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1.
Br J Cancer ; 130(3): 476-482, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-38135713

RESUMEN

BACKGROUND: Our preclinical work revealed tumour hypoxia induces homologous recombination deficiency (HRD), increasing sensitivity to Poly (ADP-ribose) polymerase inhibitors. We aimed to induce tumour hypoxia with ramucirumab thereby sensitising tumours to olaparib. PATIENTS AND METHODS: This multi-institution single-arm Phase 1/2 trial enrolled patients with metastatic gastroesophageal adenocarcinoma refractory to ≥1 systemic treatment. In dose escalation, olaparib was evaluated at escalating dose levels with ramucirumab 8 mg/kg day 1 in 14-day cycles. The primary endpoint of Phase 1 was the recommended Phase 2 dose (RP2D), and in Phase 2 the primary endpoint was the overall response rate (ORR). RESULTS: Fifty-one patients received ramucirumab and olaparib. The RP2D was olaparib 300 mg twice daily with ramucirumab 8 mg/kg. In evaluable patients at the RP2D the ORR was 6/43 (14%) (95% CI 4.7-25.6). The median progression-free survival (PFS) was 2.8 months (95% CI 2.3-4.2) and median overall survival (OS) was 7.3 months (95% CI 5.7-13.0). Non-statistically significant improvements in PFS and OS were observed for patients with tumours with mutations in HRD genes. CONCLUSIONS: Olaparib and ramucirumab is well-tolerated with efficacy that exceeds historical controls with ramucirumab single agent for gastric cancer in a heavily pre-treated patient population.


Asunto(s)
Adenocarcinoma , Neoplasias Esofágicas , Piperazinas , Neoplasias Gástricas , Humanos , Ramucirumab , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Ftalazinas , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Unión Esofagogástrica , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos
2.
Curr Treat Options Oncol ; 25(1): 127-160, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-38177560

RESUMEN

OPINION STATEMENT: Biliary tract cancers are molecularly and anatomically diverse cancers which include intrahepatic cholangiocarcinoma, extrahepatic (perihilar and distal) cholangiocarcinoma, and gallbladder cancer. While recognized as distinct entities, the rarer incidence of these cancers combined with diagnostic challenges in classifying anatomic origin has resulted in clinical trials and guideline recommended strategies being generalized patients with all types of biliary tract cancer. In this review, we delve into the unique aspects, subtype-specific clinical trial outcomes, and multidisciplinary management of patients with extrahepatic cholangiocarcinoma. When resectable, definitive surgery followed by adjuvant chemotherapy (sometimes with selective radiation/chemoradiation) is current standard of care. Due to high recurrence rates, there is growing interest in the use of upfront/neoadjuvant therapy to improve surgical outcomes and to downstage patients who may not initially be resectable. Select patients with perihilar cholangiocarcinoma are being successfully treated with novel approaches such as liver transplant. In the advanced disease setting, combination gemcitabine and cisplatin remains the standard base for systemic therapy and was recently improved upon with the addition of immune checkpoint blockade to the chemotherapy doublet in the recently reported TOPAZ-1 and KEYNOTE-966 trials. Second-line all-comer treatments for these patients remain limited in both options and efficacy, so clinical trial participation should be strongly considered. With increased use of molecular testing, detection of actionable mutations and opportunities to receive indicated targeted therapies are on the rise and are the most significant driver of improved survival for patients with advanced stage disease. Though these targeted therapies are currently reserved for the second or later line, future trials are looking at moving these to earlier treatment settings and use in combination with chemotherapy and immunotherapy. In addition to cross-disciplinary management with surgical, medical, and radiation oncology, patient-centered care should also include collaboration with advanced endoscopists, palliative care specialists, and nutritionists to improve global patient outcomes.


Asunto(s)
Neoplasias de los Conductos Biliares , Neoplasias del Sistema Biliar , Colangiocarcinoma , Humanos , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/terapia , Colangiocarcinoma/patología , Neoplasias del Sistema Biliar/patología , Gemcitabina , Neoplasias de los Conductos Biliares/diagnóstico , Neoplasias de los Conductos Biliares/terapia , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/patología
3.
Br J Cancer ; 128(12): 2227-2235, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37087488

RESUMEN

BACKGROUND: Indoleamine 2,3-dioxygenase 1 (IDO1), an interferon-inducible enzyme, contributes to tumor immune intolerance. Immune checkpoint inhibition may increase interferon levels; combining IDO1 inhibition with immune checkpoint blockade represents an attractive strategy. Epigenetic agents trigger interferon responses and may serve as an immunotherapy priming method. We evaluated whether epigenetic therapy plus IDO1 inhibition and immune checkpoint blockade confers clinical benefit to patients with advanced solid tumors. METHODS: ECHO-206 was a Phase I/II study where treatment-experienced patients with advanced solid tumors (N = 70) received azacitidine plus an immunotherapy doublet (epacadostat [IDO1 inhibitor] and pembrolizumab). Sequencing of treatment was also assessed. Primary endpoints were safety/tolerability (Phase I), maximum tolerated dose (MTD) or pharmacologically active dose (PAD; Phase I), and investigator-assessed objective response rate (ORR; Phase II). RESULTS: In Phase I, no dose-limiting toxicities were reported, the MTD was not reached; a PAD was not determined. ORR was 5.7%, with four partial responses. The most common treatment-related adverse events (AEs) were fatigue (42.9%) and nausea (42.9%). Twelve (17.1%) patients experienced ≥1 fatal AE, one of which (asthenia) was treatment-related. CONCLUSIONS: Although the azacitidine-epacadostat-pembrolizumab regimen was well tolerated, it was not associated with substantial clinical response in patients with advanced solid tumors previously exposed to immunotherapy.


Asunto(s)
Azacitidina , Neoplasias , Humanos , Azacitidina/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Interferones/uso terapéutico
4.
Ann Emerg Med ; 80(3): 235-242, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35752517

RESUMEN

STUDY OBJECTIVE: Abnormal findings unrelated to the indication for testing are identified on emergency department (ED) imaging studies. We report the design and implementation of an electronic health record-based interdisciplinary referral system and our experience from the first 13 months of ensuring that patients with incidental radiology findings were connected with the appropriate outpatient surveillance. METHODS: Our informatics team standardized the contemporaneous reporting of critical radiology alerts using our ED trackboard and created a companion follow-up request form for the treating ED clinicians to complete. The forms were routed to nurse case managers, who arranged follow-ups based on the findings and clinical significance. The primary outcome was the proportion of ED patient visits with identified incidental findings that had documented communication of the incidental findings and surveillance plans. RESULTS: Over the first 13 months after implementation, 932 ED patient visits had critical radiology alert referrals, for a total of 982 incidental findings. The primary outcome (confirmed post-ED communication and documented follow-up plan) was attained in 888 (95.3%, 95% confidence interval [CI] 93.9% to 96.6%) ED patient visits with confirmed post-ED communication and documented follow-up plans. The team was unable to contact or confirm follow-up with 44 (4.7%, 95% CI 3.4 to 6.1) patients by telephone or through the health care system's electronic communication tools. CONCLUSION: We report the implementation of a standardized notification and referral system for ED patients with incidental radiology findings. The development of a reliable notification and follow-up system is an important patient safety intervention given the opportunity to potentially identify undiagnosed malignancies.


Asunto(s)
Servicio de Urgencia en Hospital , Radiología , Comunicación , Diagnóstico por Imagen , Estudios de Seguimiento , Humanos , Radiología/métodos
5.
Am J Transplant ; 20(3): 879-883, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31550417

RESUMEN

Nivolumab is an immune checkpoint inhibitor (ICI) currently in phase 3 clinical trials for hepatocellular carcinoma. The safety of ICIs in recipients of organ allotransplant is unclear, and several reports of fatal alloimmune injury after posttransplant ICI use have been published. We present the first published case of nivolumab used in the pretransplant setting for HCC resulting in fatal acute hepatic necrosis in the immediate postoperative period from a profound immune reaction likely propagated by nivolumab. Further investigation and significant caution are needed in the evaluation of patients awaiting transplant who are receiving ICI therapy.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Trasplante de Hígado , Anticuerpos Monoclonales/efectos adversos , Carcinoma Hepatocelular/tratamiento farmacológico , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Trasplante de Hígado/efectos adversos , Necrosis/inducido químicamente , Nivolumab/efectos adversos , Receptor de Muerte Celular Programada 1
6.
Oncologist ; 25(8): 669-679, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-31943525

RESUMEN

INTRODUCTION: Immune-related adverse event (IRAE) onset may represent a clinical biomarker for anti-programmed cell death protein 1 (PD-1) antibody response based on emerging evidence from patients with various advanced malignancies. This phenomenon has not been previously reported in a multidisease cohort of patients with gastrointestinal (GI) cancer with Food and Drug Administration (FDA)-approved indications to receive immune checkpoint inhibitor therapy. MATERIALS AND METHODS: The study was a multicenter retrospective cohort analysis of 76 patients with GI cancer who had received anti-PD-1 antibodies for FDA-approved indications. The primary and secondary outcomes of the study were progression-free survival (PFS) and overall survival (OS) in patients based upon IRAE presence, respectively. PFS and OS were estimated by the Kaplan-Meier method; a Cox proportional-hazards model adjusted for IRAE onset, patient age, and enrolling institution was used to analyze outcomes. RESULTS: Median PFS and OS were prolonged in patients who experienced IRAEs compared with those who did not experience them (PFS: not reached [NR] vs. 3.9 months [hazard ratio (HR) 0.13, 95% confidence interval (CI) 0.05-0.3, p < .001]; OS: NR vs. 7.4 months [HR 0.11, 95% CI 0.03-0.36, p < .001]). Among patients who experienced IRAEs, there were no significant differences in PFS and OS by either initial IRAE severity, management, or time to onset. CONCLUSION: Patients with gastrointestinal cancer who experienced IRAEs while on anti-PD-1 antibodies demonstrated significant improvements in PFS and OS compared with their counterparts who did not develop IRAEs. Although these findings add to results from studies in other tumor types, larger prospective studies are needed prior to clinical adoption of IRAE onset as a biomarker for immune checkpoint inhibitor response. IMPLICATIONS FOR PRACTICE: Predictive clinical biomarkers for immune checkpoint inhibitor response have been understudied in the field of immuno-oncology. Immune-related adverse event onset appears to be one such biomarker. Across tumor types, immune-related adverse event onset has been associated with response to anti-programmed cell death protein 1 (PD-1) antibodies. The results of this study demonstrate this for the first time in patients with gastrointestinal cancer receiving anti-PD-1 antibodies. Before immune-related adverse event onset can be adopted clinically as a predictive biomarker for immune checkpoint inhibitor response, however, larger prospective studies are needed to better understand the nuances between immune-related adverse event characteristics (severity, site, management, timing of onset) and immune checkpoint inhibitor effectiveness.


Asunto(s)
Neoplasias Gastrointestinales , Inhibidores de Puntos de Control Inmunológico , Neoplasias Gastrointestinales/tratamiento farmacológico , Humanos , Inmunoterapia/efectos adversos , Estudios Prospectivos , Estudios Retrospectivos , Estados Unidos , United States Food and Drug Administration
7.
Cancer ; 125(24): 4426-4434, 2019 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-31454426

RESUMEN

BACKGROUND: Although gemcitabine plus platinum chemotherapy is the established first-line regimen for advanced biliary cancer (ABC), there is no standard second-line therapy. This study evaluated current practice and outcomes for second-line chemotherapy in patients with ABC across 3 US academic medical centers. METHODS: Institutional registries were reviewed to identify patients who had received second-line chemotherapy for ABC from April 2010 to March 2015 along with their demographics, diagnoses and staging, treatment histories, and clinical outcomes. Overall survival from the initiation of second-line chemotherapy (OS2) was estimated with Kaplan-Meier methods. RESULTS: This study identified 198 patients with cholangiocarcinoma (intrahepatic [61.1%] or extrahepatic [14.1%]) or gallbladder carcinoma (24.8%); 52% received at least 3 lines of systemic chemotherapy. The median OS2 was 11 months (95% confidence interval [CI], 8.8-13.1 months). The median OS2 for patients with intrahepatic cholangiocarcinoma was 13.4 months (95% CI, 10.7-17.8 months), which was longer than that for patients with extrahepatic cholangiocarcinoma (6.8 months; 95% CI, 5-10.6 months) or gallbladder carcinoma (9.4 months; 95% CI, 7.2-12.3 months; P = .018). The median time to second-line treatment failure was 2.2 months (95% CI, 1.8-2.7 months), and it was similar across tumor locations (P = .60). CONCLUSIONS: In this large cohort of patients with ABC treated across 3 academic medical centers after the failure of first-line chemotherapy, the time to treatment failure on standard therapies was short, although the median OS2 was longer than has been reported previously, and more than half of the patients received additional lines of treatment. This multicenter collaboration represents the largest cohort studied to date of second-line chemotherapy for ABC and provides a contemporary benchmark for future clinical trials.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Biliar/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias del Sistema Biliar/diagnóstico , Neoplasias del Sistema Biliar/mortalidad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Retratamiento , Estudios Retrospectivos , Insuficiencia del Tratamiento , Resultado del Tratamiento , Adulto Joven
8.
Ann Surg Oncol ; 26(13): 4489-4497, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31418130

RESUMEN

BACKGROUND: There is considerable interest in a neoadjuvant approach for resectable pancreatic ductal adenocarcinoma (PDAC). This study evaluated perioperative gemcitabine + erlotinib (G+E) for resectable PDAC. METHODS: A multicenter, cooperative group, single-arm, phase II trial was conducted between April 2009 and November 2013 (ACOSOG Z5041). Patients with biopsy-confirmed PDAC in the pancreatic head without evidence of involvement of major mesenteric vessels (resectable) were eligible. Patients (n = 123) received an 8-week cycle of G+E before and after surgery. The primary endpoint was 2-year overall survival (OS), and secondary endpoints included toxicity, response, resection rate, and time to progression. Resectability was assessed retrospectively by central review. The study closed early due to slow accrual, and no formal hypothesis testing was performed. RESULTS: Overall, 114 patients were eligible, consented, and initiated protocol treatment. By central radiologic review, 97 (85%) of the 114 patients met the protocol-defined resectability criteria. Grade 3+ toxicity was reported in 60% and 79% of patients during the neoadjuvant phase and overall, respectively. Twenty-two of 114 (19%) patients did not proceed to surgery; 83 patients (73%) were successfully resected. R0 and R1 margins were obtained in 67 (81%) and 16 (19%) resected patients, respectively, and 54 patients completed postoperative G+E (65%). The 2-year OS rate for the entire cohort (n = 114) was 40% (95% confidence interval [CI] 31-50), with a median OS of 21.3 months (95% CI 17.2-25.9). The 2-year OS rate for resected patients (n = 83) was 52% (95% CI 41-63), with a median OS of 25.4 months (95% CI 21.8-29.6). CONCLUSIONS: For resectable PDAC, perioperative G+E is feasible. Further evaluation of neoadjuvant strategies in resectable PDAC is warranted with more active systemic regimens.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/cirugía , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/cirugía , Pancreaticoduodenectomía , Adulto , Anciano , Anciano de 80 o más Años , Terapia Combinada , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Clorhidrato de Erlotinib/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Gemcitabina
9.
Invest New Drugs ; 37(2): 315-322, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30191522

RESUMEN

Overexpression and cellular mis-localization of aurora kinase A (AURKA) in gastrointestinal cancers results in chromosomal instability, activation of multiple oncogenic pathways, and inhibition of pro-apoptotic signaling. Inhibition of AURKA causes mitotic delays, severe chromosome congression, and activation of p53/p73 leading to cell death. Our preclinical data showed cooperative activity with the AURKA inhibitor alisertib and platinum agents in cell lines and xenografts, and suggested an optimal treatment window. Therefore, this study was designed to determine the maximum-tolerated dose (MTD) of alisertib in combination with modified FOLFOX (mFOLFOX), as this is a standard platinum-based therapy for gastrointestinal cancers. Standard 3 + 3 dose escalation was used, where the starting dose of alisertib was 10 mg twice daily (Days 1-3), with leucovorin (400 mg/m2) and oxaliplatin (85 mg/m2) on Day 2 followed by continuous 46-h 5-FU (2400 mg/m2) infusion on Days 2-4 in 14-day cycles. Fourteen patients with advanced gastrointestinal cancers were enrolled and two doses explored; two patients were not evaluable for dose-limiting toxicity (DLT) and replaced. Two patients experienced DLTs at 20 mg of alisertib (Grade 3 fatigue (n = 2); Grade 3 nausea, vomiting, dehydration with hospitalization (n = 1)). MTD was 10 mg alisertib with 85 mg/m2 oxaliplatin and 2400 mg/m2 5-FU. Most frequent toxicities were nausea (57%), diarrhea, fatigue, neuropathy, and vomiting (43%), and anorexia and anemia (36%); most were Grade 1-2. One patient with colorectal cancer had a partial response of 12 evaluable patients, and four patients had stable disease. Alisertib in combination with mFOLFOX did not demonstrate unexpected side effects, but the regimen was only tolerable at the lowest dose investigated.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Aurora Quinasa A/antagonistas & inhibidores , Neoplasias Gastrointestinales/tratamiento farmacológico , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Azepinas/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Neoplasias Gastrointestinales/metabolismo , Neoplasias Gastrointestinales/patología , Humanos , Leucovorina/administración & dosificación , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Pronóstico , Pirimidinas/administración & dosificación , Tasa de Supervivencia , Distribución Tisular
10.
Invest New Drugs ; 36(3): 442-450, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-28990119

RESUMEN

Pancreatic adenocarcinoma remains a major therapeutic challenge, as the poor (<8%) 5-year survival rate has not improved over the last three decades. Our previous preclinical data showed cooperative attenuation of pancreatic tumor growth when dasatinib (Src inhibitor) was added to erlotinib (EGFR inhibitor) and gemcitabine. Thus, this study was designed to determine the maximum-tolerated dose of the triplet combination. Standard 3 + 3 dose escalation was used, starting with daily oral doses of 70 mg dasatinib and 100 mg erlotinib with gemcitabine on days 1, 8, and 15 (800 mg/m2) of a 28-day cycle (L0). Nineteen patients were enrolled, yet 18 evaluable for dose-limiting toxicities (DLTs). One DLT observed at L0, however dasatinib was reduced to 50 mg (L-1) given side effects observed in the first two patients. At L-1, a DLT occurred in 1/6 patients and dose was re-escalated to L0, where zero DLTs reported in next four patients. Dasatinib was escalated to 100 mg (L1) where 1/6 patients experienced a DLT. Although L1 was tolerable, dose escalation was stopped as investigators felt L1 was within the optimal therapeutic window. Most frequent toxicities were anemia (89%), elevated aspartate aminotransferase (79%), fatigue (79%), nausea (79%), elevated alanine aminotransferase (74%), lymphopenia (74%), leukopenia (74%), neutropenia (63%), and thrombocytopenia (63%), most Grade 1/2. Stable disease as best response was observed in 69% (9/13). Median progression-free and overall survival was 3.6 and 8 months, respectively. Dasatinib, erlotinib, and gemcitabine was safe with manageable side effects, and with encouraging preliminary clinical activity in advanced pancreatic cancer.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Familia-src Quinasas/antagonistas & inhibidores , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígeno CA-19-9/metabolismo , Desoxicitidina/efectos adversos , Desoxicitidina/uso terapéutico , Imagen de Difusión por Resonancia Magnética , Receptores ErbB/antagonistas & inhibidores , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/diagnóstico por imagen , Inhibidores de Proteínas Quinasas/efectos adversos , Gemcitabina
11.
Invest New Drugs ; 36(6): 1158, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30334109

RESUMEN

The authors would like to note that the investigator affiliations have been corrected to reflect the actual affiliations of each author. The authors would also like to note an amendment to the first name of the second author. Nilo Azad was changed to reflect the full name of the author, which is Nilofer S. Azad as shown above. The original article has been corrected.

12.
Invest New Drugs ; 35(4): 491-498, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28353122

RESUMEN

Background Targeting angiogenesis in advanced colorectal cancer (CRC) has been one of the many factors prolonging survival. Bevacizumab was the first agent to demonstrate this, but even after progression on bevacizumab, continued VEGF-inhibition continues to improve survival. Combining epidermal growth factor receptor monoclonal antibodies with standard frontline therapies have also improved clinical outcomes, yet the improved benefit is not observed in patients with mutant KRAS. Thus, an unmet medical need exists to develop additional therapeutic options for patients with KRAS mutant CRC. Methods Patients received the anti-angiogenic agent linifanib at the recommended phase II dose of 17.5 mg. Primary endpoint was objective response rate (ORR), with a goal of 10%. Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Simon's optimal two-stage design was used to assess futility. Linifanib was considered inactive if two or fewer patients among the first 30 achieved an objective response. Results Thirty patients were enrolled on study. Grade 3 treatment-related toxicities occurring in at least two patients were fatigue, hypertension, proteinuria, diarrhea, nausea, oral pain, vomiting, thrombocytopenia, and arthralgia. Although no responses were observed, 63.5% of patients achieved stable disease. The median PFS and OS were 4.7 months and 9.5 months, respectively. Stopping rules for lack of clinical efficacy led to study closure. Conclusion Despite observing zero responses, a majority of patients had stable disease and eight patients had stable disease lasting longer than 5 months. These results suggest that linifanib has some anti-tumor activity in KRAS mutant metastatic and refractory CRC.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Indazoles/uso terapéutico , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/genética , Adulto , Anciano , Inhibidores de la Angiogénesis/efectos adversos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos , Femenino , Humanos , Indazoles/efectos adversos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Masculino , Persona de Mediana Edad , Mutación , Compuestos de Fenilurea/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Tomografía Computarizada por Rayos X , Resultado del Tratamiento
13.
Invest New Drugs ; 35(1): 95-104, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27853997

RESUMEN

Advanced biliary tract cancers (ABTC) are among the deadliest malignancies with limited treatment options after progression on standard-of-care chemotherapy, which includes gemcitabine (GEM) and oxaliplatin (OX). The epidermal growth factor receptor inhibitor erlotinib has been explored in ABTC with modest efficacy. Erlotinib given continuously may antagonize the action of chemotherapy against cycling tumor cells, but pulsatile dosing of erlotinib with chemotherapy may improve efficacy. The purpose of this study was to assess the safety of pulsatile erlotinib with GEMOX. This was a single-institution phase Ib study that enrolled adult patients with unresectable or metastatic biliary tract, pancreas, duodenal, or ampullary carcinomas that have not received any prior treatment for their disease. Dose escalation followed a standard 3 + 3 design, and dose-limiting toxicities (DLTs) were any treatment-related, first course non-hematologic grade ≥ 3 toxicity, except nausea/vomiting, or grade 4 hematologic toxicity. A dose expansion cohort in ABTC was treated at the MTD. Twenty-eight patients were enrolled and 4 dose levels were explored. The MTD was erlotinib 150 mg + GEM 800 mg/m2 + OX 85 mg/m2. DLTs were diarrhea and anemia. Most frequent toxicities were nausea (78 %), fatigue (71 %), neuropathy (68 %), and diarrhea (61 %), predominantly grade 1-2. In the ABTC patients, the objective response and disease control rates were 29 % and 94 %, respectively, and median overall survival was 18 months. Erlotinib plus GEMOX was well tolerated. Encouraging anti-tumor activity was seen as evidenced by a high disease control rate and longer median OS than standard chemotherapy in the patients with ABTC.


Asunto(s)
Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias del Sistema Biliar/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Clorhidrato de Erlotinib/administración & dosificación , Compuestos Organoplatinos/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Biliar/genética , Neoplasias del Sistema Biliar/metabolismo , Cadherinas/metabolismo , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/uso terapéutico , Esquema de Medicación , Receptores ErbB/genética , Clorhidrato de Erlotinib/efectos adversos , Clorhidrato de Erlotinib/uso terapéutico , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mutación , Compuestos Organoplatinos/efectos adversos , Compuestos Organoplatinos/uso terapéutico , Oxaliplatino , Proteínas Proto-Oncogénicas p21(ras)/genética , Resultado del Tratamiento , Vimentina/metabolismo , Gemcitabina
14.
Curr Treat Options Oncol ; 18(11): 67, 2017 10 27.
Artículo en Inglés | MEDLINE | ID: mdl-29080006

RESUMEN

OPINION STATEMENT: Most patients with hepatocellular carcinoma present with intermediate to advanced disease, where curative therapies are no longer an option. These patients with intermediate to advanced disease represent a heterogeneous population with regard to tumor burden, liver function, and performance status. While the Barcelona Clinic Liver Cancer (BCLC) staging system offers guidelines for the management of these patients, strict adherence to these guidelines may limit treatment options for these patients. Several locoregional therapies exist for these patients, including conventional transarterial chemoembolization (cTACE), transarterial embolization (TAE), drug-eluting embolization (DEE), and radioembolization. Evidence is also emerging for the role of radiation therapy including most notably stereotactic body radiation therapy and proton therapy, although at the current time, clinical trial participation is encouraged. While cTACE is traditionally recommended for BCLC B disease, both cTACE and radioembolization are increasingly used for patients with intermediate disease, as well as in select patients with BCLC A and C disease. TAE and DEE are limited in their use currently, due to lack of clear survival benefits or clinical advantages over cTACE. While several studies have demonstrated similar OS between cTACE and radioembolization, radioembolization provides a longer time to progression and fewer toxicities compared to cTACE. This is particularly relevant in the setting of advanced BCLC B and early BCLC C disease, where patients may have limited reserve. Radioembolization also has additional roles as an alternative to ablation, inducing liver hypertrophy, treating patients with PVT, and downstaging lesions to transplant. Ongoing studies will further define the role of locoregional treatment potentially in combination with and in light of developments in systemic therapy.


Asunto(s)
Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Animales , Progresión de la Enfermedad , Humanos , Radiofármacos/administración & dosificación , Carga Tumoral/efectos de los fármacos
15.
Mol Cancer ; 14: 106, 2015 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-25987188

RESUMEN

Gastrointestinal (GI) cancers are a major cause of cancer-related deaths. During the last two decades, several studies have shown amplification and overexpression of Aurora kinase A (AURKA) in several GI malignancies. These studies demonstrated that AURKA not only plays a role in regulating cell cycle and mitosis, but also regulates a number of key oncogenic signaling pathways. Although AURKA inhibitors have moved to phase III clinical trials in lymphomas, there has been slower progress in GI cancers and solid tumors. Ongoing clinical trials testing AURKA inhibitors as a single agent or in combination with conventional chemotherapies are expected to provide important clinical information for targeting AURKA in GI cancers. It is, therefore, imperative to consider investigations of molecular determinants of response and resistance to this class of inhibitors. This will improve evaluation of the efficacy of these drugs and establish biomarker based strategies for enrollment into clinical trials, which hold the future direction for personalized cancer therapy. In this review, we will discuss the available data on AURKA in GI cancers. We will also summarize the major AURKA inhibitors that have been developed and tested in pre-clinical and clinical settings.


Asunto(s)
Aurora Quinasa A/metabolismo , Neoplasias Gastrointestinales/enzimología , Terapia Molecular Dirigida , Animales , Aurora Quinasa A/antagonistas & inhibidores , Ensayos Clínicos como Asunto , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/patología , Humanos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Transducción de Señal/efectos de los fármacos
16.
Invest New Drugs ; 33(1): 159-68, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25294187

RESUMEN

PURPOSE: This phase I study evaluated the safety, tolerability, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of tivantinib combined with sorafenib in patients with advanced solid tumors. MATERIALS AND METHODS: A standard 3 + 3 dose escalation design was used. At the RP2D, expansion cohorts in 5 tumor types could be enrolled. Pharmacogenetic and pharmacodynamic analysis were performed. RESULTS: Eighty-seven patients received the study treatment. The combination had no unexpected toxicities. The most common treatment-related adverse events (AE) were rash (40 %), diarrhea (38 %), and anorexia (33 %). The RP2D was tivantinib 360 mg BID and sorafenib 400 mg BID for all cancer histologies, except in hepatocellular carcinoma (HCC) patients tivantinib was 240 mg BID plus sorafenib 400 mg BID. The overall response rate was 12 % in all patients, 26 % in melanoma, 15 % in renal cell carcinoma (RCC), 10 % in HCC, and 0 % in other patients. Disease control rate (CR, PR and SD ≥8 weeks) was 58 % in all patients, 90 % in RCC, 65 % in HCC, 63 % in melanoma, 40 % in breast cancer, and 8 % in NSCLC patients. CONCLUSIONS: The combination treatment could be administered at full standard single-agent doses in all patients except those with HCC, where tivantinib was lowered to 240 mg BID. Preliminary evidence of anticancer activity was observed in patients with RCC, HCC, and melanoma, including patients refractory to sorafenib and/or other anti-VEGF pathway therapies. The combination treatment has therapeutic potential in treating a variety of solid tumors.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Citocromo P-450 CYP2C19/genética , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/genética , Neoplasias/metabolismo , Niacinamida/administración & dosificación , Niacinamida/efectos adversos , Niacinamida/análogos & derivados , Niacinamida/farmacocinética , Niacinamida/farmacología , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/efectos adversos , Compuestos de Fenilurea/farmacocinética , Compuestos de Fenilurea/farmacología , Polimorfismo Genético , Proteínas Proto-Oncogénicas c-met/metabolismo , Pirrolidinonas/administración & dosificación , Pirrolidinonas/efectos adversos , Pirrolidinonas/farmacocinética , Pirrolidinonas/farmacología , Quinolinas/administración & dosificación , Quinolinas/efectos adversos , Quinolinas/farmacocinética , Quinolinas/farmacología , Sorafenib , Resultado del Tratamiento , Adulto Joven
17.
Oncologist ; 19(6): 616-22, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24797823

RESUMEN

BACKGROUND: Oncogenic genetic alterations "drive" neoplastic cell proliferation. Small molecule inhibitors and antibodies are being developed that target an increasing number of these altered gene products. Next-generation sequencing (NGS) is a powerful tool to identify tumor-specific genetic changes. To determine the clinical impact of extensive genetic analysis, we reviewed our experience using a targeted NGS platform (FoundationOne) in advanced cancer patients. PATIENTS AND METHODS: We retrospectively assessed demographics, NGS results, and therapies received for patients undergoing targeted NGS (exonic sequencing of 236 genes and selective intronic sequencing from 19 genes) between April 2012 and August 2013. Coprimary endpoints were the percentage of patients with targeted therapy options uncovered by mutational profiling and the percentage who received genotype-directed therapy. RESULTS: Samples from 103 patients were tested, most frequently breast carcinoma (26%), head and neck cancers (23%), and melanoma (10%). Most patients (83%) were found to harbor potentially actionable genetic alterations, involving cell-cycle regulation (44%), phosphatidylinositol 3-kinase-AKT (31%), and mitogen-activated protein kinase (19%) pathways. With median follow-up of 4.1 months, 21% received genotype-directed treatments, most in clinical trials (61%), leading to significant benefit in several cases. The most common reasons for not receiving genotype-directed therapy were selection of standard therapy (35%) and clinical deterioration (13%). CONCLUSION: Mutational profiling using a targeted NGS panel identified potentially actionable alterations in a majority of advanced cancer patients. The assay identified additional therapeutic options and facilitated clinical trial enrollment. As time progresses, NGS results will be used to guide therapy in an increasing proportion of patients.


Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de Cabeza y Cuello/genética , Melanoma/genética , Proteínas de Neoplasias/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , Femenino , Neoplasias de Cabeza y Cuello/patología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Melanoma/patología , Persona de Mediana Edad , Estadificación de Neoplasias
18.
J Clin Oncol ; 42(15): 1830-1850, 2024 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-38502889

RESUMEN

PURPOSE: To update an evidence-based guideline to assist in clinical decision-making for patients with advanced hepatocellular carcinoma (HCC). METHODS: ASCO convened an Expert Panel to update the 2020 guideline on systemic therapy for HCC. The panel updated the systematic review to include randomized controlled trials (RCTs) published through October 2023 and updated recommendations. RESULTS: Ten new RCTs met the inclusion criteria and were added to the evidence base. RECOMMENDATIONS: Atezolizumab + bevacizumab (atezo + bev) or durvalumab + tremelimumab (durva + treme) may be offered first-line for patients with advanced HCC, Child-Pugh class A liver disease, and Eastern Cooperative Oncology Group performance status 0-1. Where there are contraindications to these therapies, sorafenib, lenvatinib, or durvalumab may be offered first-line. Following first-line treatment with atezo + bev, second-line therapy with a tyrosine kinase inhibitor (TKI), ramucirumab (for patients with alpha-fetoprotein [AFP] ≥400 ng/mL), durva + treme, or nivolumab + ipilimumab (nivo + ipi) may be recommended for appropriate candidates. Following first-line therapy with durva + treme, second-line therapy with a TKI is recommended. Following first-line treatment with sorafenib or lenvatinib, second-line therapy options include cabozantinib, regorafenib for patients who previously tolerated sorafenib, ramucirumab (AFP ≥400 ng/mL), nivo + ipi, or durvalumab; atezo + bev or durva + treme may be considered for patients who did not have access to these therapies in the first-line setting, and do not have contraindications. Pembrolizumab or nivolumab are also options for appropriate patients following sorafenib or lenvatinib. Third-line therapy may be considered in Child-Pugh class A patients with good PS, using one of the agents listed previously that has a nonidentical mechanism of action with previously received therapy. A cautious approach to systemic therapy is recommended for patients with Child-Pugh class B advanced HCC. Further guidance on choosing between options is included within the guideline.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto
19.
Curr Treat Options Oncol ; 14(3): 337-49, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23686724

RESUMEN

OPINION STATEMENT: Cancers of the biliary tree represent a rare group of diseases with a devastating impact on patients. Gallbladder cancer often is associated with cholelithiasis. Cholangiocarcinoma may arise in the setting of biliary inflammation, such as primary sclerosing cholangitis, but most commonly occurs in patients without a particular risk factor. Surgical removal of biliary cancer is essential for cure, but it is associated with a very high rate of recurrence and for many patients is not possible at the time of diagnosis. Although risk factors differ for each anatomic site, systemic treatment is generally similar. Various adjunctive therapies, such as radiation and embolization, have been investigated for biliary tract cancers with modest success and efforts are ongoing to understand how to optimize these tools. Retrospective series and pooled analysis suggest a benefit for adjuvant treatment following resection, but prospective data are limited. Ongoing and planned phase 3 trials should help to clarify the role of adjuvant chemotherapy and radiation. For advanced disease, chemotherapy improves quality of life and survival, and gemcitabine with cisplatin represents the standard of care. However, all patients ultimately progress on this therapy, so clinical trials of new and better agents are essential to expand the existing treatment options for patients.


Asunto(s)
Neoplasias del Sistema Biliar/terapia , Sistema Biliar/patología , Quimioterapia Adyuvante/métodos , Recurrencia Local de Neoplasia/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias del Sistema Biliar/patología , Quimioterapia Adyuvante/efectos adversos , Cisplatino/administración & dosificación , Ensayos Clínicos como Asunto , Ensayos Clínicos Fase III como Asunto , Terapia Combinada , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Humanos , Recurrencia Local de Neoplasia/patología , Estudios Retrospectivos , Gemcitabina
20.
Clin Adv Hematol Oncol ; 11(1): 28-34, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23416860

RESUMEN

Biliary tract cancers, although uncommon, are highly fatal malignancies. Current treatments fail to cure or control the majority of tumors. Given the complexity of the anatomy and the often aggressive nature of the disease, multidisciplinary treatment, including palliation, is often required. However, systemic therapy with cytotoxics and/or targeted agents is routinely the mainstay of treatment for patients with advanced biliary tract cancers, and new targets and agents provide hope for this disease. This article focuses on recent advances in the management of biliary tract cancers, with a special focus on the molecular basis for current therapeutic investigation in this disease.


Asunto(s)
Neoplasias del Sistema Biliar/terapia , Antineoplásicos/uso terapéutico , Neoplasias del Sistema Biliar/mortalidad , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Humanos , Trasplante de Hígado , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Terapia Neoadyuvante , Receptor ErbB-2/antagonistas & inhibidores
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