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1.
Gynecol Oncol ; 153(1): 127-134, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30686551

RESUMO

OBJECTIVE: Poly(ADP-ribose) polymerase (PARP) inhibitors have shown substantial activity in homologous recombination- (HR-) deficient ovarian cancer and are undergoing testing in other HR-deficient tumors. For reasons that are incompletely understood, not all patients with HR-deficient cancers respond to these agents. Preclinical studies have demonstrated that changes in alternative DNA repair pathways affect PARP inhibitor (PARPi) sensitivity in ovarian cancer models. This has not previously been assessed in the clinical setting. METHODS: Clonogenic and plasmid-based HR repair assays were performed to compare BRCA1-mutant COV362 ovarian cancer cells with or without 53BP1 gene deletion. Archival biopsies from ovarian cancer patients in the phase I, open-label clinical trial of PARPi ABT-767 were stained for PARP1, RAD51, 53BP1 and multiple components of the nonhomologous end-joining (NHEJ) DNA repair pathway. Modified histochemistry- (H-) scores were determined for each repair protein in each sample. HRD score was determined from tumor DNA. RESULTS: 53BP1 deletion increased HR in BRCA1-mutant COV362 cells and decreased PARPi sensitivity in vitro. In 36 women with relapsed ovarian cancer, responses to the PARPi ABT-767 were observed exclusively in cancers with HR deficiency. In this subset, 7 of 18 patients (39%) had objective responses. The actual HRD score did not further correlate with change from baseline tumor volume (r = 0.050; p = 0.87). However, in the HR-deficient subset, decreased 53BP1 H-score was associated with decreased antitumor efficacy of ABT-767 (r = -0.69, p = 0.004). CONCLUSION: Differences in complementary repair pathways, particularly 53BP1, correlate with PARPi response of HR-deficient ovarian cancers.


Assuntos
Benzamidas/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Sulfonamidas/administração & dosagem , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/genética , Linhagem Celular Tumoral , Reparo do DNA , Resistencia a Medicamentos Antineoplásicos , Feminino , Genes BRCA1 , Genes BRCA2 , Recombinação Homóloga , Humanos , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/biossíntese , Poli(ADP-Ribose) Polimerase-1/genética , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/biossíntese , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/deficiência
2.
Invest New Drugs ; 36(5): 828-835, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29313279

RESUMO

Purpose This phase 1 study examined safety, pharmacokinetics (PK), and efficacy of the poly(ADP-ribose) polymerase (PARP) inhibitor ABT-767 in patients with advanced solid tumors and BRCA1/2 mutations or with high-grade serous ovarian, fallopian tube, or primary peritoneal cancer. Methods Patients received ABT-767 monotherapy orally until disease progression or unacceptable toxicity. Dose was escalated from 20 mg once daily to 500 mg twice daily (BID). Dose-limiting toxicities, recommended phase 2 dose (RP2D), food effect, objective response rate, and biomarkers predicting response were determined. Results Ninety-three patients were treated with ABT-767; 80 had a primary diagnosis of ovarian cancer. ABT-767 demonstrated dose-proportional PK up to 500 mg BID and half-life of ~2 h. Food had no effect on ABT-767 bioavailability. Most common grade 3/4 treatment-related adverse events were nausea, fatigue, decreased appetite, and anemia. Anemia showed dose-dependent increase. RP2D was 400 mg BID. Objective response rate by RECIST 1.1 was 21% (17/80) in all evaluable patients and 20% (14/71) in evaluable patients with ovarian cancer. Response rate by RECIST 1.1 and/or CA-125 was 30% (24/80) in patients with ovarian cancer. Mutations in BRCA1 or BRCA2, homologous recombination deficiency (HRD), and platinum sensitivity were associated with tumor response. Median progression-free survival was longer for HRD positive (6.7 months) versus HRD negative patients (1.8 months) with ovarian cancer. Conclusions ABT-767 had an acceptable safety profile up to the established RP2D of 400 mg BID and dose-proportional PK. Patients with BRCA1 or BRCA2 mutation, HRD positivity, and platinum sensitivity were more sensitive to ABT-767.


Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/induzido quimicamente , Antineoplásicos/farmacocinética , Proteína BRCA1/genética , Proteína BRCA2/genética , Benzamidas/farmacocinética , Neoplasias das Tubas Uterinas/genética , Fadiga/induzido quimicamente , Feminino , Interações Alimento-Droga , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Mutação , Náusea/induzido quimicamente , Neoplasias Ovarianas/genética , Neoplasias Peritoneais/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacocinética , Sulfonamidas/farmacocinética , Resultado do Tratamento
3.
Eur J Nucl Med Mol Imaging ; 45(13): 2404-2412, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30032322

RESUMO

PURPOSE: Response evaluation in patients with glioblastoma after chemoradiotherapy is challenging due to progressive, contrast-enhancing lesions on MRI that do not reflect true tumour progression. In this study, we prospectively evaluated the ability of the PET tracer 18F-fluorothymidine (FLT), a tracer reflecting proliferative activity, to discriminate between true progression and pseudoprogression in newly diagnosed glioblastoma patients treated with chemoradiotherapy. METHODS: FLT PET and MRI scans were performed before and 4 weeks after chemoradiotherapy. MRI scans were also performed after three cycles of adjuvant temozolomide. Pseudoprogression was defined as progressive disease on MRI after chemoradiotherapy with stabilisation or reduction of contrast-enhanced lesions after three cycles of temozolomide, and was compared with the disease course during long-term follow-up. Changes in maximum standardized uptake value (SUVmax) and tumour-to-normal uptake ratios were calculated for FLT and are presented as the mean SUVmax for multiple lesions. RESULTS: Between 2009 and 2012, 30 patients were included. Of 24 evaluable patients, 7 showed pseudoprogression and 7 had true progression as defined by MRI response. FLT PET parameters did not significantly differ between patients with true progression and pseudoprogression defined by MRI. The correlation between change in SUVmax and survival (p = 0.059) almost reached the standard level of statistical significance. Lower baseline FLT PET uptake was significantly correlated with improved survival (p = 0.022). CONCLUSION: Baseline FLT uptake appears to be predictive of overall survival. Furthermore, changes in SUVmax over time showed a tendency to be associated with improved survival. However, further studies are necessary to investigate the ability of FLT PET imaging to discriminate between true progression and pseudoprogression in patients with glioblastoma.


Assuntos
Didesoxinucleosídeos , Progressão da Doença , Glioblastoma/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Adulto , Idoso , Proliferação de Células , Quimiorradioterapia , Diagnóstico Diferencial , Feminino , Seguimentos , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Imagem Multimodal
4.
Oncologist ; 21(8): 995-1001, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27328932

RESUMO

BACKGROUND: In metastatic testicular cancer patients treated with bleomycin, etoposide, and cisplatin (BEP) chemotherapy, bleomycin-induced pneumonitis is a well-known and potentially fatal side effect. We sought to determine the prevalence of lesions as signs of bleomycin-induced pulmonary changes on restaging computed tomography (CT) scans after treatment and to ascertain whether fibrosis markers were predictive of these changes. PATIENTS AND METHODS: This prospective nonrandomized cohort study included metastatic testicular cancer patients, 18-50 years of age, treated with BEP chemotherapy. Restaging CT scans were examined for lesions as signs of bleomycin-induced pulmonary changes by two independent radiologists and graded as minor, moderate, or severe. Plasma samples were collected before, during, and after treatment and were quantified for transforming growth factor-ß1 (TGF-ß1), growth differentiation factor-15 (GDF-15), and high-sensitivity C-reactive protein (hs-CRP). RESULTS: In total, 66 patients were included: forty-five (68%) showed signs of bleomycin-induced pulmonary changes on the restaging CT scan, 37 of which were classified as minor and 8 as moderate. No differences in TGF-ß1, GDF-15, or hs-CRP plasma levels were found between these groups. CONCLUSION: Bleomycin-induced pulmonary changes are common on restaging CT scans after BEP chemotherapy for metastatic testicular cancer. Changes in TGF-ß1, GDF-15, and hs-CRP plasma levels do not differ between patients with and without radiological lesions as signs of bleomycin-induced pulmonary changes and are therefore not helpful as predictive biomarkers. IMPLICATIONS FOR PRACTICE: Bleomycin-induced pneumonitis (BIP) is a well-known and potentially fatal side effect in metastatic testicular cancer patients treated with bleomycin, etoposide, and cisplatin chemotherapy. Currently, the decision to discontinue bleomycin administration is made during treatment and is based on clinical signs. An upfront or early marker or biomarker that identifies patients likely to develop BIP would be preferable. This study found that bleomycin-induced pulmonary changes are common on restaging computed tomography scans and mostly resolve. No correlation was seen between these changes and fibrosis or inflammation markers (transforming growth factor-ß1, growth differentiation factor-15, and high-sensitivity C-reactive protein).


Assuntos
Bleomicina/efeitos adversos , Pulmão/fisiopatologia , Pneumonia/diagnóstico por imagem , Neoplasias Testiculares/tratamento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bleomicina/administração & dosagem , Proteína C-Reativa/genética , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Fibrose/induzido quimicamente , Fibrose/diagnóstico por imagem , Fibrose/fisiopatologia , Fator 15 de Diferenciação de Crescimento/genética , Humanos , Pulmão/diagnóstico por imagem , Pulmão/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Pneumonia/induzido quimicamente , Pneumonia/fisiopatologia , Neoplasias Testiculares/complicações , Neoplasias Testiculares/diagnóstico por imagem , Neoplasias Testiculares/fisiopatologia , Tomografia Computadorizada por Raios X , Fator de Crescimento Transformador beta1/genética
5.
Clin Colorectal Cancer ; 14(1): 18-24.e1, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25591799

RESUMO

BACKGROUND: Tivozanib hydrochloride (tivozanib) is a potent and selective tyrosine kinase inhibitor of all 3 vascular endothelial growth factor receptors with antitumor activity additive to 5-fluorouracil in preclinical models. This study was conducted to determine maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PKs), and antitumor activity of escalating doses of tivozanib with a modified (m)FOLFOX-6 (leucovorin, 5-fluorouracil [5-FU], and 85 mg/kg(2) oxaliplatin) regimen in patients with advanced gastrointestinal tumors. PATIENTS AND METHODS: Tivozanib was administered orally once daily for 21 days in 28-day cycles, with mFOLFOX-6 administered every 14 days. Patients were allowed to continue tivozanib after discontinuation of mFOLFOX-6. RESULTS: Thirty patients were assigned to tivozanib 0.5 mg (n = 9), 1.0 mg (n = 3), or 1.5 mg (n = 18) with mFOLFOX-6. Patients received a median of 5.2 (range, 0.03-26.9) months of tivozanib. DLTs were observed in 2 patients: Grade 3/4 transaminase level increases with tivozanib 0.5 mg, and Grade 3 dizziness with tivozanib 1.5 mg. Other Grade 3/4 adverse events included hypertension (n = 8), fatigue (n = 8), and neutropenia (n = 6). MTD for tivozanib with mFOLFOX-6 was confirmed as 1.5 mg. No PK interactions between tivozanib and mFOLFOX-6 were observed. One patient had an ongoing clinical complete response, 10 had a partial response, and 11 obtained prolonged stable disease. CONCLUSION: Tivozanib and mFOLFOX-6 is feasible and appears to be safe. The recommended dose for tivozanib with mFOLFOX-6 is 1.5 mg/d. Observed clinical activity merits further exploration in gastrointestinal tumors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Leucovorina/uso terapêutico , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Compostos Organoplatínicos/uso terapêutico , Compostos de Fenilureia/administração & dosagem , Quinolinas/administração & dosagem , Resultado do Tratamento
6.
J Nucl Med ; 56(9): 1310-4, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26135113

RESUMO

UNLABELLED: Transforming growth factor-ß (TGF-ß) signaling is involved in glioma development. The monoclonal antibody fresolimumab (GC1008) can neutralize all mammalian isoforms of TGF-ß, and tumor uptake can be visualized and quantified with (89)Zr-fresolimumab PET in mice. The aim of this study was to investigate the fresolimumab uptake in recurrent high-grade gliomas using (89)Zr-fresolimumab PET and to assess treatment outcome in patients with recurrent high-grade glioma treated with fresolimumab. METHODS: Patients with recurrent glioma were eligible. After intravenous administration of 37 MBq (5 mg) of (89)Zr-fresolimumab, PET scans were acquired on day 2 or day 4 after tracer injection. Thereafter, patients were treated with 5 mg of fresolimumab per kilogram intravenously every 3 wk. (89)Zr-fresolimumab tumor uptake was quantified as maximum standardized uptake value (SUVmax). MR imaging for response evaluation was performed after 3 infusions or as clinically indicated. RESULTS: Twelve patients with recurrent high-grade glioma were included: 10 glioblastomas, 1 anaplastic oligodendroglioma, and 1 anaplastic astrocytoma. All patients underwent (89)Zr-fresolimumab PET 4 d after injection. In 4 patients, an additional PET scan was obtained on day 2 after injection. SUVmax on day 4 in tumor lesions was 4.6 (range, 1.5-13.9) versus a median SUVmean of 0.3 (range, 0.2-0.5) in normal brain tissue. All patients showed clinical or radiologic progression after 1-3 infusions of fresolimumab. Median progression-free survival was 61 d (range, 25-80 d), and median overall survival was 106 d (range, 37-417 d). CONCLUSION: (89)Zr-fresolimumab penetrated recurrent high-grade gliomas very well but did not result in clinical benefit.


Assuntos
Anticorpos Monoclonais/farmacocinética , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Glioma/radioterapia , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/radioterapia , Adulto , Idoso , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/radioterapia , Linhagem Celular Tumoral , Feminino , Glioma/diagnóstico por imagem , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Radioisótopos/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual , Fator de Crescimento Transformador beta/imunologia , Zircônio/farmacocinética
7.
Cancer Lett ; 332(2): 194-201, 2013 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-22531313

RESUMO

The extrinsic apoptotic pathway can be activated by the endogenous ligand TRAIL (Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand) by binding to the death receptors TRAIL-R1 and TRAIL-R2 on the cell surface. This pathway is currently evaluated as an anticancer treatment strategy. Both recombinant human TRAIL and several agonistic antibodies against TRAIL-R1 and R2 have been studied in single agent and combination studies and proved to be safe and well tolerated. In this article, the clinical studies published to date will be reviewed. Also, future perspectives and biomarker studies for selecting patients that will benefit from these agents will be discussed.


Assuntos
Neoplasias/tratamento farmacológico , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Apoptose , Biomarcadores Tumorais/metabolismo , Membrana Celular/metabolismo , Ensaios Clínicos como Assunto , Humanos , Proteínas Recombinantes/metabolismo , Transdução de Sinais , Ligante Indutor de Apoptose Relacionado a TNF/uso terapêutico
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