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1.
Ann Oncol ; 33(5): 522-533, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35176457

RESUMO

BACKGROUND: The phase I/II FIGHT-101 study (NCT02393248) evaluated safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of pemigatinib, a potent and selective fibroblast growth factor receptor (FGFR) 1-3 inhibitor, as monotherapy or in combination therapy, for refractory advanced malignancies, with and without fibroblast growth factor (FGF) and receptor (FGFR) gene alterations. PATIENTS AND METHODS: Eligible, molecularly unselected patients with advanced malignancies were included in part 1 (dose escalation; 3 + 3 design) to determine the maximum tolerated dose. Part 2 (dose expansion) evaluated the recommended phase II dose in tumors with or where FGF/FGFR activity is relevant. RESULTS: Patients (N = 128) received pemigatinib 1-20 mg once daily intermittently (2 weeks on/1 week off; n = 70) or continuously (n = 58). No dose-limiting toxicities were reported. Doses ≥4 mg were pharmacologically active (maximum tolerated dose not reached; recommended phase II dose 13.5 mg once daily). The most common treatment-emergent adverse event (TEAE) was hyperphosphatemia (75.0%; grade ≥3, 2.3%); the most common grade ≥3 TEAE was fatigue (10.2%). Dose interruption, dose reduction, and TEAE-related treatment discontinuation occurred in 66 (51.6%), 14 (10.9%), and 13 (10.2%) patients, respectively. Overall, 12 partial responses were achieved, most commonly in cholangiocarcinoma (n = 5) as well as in a broad spectrum of tumors including head and neck, pancreatic, gallbladder, uterine, urothelial carcinoma, recurrent pilocytic astrocytoma, and non-small-cell lung cancer (each n = 1); median duration of response was 7.3 months [95% confidence interval (CI) 3.3-14.5 months]. Overall response rate was highest for patients with FGFR fusions/rearrangements [n = 5; 25.0% (95% CI 8.7% to 49.1%)], followed by those with FGFR mutations [n = 3; 23.1% (95% CI 5.0% to 53.8%)]. CONCLUSIONS: Pemigatinib was associated with a manageable safety profile and pharmacodynamic and clinical activity, with responses seen across tumors and driven by FGFR fusions/rearrangements and mutations. These results prompted a registrational study in cholangiocarcinoma and phase II/III trials in multiple tumor types demonstrating the benefit of precision therapy, even in early phase trials.


Assuntos
Neoplasias dos Ductos Biliares , Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células de Transição , Colangiocarcinoma , Neoplasias Pulmonares , Neoplasias , Neoplasias da Bexiga Urinária , Neoplasias dos Ductos Biliares/tratamento farmacológico , Ductos Biliares Intra-Hepáticos/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células de Transição/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Feminino , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Morfolinas , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias/induzido quimicamente , Neoplasias/tratamento farmacológico , Neoplasias/genética , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas , Pirróis , Receptores de Fatores de Crescimento de Fibroblastos/genética , Neoplasias da Bexiga Urinária/tratamento farmacológico
2.
Ann Oncol ; 31(9): 1223-1230, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32464281

RESUMO

BACKGROUND: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor approved for extended adjuvant treatment in early-stage HER2-positive breast cancer based on the phase III ExteNET study. In that trial, in which no antidiarrheal prophylaxis was mandated, grade 3 diarrhea was observed in 40% of patients and 17% discontinued due to diarrhea. The international, open-label, sequential-cohort, phase II CONTROL study is investigating several strategies to improve tolerability. PATIENTS AND METHODS: Patients who completed trastuzumab-based adjuvant therapy received neratinib 240 mg/day for 1 year plus loperamide prophylaxis (days 1-28 or 1-56). Sequential cohorts evaluated additional budesonide or colestipol prophylaxis (days 1-28) and neratinib dose escalation (DE; ongoing). The primary end point was the incidence of grade ≥3 diarrhea. RESULTS: Final data for loperamide (L; n = 137), budesonide + loperamide (BL; n = 64), colestipol + loperamide (CL; n = 136), and colestipol + as-needed loperamide (CL-PRN; n = 104) cohorts, and interim data for DE (n = 60; completed ≥six cycles or discontinued; median duration 11 months) are available. No grade 4 diarrhea was observed. Grade 3 diarrhea rates were lower than ExteNET in all cohorts and lowest in DE (L 31%, BL 28%, CL 21%, CL-PRN 32%, DE 15%). Median number of grade 3 diarrhea episodes was one; median duration per grade 3 episode was 1.0-2.0 days across cohorts. Most grade 3 diarrhea and diarrhea-related discontinuations occurred in month 1. Diarrhea-related discontinuations were lowest in DE (L 20%, BL 8%, CL 4%, CL-PRN 8%, DE 3%). Decreases in health-related quality of life did not cross the clinically important threshold. CONCLUSIONS: Neratinib tolerability was improved with preemptive prophylaxis or DE, which reduced the rate, severity, and duration of neratinib-associated grade ≥3 diarrhea compared with ExteNET. Lower diarrhea-related treatment discontinuations in multiple cohorts indicate that proactive management can allow patients to stay on neratinib for the recommended time period. CLINICALTRIALS.GOV: NCT02400476.


Assuntos
Neoplasias da Mama , Quinolinas , Receptor ErbB-2 , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Humanos , Qualidade de Vida , Quinolinas/uso terapêutico , Receptor ErbB-2/genética , Trastuzumab/uso terapêutico
3.
Ann Oncol ; 28(9): 2241-2247, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28911085

RESUMO

BACKGROUND: Eribulin is a microtubule dynamics inhibitor with a novel mechanism of action. This phase 3 study aimed to compare overall survival (OS) in patients with heavily pretreated non-small cell lung cancer (NSCLC) receiving eribulin to treatment of physician's choice (TPC). PATIENTS AND METHODS: Patients with advanced NSCLC who had received ≥2 prior therapies, including platinum-based doublet and epidermal growth factor receptor tyrosine kinase inhibitor, were randomly assigned to receive eribulin or TPC (gemcitabine, pemetrexed, vinorelbine, docetaxel). The primary endpoint was OS. Secondary endpoints were progression-free survival and objective response rate. RESULTS: Five hundred and forty patients were randomized to either eribulin (n = 270) or TPC (n = 270). Median OS for eribulin and TPC was the same: 9.5 months [hazard ratio (HR): 1.16; 95% confidence interval: 0.95-1.41; P = 0.13]. Progression-free survival for eribulin and TPC was 3.0 and 2.8 months, respectively (HR: 1.09; 95% confidence interval: 0.90-1.32; P = 0.39). The objective response rate was 12% for eribulin and 15% for TPC. Clinical benefit rate (eribulin, 57%; TPC, 55%) and disease control rate (eribulin, 63%; TPC, 58%) were similar between treatment arms. The most common adverse event was neutropenia, which occurred in 57% of eribulin patients and 49% of TPC patients at all grades. Other non-hematologic side-effects were manageable and similar in both groups except for peripheral sensory neuropathy (all grades; eribulin, 16%; TPC, 9%). CONCLUSION: This phase 3 study did not demonstrate superiority of eribulin over TPC with regard to overall survival. However, eribulin does show activity in the third-line setting for NSCLC. TRIAL REGISTRATION ID: www.ClinicalTrials.gov; NCT01454934.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Furanos/uso terapêutico , Cetonas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Furanos/efeitos adversos , Humanos , Cetonas/efeitos adversos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida
4.
Ann Oncol ; 25(8): 1578-84, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24827127

RESUMO

BACKGROUND: This phase II, open-label study investigated intercalated combinations of eribulin and erlotinib in unselected patients with advanced non-small-cell lung cancer previously treated with platinum-based chemotherapies. PATIENTS AND METHODS: Eligible patients were randomized to eribulin mesylate 2.0 mg/m(2) on day 1 with erlotinib 150 mg on days 2-16 (21-day regimen) or eribulin mesylate 1.4 mg/m(2) on days 1 and 8 with erlotinib 150 mg on days 15-28 (28-day regimen). The primary end point was objective response rate (ORR). RESULTS: One hundred and twenty-three patients received ≥ 1 cycle of therapy (63, 21-day regimen; 60, 28-day regimen). ORRs were 13% [95% confidence interval (CI) 6%-24%] and 17% (95% CI 8%-29%), and disease control rates were 48% (95% CI 35%-61%) and 63% (95% CI 50%-75%) for the 21- and 28-day regimens, respectively. The median progression-free survival and overall survival were similar with both regimens. Both regimens were well tolerated with common grade ≥ 3 toxicities being neutropenia, asthenia/fatigue, and dyspnoea. Sequential administration of erlotinib did not interfere with the pharmacokinetic profile of eribulin. CONCLUSION: Intercalated combination of eribulin and erlotinib demonstrated modest activity and the addition of erlotinib did not appear to improve treatment outcome in an unselected population. The 28-day regimen is suitable for further investigation. Clinicaltrials.gov identifier: NCT01104155.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Furanos/administração & dosagem , Cetonas/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/patologia , Quimioterapia Adjuvante , Progressão da Doença , Intervalo Livre de Doença , Esquema de Medicação , Cloridrato de Erlotinib , Feminino , Furanos/farmacocinética , Humanos , Cetonas/farmacocinética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Quinazolinas/farmacocinética
5.
Ann Oncol ; 24(2): 420-428, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23028040

RESUMO

BACKGROUND: We previously reported results of a prospective trial evaluating the significance of circulating tumor cells (CTCs) in patients with metastatic colorectal cancer (mCRC). This secondary analysis assessed the relationship of the CTC number with carcinoembryonic antigen (CEA) and overall survival. PATIENTS AND METHODS: Patients with mCRC had CTCs measured at baseline and specific time points after the initiation of new therapy. Patients with a baseline CEA value ≥ 10 ng/ml and CEA measurements within ± 30 days of the CTC collection were included. RESULTS: We included 217 patients with mCRC who had a CEA value of ≥ 10 ng/ml. Increased baseline CEA was associated with shorter survival (15.8 versus 20.7 months, P = 0.012). Among all patients with a baseline CEA value of ≥ 25 ng/ml, patients with low baseline CTCs (<3, n = 99) had longer survival than those with high CTCs (≥ 3, n = 58; 20.8 versus 11.7 months, P = 0.001). CTCs added prognostic information at the 3-5- and 6-12-week time points regardless of CEA. In a multivariate analysis, CTCs at baseline but not CEA independently predicted survival and both CTCs and CEA independently predicted survival at 6-12 weeks. CONCLUSIONS: This study demonstrates that both CEA and CTCs contribute prognostic information for patients with mCRC.


Assuntos
Antígeno Carcinoembrionário/sangue , Neoplasias Colorretais , Células Neoplásicas Circulantes , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Neoplasias Colorretais/sangue , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Sobrevida , Adulto Jovem
6.
Ann Oncol ; 20(7): 1223-9, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19282466

RESUMO

BACKGROUND: We demonstrated that circulating tumor cell (CTC) number at baseline and follow-up is an independent prognostic factor in metastatic colorectal cancer (mCRC). This analysis was undertaken to explore whether patient and treatment characteristics impact the prognostic value of CTCs. PATIENTS AND METHODS: CTCs were enumerated with immunomagnetic separation from the blood of 430 patients with mCRC at baseline and on therapy. Patients were stratified into unfavorable and favorable prognostic groups based on CTC levels of > or = 3 or <3 CTCs/7.5 ml, respectively. Subgroups were analyzed by line of treatment, liver involvement, receipt of oxaliplatin, irinotecan, or bevacizumab, age, and Eastern Cooperative Oncology Group performance status (ECOG PS). RESULTS: Seventy-one percent of deaths have occurred. Median follow-up for living patients is 25.8 months. For all patients, progression-free survival (PFS) and overall survival (OS) for unfavorable compared with favorable baseline CTCs is shorter (4.4 versus 7.8 m, P = 0.004 for PFS; 9.4 versus 20.6 m, P < 0.0001 for OS). In all patient subgroups, unfavorable baseline CTC was associated with inferior OS (P < 0.001). In patients receiving first- or second-line therapy (P = 0.003), irinotecan (P = 0.0001), having liver involvement (P = 0.002), >/=65 years (P = 0.0007), and ECOG PS of zero (P = 0.04), unfavorable baseline CTC was associated with inferior PFS. CONCLUSION: Baseline CTC count is an important prognostic factor within specific subgroups defined by treatment or patient characteristics.


Assuntos
Neoplasias Colorretais/patologia , Metástase Neoplásica/patologia , Células Neoplásicas Circulantes/patologia , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Bevacizumab , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Progressão da Doença , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Irinotecano , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina , Valor Preditivo dos Testes , Prognóstico , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento
7.
Br J Cancer ; 98(10): 1608-13, 2008 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-18475293

RESUMO

Paclitaxel poliglumex (PPX), a macromolecule drug conjugate linking paclitaxel to polyglutamic acid, reduces systemic exposure to peak concentrations of free paclitaxel. Patients with non-small-cell lung cancer (NSCLC) who had received one prior platinum-based chemotherapy received 175 or 210 mg m(-2) PPX or 75 mg m(-2) docetaxel. The study enrolled 849 previously treated NSCLC patients with advanced disease. Median survival (6.9 months in both arms, hazard ratio=1.09, P=0.257), 1-year survival (PPX=25%, docetaxel=29%, P=0.134), and time to progression (PPX=2 months, docetaxel=2.6 months, P=0.075) were similar between treatment arms. Paclitaxel poliglumex was associated with significantly less grade 3 or 4 neutropenia (P<0.001) and febrile neutropenia (P=0.006). Grade 3 or 4 neuropathy (P<0.001) was more common in the PPX arm. Patients receiving PPX had less alopecia and did not receive routine premedications. More patients discontinued due to adverse events in the PPX arm compared to the docetaxel arm (34 vs 16%, P<0.001). Paclitaxel poliglumex and docetaxel produced similar survival results but had different toxicity profiles. Compared with docetaxel, PPX had less febrile neutropenia and less alopecia, shorter infusion times, and elimination of routine use of medications to prevent hypersensitivity reactions. Paclitaxel poliglumex at a dose of 210 mg m(-2) resulted in increased neurotoxicity compared with docetaxel.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/análogos & derivados , Ácido Poliglutâmico/análogos & derivados , Taxoides/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos Fitogênicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/patologia , Docetaxel , Esquema de Medicação , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Paclitaxel/uso terapêutico , Seleção de Pacientes , Ácido Poliglutâmico/administração & dosagem , Ácido Poliglutâmico/efeitos adversos , Ácido Poliglutâmico/uso terapêutico , Qualidade de Vida , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Resultado do Tratamento
8.
J Cancer Res Clin Oncol ; 117(2): 151-5, 1991.
Artigo em Inglês | MEDLINE | ID: mdl-2007612

RESUMO

Previous pharmacological and clinical data have suggested that it is possible to increase significantly the dose of "active" cisplatin delivered systemically by the simultaneous administration of intravenous sodium thiosulfate. In order to define more critically the toxicity and potential efficacy of this therapeutic approach, 36 patients with a variety of solid tumors and limited pretreatment were entered into a phase-1 trial of high-dose intravenous cisplatin plus sodium thiosulfate. The maximally tolerated dose of cisplatin was found to be 200 mg/m2, excessive renal toxicity being observed at a dose of 225 mg/m2 (6/14 courses associated with serum creatinine rise to greater than 2.0 mg-%). Following several courses of high-dose cisplatin, peripheral neuropathy becomes the limiting toxicity (9/15 patients receiving at least three courses of cisplatin at greater than or equal to 150 mg/m2 experienced at least grade-1 neuropathy). Significant ototoxicity developed after only one or two treatment courses, but with continued treatment hearing loss appeared to stabilize in the moderately severe range in most patients. Major responses (PR/CR) were observed in 7/27 evaluable patients. We conclude that cisplatin can be administered at a dose at 200 mg/m2 as a 2-h infusion (with simultaneous sodium thiosulfate) with significant but acceptable toxicities and without evidence of loss of anti-neoplastic activity (secondary to the presence of thiosulfate). However, owing to the development of neurotoxicity most patients will be unable to receive more than three courses of this high-dose treatment regimen.


Assuntos
Cisplatino/uso terapêutico , Tiossulfatos/uso terapêutico , Adulto , Idoso , Antídotos/efeitos adversos , Antídotos/uso terapêutico , Medula Óssea/efeitos dos fármacos , Cisplatino/efeitos adversos , Combinação de Medicamentos , Avaliação de Medicamentos , Sinergismo Farmacológico , Feminino , Audição/efeitos dos fármacos , Humanos , Injeções Intravenosas , Rim/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Neurônios/efeitos dos fármacos , Tiossulfatos/efeitos adversos , Vômito/induzido quimicamente
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