RESUMO
PF-06647263, a novel antibody-drug conjugate consisting of an anti-EFNA4 antibody linked to a calicheamicin payload, has shown potent antitumor activity in human xenograft tumor models, including triple-negative breast cancer (TNBC). In the dose-escalation part 1 of this multicenter, open-label, phase I study (NCT02078752), successive cohorts of patients (n, 48) with advanced solid tumors and no available standard therapy received PF-06647263 every 3 weeks (Q3W) or every week (QW), following a modified toxicity probability interval (mTPI) method (initial dosing: 0.015 mg/kg Q3W). Primary objective in part 1 was to estimate the maximum tolerated dose (MTD) and select the recommended phase 2 dose (RP2D). In part 2 (dose-expansion cohort), 12 patients with pretreated, metastatic TNBC received PF-06647263 at the RP2D to further evaluate tumor response and overall safety. PF-06647263 QW administration (n, 23) was better tolerated than the Q3W regimen (n, 25) with only 1 DLT reported (thrombocytopenia). The most common AEs with the QW regimen (fatigue, nausea, vomiting, mucosal inflammation, thrombocytopenia, and diarrhea) were mostly mild to moderate in severity. The MTD was not estimated. PF-06647263 exposures increased in a dose-related manner across the doses evaluated. The RP2D was determined to be 0.015 mg/kg QW. Six (10%) patients achieved a confirmed partial response and 22 (36.7%) patients had stable disease. No correlations were observed between tumor responses and EFNA4 expression levels. Study findings showed manageable safety and favorable PK for PF-06647263 administered QW at the RP2D, with preliminary evidence of limited antitumor activity in patients with TNBC and ovarian cancer.
Assuntos
Aminoglicosídeos/administração & dosagem , Anticorpos Monoclonais Murinos/administração & dosagem , Metástase Neoplásica/tratamento farmacológico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminoglicosídeos/efeitos adversos , Animais , Anticorpos Monoclonais Murinos/efeitos adversos , Esquema de Medicação , Efrina-A4/metabolismo , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Camundongos , Pessoa de Meia-Idade , Neoplasias/metabolismo , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismoRESUMO
BACKGROUND: Bone metastases in patients with metastatic castration-resistant prostate cancer (mCRPC) are associated with debilitating pain and functional compromise. OBJECTIVE: To compare pain palliation as the primary endpoint for cabozantinib versus mitoxantrone-prednisone in men with mCRPC and symptomatic bone metastases using patient-reported outcome measures. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind phase 3 trial (COMET-2; NCT01522443) in men with mCRPC and narcotic-dependent pain from bone metastases who had progressed after treatment with docetaxel and either abiraterone or enzalutamide. INTERVENTION: Cabozantinib 60mg once daily orally versus mitoxantrone 12mg/m2 every 3wk plus prednisone 5mg twice daily orally. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was pain response at week 6 confirmed at week 12 (≥30% decrease from baseline in patient-reported average daily worst pain score via the Brief Pain Inventory without increased narcotic use). The planned sample size was 246 to achieve ≥90% power. RESULTS AND LIMITATIONS: Enrollment was terminated early because cabozantinib did not demonstrate a survival benefit in the companion COMET-1 trial. At study closure, 119 participants were randomized (cabozantinib: N=61; mitoxantrone-prednisone: N=58). Complete pain and narcotic use data were available at baseline, week 6, and week 12 for 73/106 (69%) patients. There was no significant difference in the pain response with cabozantinib versus mitoxantrone-prednisone: the proportions of responders were 15% versus 17%, a -2% difference (95% confidence interval: -16% to 11%, p=0.8). Barriers to accrual included pretreatment requirements for a washout period of prior anticancer therapy and a narcotic optimization period to maximize analgesic dosing. CONCLUSIONS: Cabozantinib treatment did not demonstrate better pain palliation than mitoxantrone-prednisone in heavily pretreated patients with mCRPC and symptomatic bone metastases. Future pain-palliation trials should incorporate briefer timelines from enrollment to treatment initiation. PATIENT SUMMARY: Cabozantinib was not better than mitoxantrone-prednisone for pain relief in patients with castration-resistant prostate cancer and debilitating pain from bone metastases.
Assuntos
Analgésicos/administração & dosagem , Anilidas/uso terapêutico , Neoplasias Ósseas/complicações , Neoplasias Ósseas/secundário , Dor do Câncer/tratamento farmacológico , Dor do Câncer/etiologia , Mitoxantrona/administração & dosagem , Manejo da Dor/métodos , Prednisona/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/patologia , Piridinas/uso terapêutico , Idoso , Método Duplo-Cego , Combinação de Medicamentos , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Estudos ProspectivosRESUMO
BACKGROUND: We assessed whether oxidant-stress and inflammation in beta-thalassemia could be controlled by the novel oral iron chelator deferasirox as effectively as by deferoxamine. DESIGN AND METHODS: Forty-nine subjects were enrolled from seven sites and studied at baseline, and after 1, 6, and 12 months of therapy. Malondialdehyde, protein carbonyls, vitamins E and C, total non-transferrin bound iron, transferrin saturation, C-reactive protein, cytokines, serum ferritin concentration and liver iron concentration were measured. RESULTS: Liver iron concentration and ferritin declined significantly in both treatment groups during the study. This paralleled a significant decline in the oxidative-stress marker malondialdehyde (deferasirox -22%/year, deferoxamine -28%/year, average decline p=0.006). The rates of decline did not differ between treatment groups. Malondialdehyde was higher in both treatment groups than in a group of 30 non-thalassemic controls (p < 0.001). The inflammatory marker high-sensitivity C-reactive protein decreased significantly only in the group receiving deferasirox (deferasirox -51%/year, deferoxamine +8.5%/year, p = 0.02). This result was confounded by a chance difference in the level of high-sensitivity C-reactive protein between the two groups at baseline, but analyses controlling for this difference suggested an equally large treatment effect. CONCLUSIONS: Iron chelation therapy with deferoxamine or with deferasirox was equally effective in decreasing iron burden and malondialdehyde. The possible differential effect of the two chelators on inflammation warrants further investigation.
Assuntos
Benzoatos/farmacologia , Desferroxamina/farmacologia , Quelantes de Ferro/farmacologia , Oxidantes/metabolismo , Triazóis/farmacologia , Talassemia beta/tratamento farmacológico , Adolescente , Adulto , Ácido Ascórbico/metabolismo , Benzoatos/efeitos adversos , Proteína C-Reativa/metabolismo , Criança , Deferasirox , Desferroxamina/efeitos adversos , Feminino , Humanos , Quelantes de Ferro/efeitos adversos , Peroxidação de Lipídeos , Masculino , Estresse Oxidativo , Triazóis/efeitos adversos , Vitamina E/metabolismo , Talassemia beta/patologiaRESUMO
Background: Cabozantinib is a tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 (VEGFR2) and MET that has demonstrated clinical activity in advanced solid tumors. This open-label, phase II trial evaluated cabozantinib in patients with recurrent or refractory glioblastoma (GBM). Methods: Patients were initially enrolled at a starting dose of 140 mg/day, but the starting dose was amended to 100 mg/day because of toxicity. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate assessed by an independent radiology facility using modified Response Assessment in Neuro-Oncology criteria. Additional endpoints included duration of response, 6-month and median progression-free survival, overall survival, and safety. Results: Among 152 patients naive to prior antiangiogenic therapy, the objective response rate was 17.6% and 14.5% in the 140 mg/day and 100 mg/day groups, respectively, which did not meet the predefined statistical target for success. The proportions of patients alive and progression free at 6 months were 22.3% and 27.8%, respectively. Median progression-free survival was 3.7 months in both groups, and median overall survival was 7.7 months and 10.4 months, respectively. The incidence of grade 3/4 adverse events (AEs) was 79.4% and 84.7% in the 140 mg/day and 100 mg/day groups, respectively, and dose reductions due to AEs were experienced by 61.8% and 72.0%, respectively. Common grade 3/4 AEs included fatigue, diarrhea, and palmar-plantar erythrodysesthesia syndrome. Conclusions: Cabozantinib showed evidence of clinical activity in patients with recurrent GBM naive to antiangiogenic therapy, although the predefined statistical target for success was not met. At the starting doses assessed, AEs were frequently managed with dose reductions. Clinical Trials Registration Number: NCT00704288 (https://www.clinicaltrials.gov/ct2/show/NCT00704288).
Assuntos
Inibidores da Angiogênese/uso terapêutico , Anilidas/uso terapêutico , Glioblastoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Adulto , Idoso , Análise de Dados , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Background: Cabozantinib is a potent, multitarget inhibitor of MET and vascular endothelial growth factor receptor 2 (VEGFR2). This open-label, phase II trial evaluated cabozantinib in patients with recurrent or progressive glioblastoma (GBM). Methods: Patients were initially enrolled to a starting cabozantinib dose of 140 mg/day, but the starting dose was amended to 100 mg/day because of safety concerns. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate, assessed by an independent radiology facility using modified Response Assessment in Neuro-Oncology criteria. Additional endpoints included duration of response, 6-month and median progression-free survival, overall survival, glucocorticoid use, and safety. Results: Among 222 patients enrolled, 70 had received prior antiangiogenic therapy. Herein, we report results in this subset of 70 patients. The objective response rate was 4.3%, and the median duration of response was 4.2 months. The proportion of patients alive and progression free at 6 months was 8.5%. Median progression-free survival was 2.3 months, and median overall survival was 4.6 months. The most common adverse events reported in all patients, regardless of dose group, included fatigue (74.3%), diarrhea (47.1%), increased alanine aminotransferase (37.1%), headache (35.7%), hypertension (35.7%), and nausea (35.7%); overall, 34 (48.6%) patients experienced adverse events that resulted in dose reductions. Conclusions: Cabozantinib treatment appeared to have modest clinical activity with a 4.3% response rate in patients who had received prior antiangiogenic therapy for GBM. Clinical Trials Registration Number: NCT00704288 (https://www.clinicaltrials.gov/ct2/show/NCT00704288).
Assuntos
Inibidores da Angiogênese/uso terapêutico , Anilidas/uso terapêutico , Glioblastoma/tratamento farmacológico , Piridinas/uso terapêutico , Adulto , Idoso , Análise de Dados , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Background: To overcome challenges with traditional response assessment in anti-angiogenic agents, the current study uses T1 subtraction maps to quantify volumetric radiographic response in monotherapy with cabozantinib, an orally bioavailable tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 (VEGFR2), hepatocyte growth factor receptor (MET), and AXL, in an open-label, phase II trial in patients with recurrent glioblastoma (GBM) (NCT00704288). Methods: A total of 108 patients with adequate imaging data and confirmed recurrent GBM were included in this retrospective study from a phase II multicenter trial of cabozantinib monotherapy (XL184-201) at either 100 mg (N = 87) or 140 mg (N = 21) per day. Contrast enhanced T1-weighted digital subtraction maps were used to define volume of contrast-enhancing tumor at baseline and subsequent follow-up time points. Volumetric radiographic response (>65% reduction in contrast-enhancing tumor volume from pretreatment baseline tumor volume sustained for more than 4 wk) was tested as an independent predictor of overall survival (OS). Results: Volumetric response rate for all therapeutic doses was 38.9% (41.4% and 28.6% for 100 mg and 140 mg doses, respectively). A log-linear association between baseline tumor volume and OS (P = 0.0006) and a linear correlation between initial change in tumor volume and OS (P = 0.0256) were observed. A significant difference in OS was observed between responders (median OS = 20.6 mo) and nonresponders (median OS = 8.0 mo) (hazard ratio [HR] = 0.3050, P < 0.0001). Multivariable analyses showed that continuous measures of baseline tumor volume (HR = 1.0233, P < 0.0001) and volumetric response (HR = 0.2240, P < 0.0001) were independent predictors of OS. Conclusions: T1 subtraction maps provide value in determining response in recurrent GBM treated with cabozantinib and correlated with survival benefit.
Assuntos
Anilidas/uso terapêutico , Neoplasias Encefálicas/mortalidade , Meios de Contraste , Glioblastoma/mortalidade , Imageamento por Ressonância Magnética/métodos , Recidiva Local de Neoplasia/mortalidade , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Adulto , Idoso , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Feminino , Seguimentos , Glioblastoma/diagnóstico por imagem , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Carga Tumoral , Adulto JovemRESUMO
Cabozantinib is a tyrosine kinase inhibitor approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. Two clinical pharmacology studies were conducted to characterize single-dose pharmacokinetics (PK) of cabozantinib in renally or hepatically impaired subjects. Study 1 enrolled 10 subjects, each with mild or moderate impairment of renal function; 12 healthy subjects were matched to the moderate group for age, sex, and body mass index (BMI). Study 2 enrolled 8 males each with mild or moderate hepatic impairment; 10 healthy males were matched to the moderate group for age, BMI, and ethnicity. All subjects received one 60 mg cabozantinib oral capsule dose followed by PK sampling over 21 days. Plasma concentration and protein binding were determined by liquid chromatography tandem mass spectrometry and equilibrium dialysis, respectively. PK parameters were computed using noncompartmental methods. Geometric least squared mean (LSM) ratios for plasma cabozantinib AUC0-∞ for impaired to normal organ function cohorts were (1) approximately 30% and 6% higher in subjects with mild and moderate renal impairment, respectively, and (2) approximately 81% and 63% higher in subjects with mild and moderate hepatic impairment, respectively. The percentage of unbound drug was slightly higher in both moderately impaired cohorts. No deaths or discontinuations due to adverse events occurred in either study. Cabozantinib should be used with caution in subjects with mild or moderate renal impairment. Subjects with mild or moderate hepatic impairment administered cabozantinib should be monitored closely for potential treatment-emergent drug toxicity that may necessitate a dose hold or reduction.
Assuntos
Anilidas/sangue , Hepatopatias/sangue , Piridinas/sangue , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Insuficiência Renal/sangue , Idoso , Anilidas/efeitos adversos , Anilidas/farmacocinética , Área Sob a Curva , Estudos de Coortes , Feminino , Humanos , Hepatopatias/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Piridinas/efeitos adversos , Piridinas/farmacocinética , Insuficiência Renal/tratamento farmacológico , Resultado do TratamentoRESUMO
Cabozantinib is a small-molecule tyrosine kinase inhibitor that has been approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. In vitro data indicate that (1) cytochrome P450 (CYP) 3A4 is the primary CYP isoenzyme involved in the metabolism of cabozantinib, and (2) CYP2C8 is the CYP isoenzyme most potently inhibited by cabozantinib with potential for in vivo inhibition at clinically relevant plasma exposures. Pharmacokinetic (PK) drug-drug interactions (DDIs) were evaluated clinically between cabozantinib and (1) a CYP3A inducer (rifampin) in healthy volunteers, (2) a CYP3A inhibitor (ketoconazole) in healthy volunteers, and (3) a CYP2C8 substrate (rosiglitazone) in patients with solid tumors. Compared with cabozantinib given alone, coadministration with rifampin resulted in a 4.3-fold higher plasma clearance (CL/F) of cabozantinib and a 77% decrease in cabozantinib plasma AUC0-inf , whereas coadministration with ketoconazole decreased cabozantinib CL/F by 29% and increased cabozantinib AUC0-inf by 38%. Chronic coadministration with cabozantinib resulted in no significant effect on rosiglitazone plasma Cmax , AUC0-24 , or AUC0-inf . In summary, chronic use of strong CYP3A inducers and inhibitors should be avoided when cabozantinib is administered, and cabozantinib at clinically relevant exposures is not anticipated to markedly affect the PK of concomitant medications via CYP enzyme inhibition.
Assuntos
Anilidas/administração & dosagem , Anilidas/farmacocinética , Cetoconazol/farmacocinética , Piridinas/administração & dosagem , Piridinas/farmacocinética , Rifampina/farmacocinética , Tiazolidinedionas/farmacocinética , Anilidas/sangue , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Área Sob a Curva , Citocromo P-450 CYP2C8/metabolismo , Indutores do Citocromo P-450 CYP3A/administração & dosagem , Indutores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/sangue , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Interações Medicamentosas , Meia-Vida , Humanos , Hipoglicemiantes/sangue , Hipoglicemiantes/farmacocinética , Cetoconazol/administração & dosagem , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Piridinas/sangue , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Rifampina/administração & dosagem , Rosiglitazona , Tiazolidinedionas/sangueRESUMO
Cabozantinib is a small molecule tyrosine kinase inhibitor that has been approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. Cabozantinib exhibits a pH-dependent solubility profile in vitro. Two phase 1 clinical pharmacology studies were conducted in healthy subjects to evaluate whether factors that may affect cabozantinib solubility and gastric pH could alter cabozantinib bioavailability: a food effect study (study 1) and a drug-drug interaction (DDI) study with the proton pump inhibitor (PPI) esomeprazole (study 2). Following a high-fat meal (study 1), cabozantinib Cmax and AUC were increased (40.5% and 57%, respectively), and the median tmax was delayed by 2 hours. Cabozantinib should thus not be taken with food (patients should not eat for at least 2 hours before and at least 1 hour after administration). In the DDI study (study 2), the 90% confidence intervals (CIs) around the ratio of least-squares means of cabozantinib with esomeprazole versus cabozantinib alone for AUC0-inf were within the 80%-125% limits; the upper 90%CI for Cmax was 125.1%. Because of the low apparent risk of a DDI, concomitant use of PPIs or weaker gastric pH-altering agents with cabozantinib is not contraindicated.
Assuntos
Anilidas/farmacocinética , Esomeprazol/farmacologia , Inibidores de Proteínas Quinases/farmacocinética , Inibidores da Bomba de Prótons/farmacologia , Piridinas/farmacocinética , Adolescente , Adulto , Anilidas/efeitos adversos , Anilidas/sangue , Disponibilidade Biológica , Estudos Cross-Over , Interações Medicamentosas , Feminino , Alimentos , Mucosa Gástrica/metabolismo , Voluntários Saudáveis , Humanos , Concentração de Íons de Hidrogênio , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/sangue , Piridinas/efeitos adversos , Piridinas/sangue , Adulto JovemRESUMO
BACKGROUND: Cabozantinib targets tyrosine kinases including MET, vascular endothelial growth factor (VEGF) receptor 2, and rearranged during transfection (RET). Differentiated thyroid cancer (DTC) is a tumor type that may be sensitive to cabozantinib. Therefore, we evaluated cabozantinib in a cohort of heavily pretreated patients with metastatic DTC. METHODS: This single-arm open-label phase I trial assessed the safety, tolerability, and antitumor activity of cabozantinib in DTC patients taking part in a drug-drug interaction study. Adult patients with histologically confirmed metastatic or surgically unresectable DTC (including papillary, follicular, or Hürthle cell) were enrolled. Patients received daily oral dosing of 140 mg cabozantinib. Safety was assessed by evaluation of adverse events (AEs), vital signs, electrocardiograms, laboratory tests, and concomitant medications. Tumor response by magnetic resonance imaging or computed tomography scan was investigator assessed using Response Evaluation Criteria In Solid Tumors (RECIST) v1.0. RESULTS: The study enrolled 15 patients who had failed standard radioactive iodine therapy. Patients had received a median of two prior systemic agents, and 11 patients (73%) had previously received at least one VEGF pathway inhibiting therapy. Common AEs included diarrhea, nausea, fatigue, and decreased appetite. Partial response was reported in eight patients (53%). Median progression-free survival and median overall survival were not reached. CONCLUSIONS: Cabozantinib demonstrates a safety profile similar to other multitargeted VEGFR inhibitors in advanced DTC patients. The antitumor activity observed in this study warrants further investigation of cabozantinib in patients with advanced DTC.
Assuntos
Anilidas/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma/tratamento farmacológico , Diferenciação Celular , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Administração Oral , Adulto , Idoso , Anilidas/administração & dosagem , Anilidas/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma/enzimologia , Carcinoma/mortalidade , Carcinoma/secundário , Intervalo Livre de Doença , Esquema de Medicação , Humanos , Estimativa de Kaplan-Meier , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Neoplasias da Glândula Tireoide/enzimologia , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/patologia , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Estados UnidosRESUMO
Deferasirox is a once-daily, oral iron chelator developed for treating transfusional iron overload. Preclinical studies indicated that the kidney was a potential target organ of toxicity. As patients with sickle cell disease often have abnormal baseline renal function, the primary objective of this randomised, open-label, phase II trial was to evaluate the safety and tolerability of deferasirox in comparison with deferoxamine in this population. Assessment of efficacy, as measured by change in liver iron concentration (LIC) using biosusceptometry, was a secondary objective. A total of 195 adult and paediatric patients received deferasirox (n = 132) or deferoxamine (n = 63). Adverse events most commonly associated with deferasirox were mild, including transient nausea, vomiting, diarrhoea, abdominal pain and skin rash. Abnormal laboratory studies with deferasirox were occasionally associated with mild non-progressive increases in serum creatinine and reversible elevations in liver function tests. Discontinuation rates from deferasirox (11.4%) and deferoxamine (11.1%) were similar. Over 1 year, similar dose-dependent LIC reductions were observed with deferasirox and deferoxamine. Once-daily oral deferasirox has acceptable tolerability and appears to have similar efficacy to deferoxamine in reducing iron burden in transfused patients with sickle cell disease.