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PURPOSE: Simlukafusp alfa [fibroblast activation protein α-targeted IL2 variant (FAP-IL2v)], a tumor-targeted immunocytokine, comprising an IL2 variant moiety with abolished CD25 binding fused to human IgG1, is directed against fibroblast activation protein α. This phase I, open-label, multicenter, dose-escalation, and extension study (NCT02627274) evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of FAP-IL2v in patients with advanced/metastatic solid tumors. PATIENTS AND METHODS: Participants received FAP-IL2v intravenously once weekly. Dose escalation started at 5 mg; flat dosing (≤25 mg) and intraparticipant uptitration regimens (15/20, 20/25, 20/20/35, and 20/35/35 mg) were evaluated. Primary objectives were dose-limiting toxicities, maximum tolerated dose, recommended expansion dose, and pharmacokinetics. RESULTS: Sixty-one participants were enrolled. Dose-limiting toxicities included fatigue (flat dose 20 mg: n = 1), asthenia (25 mg: n = 1), drug-induced liver injury (uptitration regimen 20/25 mg: n = 1), transaminase increase (20/25 mg: n = 1), and pneumonia (20/35/35 mg: n = 1). The uptitration regimen 15/20 mg was determined as the maximum tolerated dose and was selected as the recommended expansion dose. Increases in peripheral blood absolute immune cell counts were seen for all tested doses [NK cells, 13-fold; CD4+ T cells (including regulatory T cells), 2-fold; CD8+ T cells, 3.5-fold] but without any percentage change in regulatory T cells. Clinical activity was observed from 5 mg [objective response rate, 5.1% (n = 3); disease control rate, 27.1% (n = 16)]. Responses were durable [n = 3, 2.8 (censored), 6.3, and 43.4 months]. CONCLUSIONS: FAP-IL2v had a manageable safety profile and showed initial signs of antitumor activity in advanced/metastatic solid tumors.
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Dose Máxima Tolerável , Neoplasias , Humanos , Feminino , Masculino , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/genética , Pessoa de Meia-Idade , Idoso , Adulto , Interleucina-2/administração & dosagem , Interleucina-2/efeitos adversos , Interleucina-2/farmacocinética , Interleucina-2/genética , Metástase Neoplásica , Proteínas Recombinantes de Fusão/farmacocinética , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/uso terapêutico , Resultado do Tratamento , Endopeptidases/administração & dosagem , Proteínas de MembranaAssuntos
Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Topotecan/uso terapêutico , Etoposídeo/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Platina , Cisplatino/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Background: Exercise is recommended for people with cancer. The aim of this study was to evaluate the harms of exercise in patients with cancer undergoing systemic treatment. Methods: This systematic review and meta-analysis included published and unpublished controlled trials comparing exercise interventions versus controls in adults with cancer scheduled to undergo systemic treatment. The primary outcomes were adverse events, health-care utilization, and treatment tolerability and response. Eleven electronic databases and trial registries were systematically searched with no date or language restrictions. The latest searches were performed on April 26, 2022. The risk of bias was judged using RoB2 and ROBINS-I, and the certainty of evidence for primary outcomes was assessed using GRADE. Data were statistically synthesised using pre-specified random-effect meta-analyses. The protocol for this study was registered in the PROESPERO database (ID: CRD42021266882). Findings: 129 controlled trials including 12,044 participants were eligible. Primary meta-analyses revealed evidence of a higher risk of some harms, including serious adverse events (risk ratio [95% CI]: 1.87 [1.47-2.39], I2 = 0%, n = 1722, k = 10), thromboses (risk ratio [95% CI]: 1.67 [1.11-2.51], I2 = 0%, n = 934, k = 6), and fractures (risk ratio [95% CI]: 3.07 [3.03-3.11], I2 = 0%, n = 203, k = 2) in intervention versus control. In contrast, we found evidence of a lower risk of fever (risk ratio [95% CI]: 0.69 [0.55-0.87], I2 = 0% n = 1109, k = 7) and a higher relative dose intensity of systemic treatment (difference in means [95% CI]: 1.50% [0.14-2.85], I2 = 0% n = 1110, k = 13) in intervention versus control. For all outcomes, we downgraded the certainty of evidence due to imprecision, risk of bias, and indirectness, resulting in very low certainty of evidence. Interpretation: The harms of exercise in patients with cancer undergoing systemic treatment are uncertain, and there is currently insufficient data on harms to make evidence-based risk-benefits assessments of the application of structured exercise in this population. Funding: There was no funding for this study.
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Immune checkpoint inhibition for the treatment of cancer has provided a breakthrough in oncology, and several new checkpoint inhibition pathways are currently being investigated regarding their potential to provide additional clinical benefit. However, only a fraction of patients respond to such treatment modalities, and there is an urgent need to identify biomarkers to rationally select patients that will benefit from treatment. In this study, we explore different tumor associated characteristics for their association with favorable clinical outcome in a diverse cohort of cancer patients treated with checkpoint inhibitors. We studied 29 patients in a basket trial comprising 12 different tumor types, treated with 10 different checkpoint inhibition regimens. Our analysis revealed that even across this diverse cohort, patients achieving clinical benefit had significantly higher neoepitope load, higher expression of T cell signatures, and higher PD-L2 expression, which also correlated with improved progression-free and overall survival. Importantly, the combination of biomarkers serves as a better predictor than each of the biomarkers alone. Basket trials are frequently used in modern immunotherapy trial design, and here we identify a set of biomarkers of potential relevance across multiple cancer types, allowing for the selection of patients that most likely will benefit from immune checkpoint inhibition.
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Therapy with immune checkpoint inhibitors (ICI) is effective in patients with metastatic mismatch-repair deficient (dMMR) colorectal cancer (CRC); however, data on treatment with neoadjuvant ICI in patients with locally advanced CRC are limited. From March 2019 to June 2020, five Danish oncological centers treated 10 patients with a treatment-naïve dMMR CRC with preoperative pembrolizumab, 9 with a nonmetastatic, unresectable colon cancer and 1 with a locally advanced rectum cancer. All 10 patients were evaluated regularly at a multidisciplinary team (MDT) meeting, and they all had a radical resection after a median of 8 cycles (range 2-13) of pembrolizumab. A microscopic evaluation of the resected tumors revealed no remaining tumor cells in five patients, while five still had tumor cells present. The patients were given no additional therapy. No recurrences were reported after a median follow-up of 26 months (range 23-38.5 months). Biopsies from Danish patients with CRC are routinely screened for dMMR proteins. In 2017, data from the Danish Colorectal Cancer Group showed that 19% (565/3000) of the patients with colon cancer and 1.5% (19/1279) of those with rectum cancer had an dMMR tumor. Among the patients with MMR determination, 26% (99/384) patients had a T4 dMMR colon cancer; thus, the 10 patients treated with neoadjuvant pembrolizumab comprised about 9% of the patients with a T4 dMMR colon cancer (9/99) and 5% of patients with dMMR rectal cancer (1/19). Therapy with pembrolizumab was feasible and effective. Larger prospective trials are needed to confirm our findings.
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Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Estudos Prospectivos , Reparo de Erro de Pareamento de DNA , Neoplasias Colorretais/patologia , Instabilidade de MicrossatélitesRESUMO
BACKGROUND: Preclinical studies showed that capmatinib reversibly inhibits cytochrome P450 (CYP) 3A4 and CYP1A2 in a time-dependent manner. In this study, we evaluated the effect of capmatinib on the exposure of sensitive substrates of CYP3A (midazolam) and CYP1A2 (caffeine) in patients with mesenchymal-epithelial transition (MET)-dysregulated solid tumours. Besides pharmacokinetics, we assessed treatment response and safety. METHODS: This open-label, multicentre, single-sequence study consisted of a molecular prescreening period, a screening/baseline period of ≤28 days and a drug-drug interaction (DDI) phase of 12 days. On day 1 of the DDI phase, 37 patients received a single oral dose of midazolam 2.5 mg and caffeine 100 mg as a two-drug cocktail. Capmatinib 400 mg bid was administered from day 4 on a continuous dosing schedule. On day 9 of the DDI phase, patients were re-exposed to midazolam and caffeine. After the DDI phase, patients received capmatinib on continuous 21-day cycles until disease progression at the discretion of the investigator. RESULTS: A 22% (90% confidence interval [CI] 7-38%) increase in the midazolam maximum plasma concentration (Cmax ) was noted when administered with capmatinib, but this was deemed not clinically meaningful. Co-administration with capmatinib resulted in 134% (90% CI 108-163%) and 122% (90% CI 95-153%) increases in the caffeine area under the plasma concentration-time curve from time zero to infinity (AUCinf ) and area under the plasma concentration-time curve from time zero to the last measurable point (AUClast ), respectively, with no change in Cmax . Adverse events were consistent with the known capmatinib safety profile. No new safety signals were reported in this study. CONCLUSION: The data from this study demonstrated that capmatinib is a moderate CYP1A2 inhibitor. Capmatinib administration did not cause any clinically relevant changes in midazolam exposure.
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Cafeína , Citocromo P-450 CYP1A2 , Humanos , Citocromo P-450 CYP1A2/metabolismo , Cafeína/farmacocinética , Midazolam/farmacocinética , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/metabolismo , Área Sob a Curva , Interações MedicamentosasRESUMO
PURPOSE: Selinexor is an oral selective inhibitor of exportin-1 (XPO1) with efficacy in various solid and hematologic tumors. We assessed intratumoral penetration, safety, and efficacy of selinexor monotherapy for recurrent glioblastoma. PATIENTS AND METHODS: Seventy-six adults with Karnofsky Performance Status ≥ 60 were enrolled. Patients undergoing cytoreductive surgery received up to three selinexor doses (twice weekly) preoperatively (Arm A; n = 8 patients). Patients not undergoing surgery received 50 mg/m2 (Arm B, n = 24), or 60 mg (Arm C, n = 14) twice weekly, or 80 mg once weekly (Arm D; n = 30). Primary endpoint was 6-month progression-free survival rate (PFS6). RESULTS: Median selinexor concentrations in resected tumors from patients receiving presurgical selinexor was 105.4 nmol/L (range 39.7-291 nmol/L). In Arms B, C, and D, respectively, the PFS6 was 10% [95% confidence interval (CI), 2.79-35.9], 7.7% (95% CI, 1.17-50.6), and 17% (95% CI, 7.78-38.3). Measurable reduction in tumor size was observed in 19 (28%) and RANO-response rate overall was 8.8% [Arm B, 8.3% (95% CI, 1.0-27.0); C: 7.7% (95% CI, 0.2-36.0); D: 10% (95% CI, 2.1-26.5)], with one complete and two durable partial responses in Arm D. Serious adverse events (AEs) occurred in 26 (34%) patients; 1 (1.3%) was fatal. The most common treatment-related AEs were fatigue (61%), nausea (59%), decreased appetite (43%), and thrombocytopenia (43%), and were manageable by supportive care and dose modification. Molecular studies identified a signature predictive of response (AUC = 0.88). CONCLUSIONS: At 80 mg weekly, single-agent selinexor induced responses and clinically relevant PFS6 with manageable side effects requiring dose reductions. Ongoing trials are evaluating safety and efficacy of selinexor in combination with other therapies for newly diagnosed or recurrent glioblastoma.
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Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Hidrazinas/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Triazóis/administração & dosagem , Administração Oral , Adulto , Idoso , Encéfalo/metabolismo , Neoplasias Encefálicas/cirurgia , Procedimentos Cirúrgicos de Citorredução , Feminino , Glioblastoma/cirurgia , Humanos , Hidrazinas/efeitos adversos , Hidrazinas/metabolismo , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Triazóis/efeitos adversos , Triazóis/metabolismo , Adulto JovemRESUMO
BACKGROUND: Psychological distress may be present among patients who are considering enrollment in phase 1 cancer trials, as they have advanced cancer and no documented treatment options remain. However, the prevalence of psychological distress has not been previously investigated in larger cohorts. In complex phase 1 cancer trials, it is important to ensure adequate understanding of the study premises, such as the undocumented effects and the risk of adverse events. MATERIALS AND METHODS: In a prospective study, patients completed questionnaires at two time points. We investigated psychological distress, measured as stress, anxiety, and depression, among patients at their first visit to the phase 1 unit (N = 229). Further, we investigated the understanding of trial information among patients who were enrolled in a phase 1 cancer trial (N = 57). RESULTS: We enrolled 75% of 307 eligible patients. We found a lower mean score of stress in our population compared to population norms, while the mean scores of anxiety and depression were higher. A total of 9% showed moderate to severe symptoms of anxiety and 11% showed moderate to severe symptoms of depression, which indicates higher levels than cancer patients in general. A total of 46 (81% of enrolled patients) completed questionnaires on trial information and consent. The understanding of the information on phase 1 cancer trials in these patients was slightly lower than the level reported for cancer trials in general. Some aspects relating to purpose, benefit, and additional risks were understood by fewer than half of the patients. CONCLUSION: Our results suggest that distress is not as prevalent in the population of patients referred to phase 1 cancer trials as in the general cancer population. Although patients' understanding of trial information was reasonable, some aspects of complex phase 1 cancer trials were not easily understood by enrolled patients.
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Neoplasias , Angústia Psicológica , Ansiedade/epidemiologia , Ansiedade/etiologia , Ansiedade/psicologia , Depressão/epidemiologia , Depressão/etiologia , Depressão/psicologia , Humanos , Neoplasias/psicologia , Neoplasias/terapia , Estudos Prospectivos , Estresse Psicológico/epidemiologia , Estresse Psicológico/etiologia , Estresse Psicológico/psicologiaRESUMO
Circulating tumour DNA analysis has a potential to improve multiple aspects of cancer management. This includes: a) early cancer detection in asymptomatic individuals, b) identification of patients with residual disease after curative intended treatment, c) patient stratification in relation to treatment decisions like adjuvant therapy and intensity of radiological surveillance, d) monitoring treatment effect for optimised adaptive therapy, e) identification of actionable targets, and f) early recurrence detection. These points are summarised in this review.
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DNA Tumoral Circulante , Neoplasias , DNA Tumoral Circulante/genética , Detecção Precoce de Câncer , Humanos , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Neoplasias/genéticaRESUMO
Exercise training is emerging as a supportive treatment strategy in surgical oncology, but its effects remain uncertain in patients with gastrointestinal cancer. The primary objective of this systematic review and meta-analysis was to evaluate the effects of perioperative exercise training on gastrointestinal cancer-specific mortality, recurrence, and surgical outcomes (postoperative complications, hospitalization, surgical stress) in patients with gastrointestinal cancer. Randomized or quasi-randomized controlled trials evaluating the effects of perioperative exercise training versus control in patients with GI cancer were eligible. MEDLINE, EMBASE, CENTRAL, CINAHL, PEDro, and SPORTDiscus were systematically searched on June 20, 2020. Data were synthesized using random-effects meta-analyses. Risk of bias was assessed using the Cochrane risk of bias tool 2, and the certainty of evidence was assessed using GRADE. Study selection, data extraction, risk of bias, and GRADE assessments were performed independently by two authors. Ten randomized controlled trials comprising 448 participants with gastrointestinal cancer were eligible. Meta-analyses indicated no statistical effects of exercise on postoperative complications (risk ratio: 1.11, 95% CI: 0.84; 1.47), readmissions (risk ratio: 2.76; 95% CI: 0.00, 9394.76), or postoperative length of stay (difference in means: -0.47, 95% CI: -17.2; 16.2 days). None of the eligible studies assessed gastrointestinal cancer-specific mortality or recurrence. Overall risk of bias was high or of some concerns in all studies, and the certainty of evidence was very low. The effects of perioperative exercise on cancer-specific and surgical outcomes are unknown in patients with gastrointestinal cancer due to lack of studies and very low certainty of evidence.
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Neoplasias Gastrointestinais/cirurgia , Exercício Pré-Operatório , Neoplasias Gastrointestinais/mortalidade , Hospitalização , Humanos , Recidiva Local de Neoplasia , Complicações Pós-Operatórias/prevenção & controleRESUMO
BACKGROUND: HER2 aberrations in salivary gland carcinomas (SGC) as well as benefit of HER2 directed therapy have been reported in small studies. However, reliable estimates of the prevalence of HER2 positivity in SGC and its various histological subtypes are lacking. OBJECTIVE: To assess the prevalence of HER2 positivity in histological subtypes of salivary gland carcinomas (SGC). METHODS: Studies were identified by a systematic review of the literature. Data on in situ hybridization (ISH) and immunohistochemistry (IHC) were extracted to derive pooled prevalence estimates calculated by a random effects model. Characteristics of the studies were extracted for subgroup analysis. RESULTS: Fifty studies including 3372 patients were identified, providing data on sixteen histological subtypes. Based on the meta-analysis, the estimated prevalence of HER2 positivity were 43% (95% CI: 36% - 51%) in salivary duct carcinoma (SDC), 39% (95% CI: 32% - 45%) in carcinoma ex pleomorphic adenoma (CEP), 17% (95% CI: 7.5% - 33%) in squamous cell carcinoma (SCC), 13% (95% CI: 7.6% - 21%) in adenocarcinoma NOS (ADC), 6.7% (95% CI: 0.17%-32%) in poorly differentiated carcinoma, 5.5% (95% CI: 2.9% - 9.6%) in mucoepidermoid carcinoma, 4.3% (95% CI: 1.4% - 13%) in myoepithelial carcinoma, 1.8% (95% CI: 0.04%-9.6%) in epithelial-myoepithelial carcinoma, 0.45% (95% CI: 0.0097% - 18%) in acinic cell carcinoma and 0.15% (0.037% - 5.4%) in adenoid cystic carcinoma. Estimates for five additional subtypes were assessed. CONCLUSION: Prevalence of HER 2 positivity in SGC varies greatly based on histological subtype, with SDC, CEP, SCC, and ADC displaying the highest rates.
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Accurate data on HER2 positivity in esophageal squamous cell carcinoma patients (ESCC) is lacking. We conducted a systematic review and meta-analysis (Single Incidence Rates; metarate package, R) to examine the prevalence of HER2 in ESCC. Data on in situ hybridization (ISH) and immunohistochemistry (IHC) were extracted to derive pooled prevalence estimates, characteristics of the studies were extracted for subgroup analysis. Eighteen studies with 1505 patients were identified. HER2 gene amplification by ISH were prevalent in 10 % (95 % CI 6.9 %-15 %). Prevalence of HER2 overexpression (IHC3+) and borderline HER2 expression (IHC2+) were 6 % (95 % CI: 3.5 %-8.7 %) and 10 % (95 % CI: 6.0 %-17 %), respectively. An estimated 8.6 % (95 % CI: 5.5 %-13 %) of ESCC were HER2 positive using initial IHC followed by reflex ISH confirmation of borderline HER2 expression. In conclusion: Estimated prevalence of HER 2 positivity in ESCC were 10 % assessed by ISH and 8.6 % assessed by initial IHC followed by ISH.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Biomarcadores Tumorais , Neoplasias Esofágicas/epidemiologia , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/epidemiologia , Carcinoma de Células Escamosas do Esôfago/genética , Humanos , Prevalência , Receptor ErbB-2/genéticaRESUMO
PURPOSE: Ceritinib is an ALK receptor tyrosine kinase inhibitor approved as first- and second-line treatment in adult patients with ALK + metastatic non-small cell lung cancer (NSCLC). The study investigated the drug-drug interaction (DDI) potential of ceritinib when coadministered with midazolam and warfarin as probe substrates for CYP3A and CYP2C9 activity, respectively. METHODS: This was a phase I, multicenter, open-label, single sequence, crossover DDI study in 33 adult patients with ALK + NSCLC or other advanced tumors. A single dose of a cocktail consisting of midazolam and warfarin was administered with and without concomitant administration of ceritinib. The primary objective was to evaluate the pharmacokinetics of midazolam and warfarin. Secondary objectives included pharmacokinetics, safety, tolerability, overall response rate (ORR), and duration of response (DOR) of ceritinib 750 mg once daily. RESULTS: Ceritinib inhibited CYP3A-mediated metabolism of midazolam, resulting in a markedly increased AUC (geometric mean ratio [90% confidence interval]) by 5.4-fold (4.6, 6.3). Ceritinib also led to an increase in the AUC of S-warfarin by 54% (36%, 75%). The pharmacokinetics and safety profile of ceritinib in this study are consistent with previous reports and no new safety signals were reported. Among the 19 patients with NSCLC, efficacy (ORR: 42.1% and DCR: 63.2%) was similar to that reported previously in studies of pretreated patients with ALK + NSCLC. CONCLUSION: Ceritinib is a strong CYP3A inhibitor and a weak CYP2C9 inhibitor. These findings should be reflected as actionable clinical recommendations in the prescribing information for ceritinib with regards to concomitant medications whose pharmacokinetics may be altered by ceritinib.
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Quinase do Linfoma Anaplásico/antagonistas & inibidores , Citocromo P-450 CYP2C9/fisiologia , Citocromo P-450 CYP3A/fisiologia , Pirimidinas/farmacologia , Sulfonas/farmacologia , Adulto , Idoso , Quinase do Linfoma Anaplásico/análise , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Estudos Cross-Over , Interações Medicamentosas , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Midazolam/farmacocinética , Pessoa de Meia-Idade , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Sulfonas/efeitos adversos , Sulfonas/farmacocinética , Varfarina/farmacocinética , Adulto JovemRESUMO
BACKGROUND: This open-label, phase 1 trial (NCT02316197) aimed to determine the maximum-tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of peposertib (formerly M3814), a DNA-dependent protein kinase (DNA-PK) inhibitor in patients with advanced solid tumours. Secondary/exploratory objectives included safety/tolerability, pharmacokinetic/pharmacodynamic profiles and clinical activity. METHODS: Adult patients with advanced solid tumours received peposertib 100-200 mg once daily or 150-400 mg twice daily (BID) in 21-day cycles. RESULTS: Thirty-one patients were included (median age 66 years, 61% male). One dose-limiting toxicity, consisting of mainly gastrointestinal, non-serious adverse events (AEs) and long recovery duration, was reported at 300 mg BID. The most common peposertib-related AEs were nausea, vomiting, fatigue and pyrexia. The most common peposertib-related Grade 3 AEs were maculopapular rash and nausea. Peposertib was quickly absorbed systemically (median Tmax 1.1-2.5 h). The p-DNA-PK/t-DNA-PK ratio decreased consistently in peripheral blood mononuclear cells 3-6 h after doses ≥100 mg. The best overall response was stable disease (12 patients), lasting for ≥12 weeks in seven patients. CONCLUSIONS: Peposertib was well-tolerated and demonstrated modest efficacy in unselected tumours. The MTD was not reached; the RP2D was declared as 400 mg BID. Further studies, mainly with peposertib/chemo-radiation, are ongoing. CLINICAL TRIAL REGISTRATION: NCT02316197.
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Proteína Quinase Ativada por DNA/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Piridazinas/administração & dosagem , Piridazinas/efeitos adversos , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Adulto , Idoso , Proteína Quinase Ativada por DNA/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Neoplasias/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Piridazinas/farmacocinética , Quinazolinas/farmacocinéticaRESUMO
PURPOSE: Biliary tract cancer (BTC) is a heterogeneous group of rare gastrointestinal malignancies with dismal prognosis often associated with inflammation. We assessed the prognostic value of IL6 and YKL-40 compared with CA19-9 before and during palliative chemotherapy. We also investigated in mice whether IL6R inhibition in combination with gemcitabine could prolong chemosensitivity. EXPERIMENTAL DESIGN: A total of 452 Danish participants with advanced (locally advanced and metastatic) BTC were included from six clinical trials (February 2004 to March 2017). Serum CA19-9, IL6, and YKL-40 were measured before and during palliative treatment. Associations between candidate biomarkers and progression-free survival (PFS) and overall survival (OS) were analyzed by univariate and multivariate Cox regression. Effects of inhibiting IL6R and YKL-40 were assessed in vitro, and of IL6R inhibition in vivo. RESULTS: High pretreatment levels of CA19-9, IL6, and YKL-40, and increasing levels during treatment, were associated with short PFS and OS in patients with advanced BTC. IL6 provided independent prognostic information, independent of tumor location and in patients with normal serum CA19-9. ROC analyses showed that IL6 and YKL-40 were predictive of very short OS (OS < 6 months), whereas CA19-9 was best to predict OS > 1.5 years. Treatment with anti-IL6R and gemcitabine significantly diminished tumor growth when compared with gemcitabine monotherapy in an in vivo transplant model of BTC. CONCLUSIONS: Serum IL6 and YKL-40 are potential new prognostic biomarkers in BTC. IL6 provides independent prognostic information and may be superior to CA19-9 in certain contexts. Moreover, anti-IL6R should be considered as a new treatment option to sustain gemcitabine response in patients with BTC.
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Neoplasias do Sistema Biliar/tratamento farmacológico , Proteína 1 Semelhante à Quitinase-3/genética , Desoxicitidina/análogos & derivados , Interleucina-6/sangue , Receptores de Interleucina-6/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antígenos Glicosídicos Associados a Tumores/sangue , Antígenos Glicosídicos Associados a Tumores/genética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Sistema Biliar/sangue , Neoplasias do Sistema Biliar/genética , Neoplasias do Sistema Biliar/patologia , Biomarcadores Tumorais/sangue , Proliferação de Células/efeitos dos fármacos , Proteína 1 Semelhante à Quitinase-3/sangue , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Interleucina-6/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Cuidados Paliativos , Prognóstico , Intervalo Livre de Progressão , Receptores de Interleucina-6/antagonistas & inibidores , Receptores de Interleucina-6/genética , GencitabinaRESUMO
HER2 mutations define a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversible pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with HER2-mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER+ patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating HER2 or HER3 alterations were associated with poor treatment outcome. Similarly, acquisition of multiple HER2-activating events, as well as gatekeeper alterations, were observed at disease progression in a high proportion of patients deriving clinical benefit from neratinib. Collectively, these data define HER2 mutations as a therapeutic target in breast cancer and suggest that coexistence of additional HER signaling alterations may promote both de novo and acquired resistance to neratinib. SIGNIFICANCE: HER2 mutations define a targetable breast cancer subset, although sensitivity to irreversible HER kinase inhibition appears to be modified by the presence of concurrent activating genomic events in the pathway. These findings have implications for potential future combinatorial approaches and broader therapeutic development for this genomically defined subset of breast cancer.This article is highlighted in the In This Issue feature, p. 161.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama Masculina/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/antagonistas & inibidores , Receptores de Estrogênio/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama Masculina/genética , Neoplasias da Mama Masculina/patologia , Linhagem Celular Tumoral , Análise Mutacional de DNA , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Antagonistas do Receptor de Estrogênio/farmacologia , Antagonistas do Receptor de Estrogênio/uso terapêutico , Feminino , Fulvestranto/farmacologia , Fulvestranto/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Prospectivos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Resultado do TratamentoRESUMO
BACKGROUND: Combining poly(ADP-ribose) polymerase (PARP) inhibitors with antiangiogenic agents appeared to enhance activity vs PARP inhibitors alone in a randomized phase II trial. MATERIALS AND METHODS: In AVANOVA (NCT02354131) part 1, patients with measurable/evaluable high-grade serous/endometrioid platinum-sensitive ovarian cancer received bevacizumab 15 mg/kg every 21 days with escalating doses of niraparib capsules (100, 200, or 300 mg daily) in a 3 + 3 dose-escalation design. Primary objectives were to evaluate safety and tolerability and to determine the recommended phase II dose (RP2D). RESULTS: Three of 12 enrolled patients had germline BRCA2 mutations. In cycle 1, nine patients experienced grade 3 toxicities: five with hypertension, three with anemia, and one with thrombocytopenia. There was one dose-limiting toxicity (grade 4 thrombocytopenia with niraparib 300 mg), thus the RP2D was bevacizumab 15 mg/kg with niraparib 300 mg. The response rate was 50%; disease was stabilized in a further 42%. Median progression-free survival was 11.6 (95% confidence interval 8.4-20.1) months. Niraparib pharmacokinetics were consistent with historical single-agent data. Overlapping exposure was observed across the dose ranges tested on days 1 and 21. CONCLUSIONS: There was one dose-limiting toxicity; other adverse events were typical PARP inhibitor and antiangiogenic class effects. Niraparib-bevacizumab showed promising activity; Part 2 (vs bevacizumab) was recently reported and phase III comparison with standard-of-care therapy is planned.
Assuntos
Bevacizumab , Carcinoma Epitelial do Ovário , Indazóis , Neoplasias Ovarianas , Piperidinas , Adulto , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Bevacizumab/farmacocinética , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/patologia , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Indazóis/administração & dosagem , Indazóis/efeitos adversos , Indazóis/farmacocinética , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Piperidinas/farmacocinética , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacocinética , Intervalo Livre de ProgressãoRESUMO
Genomic screening of cancer patients for predisposing variants is traditionally based on age at onset, family history and type of cancer. Whereas the clinical guidelines have proven efficient in identifying families exhibiting classical attributes of hereditary cancer, the frequency of patients with alternative presentations is unclear. We identified and characterized germline variants in 636 patients with advanced solid cancer using whole exome sequencing. Pathogenic and likely pathogenic germline variants among 168 genes associated with hereditary cancer were considered. These variants were identified in 17.8% of the patients and within a wide range of cancer types. In particular, patients with mesothelioma, ovarian cancer, cervical cancer, urothelial cancer, and cancer of unknown primary origin displayed high frequencies of pathogenic variants. Variants were predominantly found in DNA-repair pathways and about half were within genes involved in homologous recombination repair. Twenty-two BRCA1 and BRCA2 germline variants were identified in 12 different cancer types, of which 10 (45%) were not previously identified in these patients based on the current clinical guidelines. Loss of heterozygosity and somatic second hits were identified in several of the affected genes, supporting possible causality for cancer development. A potential treatment target based on the pathogenic germline variant could be suggested in 25 patients (4%). The study demonstrates a high frequency of pathogenic germline variants in the homologous recombination pathway in patients with advanced solid cancers. We infer that genetic screening in this group of patients may reveal high-risk families and identify patients with potential PARP inhibitor sensitive tumors.
RESUMO
BACKGROUND: Olaparib, a potent oral poly(ADP-ribose) polymerase inhibitor, is partially renally cleared. We investigated the pharmacokinetics and safety of olaparib in patients with mild or moderate renal impairment to provide dosing recommendations. METHODS: This phase I open-label study assessed the pharmacokinetics, safety and tolerability of single-dose, oral 300-mg olaparib tablets in adults (aged 18-75 years) with solid tumours. Patients had normal renal function, or mild or moderate renal impairment (estimated creatinine clearance ≥ 81, 51-80 or 31-50 mL/min, respectively). Blood was collected for 96 h, and urine samples collected for 24 h post-dose. Patients could continue taking olaparib 300 mg twice daily for a long-term safety assessment. RESULTS: Overall, 44 patients received one or more doses of olaparib and 38 were included in the pharmacokinetic assessment. Patients with mild renal impairment had an area under the curve geometric least-squares mean ratio of 1.24 (90% confidence interval 1.06-1.47) and a geometric least-squares mean maximum plasma concentration ratio of 1.15 (90% confidence interval 1.04-1.27) vs. those with normal renal function. In patients with moderate renal impairment, the geometric least-squares mean ratio for the area under the curve was 1.44 (90% confidence interval 1.10-1.89) and for the maximum plasma concentration was 1.26 (90% confidence interval 1.06-1.48) vs. those with normal renal function. No new safety signals were detected in patients with mild or moderate renal impairment. CONCLUSIONS: In patients with mild renal impairment, the small increase in exposure to olaparib was not considered clinically relevant. In patients with moderate renal impairment, exposure to olaparib increased by 44%; thus, these patients should be carefully monitored and the tablet dose should be adjusted to 200 mg twice daily. CLINICAL TRIALS REGISTRATION: NCT01894256.