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BACKGROUND: Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate comprising a folate receptor alpha (FRα)-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent. The randomized, open-label, phase III study FORWARD I compared MIRV and investigator's choice chemotherapy in patients with platinum-resistant epithelial ovarian cancer (EOC). PATIENTS AND METHODS: Eligible patients with 1-3 prior lines of therapy and whose tumors were positive for FRα expression were randomly assigned, in a 2 : 1 ratio, to receive MIRV (6 mg/kg, adjusted ideal body weight) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary endpoint was progression-free survival [PFS, Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, blinded independent central review] in the intention-to-treat (ITT) population and in the prespecified FRα high population. RESULTS: A total of 366 patients were randomized; 243 received MIRV and 109 received chemotherapy. The primary endpoint, PFS, did not reach statistical significance in either the ITT [hazard ratio (HR), 0.98, P = 0.897] or the FRα high population (HR, 0.69, P = 0.049). Superior outcomes for MIRV over chemotherapy were observed in all secondary endpoints in the FRα high population including improved objective response rate (24% versus 10%), CA-125 responses (53% versus 25%), and patient-reported outcomes (27% versus 13%). Fewer treatment-related grade 3 or higher adverse events (25.1% versus 44.0%), and fewer events leading to dose reduction (19.8% versus 30.3%) and treatment discontinuation (4.5% versus 8.3%) were seen with MIRV compared with chemotherapy. CONCLUSIONS: In patients with platinum-resistant EOC, MIRV did not result in a significant improvement in PFS compared with chemotherapy. Secondary endpoints consistently favored MIRV, particularly in patients with high FRα expression. MIRV showed a differentiated and more manageable safety profile than chemotherapy.
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Imunoconjugados , Maitansina , Neoplasias Ovarianas , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Epitelial do Ovário/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Imunoconjugados/uso terapêutico , Maitansina/efeitos adversos , Maitansina/análogos & derivados , Neoplasias Ovarianas/tratamento farmacológicoRESUMO
This manuscript reports the consensus statements regarding the design and conduct of clinical trials in patients with newly diagnosed and recurrent epithelial ovarian cancer (EOC), following deliberation at the Fifth Ovarian Cancer Consensus Conference (OCCC), held in Tokyo in November 2015. Three important questions were identified for discussion prior to the meeting and achieved consensus during the meeting: (i) What are the most important factors to be evaluated prior to initial therapy? (ii) What are the most important factors to be evaluated specifically in recurrent disease? (iii) Are there specific considerations for special patient subpopulations? In addition, we report a list of important unmet needs compiled during the consensus process, which is intended to guide future research initiatives.
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Neoplasias Epiteliais e Glandulares/terapia , Neoplasias Ovarianas/terapia , Medicina de Precisão/métodos , Carcinoma Epitelial do Ovário , Feminino , HumanosRESUMO
Introduction This was an open-label, dose escalation (3 + 3 design), Phase I study of SOR-C13 in patients with advanced tumors of epithelial origin. Primary objectives were to assess safety/tolerability and pharmacokinetics. Secondary goals were to assess pharmacodynamics and efficacy of SOR-C13. Methods SOR-C13 was administered IV QD on days 1-3 and 8-10 of a 21-day cycle. Doses were 2.75 and 5.5 mg/kg (20-min infusion) and 1.375, 2.75, 4.13 and 6.2 mg/kg (90-min infusion). Toxicity was assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Dose limiting toxicity (DLT) was assessed within the first treatment cycle. Tumors were evaluated, using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, after two cycles. Results Twenty-three patients were treated. No drug-related serious adverse events occurred. DLTs occurred in six patients: asymptomatic, drug-related, transient Grade 2 hypocalcemia (4 patients), and unrelated Grade 3 anemia and Grade 3 atrial fibrillation, 1 patient each. Calcium and vitamin D supplementation eliminated further Grade 2 hypocalcemia. One Grade 3 treatment emergent adverse event, urticaria, was definitely related to SOR-C13. Four possibly drug-related, Grade 3 events (alanine aminotransferase and aspartate aminotransferase elevation, headache, and hypokalemia) were observed. Of 22 evaluable patients, 54.5% showed stable disease ranging from 2.8 to 12.5 months. The best response was a 27% reduction in a pancreatic tumor with a 55% reduction in CA19-9 levels at 6.2 mg/kg. Conclusion SOR-C13 was safe and tolerated up to 6.2 mg/kg. The Maximal Tolerated Dose (MTD) was not established. Stable disease suggested antitumor activity.
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Antineoplásicos , Bloqueadores dos Canais de Cálcio , Neoplasias/tratamento farmacológico , Canais de Cátion TRPV/antagonistas & inibidores , Adulto , Idoso , Alanina Transaminase/sangue , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Aspartato Aminotransferases/sangue , Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/farmacocinética , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio/genética , Feminino , Cefaleia/induzido quimicamente , Humanos , Hipocalcemia/induzido quimicamente , Hipopotassemia/induzido quimicamente , Queratina-18/sangue , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/metabolismo , Peptídeos/efeitos adversos , Peptídeos/farmacocinética , Peptídeos/farmacologia , Peptídeos/uso terapêutico , RNA Mensageiro/sangue , Canais de Cátion TRPV/efeitos adversos , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/farmacocinética , Canais de Cátion TRPV/farmacologia , Canais de Cátion TRPV/uso terapêutico , Resultado do Tratamento , Urticária/induzido quimicamenteRESUMO
PURPOSE: Cediranib is a potent multitargeted inhibitor of vascular endothelial growth factor receptor (VEGFR) 1, 2 and 3. The study was initiated to evaluate the activity of cediranib in patients (pts) with recurrent ovarian, peritoneal or fallopian tube cancer (OC). METHODS: Eligible pts had persistent/recurrent OC following one prior platinum-based chemotherapy with measurable disease or progression based on Gynecologic Cancer Inter Group CA-125 criteria. Because of toxicities observed in the first 23 pts, the initial starting dose of oral daily (od) cediranib was reduced from 45mg to 30mg. The primary endpoint was objective response rate at 16weeks. This study was stratified into two arms: platinum-sensitive (PL-S) and platinum-resistant (PL-R). RESULTS: 74 pts were enrolled; 39 were PL-S and 35 PL-R, with a median age of 58years [31-87]. In PL-S group, 10 (26%) partial responses (PR) and 20 (51%) stable disease (SD) were confirmed while in the PL-R arm there were no confirmed PR and 23 pts (66%) had SD. The main grade 3/4 toxicities observed at the 30 mg starting dose were hypertension (27%), fatigue (20%) and diarrhea (14%). The median progression-free survival for all patients was 4.9months [3.9-7.0], 7.2months [4.3-9] for PL-S and 3.7months [2.6-4.5] for PL-R groups. The median overall survival was 18.9months (95% CI: 13.5-31.5); 27.7months [17.8-43.3] for PL-S and 11.9months [8.1-18.9] for PL-R groups. CONCLUSION: Cediranib shows significant activity in recurrent platinum sensitive OC. The toxicities were expected and manageable at the dose of 30mg od.
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Antineoplásicos/administração & dosagem , Neoplasias das Tubas Uterinas/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Quinazolinas/administração & dosagem , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Quinazolinas/efeitos adversosRESUMO
BACKGROUND: Systemic therapy options are needed for women with recurrent, metastatic, or persistent cervical cancer. This systematic review and clinical practice guideline were developed to address that need, and to update a 2007 guideline from Cancer Care Ontario's Program in Evidence-Based Care. METHODS: The literature between 2006 and April 2014 in the medline and embase databases, the Cochrane Database of Systematic Reviews (Issue 4, 2014), the Cochrane Central Register of Controlled Trials (Issue 3, 2014), relevant guideline databases, and conference proceedings of the American Society of Clinical Oncology (2007-2013) was searched. A working group developed draft guidelines and incorporated comments and feedback from internal and external reviewers. RESULTS: Four phase iii randomized controlled trials met the inclusion criteria for the review and provided the basis for draft recommendations. Feedback was obtained from Ontario practitioners and others abroad, which led to modifications to the draft recommendations. Three key recommendations were developed. CONCLUSIONS: The working group concluded that all patients should be offered the opportunity to participate in appropriate randomized clinical trials. Cisplatin-paclitaxel, cisplatin-vinorelbine, cisplatin-gemcitabine, and cisplatin-topotecan are recommended combinations for this patient population. The substitution of carboplatin for cisplatin in the foregoing combinations can also be recommended because carboplatin is associated with fewer adverse effects and greater ease of administration. Selection of combination chemotherapy will depend on the toxicity profile, patient preference, and other factors. Finally, bevacizumab in combination with cisplatin-paclitaxel or carboplatin-paclitaxel is recommended for a specific subset of the target population as outlined in Gynecologic Oncology Group study 0240.
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BACKGROUND: AT7519 is a small-molecular inhibitor of multiple cyclin-dependent kinases (CDKs). It shows encouraging anti-cancer activity against multiple cell lines and in tumour xenografts. This phase I study was conducted to evaluate the safety and tolerability of AT7519 given as 1-h intravenous infusion on days 1, 4, 8 and 11 every 3 weeks. METHODS: Patients with advanced refractory solid tumours or non-Hodgkin's lymphoma were enroled. Dose escalation occurred in a 3+3 manner based on toxicity assessment. Pharmacokinetic samples were collected after first AT7519 infusion, whereas pharmacodynamics (PD) samples were obtained in selected patients. RESULTS: Thirty-four patients were enroled, and 32 received study treatments over 4 dose levels. Dose-limiting toxicities included mucositis, febrile neutropenia, rash, fatigue and hypokalemia. The recommended phase II dose (RP2D) was 27.0 mg m(-2). Ten of 19 patients evaluable for efficacy had stable disease as the best response (median duration: 3.3 months; range: 2.5 to 11.1 months). There was no clinically significant QTc prolongation. There was an apparent dose proportional increase in AT7519 exposure. The PD studies showed reduction in markers of CDK activity in selected patients' skin biopsies post treatment. CONCLUSIONS: AT7519, when administered as an intravenous infusion on days 1, 4, 8 and 11, was well tolerated. The RP2D is 27.0 mg m(-2). At this dose level, plasma AT7519 concentrations were above the biologically active concentrations, and preliminary anti-cancer activity was observed in patients. This dosing schedule is being further evaluated in multiple phase II studies.
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Quinases Ciclina-Dependentes/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Piperidinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Pirazóis/administração & dosagem , Adulto , Idoso , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/enzimologia , Neoplasias/metabolismo , Piperidinas/efeitos adversos , Piperidinas/farmacocinética , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/efeitos adversos , Pirazóis/farmacocinéticaRESUMO
BACKGROUND: The Notch signalling pathway has been implicated in tumour initiation, progression, angiogenesis and development of resistance to vascular endothelial growth factor (VEGF) targeting, providing a rationale for the combination of RO4929097, a γ-secretase inhibitor, and cediranib, a VEGF receptor tyrosine kinase inhibitor. METHODS: Patients received escalating doses of RO4929097 (on a 3 days-on and 4 days-off schedule) in combination with cediranib (once daily). Cycle 1 was 42 days long with RO4929097 given alone for the first 3 weeks followed by the co-administration of both RO4929097 and cediranib starting from day 22. Cycle 2 and onwards were 21 days long. Soluble markers of angiogenesis were measured in plasma samples. Archival tumour specimens were assessed for expression of three different components of Notch signalling pathway and genotyping. RESULTS: In total, 20 patients were treated in three dose levels (DLs). The recommended phase II dose was defined as 20 mg for RO4929097 on 3 days-on and 4 days-off schedule and 30 mg daily for cediranib. The most frequent treatment-related adverse events (AEs) were diarrhoea, hypertension, fatigue and nausea. Eleven patients had a best response of stable disease and one patient achieved partial response. We did not detect any correlation between tested biomarkers of angiogenesis or the Notch pathway and treatment effect. There was no correlation between mutational status and time to treatment failure. CONCLUSION: RO4929097 in combination with cediranib is generally well tolerated at the DLs tested. Preliminary evidence of antitumour efficacy with prolonged disease stabilisation in some patients with progressive malignancies warrants further clinical investigation of this treatment strategy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Benzazepinas/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Carcinoma Neuroendócrino , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Feminino , Humanos , Neoplasias Renais/tratamento farmacológico , Leiomiossarcoma/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Quinazolinas/administração & dosagem , Sarcoma do Estroma Endometrial/tratamento farmacológico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Resultado do Tratamento , Neoplasias Uterinas/tratamento farmacológico , Adulto JovemRESUMO
BACKGROUND: The purpose of the study was to assess the safety, tolerability, recommended phase II dose (RPTD), and preliminary antitumor activity of the combination of carboplatin-paclitaxel (Taxol)-temsirolimus. MATERIALS AND METHODS: Patients with solid malignancies suitable for carboplatin-paclitaxel (CP) chemotherapy and two or less prior lines of chemotherapy received 15, 20, or 25 mg of temsirolimus per week with CP given every 21 days. Thirty-eight eligible patients were entered into six dose levels with the first two levels administering temsirolimus on days 8 and 15 and the subsequent four dose levels switching to days 1 and 8 temsirolimus administration. RESULTS: Days 8 and 15 administration of temsirolimus was not feasible due to myelosuppression on day 15. CP on day 1 with temsirolimus on days 1 and 8 was well tolerated. Dose-limiting toxicity (DLT) was grade 4 thrombocytopenia (n=2) and grade 3 fatigue (n=1). Relative dose intensities for carboplatin, paclitaxel, and temsirolimus at the RPTD were 92%, 82%, and 56%, respectively. Non-DLT treatment-related adverse events occurring in >20% of patients included fatigue, mucositis, alopecia, neuropathy, nausea, neutropenia, thrombocytopenia, and infection. Grade 3/4 non-hematological toxicity was rare. Partial responses (PRs) and disease stabilization were seen in 46% and 49% of patients, respectively. Nine of 11 (82%) endometrial cancer patients had objective PRs. CONCLUSION: Carboplatin-paclitaxel-temsirolimus is well tolerated and the RPTD is carboplatin area under the curve 5 mg/ml/min, paclitaxel 175 mg/m2, both given on day 1 with temsirolimus 25 mg on days 1 and 8.
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Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Sirolimo/análogos & derivadosRESUMO
BACKGROUND: The addition of anthracyclines to platinum-based chemotherapy may provide benefit in survival in ovarian cancer patients. We evaluated the effect on survival of adding epirubicin to standard carboplatin and paclitaxel. PATIENTS AND METHODS: We carried out a prospectively randomized phase III study comparing carboplatin plus paclitaxel (TC; area under the curve 5 and 175 mg/m(2)) with the same combination and epirubicin (TEC; 75 mg/m(2) i.v.). Between March 1999 and August 2001, 887 patients with epithelial ovarian, tubal or peritoneal cancer International Federation of Gynecology and Obstetrics stages IIB-IV were randomized to receive either TC (442 patients) or TEC (445 patients). RESULTS: Median time to progression was 16.4 months in the TEC arm and 16.0 months in the TC arm (hazard ratio 0.99; 95% confidence interval [CI]: 0.9-1.2). Median overall survival time was 42.4 months for the TEC arm and 40.2 for the TC arm (hazard ratio 0.96; 95% CI: 0.8-1.1). Grade 3/4 hematologic toxic effects and most grade 3/4 non-hematologic toxic effects were more frequent in the TEC arm. Accordingly, a quality-of-life analysis showed inferiority of TEC versus TC. CONCLUSION: The addition of epirubicin to standard carboplatin and paclitaxel treatment did not improve survival in patients with advanced ovarian, tubal or peritoneal cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Carboplatina/administração & dosagem , Epirubicina/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/fisiopatologia , Paclitaxel/administração & dosagem , Cooperação do Paciente , Estudos Prospectivos , Qualidade de Vida , Análise de SobrevidaRESUMO
OBJECTIVE: The aim of this multi-institutional non randomized phase II trial was to determine the efficacy and safety of single agent aflibercept (VEGF Trap), a recombinant fusion protein that blocks multiple vascular endothelial growth factor isoforms, in women with gynecologic soft tissue sarcoma. METHODS: Patients were enrolled in two cohorts each with Simon two stage designs: uterine leiomyosarcoma and carcinosarcoma of endometrial, ovarian or fallopian tube origin. Eligibility criteria included ≤2 prior lines of chemotherapy for metastatic disease and ECOG performance status of ≤2. Aflibercept 4mg/kg was administered intravenously on day 1 of a 14 day cycle. Primary endpoints were objective response and disease stabilization (Progression Free Survival (PFS) at 6 months). RESULTS: 41 patients with uterine leiomyosarcoma and 22 patients with carcinosarcoma (19 uterine, 3 ovarian) were enrolled on study. In the leiomyosarcoma cohort, eleven (27%) patients had stable disease (SD), 4 with SD lasting at least 24 weeks. The 6 month PFS was 17%, with median time to progression (TTP) of 1.8 (95% CI:1.6-2.1) months. In the carcinosarcoma cohort, two (9%) patients had SD, one lasting >24 weeks, median TTP was 1.6 months (95%CI: 1.1-1.7) No partial responses were observed in patients from either cohort. Grade 3 or more aflibercept related toxicity was uncommon and included hypertension, fatigue, headache and abdominal pain. CONCLUSIONS: Single agent aflibercept has modest activity in patients with uterine leiomyosarcoma and minimal activity in women with carcinosarcoma.
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Antineoplásicos/uso terapêutico , Carcinossarcoma/tratamento farmacológico , Neoplasias dos Genitais Femininos/tratamento farmacológico , Leiomiossarcoma/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , California , Carcinossarcoma/mortalidade , Chicago , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Neoplasias dos Genitais Femininos/mortalidade , Humanos , Estimativa de Kaplan-Meier , Leiomiossarcoma/mortalidade , Pessoa de Meia-Idade , Receptores de Fatores de Crescimento do Endotélio Vascular , Proteínas Recombinantes de Fusão/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Cediranib is a potent oral vascular endothelial growth factor (VEGF) signalling inhibitor with activity against all three VEGF receptors. The International Collaboration for Ovarian Neoplasia 6 (ICON6) trial was initiated based on evidence of single-agent activity in ovarian cancer with acceptable toxicity. METHODS: The ICON6 trial is a 3-arm, 3-stage, double-blind, placebo-controlled randomised trial in first relapse of platinum-sensitive ovarian cancer. Patients are randomised (2 : 3 : 3) to receive six cycles of carboplatin (AUC5/6) plus paclitaxel (175 mg m(-2)) with either placebo (reference), cediranib 20 mg per day, followed by placebo (concurrent), or cediranib 20 mg per day, followed by cediranib (concurrent plus maintenance). Cediranib or placebo was continued for 18 months or until disease progression. The primary outcome measure for stage I was safety, and the blinded results are presented here. RESULTS: Sixty patients were included in the stage I analysis. A total of 53 patients had received three cycles of chemotherapy and 42 patients had completed six cycles. In all, 19 out of 60 patients discontinued cediranib or placebo during chemotherapy because of adverse events/intercurrent illness (n=9); disease progression (n=1); death (n=3); patient decision (n=1); administrative reasons (n=1); and multiple reasons (n=4). Grade 3 and 4 toxicity was experienced by 30 (50%) and 3 (5%) patients, respectively. No gastrointestinal perforations were observed. CONCLUSION: The addition of cediranib to platinum-based chemotherapy is sufficiently well tolerated to expand the ICON6 trial and progress to stage II.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias das Tubas Uterinas/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carboplatina/administração & dosagem , Carcinoma Epitelial do Ovário , Cisplatino/administração & dosagem , Método Duplo-Cego , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Neoplasias das Tubas Uterinas/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Neoplasias Peritoneais/patologia , Quinazolinas/administração & dosagem , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: SB939 is an orally available, competitive histone deacetylase (HDAC) inhibitor selective for class I, II and IV histone deacetylases. Preclinical evaluation of SB939 revealed a profile suggesting improved efficacy compared to other HDAC inhibitors. This phase I study was carried out to determine the safety, dose-limiting toxicity, recommended phase II dose (RPTD), as well as pharmacokinetic (PK) and pharmacodynamic (PD) profiles of SB939 in a daily × 5 schedule in advanced solid tumours. METHODS: Sequential dose-escalating cohorts of patients were enrolled into 8 dose levels. At dose level 1, SB939 was taken on days 1-3 and 15-17 every 4 weeks, then on days 1-5 and 15-19 for other dose levels. Detailed PK sampling was performed in cycle 1, days 1 and 5. Peripheral blood mononuclear cells (PBMCs) were collected on cycle 1 at various time points for determination of acetylated histone H3 (AcH3) levels. RESULTS: In total, 38 patients received a total of 96 cycles of treatment. The maximal administered dose was 90 mg and the RPTD was 60 mg given 5 consecutive days every 2 weeks. The most frequent non-hematologic adverse events (AEs) of at least possible attribution to SB939 were fatigue, nausea, vomiting, anorexia and diarrhoea. Pharmacokinetic analysis showed dose-proportional increases in AUC across the doses evaluated. Elimination half-life was 5.6-8.9 h. There was no clear relationship between AcH3 changes and dose level or anti-tumour response. CONCLUSIONS: SB939 is well tolerated in patients with advanced solid tumours. The RPTD of this drug is 60 mg on a schedule of 5 consecutive days every 2 weeks. The toxicities of SB939 are consistent with other HDAC inhibitors.
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Antineoplásicos/uso terapêutico , Benzimidazóis/uso terapêutico , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/farmacocinética , Neoplasias/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Benzimidazóis/farmacocinética , Esquema de Medicação , Fadiga/induzido quimicamente , Feminino , Inibidores de Histona Desacetilases/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Neoplasias/metabolismo , Vômito/induzido quimicamenteRESUMO
BACKGROUND: Patients with platinum-sensitive recurrent ovarian cancer are a heterogeneous group, and it is not possible to accurately predict the progression-free survival (PFS) in these patients. We developed and validated a nomogram to help improve prediction of PFS in patients treated with platinum-based chemotherapy. METHODS: The nomogram was developed in a training cohort (n=955) from the CALYPSO trial and validated in the AGO-OVAR 2.5 Study (n=340). The proportional-hazards model (nomogram) was based on pre-treatment characteristics. RESULTS: The nomogram had a concordance index (C-index) of 0.645. Significant predictors were tumour size platinum-chemotherapy-free interval, CA-125, number of organ metastatic sites and white blood count. When the nomogram was applied without CA-125 (CA-125 was not available in validation cohort), the C-indices were 0.624 (training) and 0.594 (validation). When classification was based only on the platinum-chemotherapy-free interval, the indices were 0.571 (training) and 0.560 (validation). The calibration plot in the validation cohort based on four predictors (without CA-125) suggested good agreement between actual and nomogram-predicted 12-month PFS probabilities. CONCLUSION: This nomogram, using five pre-treatment characteristics, improves prediction of PFS in patients with platinum-sensitive ovarian cancer having platinum-based chemotherapy. It will be useful for the design and stratification of patients in clinical trials and also for counselling patients.
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Antineoplásicos/uso terapêutico , Carboplatina/uso terapêutico , Intervalo Livre de Doença , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Prognóstico , Modelos de Riscos ProporcionaisRESUMO
PURPOSE: Sunitinib is a multitargeted receptor tyrosine kinase inhibitor. We conducted a two-stage phase II study to evaluate the objective response rate of oral sunitinib in recurrent epithelial ovarian cancer. PATIENTS AND METHODS: Eligibility required measurable disease and one or two prior chemotherapies, at least one platinum based. Platinum-sensitive or -resistant disease was allowed. Initial dose schedule was sunitinib 50 mg daily, 4 of 6 weeks. Observation of fluid accumulations during off-treatment periods resulted in adoption of continuous 37.5 mg daily dosing in the second stage of accrual. RESULTS: Of 30 eligible patients, most had serous histology (67%), were platinum sensitive (73%) and had two prior chemotherapies (60%). One partial response (3.3%) and three CA125 responses (10%) were observed, all in platinum-sensitive patients using intermittent dosing. Sixteen (53%) had stable disease. Five had >30% decrease in measurable disease. Overall median progression-free survival was 4.1 months. Common adverse events included fatigue, gastrointestinal symptoms, hand-foot syndrome and hypertension. No gastrointestinal perforation occurred. CONCLUSIONS: Single-agent sunitinib has modest activity in recurrent platinum-sensitive ovarian cancer, but only at the 50 mg intermittent dose schedule, suggesting that dose and schedule may be vital considerations in further evaluation of sunitinib in this cancer setting.
Assuntos
Antineoplásicos/uso terapêutico , Indóis/uso terapêutico , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Pirróis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno Ca-125/sangue , Progressão da Doença , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva , Sunitinibe , Análise de SobrevidaRESUMO
BACKGROUND: Cediranib, an oral anti-angiogenic VEGFR 1-3 inhibitor, was studied at a daily dose of 20 mg in combination with platinum-based chemotherapy and as maintenance in a randomised trial in patients with first relapse of 'platinum-sensitive' ovarian cancer and has been shown to improve progression-free survival (PFS). PATIENTS AND METHODS: ICON6 (NCT00532194) was an international three-arm, double-blind, placebo-controlled randomised trial. Between December 2007 and December 2011, 456 women were randomised, using stratification, to receive either chemotherapy with placebo throughout (arm A, reference); chemotherapy with concurrent cediranib, followed by maintenance placebo (arm B, concurrent); or chemotherapy with concurrent cediranib, followed by maintenance cediranib (arm C, maintenance). Due to an enforced redesign of the trial in September 2011, the primary endpoint became PFS between arms A and C which we have previously published, and the overall survival (OS) was defined as a secondary endpoint, which is reported here. RESULTS: After a median follow-up of 25.6 months, strong evidence of an effect of concurrent plus maintenance cediranib on PFS was observed [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.44-0.72, P < 0.0001]. In this final update of the survival analysis, 90% of patients have died. There was a 7.4-month difference in median survival and an HR of 0.86 (95% CI: 0.67-1.11, P = 0.24) in favour of arm C. There was strong evidence of a departure from the assumption of non-proportionality using the Grambsch-Therneau test (P = 0.0031), making the HR difficult to interpret. Consequently, the restricted mean survival time (RMST) was used and the estimated difference over 6 years by the RMST was 4.8 months (95% CI: -0.09 to 9.74 months). CONCLUSIONS: Although a statistically significant difference in time to progression was seen, the enforced curtailment in recruitment meant that the secondary analysis of OS was underpowered. The relative reduction in the risk of death of 14% risk of death was not conventionally statistically significant, but this improvement and the increase in the mean survival time in this analysis suggest that cediranib may have worthwhile activity in the treatment of recurrent ovarian cancer and that further research should be undertaken.
Assuntos
Neoplasias Ovarianas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Quinazolinas/uso terapêuticoRESUMO
OBJECTIVES: Approximately 50% of ovarian cancers have elevated levels of epidermal growth factor receptor (EGFR) which correlates with a poor prognosis. Preclinical evidence suggests that EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib (OSI-774), may potentiate the anti-tumour effects of cytotoxic agents, including carboplatin. Blocking EGFR could thus potentially reverse drug resistance. The primary objective of the study was to assess the response rate to the addition of erlotinib in patients with recurrent ovarian cancer who were receiving carboplatin. METHODS: Patients enrolled on this study had either local or advanced recurrent ovarian cancer with measurable disease. They may have had up to 2 prior chemotherapy regimens, one of which must have contained platinum, and they must have responded to prior platinum therapy. Patients were stratified by platinum sensitivity and were treated with erlotinib 150 mg daily on a continuous dosing schedule, and carboplatin at an AUC of 5 every 21 days. RESULTS: Fifty patients with recurrent ovarian cancer entered the study, 33 in the platinum-sensitive arm and 17 in the platinum-resistant arm. Of patients evaluable for response, there were 14 partial responses (PR) of 30 evaluable for response (57% objective response rate (ORR)) in the platinum-sensitive arm, and 1 PR of 14 evaluable for response (7% ORR) in the platinum-resistant arm. CONCLUSIONS: The combination of erlotinib and carboplatin was active in patients with platinum-sensitive disease, but not in platinum-resistant disease. The toxicities seen were those expected with carboplatin and erlotinib.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ascite/patologia , Antígeno Ca-125/sangue , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Intervalo Livre de Doença , Sinergismo Farmacológico , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Cloridrato de Erlotinib , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/patologia , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversosRESUMO
Background: The covid-19 pandemic has presented unprecedented professional and personal challenges for the oncology community. Under the auspices of the Canadian Association of Medical Oncologists, we conducted an online national survey to better understand the impact of the pandemic on the medical oncology community in Canada. Methods: An English-language multiple-choice survey, including questions about demographics, covid-19 risk, use of personal protective equipment (ppe), personal challenges, and chemotherapy management was distributed to Canadian medical oncologists. The survey was open from 30 March to 4 April 2020, and attracted 159 responses. Results: More than 70% of medical oncologists expressed moderate-to-extreme concern about personally contracting covid-19 and about family members or patients (or both) contracting covid-19 from them. Despite that high level of concern, considerable variability in the use of ppe in direct cancer care was reported at the time of this survey, with 33% of respondents indicating no routine ppe use at their institutions and 69% indicating uncertainty about access to adequate ppe. Of the respondents, 54% were experiencing feelings of nervousness or anxiety on most days, and 52% were having feelings of depression or hopelessness on at least some days. Concern about aging parents or family and individual wellness represented the top personal challenges identified. The management of cancer patients has been affected, with adoption of telemedicine reported by 82% of respondents, and cessation of clinical trial accrual reported by 54%. The 3 factors deemed most important for treatment decision-making wereâ cancer prognosis and anticipated benefit from treatment,â risk of treatment toxicity during scarce health care access, andâ patient risk of contracting covid-19. Conclusions: This report describes the results of the first national survey assessing the impact of the covid-19 on Canadian medical oncologists and how they deliver systemic anticancer therapies. We hope that these data will provide a framework to address the challenges identified.
Assuntos
Infecções por Coronavirus , Neoplasias/terapia , Oncologistas , Pandemias , Pneumonia Viral , Ansiedade , COVID-19 , Canadá , Infecções por Coronavirus/epidemiologia , Humanos , Oncologia , Oncologistas/psicologia , Equipamento de Proteção Individual , Pneumonia Viral/epidemiologia , Inquéritos e Questionários , TelemedicinaRESUMO
A greater understanding of the factors and pathways controlling angiogenesis in tumours has allowed the development of a number of agents that selectively inhibit the pathways mediating that activity. The results to date of clinical trials with such agents and future research opportunities are reviewed.
RESUMO
In mammals, molecular mechanisms and factors involved in the tight regulation of telomerase expression and activity are still largely undefined. In this study, we provide evidence for a role of estrogens and their receptors in the transcriptional regulation of hTERT, the catalytic subunit of human telomerase and, consequently, in the activation of the enzyme. Through a computer analysis of the hTERT 5'-flanking sequences, we identified a putative estrogen response element (ERE) which was capable of binding in vitro human estrogen receptor alpha (ERalpha). In vivo DNA footprinting revealed specific modifications of the ERE region in ERalpha-positive but not ERalpha-negative cells upon treatment with 17beta-estradiol (E2), indicative of estrogen-dependent chromatin remodelling. In the presence of E2, transient expression of ERalpha but not ERbeta remarkably increased hTERT promoter activity, and mutation of the ERE significantly reduced this effect. No telomerase activity was detected in human ovary epithelial cells grown in the absence of E2, but the addition of the hormone induced the enzyme within 3 h of treatment. The expression of hTERT mRNA and protein was induced in parallel with enzymatic activity. This prompt estrogen modulation of telomerase activity substantiates estrogen-dependent transcriptional regulation of the hTERT gene. The identification of hTERT as a target of estrogens represents a novel finding which advances the understanding of telomerase regulation in hormone-dependent cells and has implications for a potential role of hormones in their senescence and malignant conversion.