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1.
Gynecol Oncol ; 127(1): 55-62, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22664059

RESUMO

PURPOSE: Based upon promising preclinical and phase 1 trial results, combined flavopiridol and cisplatin therapy was evaluated in patients with ovarian and primary peritoneal cancers. METHODS: A two cohort phase 2 trial of cisplatin (60 mg/m2 IV) immediately followed by flavopiridol (100 mg/m2 IV, 24 h infusion; 21 day cycles) was undertaken in patients with recurrent platin-sensitive or platin-resistant disease (progression>vs. ≤6 months following prior platin-based therapy). Measurable disease (RECIST)--or evaluable disease plus CA125>2X post-treatment nadir--and ECOG performance≤2 were required. RESULTS: Forty-five patients were enrolled between December 23, 2004 and February 25, 2010: 40 platin-resistant (Group 1), and 5 platin-sensitive (Group 2). In Group 1, the median number of treatment cycles was 3 (range 2-12). Only 10% of patients incurred grade 4 toxicities, but grade 3 toxicities were common (65%): neutropenia (17.5%); nausea (12.5%); vomiting, fatigue, thrombosis, anemia (10% each). Seven patients (17.5%) achieved a confirmed response (1 CR, 6 PR; median duration 118 days); ten additional patients (25%) attained maintained stable disease. Median time to progression was 4.3 months; overall survival was 16.1 months. Pilot translational studies assessed ascites flavopiridol level; surrogate marker studies were uninformative. In Group 2, although 4 of 5 patients responded (2 confirmed PRs with median time to progression, 10.8 months and median overall survival 20.6 months) the cohort was closed due to poor accrual. CONCLUSIONS: The assessed flavopiridol and cisplatin regimen displayed clinical activity in platin resistant and sensitive ovarian/primary peritoneal cancers, meriting further study.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Estudos de Coortes , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Flavonoides/administração & dosagem , Flavonoides/efeitos adversos , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/patologia , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Adulto Jovem
2.
Lancet Oncol ; 11(10): 962-72, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20851682

RESUMO

BACKGROUND: Chemotherapy has historically proven ineffective in advanced differentiated thyroid cancers, but the realisation that various tyrosine kinases are activated in the disease suggested a potential therapeutic role for tyrosine-kinase inhibitors. We investigated the safety and efficacy of pazopanib. METHODS: This phase 2 trial was done from Feb 22, 2008, to Jan 31, 2009, in patients with metastatic, rapidly progressive, radioiodine-refractory differentiated thyroid cancers. Each patient received 800 mg continuous pazopanib daily in 4-week cycles until disease progression, drug intolerance, or both occurred. Up to two previous therapies were allowed, and measurable disease with radiographic progression in the 6-month period before enrolment was a requirement for inclusion. The primary endpoint was any tumour response, according to the Response Evaluation Criteria in Solid Tumors 1.0. This study is registered with ClinicalTrials.gov, number NCT00625846. FINDINGS: 39 patients were enrolled. One patient had received no previous radioiodine therapy and another withdrew consent before treatment. Clinical outcomes could, therefore, be assessed in 37 patients (19 [51%] men, median age 63 years). The study is closed to accrual of new patients, but several enrolled patients are still being treated. Patients received a median of 12 cycles (range 1 to >23, total >383). Confirmed partial responses were recorded in 18 patients (response rate 49%, 95% CI 35-68), with likelihood of response lasting longer than 1 year calculated to be 66%. Maximum concentration of pazopanib in plasma during cycle one was significantly correlated with radiographic response (r=-0·40, p=0·021). 16 (43%) patients required dose reductions owing to adverse events, the most frequent of which (any grade) were fatigue (29 patients), skin and hair hypopigmentation (28), diarrhoea (27), and nausea (27). Two patients who died during treatment had pre-existing contributory disorders. INTERPRETATION: Pazopanib seems to represent a promising therapeutic option for patients with advanced differentiated thyroid cancers. The correlation of the patient's response and pazopanib concentration during the first cycle might indicate that treatment can be individualised to achieve optimum outcomes. Assessment of pazopanib in an expanded cohort of patients with differentiated thyroid cancer, as well as in cohorts of patients with medullary and anaplastic thyroid cancers, is presently being done. FUNDING: National Cancer Institute, supported in part by NCI CA15083 and CM62205.


Assuntos
Antineoplásicos/uso terapêutico , Diferenciação Celular , Radioisótopos do Iodo/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Compostos Radiofarmacêuticos/uso terapêutico , Sulfonamidas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Indazóis , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Radiografia , Sulfonamidas/efeitos adversos , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/radioterapia , Neoplasias da Glândula Tireoide/secundário , Fatores de Tempo , Falha de Tratamento , Estados Unidos , Adulto Jovem
3.
Thyroid ; 30(9): 1254-1262, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32538690

RESUMO

Introduction: Multikinase inhibitors have clinical activity in radioactive iodine refractory (RAIR) differentiated thyroid cancers (DTCs) but are not curative; optimal management and salvage therapies remain unclear. This study assessed clinical effects of pazopanib therapy in RAIR-DTC patients with progressive disease, examining in parallel biomarker that might forecast/precede therapeutic response. Methods: Assessment of responses and toxicities and of any association between thyroglobulin (Tg) changes cycle 1 and RECIST (response evaluation criteria in solid tumors) response to pazopanib therapy were prospectively undertaken in Tg antibody negative RAIR-DTC patients. RECIST progressive metastatic disease <6 months preceding enrollment was required. With a sample size of 68 (assuming 23 attaining partial response [PR]), there would be 90% chance of detecting a difference of >30% when the proportion of patients attaining PR whose Tg values decrease by >50% is >50% cycle 1 (one-sided α = 0.10, two sample test of proportions). Mean corpuscular volume (MCV) change or mutational status or pretreatment were also explored as early correlates of eventual RECIST response. Results: From 2009 to 2011, 60 individuals were treated and evaluated; (one additional patient withdrew; another was found ineligible before therapy initiation); 91.7% had previous systemic therapy beyond RAI. Adverse events included one death (thromboembolic) deemed possibly pazopanib associated. Twenty-two confirmed RECIST PRs resulted (36.7%, confidence interval; CI [24.6-50.1]); mean administered 4-week cycles was 10. Among 44 fully accessible patients, the Tg nadir was greater among the 20 attaining PR (median: -86.8%; interquartile range [IQR]: -90.7% to -70.9%) compared with the 28 who did not (median: -69.0%; IQR: -78.1% to -27.7%, Wilcoxon rank-sum test: p = 0.002). However, the difference in the proportion of PRs among those whose Tg fell ≥50% after cycle 1 versus those that did not were not significantly correlated (-23.5% [CI: -55.3 to 8.3]; Fisher's exact test p-value = 0.27). RECIST response was also not correlated with/predicted by early MCV change, receipt of prior therapy, or tumor mutational status. Conclusions: This trial prospectively confirmed pazopanib to have clinical activity and manageable toxicities in patients with progressive RAIR-DTC. Response to pazopanib, however, was not robustly forecast by early associated changes in Tg or MCV, by prior therapy, or by tumor mutational status. ClinicalTrials.gov NCT00625846.


Assuntos
Indazóis/uso terapêutico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Tireoglobulina/imunologia , Neoplasias da Glândula Tireoide/imunologia , Idoso , Anticorpos/química , Biomarcadores Tumorais , Diferenciação Celular , Análise Mutacional de DNA , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Radioisótopos do Iodo/farmacologia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Prospectivos , Inibidores de Proteínas Quinases/uso terapêutico , Terapia de Salvação , Neoplasias da Glândula Tireoide/terapia , Resultado do Tratamento
4.
Endocrine ; 57(2): 220-225, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28685225

RESUMO

INTRODUCTION: Pheochromocytomas and paragangliomas (Pheo/PGL) are rare, vascular, sometimes malignant endocrine tumors. Case reports indicate the activity of vascular endothelium growth factor receptor-targeted kinase inhibitors in these cancers. OBJECTIVES: To assess the antitumor activity and tolerability of pazopanib in progressive malignant Pheo/PGL. PATIENTS AND METHODS: This multicenter Phase II trial (MC107C) enrolled individuals ≥18 years old with disease progression ≤ 6 months prior to registration, Eastern Cooperative Oncology Group PS 0-2, and measurable disease (response evaluation criteria in solid tumors 1.0). Pazopanib was administered in 28-day cycles, with the regimen ultimately being as follows: cycle 1: 400 mg daily on days 1-14, cycle 2: 800 mg daily on days 1-14, and then cycle 2 + : 800 mg daily on all days. RESULTS: The study was halted due to poor accrual. Seven patients were enrolled (05/2011-11/2014). One patient withdrew consent prior to treatment, leaving six evaluable patients. Treatment was discontinued, due to the following reasons: disease progression (4); withdrawal (1); and grade 4 (Takotsubo) cardiomyopathy (1). The median number of cycles administered was 4 (range: 2-29, total: 49). Four patients had >1 dose reduction due to the following reasons: fatigue (1), abnormal liver tests (2), hypertension and (Takotsubo) cardiomyopathy (1), and headaches (1). Common severe (Common Terminology Criteria for Adverse Events v3.0 grades 3-5) toxicities were as follows: hypertension (3/6), (Takotsubo) cardiomyopathy (2/6), diarrhea (1/6), fatigue (1/6), headache (1/6), and hematuria (1/6). One confirmed partial response was observed in PGL (17%, duration 2.4 years); median progression-free survival and overall survival were 6.5 and 14.8 months, respectively. CONCLUSION: Pazopanib has activity in Pheo/PGL requiring more study; optimal alpha- and beta-blockade are imperative pre-therapy in patients with secretory tumors, as risk of hypertension and cardiomyopathy are potentially life threatening.


Assuntos
Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Neoplasias das Glândulas Endócrinas/tratamento farmacológico , Paraganglioma/tratamento farmacológico , Feocromocitoma/tratamento farmacológico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/efeitos adversos , Intervalo Livre de Doença , Eletrocardiografia , Neoplasias das Glândulas Endócrinas/patologia , Feminino , Humanos , Indazóis , Masculino , Pessoa de Meia-Idade , Paraganglioma/patologia , Feocromocitoma/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/efeitos adversos , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Sulfonamidas/efeitos adversos , Falha de Tratamento
5.
J Clin Endocrinol Metab ; 99(5): 1687-93, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24606083

RESUMO

CONTEXT: Pazopanib is a small molecule inhibitor of kinases principally including vascular endothelial growth factor receptors-1, -2, and -3; platelet-derived growth factor receptors-α and -ß; and c-Kit. We previously reported a tumor response rate of 49% in patients with advanced differentiated thyroid cancer and 0% in patients with advanced anaplastic thyroid cancer. The present report details results of pazopanib therapy in advanced medullary thyroid cancer (MTC). OBJECTIVE, DESIGN, SETTING, PATIENTS, INTERVENTION, AND OUTCOME MEASURES: Having noted preclinical activity of pazopanib in MTC, patients with advanced MTC who had disease progression within the preceding 6 months were accrued to this multiinstitutional phase II clinical trial to assess tumor response rate (by Response Evaluation Criteria In Solid Tumors criteria) and safety of pazopanib given orally once daily at 800 mg until disease progression or intolerability. RESULTS: From September 22, 2008, to December 11, 2011, 35 individuals (80% males, median age 60 y) were enrolled. All patients have been followed up until treatment discontinuation or for a minimum of four cycles. Eight patients (23%) are still on the study treatment. The median number of therapy cycles was eight. Five patients attained partial Response Evaluation Criteria In Solid Tumors responses (14.3%; 90% confidence interval 5.8%-27.7%), with a median progression-free survival and overall survival of 9.4 and 19.9 months, respectively. Side effects included treatment-requiring (new) hypertension (33%), fatigue (14%), diarrhea (9%), and abnormal liver tests (6%); 3 of 35 patients (8.6%) discontinued therapy due to adverse events. There was one death of a study patient after withdrawal from the trial deemed potentially treatment related. CONCLUSIONS: Pazopanib has promising clinical activity in metastatic MTC with overall manageable toxicities.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Carcinoma Medular/tratamento farmacológico , Pirimidinas/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/efeitos adversos , Carcinoma Medular/mortalidade , Carcinoma Medular/secundário , Progressão da Doença , Feminino , Humanos , Indazóis , Masculino , Pessoa de Meia-Idade , Pirimidinas/efeitos adversos , Sulfonamidas/efeitos adversos , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/patologia , Resultado do Tratamento
6.
J Clin Endocrinol Metab ; 97(9): 3179-84, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22774206

RESUMO

CONTEXT/OBJECTIVES: Pazopanib, an inhibitor of kinases including vascular endothelial growth factor receptor, demonstrated impressive activity in progressive metastatic differentiated thyroid cancer, prompting its evaluation in anaplastic thyroid cancer (ATC). DESIGN/SETTING/PATIENTS/INTERVENTIONS/OUTCOME MEASURES: Preclinical studies, followed by a multicenter single arm phase 2 trial of continuously administered 800 mg pazopanib daily by mouth (designed to provide 90% chance of detecting a response rate of >20% at the 0.10 significance level when the true response rate is >5%), were undertaken. The primary trial end point was Response Evaluation Criteria in Solid Tumors (RECIST) response. RESULTS: Pazopanib displayed activity in the KTC2 ATC xenograft model, prompting clinical evaluation. Sixteen trial patients were enrolled; 15 were treated: 66.7% were female, median age was 66 yr (range 45-77 yr), and 11 of 15 had progressed through prior systemic therapy. Enrollment was halted, triggered by a stopping rule requiring more than one confirmed RECIST response among the first 14 of 33 potential patients. Four patients required one to two dose reductions; severe toxicities (National Cancer Institute Common Toxicity Criteria-Adverse Events version 3.0 grades >3) were hypertension (13%) and pharyngolaryngeal pain (13%). Treatment was discontinued because of the following: disease progression (12 patients), death due to a possibly treatment-related tumor hemorrhage (one patient), and intolerability (radiation recall tracheitis and uncontrolled hypertension, one patient each). Although transient disease regression was observed in several patients, there were no confirmed RECIST responses. Median time to progression was 62 d; median survival time was 111 d. Two patients are alive with disease 9.9 and 35 months after the registration; 13 died of disease. CONCLUSIONS: Despite preclinical in vivo activity in ATC, pazopanib has minimal single-agent clinical activity in advanced ATC.


Assuntos
Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Idoso , Animais , Progressão da Doença , Intervalo Livre de Doença , Determinação de Ponto Final , Feminino , Humanos , Indazóis , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Análise de Sobrevida , Carcinoma Anaplásico da Tireoide , Ensaios Antitumorais Modelo de Xenoenxerto
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