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PURPOSE: This multicenter phase II basket trial investigated the efficacy, safety and pharmacokinetics of Debio 1347, an investigational, oral, highly selective, ATP-competitive, small molecule inhibitor of FGFR1-3, in patients with solid tumors harboring a functional FGFR1-3 fusion. PATIENTS AND METHODS: Eligible adults had a previously treated locally advanced (unresectable) or metastatic biliary tract (cohort 1), urothelial (cohort 2) or other histologic cancer type (cohort 3). Debio 1347 was administered at 80 mg once daily, continuously, in 28-day cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included duration of response, progression-free survival, overall survival, pharmacokinetics, and incidence of adverse events. RESULTS: Between March 22, 2019 and January 8, 2020, 63 patients were enrolled and treated, 30 in cohort 1, four in cohort 2, and 29 in cohort 3. An unplanned preliminary statistical review showed that the efficacy of Debio 1347 was lower than predicted and the trial was terminated. Three of 58 evaluable patients had partial responses, representing an ORR of 5%, with a further 26 (45%) having stable disease (≥6 weeks duration). Grade ≥3 treatment-related adverse events occurred in 22 (35%) of 63 patients, with the most common being hyperphosphatemia (13%) and stomatitis (5%). Two patients (3%) discontinued treatment due to adverse events. CONCLUSIONS: Debio 1347 had manageable toxicity; however, the efficacy in patients with tumors harboring FGFR fusions did not support further clinical evaluation in this setting. Our transcriptomic-based analysis characterized in detail the incidence and nature of FGFR fusions across solid tumors.
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Xevinapant is a first-in-class antagonist of inhibitor of apoptosis proteins, which enhances cancer cell sensitivity to chemotherapy and radiotherapy. In a phase II randomized study in patients with unresected locally advanced squamous cell carcinoma of the head and neck (LA SCCHN), xevinapant plus standard-of-care cisplatin-based chemoradiotherapy (CRT) showed superior efficacy versus placebo plus CRT. Here, we describe the design of TrilynX (NCT04459715), a randomized, double-blind, phase III study. In total, 700 patients with unresected LA SCCHN will be randomized 1:1 to receive xevinapant or placebo plus standard-of-care CRT followed by xevinapant monotherapy or placebo. The primary end point is event-free survival by blinded independent review committee. Secondary end points include progression-free survival, locoregional control, overall survival and safety.
Xevinapant is being developed as a new type of cancer treatment. Xevinapant works by enhancing the effects of chemotherapy and radiotherapy (chemoradiotherapy), which are standard anticancer treatments. Researchers are studying whether adding xevinapant to these treatments could be helpful for people with head and neck cancers that have not spread to other parts of the body and cannot be removed by surgery. In a study of 96 people with this disease, those treated with chemoradiotherapy plus xevinapant on average lived longer than people treated with chemoradiotherapy plus placebo (liquid that looked the same but did not contain any medicine). To confirm the results, researchers have started a larger study, called TrilynX, that will compare the same treatments in around 700 people worldwide. This study will show if adding xevinapant to chemoradiotherapy can help to keep the cancer from progressing, control symptoms better and help people live longer. Clinical trial registration: NCT04459715 (ClinicalTrials.gov).
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Protocolos de Quimioterapia Combinada Antineoplásica , Quimioradioterapia , Neoplasias de Cabeza y Cuello , Carcinoma de Células Escamosas de Cabeza y Cuello , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimioradioterapia/efectos adversos , Cisplatino/uso terapéutico , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Neoplasias de Cabeza y Cuello/terapia , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Carcinoma de Células Escamosas de Cabeza y Cuello/terapiaRESUMEN
Inhibitor of apoptosis proteins (IAPs) regulate apoptosis and modulate NF-κB signaling thereby driving expression of genes involved in immune/inflammatory responses. The orally available IAP antagonist Debio 1143 has potential to enhance tumor response to chemoradiotherapy and/or immunotherapy. Patients with pre-operative squamous cell carcinomas of the head and neck (SCCHN) received: Debio 1143 monotherapy (200 mg/day [D]1-15 +/- 2); Debio 1143 (200 mg/day D1-15 +/- 2) plus cisplatin (40 mg/m2 D 1 and 8); cisplatin alone (40 mg/m2 D 1 and 8; EudraCT: 2014-004655-31). Pharmacokinetic/pharmacodynamic effects were assessed in plasma and resected tumors. Primary end point; effect of Debio 1143 on cellular IAP-1 (cIAP-1). Levels of cIAP-1/-2, X-linked inhibitor of apoptosis protein (XIAP), tumor infiltrating lymphocytes (TILs), including CD8+ T cells, programmed cell death protein 1 (PD-1), PD-ligand 1 (PD-L1), and gene expression were also analyzed. Twenty-three of 26 patients completed treatment. In the Debio 1143 monotherapy cohort (n = 13), mean tumor concentrations of Debio 1143 were 18-fold (maximum 55.2-fold) greater than in plasma, exceeding the half-maximal inhibitory concentration for cIAPs and XIAP by 100 to 1000-fold, with significant engagement/degradation of cIAP-1 (p < 0.05). Overall, levels of CD8+ TILs, PD-1, and PD-L1 positive immune cells increased significantly (p < 0.05) following Debio 1143 treatment. Changes were observed in the expression of genes related to NF-κB signaling. Treatments were well-tolerated. Debio 1143 penetrated SCCHN tumors, engaged cIAP-1, and induced immune inflammatory changes in the tumor microenvironment. Based on the mode of action demonstrated here and in previous studies, these data support future combinations of Debio 1143 with immune-checkpoint agents.
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Proteínas Inhibidoras de la Apoptosis/farmacología , Proteínas Inhibidoras de la Apoptosis/farmacocinética , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Microambiente Tumoral/efectos de los fármacos , Ensayos Clínicos como Asunto , Estudios de Cohortes , Humanos , Proteínas Inhibidoras de la Apoptosis/administración & dosificación , FarmacogenéticaRESUMEN
We conducted next-generation DNA sequencing on 335 biliary tract cancers and characterized the genomic landscape by anatomic site within the biliary tree. In addition to frequent FGFR2 fusions among patients with intrahepatic cholangiocarcinoma (IHCC), we identified FGFR2 extracellular domain in-frame deletions (EID) in 5 of 178 (2.8%) patients with IHCC, including two patients with FGFR2 p.H167_N173del. Expression of this FGFR2 EID in NIH3T3 cells resulted in constitutive FGFR2 activation, oncogenic transformation, and sensitivity to FGFR inhibitors. Three patients with FGFR2 EIDs were treated with Debio 1347, an oral FGFR1/2/3 inhibitor, and all showed partial responses. One patient developed an acquired L618F FGFR2 kinase domain mutation at disease progression and experienced a further partial response for 17 months to an irreversible FGFR2 inhibitor, futibatinib. Together, these findings reveal FGFR2 EIDs as an alternative mechanism of FGFR2 activation in IHCC that predicts sensitivity to FGFR inhibitors in the clinic. SIGNIFICANCE: FGFR2 EIDs are transforming genomic alterations that occur predominantly in patients with IHCC. These FGFR2 EIDs are sensitive to FGFR inhibition in vitro, and patients with these alterations benefited from treatment with FGFR inhibitors in the clinic.This article is highlighted in the In This Issue feature, p. 2355.
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Neoplasias de los Conductos Biliares/tratamiento farmacológico , Colangiocarcinoma/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/patología , Colangiocarcinoma/genética , Colangiocarcinoma/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Adulto JovenRESUMEN
PURPOSE: Debio 1143 is an oral antagonist of inhibitor of apoptosis proteins, which enhances tumor response with concomitant chemoradiotherapy. Addition of Debio 1143 to cisplatin-based chemoradiotherapy in locally advanced squamous cell carcinomas of the head and neck (LA-SCCHN) was evaluated in a phase I/II study to determine the MTD and recommended phase II dose (RP2D). Here, phase I results are reported. PATIENTS AND METHODS: Treatment-naïve patients with LA-SCCHN (stages III/IVA/IVB) received Debio 1143 (100, 200, 300 mg/day), for 14 days every 3 weeks, with cisplatin (100 mg/m², every 3 weeks), for three cycles, and concomitant conventional fractionation radiotherapy (70 Gy/7 weeks). Dose-limiting toxicity (DLT) was evaluated over 9 weeks using continual reassessment. RESULTS: Fourteen patients were treated/evaluable for DLT. Median age was 64.5 years, and all patients were current/former smokers. Primary tumors were hypopharynx, oropharynx (all human papillomavirus/p16 negative), larynx, and oral cavity. Two of six patients at 200 mg/day had DLT (grade 3 tubular necrosis, grade 3 aspartate aminotransferase/alanine aminotransferase increase, grade 4 febrile neutropenia, and grade 3 lipase increase), which was considered the MTD and RP2D. Common grade 3-4 adverse events were dysphagia (36%) and mucositis (29%). Laboratory abnormalities were frequent and generally mild, including anemia, white blood cell decrease, and increased creatinine. Addition of Debio 1143 did not compromise chemotherapy administration. Overall locoregional control rate at 18 months was 85%. Overall response rate was 85%, including 69% complete responses. Progression-free survival rate at 24 months was 74%. CONCLUSIONS: The RP2D of Debio 1143 is 200 mg/day for 14 days, every 3 weeks, when combined with concomitant high-dose cisplatin chemoradiotherapy in LA-SCCHN. Debio 1143 addition to chemoradiotherapy was safe and manageable. Preliminary efficacy is encouraging and supports further development.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioradioterapia/métodos , Neoplasias de Cabeza y Cuello/terapia , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Adolescente , Adulto , Anciano , Azocinas/administración & dosificación , Compuestos de Bencidrilo/administración & dosificación , Cisplatino/administración & dosificación , Femenino , Estudios de Seguimiento , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Adulto JovenRESUMEN
BACKGROUND: Debio 1143 is an orally available antagonist of inhibitor of apoptosis proteins with the potential to enhance the antitumour activity of cisplatin and radiotherapy. The radiosensitising effect of Debio 1143 is mediated through caspase activation and TNF, IFNγ, CD8 T cell-dependent pathways. We aimed to investigate the efficacy and safety of Debio 1143 in combination with standard chemoradiotherapy in patients with high-risk locally advanced squamous cell carcinoma of the head and neck. METHODS: This double-blind, multicentre, randomised, phase 2 study by the French Head and Neck Radiotherapy Oncology Group (GORTEC) was run at 19 hospitals in France and Switzerland. Eligible patients were aged 18-75 years with locoregionally advanced, squamous cell carcinoma of the head and neck (characterised as non-metastatic, measurable stage III, IVa, or IVb [limited to T ≥2, N0-3, and M0] disease), Eastern Cooperative Oncology Group performance status of 0 or 1, a history of heavy tobacco smoking (>10 pack-years) with no previous or current treatment for invasive head and neck cancer, and no previous treatment with inhibitor of apoptosis protein antagonists. Patients were randomly assigned (1:1) to receive oral Debio 1143 (200 mg per day on days 1-14 of 21-day cycles, for three cycles) or oral placebo (20 mg/mL, administered at the same dosing schedule) using a stochastic minimisation technique according to node involvement and primary tumour site, and HPV-16 status in patients with an oropharyngeal primary tumour site. All patients received standard high-dose cisplatin chemoradiotherapy. The primary endpoint was the proportion of patients with locoregional control 18 months after chemoradiotherapy, analysed in the intention-to-treat population (primary analysis), and repeated in the per-protocol population. Responses were assessed according to Response Evaluation Criteria in Solid Tumors (version 1.1). This trial is registered with ClinicalTrials.gov, NCT02022098, and is still active but not recruiting. FINDINGS: Between Jan 25, 2016, and April 24, 2017, 48 patients were randomly assigned to the Debio 1143 group and 48 to the placebo group (one patient in the placebo group did not receive the study drug and was not included in the safety analysis). Median duration of follow-up was 25·0 months (IQR 19·6-29·4) in the Debio 1143 group and 24·2 months (6·6-26·8) in the placebo group. Locoregional control 18 months after chemoradiotherapy was achieved in 26 (54%; 95% CI 39-69) of 48 patients in the Debio 1143 group versus 16 (33%; 20-48) of 48 patients in the placebo group (odds ratio 2·69 [95% CI 1·13-6·42], p=0·026). Grade 3 or worse adverse events were reported in 41 (85%) of 48 patients in the Debio 1143 group and in 41 (87%) of 47 patients in the placebo group. The most common grade 3-4 adverse events were dysphagia (in 24 [50%] patients in the Debio 1143 group vs ten [21%] in the placebo group), mucositis (in 15 [31%] vs ten [21%]), and anaemia (in 17 [35%] vs 11 [23%]). Serious treatment-emergent adverse events were recorded in 30 (63%) of 48 patients in the Debio 1143 group and 28 (60%) of 47 in the placebo group. In the placebo group, two (4%) deaths were due to adverse events (one multiple organ failure and one asphyxia; neither was considered to be related to treatment). No deaths due to adverse events occurred in the Debio 1143 group. INTERPRETATION: To our knowledge, this is the first treatment regimen to achieve superior efficacy in this disease setting against a high-dose cisplatin chemoradiotherapy comparator in a randomised trial. These findings suggest that inhibition of inhibitor of apoptosis proteins is a novel and promising approach in this poor prognostic population and warrant confirmation in a phase 3 study with the aim of expanding the therapeutic options for these patients. FUNDING: Debiopharm.
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Cisplatino/administración & dosificación , Pronóstico , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/radioterapia , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Cisplatino/efectos adversos , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Adulto JovenRESUMEN
PURPOSE: To investigate tolerability, efficacy, and pharmacokinetics/pharmacodynamics of Debio 1347, a selective FGFR inhibitor. PATIENTS AND METHODS: This was a first-in-human, multicenter, open-label study in patients with advanced solid tumors harboring FGFR1-3 gene alterations. Eligible patients received oral Debio 1347 at escalating doses once daily until disease progression or intolerable toxicity. Dose-limiting toxicities (DLT) were evaluated during the first 4 weeks on treatment, pharmacokinetics/pharmacodynamics postfirst dose and after 4 weeks. RESULTS: A total of 71 patients were screened and 58 treated with Debio 1347 at doses from 10 to 150 mg/day. Predominant tumor types were breast and biliary duct cancer, most common gene alterations were FGFR1 amplifications (40%) and mutations in FGFR2 (12%) and FGFR3 (17%); 12 patients (21%) showed FGFR fusions. Five patients at three dose levels had six DLTs (dry mouth/eyes, hyperamylasemia, hypercalcemia, hyperbilirubinemia, hyperphosphatemia, and stomatitis). The maximum tolerated dose was not reached, but dermatologic toxicity became sometimes dose limiting beyond the DLT period at ≥80 mg/day. Adverse events required dose modifications in 52% of patients, mostly due to dose-dependent, asymptomatic hyperphosphatemia (22%). RECIST responses were seen across tumor types and mechanisms of FGFR activation. Six patients, 3 with FGFR fusions, demonstrated partial responses, 10 additional patients' tumor size regressions of ≤30%. Plasma half-life was 11.5 hours. Serum phosphate increased with Debio 1347 plasma levels and confirmed target engagement at doses ≥60 mg/day. CONCLUSIONS: Preliminary efficacy was encouraging and tolerability acceptable up to 80 mg/day, which is now used in an extension part of the study.
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Bencimidazoles/uso terapéutico , Fusión Génica , Mutación , Neoplasias/tratamiento farmacológico , Pirazoles/uso terapéutico , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Adulto , Anciano , Bencimidazoles/farmacocinética , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/genética , Neoplasias/patología , Pronóstico , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/farmacocinética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Transducción de Señal , Distribución TisularRESUMEN
Background: Debio 1143, a potent orally available SMAC mimetic, targets inhibitors of apoptosis proteins (IAPs) members and is currently in clinical trials. In this study, nuclear imaging evaluated the effects of Debio 1143 on tumor cell death and metabolism in a triple-negative breast cancer (TNBC) cell line (MDA-MB-231)-based animal model. Methods: Apoptosis induced by Debio 1143 was assessed by FACS (caspase-3, annexin 5 (A5)), binding of 99mTc-HYNIC-Annexin V, and a cell proliferation assay. 99mTc-HYNIC-Annexin V SPECT and [18F]-FDG PET were also performed in mice xenografted with MDA-MB-231 cells. Results: Debio 1143 induced early apoptosis both in vitro and in vivo 6 h after treatment. Debio 1143 inhibited tumor growth, which was associated with a decreased tumor [18F]-FDG uptake when measured during treatment. Conclusions: This imaging study combining SPECT and PET showed the early proapoptotic effects of Debio 1143 resulting in a robust antitumor activity in a preclinical TNBC model. These imaging biomarkers represent valuable noninvasive tools for translational and clinical research in TNBC.
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Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Imagen Multimodal/métodos , Radiofármacos/química , Neoplasias de la Mama Triple Negativas/diagnóstico por imagen , Animales , Apoptosis/efectos de los fármacos , Biomarcadores , Femenino , Xenoinjertos , Humanos , Imagen por Resonancia Magnética/métodos , Ratones , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radiofármacos/farmacología , Tomografía Computarizada de Emisión de Fotón Único , Investigación Biomédica Traslacional , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
BACKGROUND AND PURPOSE: Second mitochondria-derived activator of caspase (SMAC)-mimetics are a new class of targeted drugs that specifically induce apoptotic cancer cell death and block pro-survival signaling by antagonizing selected members of the inhibitor of apoptosis protein (IAP) family. MATERIAL AND METHODS: The present study was designed to investigate the radiosensitizing effect and optimal sequence of administration of the novel SMAC-mimetic Debio 1143 in vitro and in vivo. Apoptosis, alteration of DNA damage repair (DDR), and tumor necrosis factor-alpha (TNF-α) signaling were examined. RESULTS: In vitro, Debio 1143 displayed anti-proliferative activity and enhanced intrinsic radiation sensitivity in 5/6 head and neck squamous cell carcinoma (HNSCC) cell lines in a synergistic manner. In vivo, Debio 1143 dose-dependently radio-sensitized FaDu and SQ20B xenografts, resulting in complete tumor regression in 8/10 FaDu-xenografted mice at the high dose level. At the molecular level, Debio 1143 combined with radiotherapy (RT) induced enhancement of caspase-3 activity, increase in Annexin V-positive cells and karyopyknosis, and increase in TNF-α mRNA levels. Finally, in a neutralization experiment using a TNF-α-blocking antibody and a caspase inhibitor, it was shown that the radiosensitizing effect of Debio 1143 is mediated by caspases and TNF-α. CONCLUSIONS: These results demonstrate that the novel SMAC-mimetic Debio 1143 is a radiosensitizing agent that is worthy of further investigation in clinical trials in combination with radiotherapy.
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Antineoplásicos/farmacología , Azocinas/farmacología , Compuestos de Bencidrilo/farmacología , Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeza y Cuello/terapia , Fármacos Sensibilizantes a Radiaciones/farmacología , Factor de Necrosis Tumoral alfa/fisiología , Animales , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis , Caspasa 3/metabolismo , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Quimioradioterapia/métodos , Femenino , Humanos , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/farmacología , Ratones Endogámicos , Proteínas Mitocondriales/farmacología , Trasplante de Neoplasias , Transducción de Señal/efectos de los fármacos , Carcinoma de Células Escamosas de Cabeza y Cuello , Trasplante Heterólogo , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
BACKGROUND: Treatment of acute myeloid leukemia (AML) remains difficult owing to the development of treatment resistance, which might be overcome through antagonists of inhibitors of apoptosis proteins (IAPs). PATIENTS AND METHODS: The present multicenter, open-label, dose-escalation study aimed to evaluate the tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of Debio1143 (formerly AT-406), a new IAP antagonist, when given along with a standard "7 plus 3 regimen" of daunorubicin and cytarabine to poor-risk patients with AML during the induction cycle. Consecutive patient cohorts received once-daily 100, 200, 300, or 400 mg of oral Debio1143 on treatment days 1 to 5. Blood samples were collected regularly until hematologic recovery or response was documented. Bone marrow samples were collected on days 0, 14, and 29 and PK and PD samples on days 1, 3, 5, 8, and 10 and 1, 2, and 8, respectively. RESULTS: Of the 29 enrolled patients, 23 completed the study. The most common adverse events of any grade deemed related to treatment were nausea (31% of patients), diarrhea (14%), and febrile neutropenia (14%). Exposure exceeded dose proportionality, without accumulation over 5 days. Inhibition of cellular IAP1 was detectable in the CD34/CD117(+) cells and blasts. A total of 11 patients (38%) achieved complete remission, most in the 100-mg dose cohort. Of these, 6 (56%) developed a relapse within the study period. The patients with a response more frequently showed plasma increases of tumor necrosis factor-α and interleukin-8 after the first dose of Debio1143. CONCLUSION: Debio1143 ≤ 400 mg/d showed good tolerability in combination with daunorubicin and cytarabine. Additional studies in subsets of patients with AML are warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Azocinas/administración & dosificación , Compuestos de Bencidrilo/administración & dosificación , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Leucemia Mieloide Aguda/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Citarabina/administración & dosificación , Citocinas/sangre , Daunorrubicina/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Leucemia Mieloide Aguda/sangre , Masculino , Persona de Mediana EdadRESUMEN
PURPOSE: To assess safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of DEBIO1143, an antagonist of inhibitor apoptosis proteins. METHODS: This first-in-man study in patients with advanced cancer used an accelerated dose titration design. DEBIO1143 was given orally once daily on days 1-5 every 2 or 3 weeks until disease progressed or patients dropped out. The starting dose of 5 mg was escalated by 100% in single patients until related grade 2 toxicity occurred. This triggered expansion to cohorts of three and subsequently six patients and reduction in dose increments to 50%. Maximum tolerated dose (MTD) was exceeded when any two patients within the same cohort experienced dose-limiting toxicity (DLT). On days 1 and 5, PK and PD samples were taken. RESULTS: Thirty-one patients received doses from 5 to 900 mg. Only one DLT was reported at 180 mg. No MTD was found. Most common adverse drug reactions were fatigue (26%), nausea (23%), and vomiting (13%). Average t max and T 1/2 was about 1 and 6 h, respectively. Exposure increased proportionally with doses from 80 to 900 mg, without accumulation over 5 days. Plasma CCL2 increased at 3-6 h postdose and epithelial apoptosis marker M30 on day 5; cIAP-1 levels in PBMCs decreased at all doses >80 mg. Five patients (17%) had stable disease as the best treatment response. CONCLUSION: DEBIO1143 was well tolerated at doses up to 900 mg and elicited PD effects at doses greater 80 mg. Limited antitumor activity may suggest development rather as adjunct treatment.
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Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Azocinas/administración & dosificación , Azocinas/uso terapéutico , Compuestos de Bencidrilo/administración & dosificación , Compuestos de Bencidrilo/uso terapéutico , Neoplasias/tratamiento farmacológico , Administración Oral , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Azocinas/efectos adversos , Azocinas/farmacocinética , Compuestos de Bencidrilo/efectos adversos , Compuestos de Bencidrilo/farmacocinética , Quimiocina CCL2/sangre , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Proteínas Inhibidoras de la Apoptosis/sangre , Masculino , Dosis Máxima Tolerada , Neoplasias/etiología , Neoplasias/patología , Resultado del TratamientoRESUMEN
The assessment of chemotherapy-induced peripheral neurotoxicity (CIPN) is still uncertain as several of the most frequently used scales do not rely on a formal neurological evaluation and depend on patients' reports and examiners' interpretations. The aim of this study was to compare the assessment of CIPN using the National Cancer Institute Common Toxicity Criteria (NCI-CTC) scale and a formal neurological assessment scored with the Total Neuropathy Score (TNS, i.e., a composite scale designed to grade the impairment in neuropathy patients) to identify possible discrepancies in the diagnosis. In this prospective study, 155 patients treated with cisplatin/carboplatin or with paclitaxel/docetaxel and CIPN were examined in a collaborative oncological/neurological multi-center trial using the NCI-CTC scale and the TNS; the results were then extensively compared. We evidenced that the TNS allows possible misdiagnosed neuropathies to be revealed. In fact, the NCI-CTC evaluation performed by experienced examiners overestimated the occurrence of motor neuropathy, possibly because of the presence of confounding factors (e.g., fatigue, depression, cachexia), which might be difficult to be ruled out without a formal neurological examination. This study strongly indicates that a more formal neurological assessment of patients with CIPN than that achievable with the common toxicity scales (e.g., NCI-CTC) is advisable.
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Antineoplásicos/efectos adversos , Errores Diagnósticos , Síndromes de Neurotoxicidad/diagnóstico , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Índice de Severidad de la Enfermedad , Femenino , Humanos , Masculino , National Cancer Institute (U.S.) , Examen Neurológico/métodos , Síndromes de Neurotoxicidad/etiología , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Estados UnidosRESUMEN
PURPOSE: In a continuous effort to seek for anticancer treatments with minimal side effects, we aim at proving the feasibility of the Intraoperative Avidination for Radionuclide Therapy, a new procedure for partial breast irradiation. EXPERIMENTAL DESIGN: To assess doses of 90Y-DOTA-biotin to target (i.e., breast tumor bed) and nontarget organs, we did simulation studies with 111In-DOTA-biotin in 10 candidates for conservative breast surgery. Immediately after quadrantectomy, patients were injected with 100-mg avidin in the tumor bed. On the following day, patients were given 111In-DOTA-biotin (approximately 111 MBq) i.v. after appropriate chase of biotinylated albumin (20 mg) to remove circulating avidin. Biokinetic studies were done by measuring radioactivity in scheduled blood samples, 48-h urine collection, and through scintigraphic images. The medical internal radiation dose formalism (OLINDA code) enabled dosimetry assessment in target and nontarget organs. RESULTS: Images showed early and long-lasting radioactive biotin uptake in the operated breast. Rapid blood clearance (<1% at 12 h) and urine excretion (>75% at 24 h) were observed. Absorbed doses, expressed as mean+/-SD in Gy/GBq, were as low as 0.15+/-0.05 in lungs, 0.10+/-0.02 in heart, 0.06+/-0.02 in red marrow, 1.30+/-0.50 in kidneys, 1.50+/-0.30 in urinary bladder, and 0.06+/-0.02 in total body, whereas in the targeted area, they increased to 5.5+/-1.1 Gy/GBq (50% ISOROI) and 4.8+/-1.0 Gy/GBq (30% ISOROI). CONCLUSION: Our preliminary results suggest that Intraoperative Avidination for Radionuclide Therapy is a simple and feasible procedure that may improve breast cancer patients' postsurgical management by shortening radiotherapy duration.
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Avidina/administración & dosificación , Biotina/análogos & derivados , Braquiterapia/métodos , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/radioterapia , Compuestos Organometálicos/administración & dosificación , Adolescente , Adulto , Anciano , Avidina/farmacocinética , Biotina/administración & dosificación , Biotina/farmacocinética , Neoplasias de la Mama/cirugía , Terapia Combinada , Femenino , Humanos , Radioisótopos de Indio , Inyecciones Intralesiones , Inyecciones Intravenosas , Periodo Intraoperatorio , Mastectomía Segmentaria , Persona de Mediana Edad , Compuestos Organometálicos/farmacocinética , Proyectos Piloto , Estudios Prospectivos , Cintigrafía , Radiofármacos , Radioterapia Adyuvante , Biopsia del Ganglio Linfático Centinela , Distribución Tisular , Radioisótopos de ItrioRESUMEN
Chemotherapy-induced peripheral neurotoxicity (CIPN) is a major side effect of several antineoplastic drugs. However, despite its clinical importance, there is no agreement as to the best way to assess the severity and changes in CIPN. We have previously demonstrated a correlation between the severity of CIPN, assessed using the Total Neuropathy Score (TNS) or its reduced versions, and several common toxicity scales. In this study, we investigated two series of patients (total number = 173) who were evaluated at baseline and during chemotherapy with the TNS (n= 122) or the TNSc (the TNS version based exclusively on the clinical evaluation of the patients, n= 51) and with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) 2.0, with the aim of comparing the sensitivity to the changes in CIPN severity. In both series, the TNS and the TNSc had a significant correlation with the NCI-CTC in scoring the severity of CIPN, confirming the results of previous studies. Moreover, both the TNS and the TNSc showed a higher sensitivity to CIPN changes. We, therefore, propose the TNSc as a reliable method for assessing not only the severity but also the changes in CIPN.
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Antineoplásicos/efectos adversos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/patología , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neuronas Motoras/patología , Neoplasias/complicaciones , Neoplasias/patología , Examen Neurológico , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Estudios ProspectivosRESUMEN
A new procedure, known as Intraoperative Avidination for Radionuclide Therapy (IART), is described in breast cancer patients. In this paper, we provide proof of the principle that intraoperative injection of avidin in the tumour bed after quadrantectomy allows homing in of intravenously (IV) administered radioactive biotin to the target site. This approach of targeted therapy consists of two steps: (i) "avidination" of the anatomical area of the tumour with avidin injected by the surgeon, into and around the tumour bed; (ii) targeting the anatomical area of the tumour by IV injection of radiolabelled biotin. The scintigraphic images demonstrated fast and stable uptake of labelled biotin at the site of operated breast. The radiation dose released to the index quadrant was more than 5 Gy/GBq, consistent with a boost of 20 Gy for an activity of 3.7 GBq 90Y-biotin (100mCi). A further large clinical trial facing IART in combination with reduced external-beam radiotherapy is, in our opinion, fully justified.
Asunto(s)
Avidina/administración & dosificación , Biotina/administración & dosificación , Braquiterapia/métodos , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/radioterapia , Adulto , Avidina/farmacocinética , Biotina/farmacocinética , Neoplasias de la Mama/cirugía , Terapia Combinada , Femenino , Humanos , Inyecciones Intralesiones , Inyecciones Intravenosas , Periodo Intraoperatorio , Mastectomía Segmentaria , Persona de Mediana Edad , Radiometría , Cintigrafía , Dosificación Radioterapéutica , Radioterapia Adyuvante , Radioisótopos de ItrioRESUMEN
BACKGROUND: Oxaliplatin (OHP) is severely neurotoxic and induces the onset of a disabling sensory peripheral neuropathy. Acetyl-L-carnitine (ALC), a natural compound with neuroprotective action, was tested to determine whether it plays a protective role in OHP-induced neuropathy. MATERIALS AND METHODS: Peripheral neuropathy was induced in Wistar rats, and the effect of OHP alone or in combination with ALC was assessed, using behavioral and neurophysiological methods. Moreover, ALC interference on OHP antitumor activity was investigated using several in vitro and in vivo models. RESULTS: ALC-co-treatment reduced the neurotoxicity of OHP when it was coadministered. Furthermore, the administration-of OHP, once OHP-induced neuropathy was established, significantly mitigated its severity. Finally, experiments in different tumor systems indicated that ALC does not interfere with the antitumor effects of OHP. CONCLUSION: ALC is effective in the prevention and treatment of chronic OHP-induced peripheral neurotoxicity in an experimental rat model.
Asunto(s)
Acetilcarnitina/farmacología , Antineoplásicos/farmacología , Fármacos Neuroprotectores/farmacología , Compuestos Organoplatinos/farmacología , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/prevención & control , Animales , Antineoplásicos/efectos adversos , Línea Celular Tumoral , Enfermedad Crónica , Interacciones Farmacológicas , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Células HT29 , Humanos , Masculino , Ratones , Ratones Desnudos , Compuestos Organoplatinos/efectos adversos , Oxaliplatino , Dimensión del Dolor/efectos de los fármacos , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Ratas , Ratas Wistar , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Acetyl-L-carnitine (ALC) improves non-oncological neuropathies. We tested oral ALC (1 g tid) for 8 weeks in 25 patients with neuropathy grade 3 (common toxicity criteria--CTC) during paclitaxel or cisplatin therapy, or grade 2 persisting for at least three months after discontinuing the drugs. An independent neurologist assessed patients before and after ALC. All patients except one reported symptomatic relief, and only two described grade 1 nausea. The sensory neuropathy grade improved in 15 of 25 (60%), and motor neuropathy in 11 of 14 patients (79%). Total neuropathy score (TNS) that included neurophysiological measures improved in 23 (92%). Amelioration of sensory amplitude and conduction velocity (sural and peroneal nerves) was measured in 22 and 21 patients, respectively. Symptomatic improvement persisted in 12 of 13 evaluable patients at median 13 months after ALC. In view of its effect in improving established paclitaxel- and cisplatin-neuropathy, we recommend ALC testing in preventing progression or revert symptoms during neurotoxic chemotherapy.
Asunto(s)
Acetilcarnitina/administración & dosificación , Antineoplásicos/efectos adversos , Cisplatino/efectos adversos , Enfermedades del Sistema Nervioso/inducido químicamente , Paclitaxel/efectos adversos , Potenciales de Acción/efectos de los fármacos , Administración Oral , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neuronas Motoras/efectos de los fármacos , Enfermedades del Sistema Nervioso/prevención & control , Neuronas Aferentes/efectos de los fármacos , Tiempo de Reacción/efectos de los fármacosRESUMEN
AIMS AND BACKGROUND: In addition to bone marrow suppression and renal toxicity, neurotoxicity is a commonly occurring side effect of widely used chemotherapeutic agents like taxanes, cisplatin and vinca alkaloids. Neurotoxicity can cause antitumor therapy discontinuation or dose regimen modification. The aim of the present exploratory study was to investigate the activity of acetyl-L-carnitine in reversing peripheral neuropathy in patients with chemotherapy-induced peripheral neuropathy. METHODS AND STUDY DESIGN: Twenty-seven patients (16 males and 11 females) with paclitaxel and/or cisplatin-induced neuropathy (according to WHO recommendations for the grading of acute and subacute toxic effects) were enrolled. Patients received at least one cisplatin- (n = 5) or one paclitaxel- (n = 11) based regimen, or a combination of both (n = 11). Patients with chemotherapy-induced peripheral neuropathy were treated with acetyl-L-carnitine 1 g/die i.v. infusion over 1-2 h for at least 10 days. RESULTS: Twenty-six patients were evaluated for response having completed at least 10 days of acetyl-L-carnitine therapy (median, 14 days; range, 10-20). At least one WHO grade improvement in the peripheral neuropathy severity was shown in 73% of the patients. A case of insomnia related to ALC treatment was reported in one patient. Acetyl-L-carnitine seems to be an effective and well-tolerated agent for the treatment of chemotherapy-induced peripheral neuropathy. CONCLUSIONS: Our preliminary results should be confirmed in double-blind, placebo controlled studies.