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EORTC Early Clinical Studies Group early phase II trial of S-1 in patients with advanced or metastatic colorectal cancer.

ABSTRACT: Cancer of the colon and rectum is one of the most frequent malignancies both in the US and Europe. Standard palliative therapy is based on 5-fluorouracil/folinic acid combinations, with or without oxaliplatin or irinotecan, given intravenously. Oral medication has the advantage of greater patient convenience and acceptance and potential cost savings. S-1 is a new oral fluorinated pyrimidine derivative. In a nonrandomized phase II study, patients with advanced/metastatic colorectal cancer were treated with S-1 at 40 mg m-2 b.i.d. for 28 consecutive days, repeated every 5 weeks, but by amendment the dose was reduced to 35 mg m-2 during the study because of a higher than expected number of severe adverse drug reactions. In total 47 patients with colorectal cancer were included. In the 37 evaluable patients there were nine partial responses (24%), 17 stable diseases (46%) and 11 patients had progressive disease (30%). Diarrhoea occurred frequently and was often severe: in the 40 and 35 mg m-2 group, respectively, 38 and 35% of the patients experienced grade 3-4 diarrhoea. The other toxicities were limited and manageable. S-1 is active in advanced colorectal cancer, but in order to establish a safer dose the drug should be subject to further investigations.

SUBMITTER: Van den Brande J

PROVIDER: S-EPMC2376342 | biostudies-other | 2003 Mar

REPOSITORIES: biostudies-other

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Project description:Abstract BACKGROUND EORTC study 26091 showed that addition of bevacizumab (BEV) to temozolomide (TMZ) does not improve overall survival (OS) or progression-free survival (PFS) in recurrent grade II and III 1p/19q intact gliomas; regardless of isocitrate dehydrogenase (IDH) mutational status. This abstract reports the neurocognitive functioning (NCF) outcomes. METHODS NCF was evaluated before randomization and at every 12 weeks during treatment using Hopkins Verbal Learning Test (Free Recall, Delayed Recall, and Delayed Recognition), Trail Making Test (TMT A/B); and Controlled Oral Word Association Test (COWA). RESULTS 148/155 patients had at least one NCF assessment. Compliance was 91.5% at baseline and dropped to 61.9% at week 60. Primary analysis (at 5% significance level) compared NCF at the last disease assessment before or at week 60 in patients who had at least one NCF assessment after baseline. Patients in the temozolomide+bevacizumab arm did not differ from patients in the temozolomide only arm. Except for Delayed Recognition, all NCF outcomes were positively associated with WHO performance status. TMT A (p=0.03), TMT B (p=0.006) and COWA (p<0.0001) were significantly worse in patients receiving steroids at study entry. Furthermore, delayed recognition was worse in patients with larger tumors (>26.5 vs <=26.5 mm; p=0.04). Memory performance was poorer in patients with tumors in the left hemisphere (Free Recall; p=0.0002), Delayed Recall; p<0.0001, Delayed Recognition; p=0.004). Except for Free Recall and Delayed Recognition, all other baseline raw scores were associated with OS in univariate analyses. In a multivariate Cox regression model, TMT B and tumor size were identified as independent OS prognostic factors while baseline WHO performance status and steroids use were not included. CONCLUSION At the group level patients in the temozolomide+bevacizumab arm do not differ from patients with temozolomide only, individual patients’ verbal memory capacity might negatively be affected by tumor volume and tumor location.

Project description:ImportanceTreatment options for patients with unresectable and/or metastatic dedifferentiated liposarcoma (DDLPS) are limited. New drugs are required.ObjectiveTo assess whether cabazitaxel demonstrated sufficient antitumor activity in patients with metastatic or inoperable locally advanced DDLPS to justify further investigation in a phase 3 setting.Design, setting, and participantsThis international multicenter, open-label single-arm phase 2 trial was conducted at 10 institutions in 4 European countries from March 2015 to March 2019. Eligible patients had to have metastatic or locally advanced histologically proven DDLPS with evidence of disease progression within the past 6 months and had to have received no more than 1 previous line of chemotherapy.InterventionsAfter mandatory central review of tumor blocks, if the DDLPS diagnosis was confirmed, patients started treatment within 72 hours after registration. Cabazitaxel was administered at a dose of 25 mg/m2 IV infusion over 1 hour every 21 days until intolerance, progression, or withdrawal of consent.Main outcomes and measuresThe primary end point was progression-free survival (PFS) rate at 12 weeks per RECIST 1.1. Based on a Simon 2-stage design, at least 4 of 17 (stage 1) and 11 of 37 (stage 2) eligible and evaluable patients who were progression free at 12 weeks were needed. The final analysis report was completed on November 17, 2021.ResultsForty patients were registered, with 2 patients being ineligible. The number of cycles ranged from 1 to 30, with a median of 5; 26 patients (65%) received at least 4 cycles of cabazitaxel. Progression-free survival at 12 weeks was 55%, achieving the primary study end point. At a median follow-up of 21.6 months, median PFS was 6 months and median OS 21 months. Response rate (RR) was 8% with 1 clinical response (CR) and 2 partial responses (PR). Twenty-three (60.5%) patients had a stable disease (SD). Disease control (PR+SD) was achieved in 26 patients (68%).Conclusions and relevanceThis nonrandomized phase 2 clinical trial met its primary end point, with 21 of 38 patients (55%) being progression free at 12 weeks. These results suggest important activity of cabazitaxel in patients with metastatic or inoperable locally advanced DDLPS. The drug is worth being further studied in these tumors in a phase 3 setting.

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EORTC Early Clinical Studies Group early phase II trial of S-1 in patients with advanced or metastatic colorectal cancer.

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