day l during EBRT). This was followed by 4 months of the same chemotherapy, beginning 1 month following the completion of EBRT. EBRT consisted of split-course 5000 cGy/20 fractions with a 2-week planned rest after the first 10 fractions (2500 cGy). RESULTS: From 4/96 to 6/99, 45 patients were enrolled and treated. Their experience constitutes the basis of this analysis. There were 29 patients with pancreatic cancer and 16 with nonpancreatic periampullary cancer. Seventeen patients had tumors of 3 cm or more, and 39 patients had at least 1 histologically involved lymph node. Thirteen patients had a histologically positive margin of resection. The mean time to start of treatment was 63 days following surgery. During chemoradiation therapy there were no Grade 3 or worse nonhematologic toxicities and 47% Grade 3 or Grade 4 hematologic toxicities of short duration. Following chemoradiation, during chemotherapy treatment only, there was one Grade 3 hepatic and one Grade 3 pulmonary toxicity which was nondebilitating (2% each case) and 42% Grade 3 or 4 hematologic toxicity. There were 2 episodes of neutropenic fever requiring admission and no treatment-related mortalities. One patient developed a mild case of HUS, which responded to standard management. One patient developed persistent shortness of breath (nondebilitating), and another patient had occasional dyspnea on exertion, both occurring after all therapy. The majority of patients complained of increased fatigue (Grade 1-2), greatest during the combined therapy and improving post all treatment. As of 6/23/99, 20 of 45 patients have relapsed, 13 in the liver. Twelve patients have died. Median follow-up for surviving patients is 14.3 months. Disease-free survival at 12 months following surgery is 66% (as compared to 25% in our prior study), and the median disease-free survival is 17 months (as compared to 8. 3 months in our prior study). Median survival has not yet been reached, but will be greater than 17 months. CONCLUSION: With a 14.3-month median follow-up, acute toxicity has been acceptable and manageable. Observed relapses were seen 9-13 months following surgical resection. Early survival analysis suggests a trend toward increased median disease-free survival (8.3 vs. 17 months), especially for patients with nonpancreatic periampullary adenocarcinoma.
Assuntos
Adenocarcinoma/terapia , Neoplasias Pancreáticas/terapia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante , Dipiridamol/administração & dosagem , Dipiridamol/efeitos adversos , Intervalo Livre de Doença , Neoplasias Duodenais/mortalidade , Neoplasias Duodenais/patologia , Neoplasias Duodenais/terapia , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Seguimentos , Humanos , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mitomicina/administração & dosagem , Mitomicina/efeitos adversos , Recidiva Local de Neoplasia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Pancreaticoduodenectomia , Dosagem Radioterapêutica , Radioterapia Adjuvante , Fatores de TempoRESUMO
5-[(2-Aminoethyl)amino]-2-[2-(diethylamino)ethyl]-2H-[1]benzothiopyra no[4,3,2-cd]-indazol-8-ol trihydrochloride (CI-958) is the most active member of a new class of DNA intercalating compounds, the benzothiopyranoindazoles. Because of its broad spectrum and high degree of activity as well as a favorable toxicity profile in preclinical models, CI-958 was chosen for further development. The Phase I study described here was undertaken to determine the toxicity profile, maximum tolerated dose, and pharmacokinetics of CI-958 given as an i.v. infusion every 21 days. Adult patients with advanced refractory solid tumors who had adequate renal, hepatic, and hematological function, life expectancy, and performance status were eligible for this study. Written informed consent was obtained from all patients. Patients received a 1- or 2-h infusion of CI-958 at 21-day intervals. The starting dose was 5.2 mg/m2, and at least three patients were evaluated at each dose level before proceeding to a new dose level. A pharmacokinetically guided dose escalation design was used until reaching a predetermined target area under the plasma concentration versus time curve (AUC), after which a modified Fibonacci scheme was used. Forty-four patients (21 men and 23 women; median age, 59 years) received 162 courses of CI-958. Neutropenia and hepatorenal toxicity were the dose-limiting toxicities, which defined the maximum tolerated dose of CI-958 to be 875 mg/m2 when given as a 2-h infusion every 21 days. There were no tumor responses. Two patients had stable disease for >250 days. The recommended Phase II dose is 560 mg/m2 for patients with significant prior chemotherapy and 700 mg/m2 for patients with minimal prior chemotherapy. Pharmacokinetic analysis of plasma and urine concentration-time data from each patient was performed. At the recommended Phase II dose of 700 mg/m2, mean CI-958 clearance was 370 ml/min/m2, mean AUC was 33800 ng-h/ml, and mean terminal half-life (t1/2) was 15.5 days. The clearance was similar at all doses, and plasma CI-958 AUC increased proportionally with dose, consistent with linear pharmacokinetics. The percentage reduction in absolute neutrophil count from baseline was well predicted by AUC using a simple Emax model. The pharmacokinetically guided dose escalation saved five to six dose levels in reaching the maximum tolerated dose compared with a standard dose escalation scheme. This may represent the most successful application to date of this dose escalation technique.
Assuntos
Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , DNA/metabolismo , Indazóis/farmacocinética , Indazóis/uso terapêutico , Substâncias Intercalantes/farmacocinética , Substâncias Intercalantes/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/toxicidade , Área Sob a Curva , Relação Dose-Resposta a Droga , Feminino , Humanos , Indazóis/toxicidade , Substâncias Intercalantes/toxicidade , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Fatores de TempoRESUMO
Despite increasing evidence of benefit from adjuvant chemotherapy, older women with breast cancer are commonly given less aggressive treatment than younger patients. Conflicting prior data regarding age-related toxicity prompted this prospective study. Forty-four women (aged 35-79 years) with early-stage breast cancer were treated with four cycles of adjuvant therapy with doxorubicin 60 mg/m2 i.v. and cyclophosphamide 600 mg/m2 i.v. every 21 days. They were monitored for myelosuppression, cardiotoxicity, and decrease in quality of life. Pharmacokinetics were analyzed using cycle 1 plasma samples. Bone marrow granulocyte and macrophage colony-forming units (CFU-GM) were assayed in vitro for dose response to 4-hydroperoxycyclophosphamide and doxorubicin before cycle 1. There was moderate evidence of age-related decrease in nadir absolute neutrophil count (ANC) when age was viewed as a continuous variable. On average there was a 10/microliter drop in cycle 1 nadir ANC for every year increase in age (p = 0.02). However, when age was viewed as a categorical variable (age < 65 vs. > or = 65 years), a similar proportion of women in each group reached an ANC < 100 (18% vs. 19%). Neither neutropenic complications, alteration in cardiac function, nor change in quality of life scores were significantly age related (p > 0.12). Pharmacokinetic analyses did not demonstrate age-related differences in the clearance of either doxorubicin or cyclophosphamide (p > 0.8). Pharmacodynamic analysis of individual patient bone marrow progenitor cell sensitivity did not reveal any correlation with age (p > 0.48). In women undergoing adjuvant therapy for breast cancer, no clinically significant age-related trends in toxicity were observed. These data suggest that older age alone should not exclude patients from receiving adjuvant therapy with doxorubicin and cyclophosphamide.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Adulto , Fatores Etários , Idoso , Neoplasias da Mama/psicologia , Quimioterapia Adjuvante , Ciclofosfamida/efeitos adversos , Ciclofosfamida/farmacocinética , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacocinética , Feminino , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Estudos Prospectivos , Qualidade de VidaRESUMO
PURPOSE: To determine the maximum-tolerated dose (MTD), toxicities, and pharmacokinetics of oral fluorouracil (5-FU) administered twice daily in combination with oral eniluracil, an inactivator of dihydropyrimidine dehydrogenase, administered for 28 days every 35 days. PATIENTS AND METHODS: Oral 5-FU 1.35 mg/m(2) twice daily was administered with oral eniluracil 10 mg daily for 14 to 28 days, followed by a 1-week rest period. Eniluracil was started 1 day before 5-FU. Patients then received escalated doses of oral 5-FU 1. 35 to 1.8 mg/m(2) twice daily with an increased dose of eniluracil 10 mg twice daily for 28 days. A reduced dose of 5-FU 1.0 mg/m(2) with eniluracil 20 mg twice daily was evaluated. RESULTS: Thirty-six patients with solid malignancies were enrolled onto the study. Diarrhea was the principal dose-limiting toxicity of oral 5-FU and eniluracil given on this chronic schedule. The recommended phase II dose is 5-FU 1.0 mg/m(2) twice daily with eniluracil 20 mg twice daily. Mean (SD) values for terminal half-life, apparent volume of distribution, and systemic clearance of 4.5 hours (0.83 hours), 19 L/m(2) (3.0 L/m(2)), and 51 mL/min/m(2) (13 mL/min/m(2)), respectively. An average of 77% of 5-FU was excreted unchanged in urine after 28 days of treatment. The mean (range) 5-FU C(SS,min) values achieved at the 1.0 mg/m(2) dose level were 22 ng/mL (8 to 38 ng/mL). CONCLUSION: Chronic oral administration of 5-FU with oral eniluracil is tolerable and produces 5-FU steady-state concentrations similar to those achieved with protracted intravenous administration of 5-FU on clinically relevant dose schedules. Eniluracil provides an attractive means of administering 5-FU on protracted schedules.