RESUMEN
BACKGROUND: Fibroblast growth factor receptor (FGFR) 2 is overexpressed in several tumor types, including triple-negative breast cancer and gastric cancer, both of which have a high unmet medical need. Aprutumab ixadotin (BAY 1187982) is the first antibody-drug conjugate (ADC) to target FGFR2 and the first to use a novel auristatin-based payload. OBJECTIVE: This first-in-human trial was conducted to determine the safety, tolerability, and maximum tolerated dose (MTD) of aprutumab ixadotin in patients with advanced solid tumors from cancer indications known to be FGFR2-positive. PATIENTS AND METHODS: In this open-label, multicenter, phase I dose-escalation trial (NCT02368951), patients with advanced solid tumors received escalating doses of aprutumab ixadotin (starting at 0.1 mg/kg body weight), administered intravenously on day 1 of every 21-day cycle. Primary endpoints included safety, tolerability, and the MTD of aprutumab ixadotin; secondary endpoints were pharmacokinetic evaluation and tumor response to aprutumab ixadotin. RESULTS: Twenty patients received aprutumab ixadotin across five cohorts, at doses of 0.1-1.3 mg/kg. The most common grade ≥ 3 drug-related adverse events were anemia, aspartate aminotransferase increase, proteinuria, and thrombocytopenia. Dose-limiting toxicities were thrombocytopenia, proteinuria, and corneal epithelial microcysts, and were only seen in the two highest dosing cohorts. The MTD was determined to be 0.2 mg/kg due to lack of quantitative data following discontinuations at 0.4 and 0.8 mg/kg doses. One patient had stable disease; no responses were reported. CONCLUSIONS: Aprutumab ixadotin was poorly tolerated, with an MTD found to be below the therapeutic threshold estimated preclinically; therefore, the trial was terminated early. CLINICALTRIALS. GOV IDENTIFIER: NCT02368951.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Colangiocarcinoma/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Inmunoconjugados/uso terapéutico , Oligopéptidos/uso terapéutico , Adulto , Anciano , Terminación Anticipada de los Ensayos Clínicos , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Estadificación de Neoplasias , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/inmunología , Insuficiencia del Tratamiento , Adulto JovenRESUMEN
We report an 86-year-old patient successfully treated by multimodality treatment for advanced pancreatic cancer with synchronous multiple liver metastases and liver dysfunction. Systemic chemotherapy(SC)(gemcitabine[GEM]1 g and 5-FU 1 g biweekly)was initiated. Two weeks after, the radiation therapy(55 Gy/25 days)was added. Three weeks after, the short period's high dose hepatic artery infusion(SPHDHAI)(5-FU[1 g]×3 days: 1 day rest: 5-FU[1 g]×3 days)was started. By these treatments, liver dysfunction was completely improved and abdominal pain was disappeared. After 2 times of weekly high dose hepatic artery infusion(WHDHAI)(5-FU 1,500mg), the mixed chemotherapy(MC)(GEM 800 mg[systemic] and 5-FU 1,500 mg hepatic artery infusion:[HAI]biweekly)were started. She could live without admission for about 1 year. About 13 months after lung metastases was appeared and she died about 19 months after first chemotherapy. Our multimodality treatment(systemic and HAI therapy and radiation)was effective for keeping patient quality of life and for improving the survival even if the patient was a very old age and showed liver dysfunction.
Asunto(s)
Neoplasias Hepáticas , Neoplasias Pancreáticas , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Fluorouracilo/administración & dosificación , Arteria Hepática , Humanos , Infusiones Intraarteriales , Neoplasias Hepáticas/secundario , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/terapia , Calidad de VidaRESUMEN
The patient was a 73-year-old woman who underwent distalpancreatectomy for pancreas tailcancer (T3, N0, M0, stage III ). Hepatic arterialinfusion(HAI)using high-dose 5-fluorouracil(5-FU)(6,000mg/week)was performed 35 days after curative resection to prevent liver metastases. Although chemotherapy with gemcitabine(GEM)was administered for 2 weeks, the patient was aware of a nodule(1 cm in diameter)on the right lower quadrant of the abdomen. Resection of the cutaneous mass was performed and histological findings revealed metastatic adenocarcinoma from the pancreas cancer. Six courses of chemotherapy with GEM were administered as adjuvant therapy. Two years after the treatment with GEM, neurological symptoms appeared, and computed tomography(CT)and magnetic resonance imaging(MRI)revealed a solitary metastatic thalamus tumor(2 cm in diameter). After stereotactic radiotherapy, the patient was transferred to a different hospitalfor physicaltherapy. Herein, we report on a case of 2 year recurrence free survivalafter the resection of a cutaneous metastasis from pancreatic cancer.
Asunto(s)
Adenocarcinoma/secundario , Adenocarcinoma/terapia , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/terapia , Neoplasias Cutáneas/secundario , Anciano , Antimetabolitos Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundario , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Femenino , Humanos , Recurrencia , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/cirugía , Tálamo/patología , Factores de Tiempo , GemcitabinaRESUMEN
The patient was an 83-year-old man who underwent distal gastrectomy for gastric cancer (T3, N1, M0, P0, M0, stage â ¡B) at a different hospital from ours. A metastatic lesion was detected in the liver 5 months after gastrectomy. Although chemotherapy with S-1 or bi-weekly CPT-11 was administered for 6 months, the liver tumor increased in size. The patient was referred to our hospital for treatment of the liver metastasis. Abdominal-computed tomography (CT) and magnetic resonance imaging (MRI) revealed a solitary metastatic liver tumor (9 cm in diameter: S7/S6/S8) with a hypervascular tumor stain. Transcatheter arterial chemoembolization (TACE) using degradable starch microspheres (DSM) plus mitomycin C, and hepatic arterial infusion (HAI) using high-dose 5-fluorouracil (5-FU) (6,000 mg/week), were performed 54 days before curative resection of the liver (S6+S7+S8+S5b/c). Histological findings revealed metastatic adenocarcinoma with a tumor thrombus in the posterior branch of the portal vein. The patient was treated with 2 courses of adjuvant chemotherapy with paclitaxel. No recurrence was observed 8 months after hepatectomy. This case suggests that combined treatment with TACE/HAI as a multimodal treatment might be effective in the management of hypervascular liver metastasis from gastric cancer.
Asunto(s)
Neoplasias Hepáticas/terapia , Neoplasias Gástricas/patología , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Quimioembolización Terapéutica , Terapia Combinada , Fluorouracilo/administración & dosificación , Gastrectomía , Hepatectomía , Humanos , Infusiones Intraarteriales , Irinotecán , Neoplasias Hepáticas/secundario , Masculino , Neoplasias Gástricas/terapiaRESUMEN
A 58-year-old woman was suffering from abdominal pain due to large liver metastases(LM)and lung metastasis from sigmoid colon cancer. After laparoscopic sigmoidectomy, three 6 g/wk high dose hepatic arterial infusions(HDHAI)of5 - fluorouracil (5-FU) were administered and the tumor decreased in size. Unfortunately, the patient had an infectious pseudoaneurysm at the site of puncture. She was given a drainage and femoro-femoral(F-F)bypass. At last, a hepatectomy, radiofrequency ablation(RFA), and catheter insertion from gastroepiploic artery, were performed successfully. Subsequently, she received a half HDHAI and several systemic chemotherapy drugs. However, residual liver metastases developed thrice and we operated on all of them. Finally, when the hepatic arterial infusion(HAI)catheter became unavailable, we only continued the systemic therapy (Erbitux+FOLFIRI). However, inoperable residual liver metastases(maximum 13 cm in size)occurred. We chose to administer hepatic transarterial embolization(TAE)therapy 3 times. From the second time, we performed TAE from the right subphrenic artery and in the third time, we added 1-day HAI therapy. Finally, the tumor size decreased(maximum 9 cm). The patient is still an outpatient 5 years after the first HDHAI.
Asunto(s)
Neoplasias Hepáticas/terapia , Neoplasias del Colon Sigmoide/patología , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/uso terapéutico , Ablación por Catéter , Terapia Combinada , Embolización Terapéutica , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/uso terapéutico , Hepatectomía , Arteria Hepática , Humanos , Infusiones Intraarteriales , Neoplasias Hepáticas/secundario , Persona de Mediana Edad , Neoplasias del Colon Sigmoide/terapiaRESUMEN
OBJECTIVES: Unsatisfactory efficacy of current treatments for advanced lung cancer has prompted the search for new therapies, with sorafenib, a multikinase inhibitor, being one candidate drug. This phase I trial was conducted to evaluate drug safety and pharmacokinetics as well as tumor response of sorafenib in combination with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Eligible patients received paclitaxel (200 mg/m(2)) and carboplatin (area under the curve [AUC]of 6 mg min mL(-1)) on day 1 and sorafenib (400 mg, twice daily) on days 2 through 19 of a 21-day cycle. RESULTS: Four of the initial six patients (cohort 1) experienced dose-limiting toxicities (DLTs), resulting in amendment of the treatment protocol. An additional seven patients (cohort 2) were enrolled, two of whom developed DLTs. DLTs included erythema multiforme, hand-foot skin reaction, and elevated plasma alanine aminotransferase in cohort 1 as well as gastrointestinal perforation at a site of metastasis and pneumonia in cohort 2. Most adverse events were manageable. One complete and six partial responses were observed among the 12 evaluable patients. Coadministration of the three drugs had no impact on their respective pharmacokinetics. CONCLUSION: The present study confirmed that sorafenib at 400 mg once daily in combination with carboplatin AUC 5 mg min mL(-1) and paclitaxel 200 mg/m(2) is feasible in Japanese patients with advanced NSCLC. The results of this study also showed that this combination therapy had encouraging antitumor activity and was not associated with relevant pharmacokinetic interaction in Japanese NSCLC patients.
Asunto(s)
Bencenosulfonatos/farmacocinética , Bencenosulfonatos/uso terapéutico , Carboplatino/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Paclitaxel/uso terapéutico , Piridinas/farmacocinética , Piridinas/uso terapéutico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencenosulfonatos/administración & dosificación , Bencenosulfonatos/efectos adversos , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Carboplatino/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Demografía , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Niacinamida/análogos & derivados , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Paclitaxel/farmacocinética , Compuestos de Fenilurea , Piridinas/administración & dosificación , Piridinas/efectos adversos , Radiografía , Sorafenib , Resultado del TratamientoRESUMEN
A 63-year-old man admitted to emergency center of our hospital with fever and obstructive jaundice. Computed tomography (CT) showed a mass in the head of the pancreas and a dilated bile duct. After performing preoperative biliary drainage, we conducted pancreatico-duodenectomy (PD-II: T3, N1, stage III). As adjuvant chemotherapy, the patient received a hepatic arterial infusion with 5-FU to prevent liver metastasis. A catheter was placed in the right femoral artery and intra-arterial chemotherapy was carried out for one week. After the completion of chemotherapy, swelling and redness of the right inguinal region was observed. CT revealed an infected pseudo-aneurysm of the femoral artery. Despite intravenous antibiotic therapy for 2 days, bleeding and pus discharge at the catheter root were observed. He immediately underwent drainage and primary suture to stop the bleeding. Two weeks after surgery for the infected pseudo-aneurysm, a right external iliac-femoral bypass operation was performed. Five weeks after surgery, he was discharged without further incident. In such cases, it is advisable to drain the infected pseudo-aneurysm following a prompt diagnosis, and perform a secondary bypass operation.