11 research outputs found
Phase I clinical and pharmacokinetic study of sorafenib in combination with carboplatin and paclitaxel in patients with advanced nonâsmall cell lung cancer
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/m2) and carboplatin (area under the curve [AUC]of 6 mg min mLâ1) 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 mLâ1 and paclitaxel 200 mg/m2 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
Vesicocutaneous fistula formation during treatment with sunitinib malate: Case report
<p>Abstract</p> <p>Background</p> <p>The oral multi-kinase inhibitor sunitinib malate improves the survival of patients with gastrointestinal stromal tumors (GIST) after the disease progresses or intolerance to imatinib mesylate develops. Urinary fistulae arising during treatment with sunitinib for GIST have not been described.</p> <p>Case presentation</p> <p>We describe a 62-year-old female patient diagnosed with unresectable GIST that involved the abdominal wall, urinary bladder wall, bowel, mesentery and peritoneum in the pelvic cavity. Intestinocutaneous fistulae developed on a surgical lesion after orally administered imatinib was supplemented by an arterial infusion of 5-flurouracil. Sunitinib was started after the patient developed resistance to imatinib. On day 4 of the fourth course of sunitinib, a widely dilated cutaneous fistula discharged large amounts of fluid accompanied by severe abdominal pain. Urinary communication was indicated based on the results of an intravenous injection of indigo carmine. Computed tomography findings suggested a small opening on the anterior urinary bladder wall and fistulous communication between the bladder and abdominal walls bridged by a subcutaneous cavity. The fistula closed and the amount of discharge decreased when sunitinib was discontinued. Therefore, sunitinib might have been associated with the development of the vesicocutaneous fistula in our patient.</p> <p>Conclusion</p> <p>This is the first description of a vesicocutaneous fistula forming while under sunitinib treatment. Clinicians should be aware of the possible complication of vesicocutaneous fistula formation during treatment with molecular targeting agents in patients with extravesical invasion and peritoneal dissemination of GIST.</p
Phase II study of IRInotecan treatment after COmbined chemoâimmunotherapy for extensiveâstage small cell lung cancer: Protocol of IRICO study
Abstract Introduction Combined treatment using antiâprogrammed deathâligand 1 antibody (antiâPDâL1) and platinumâetoposide is the current standard firstâline treatment for patients with extensiveâstage (ES) small cell lung cancer (SCLC). However, the best treatment for relapsed ESâSCLC after the firstâline treatment remains unclear. There are some approved chemotherapeutic agents that can be used against ESâSCLC, and treatment with irinotecan is well established as both a monotherapy and a combined therapy, in combination with platinum. Therefore, we conduct a phase II study with irinotecan in the secondâ or laterâline setting for patients with ESâSCLC who have been previously treated with combined treatment. Methods Our study will enroll total 30 patients who are diagnosed with ESâSCLC and have experienced disease progression after the combined treatment. Patients will receive irinotecan on days 1, 8, and 15, which will be repeated every 4âweeks. Doses of irinotecan (100/80/60âmg/m2) will be determined according to the type of UGT1A1 gene polymorphism, and the treatment will be discontinued following disease progression, intolerance, withdrawal of patient consent, and based on the investigator's decision. The primary endpoint of the study is the response rate, and the secondary endpoints are overall survival, progressionâfree survival, and safety. Discussion Since the present firstâline treatment has been changed to the combined treatment, the secondâ or laterâline treatment should be reâevaluated for patients with relapsed SCLC. Irinotecan is a major chemotherapeutic agent used for SCLC. This study demonstrates and reâevaluates the clinical benefits of irinotecan after combined treatment with antiâPDâL1 and platinumâetoposide for patients with ESâSCLC. Registration details This study was registered in the Japan Registry of Clinical Trials (no. jRCT s071210090) on November 4, 2021
High Incidence of C797S Mutation in Patients With Long Treatment History of EGFR Tyrosine Kinase Inhibitors Including Osimertinib
Introduction: Although treatment with osimertinib confers survival benefits in patients with lung cancer with the EGFR T790M mutation, the mechanism of acquired resistance to osimertinib remains poorly understood. We conducted a prospective observational study to identify the mechanism on the basis of repeated tissue biopsies. Methods: Patients with EGFR-mutated advanced lung cancer with a T790M mutation detected on a tissue biopsy underwent a rebiopsy after developing acquired resistance to osimertinib. Nucleic acids extracted from the biopsy samples were subjected to targeted resequencing (Oncomine Comprehensive Assay), and circulating cell-free DNA (ccfDNA) was analyzed by CAncer Personalized Profiling by deep Sequencing (AVENIO ctDNA Surveillance Kit). Results: Between November 2016 and March 2020, a total of 87 patients were screened. Among them, 44 developed acquired resistance. Of these, 19 samples from rebiopsies and 12 from preosimertinib biopsies were able to be analyzed by an Oncomine Comprehensive Assay. A ccfDNA analysis was performed in 16 patients. Regarding the mechanisms of acquired resistance, structural change in EGFR, namely, C797S, G796S, or L792V, was the most frequent alteration, being observed in 57.9% of the cases. MET gain was observed in 31.6% of the cases, and gains in cell cycle genes were observed in 26.3% of the cases. In addition, we identified GAS6 gain and an ATM mutation in a patient with small-cell transformation and a BRAF V600E mutation in a patient with oligoprogressive disease. Conclusions: A repeated tissue biopsy and a ccfDNA analysis were useful in analyzing the mechanisms underlying acquired resistance. A long treatment history of EGFR TKIs may result in a high percentage of EGFR structural change