TS-1 in Combination With Calcium Folinate in Patients With Heavily Pre-treated mCRC
Ontology highlight
ABSTRACT:
DISEASE(S): Metastatic Colorectal Cancer,Colorectal Neoplasms
PROVIDER: 2272349 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Intro: Lymphatic filariasis (LF) is a neglected tropical disease caused by the nematode parasite Wuchereria bancrofti. The primary tool used by the Global Program to Eliminate LF is mass drug administration (MDA), and some 500 million people take the medications each year. Mild to moderate adverse events (AEs) are common after LF treatment, and these pose a challenge for the LF elimination program. To better understand the pathogenesis of AEs, we studied patients from a LF treatment trial in Côte d’Ivoire. Method: Total RNA was extracted from peripheral blood leukocytes collected before and 24h after treatment (when AEs peak). Global RNA sequencing was performed for 9 individuals with systemic moderate AEs and for 9 matched controls without AEs. Differential gene expression analysis (DESeq) identified transcriptional signatures (TS) associated with post-treatment AEs. Results: Out of the 36 sequenced samples, the 9 post-treatment samples from subjects with AEs had a distinct TS (P=0.006 by clustering analysis); 744 genes were significantly upregulated in this group (post vs pre-treatment, paired). These genes were enriched for many biological pathways that included pro-inflammatory pathways such as TLR and NF-kappa B signaling. Genes upregulated in AEs were also significantly enriched for having STAT1/2/3 transcription factor binding sites indicating the importance for interferons in the AEs pathogenesis.
2019-08-20 | GSE110146 | GEO
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2026-03-29 | GSE325923 | GEO
Project description:Purpose: Recurrent ovarian cancer (rOC) remains an unmet need. This first-in-human phase 1 trial evaluated GC203, an autologous tumor-infiltrating lymphocyte (TIL) product genetically modified via piggyBac transposon to overcome the immunosuppressive tumor microenvironment (TME). Patients and Methods: A cohort of 18 patients with rOC who were heavily pretreated (median, 3.5 prior lines of therapy) underwent lymphodepletion with cyclophosphamide and hydroxychloroquine, followed by GC203 infusion. The primary endpoints were safety and tolerability. Secondary endpoints, assessed in the full analysis set (FAS) using RECIST 1.1 guidelines, encompassed objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Exploratory analyses included the Morisita Overlap Index (MOI) to quantify T cell receptor (TCR) repertoire similarity between infused TILs and circulating T cells. Results: The GC203 regimen demonstrated a favorable safety profile. Treatment-related adverse events were primarily hematological, with grade≥3 lymphopenia and neutropenia each occurring in 57% of patients. All proved to be transient with a median resolution 7 days. The regimen achieved an unconfirmed ORR of 33.3% (6/18 patients) alongside a disease control rate (DCR) of 83.3%. Survival analyses revealed a median PFS of 7.2 months (95% CI: 1.0-13.4) and a median OS of 17.1 months (95% CI: 9.5-24.7). A key exploratory analysis identified the MOI as a significant predictor of treatment response, achieving an area under the curve (AUC) of 0.79. Conclusion: The GC203 regimen, combining piggyBac-mbIL-7 autologous TILs with anti-PD-1 antibody, demonstrates favorable safety and promising efficacy in heavily pretreated rOC, which supports its further development in this high-need population.
2026-05-20 | GSE331278 | GEO
Project description:Metastatic pancreatic cancer (mPC) has a dismal prognosis, with first line systemic therapy relying primarily on FOLFIRINOX (5FU/irinotecan/oxaliplatin) or AG (Gemcitabine/Nab-Paclitaxel). Therapeutic options for mPC refractory to these regimens remain poorly-defined, and data on later lines options are scare. This prospective, single-arm study (NCT05481463) evaluated the safety and preliminary efficacy of combining the anti-angiogenic agent surufatinib with the cytotoxic drug TAS-102 (Trifluridine/Tipiracil) in mPC patients who had progressed on ≥ 2 prior lines of therapy. Primary and secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Among 20 patients analyzed for efficacy, median PFS was 2.35 months (95% CI: 1.91-3.94) and median OS was 6.34 months (95% CI: 3.81-10.09). The ORR and DCR were 20% (4/20; all partial response) and 30% (6/20), respectively. All patients experienced treatment emergent adverse events (TEAEs), with anemia (59.1%), neutropenia (54.6%), leukopenia (50.0%), and lymphopenia (45.5%) as the most common any-grade events. Grade ≥3 TEAEs including neutropenia (31.8%), lymphopenia (13.6%), and anemia (9.1%), were observed in 50.0% (11/22) of patients. Subgroup analysis identified metastases involving > 2 organs or hepatic sites as potential predicative biomarkers for inferior efficacy. Proteomic screening revealed that overexpressed OCIAD2 correlated with poor prognosis, a finding validated in two publicly available external cohorts (CPTAC database and RuiJin cohort). In conclusion, combination of TAS-102 and surufatinib demonstrates clinically meaningful efficacy and manageable toxicity as a later line therapeutic option for refractory mPC. The biomarkers identified in this study may hold the potential to guide patient stratification and warrant further investigation to optimize precision application of this regimen.
2025-10-02 | PXD064308 | Pride
Project description:Purpose: To determine the 8-week disease control rate (DCR) of sorafenib monotherapy in patients with advanced non-small-cell lung cancer (NSCLC) in the BATTLE trial. Methods: Patients with pre-treated NSCLC consented to baseline biopsies for pre-specified biomarkers assessment and biomarker discovery. Sorafenib was given at 400 mg orally twice daily until tumor progression or unacceptable toxicity. Outcomes by pre-specified biomarkers were analyzed and a Sorafenib sensitivity signature developed using high-throughput gene expression profiles of NSCLC cell lines and baseline biopsies. Results: 105 patients were eligible and 98 patients were evaluable. Median age was 62 (range 34-81) years, 51% of patients were male, 75% were former/current smokers, and 89% had an ECOG performance status of 0-1. Median prior chemotherapies for stage IV NSCLC were two. Median follow-up was 9.4 (range: 1.3-32.2) months. Overall, 8-week DCR was 58.2%. Patients with EGFR mutations had significantly lower 8-week DCR compared to patients with wild-type tumors (23.1% vs. 64.2%, P=0.0119), and patients with K-RAS mutations had the highest 8-week DCR (67%). Most commonly reported treatment-related adverse events include hand-foot syndrome (59.6%), fatigue (42.3%), rash (40.4%), diarrhea (38.5%), and weight loss (38.5%). Sorafenib sensitivity signature developed in cell lines was associated with an improved outcome. Conclusion: Patients with wild-type EGFR, including those with K-RAS mutation, may benefit from sorafenib as opposed to patients with EGFR mutation. We identify a gene expression signature associated with an improved outcome in patients with wild-type EGFR treated with sorafenib. BATTLE-2 trial is ongoing to validate those results. ClinicalTrials.gov number, NCT00411671.
2014-06-01 | GSE31428 | GEO
Project description:Purpose: To determine the 8-week disease control rate (DCR) of sorafenib monotherapy in patients with advanced non-small-cell lung cancer (NSCLC) in the BATTLE trial. Methods: Patients with pre-treated NSCLC, ECOG performance status (PS) 0-2, consented to biopsies to test for biomarker assessment. Sorafenib was given at 400 mg orally twice daily until tumor progression or an unacceptable toxicity. Tumor evaluations were performed at baseline and every 8 weeks. Correlations of outcomes by biomarker groups were analyzed. Results: 105 patients were eligible and 98 patients were evaluable. Median age was 62 (range 34-81) years, 51% of patients were male, 75% were former/current smokers, and 89% had an ECOG PS of 0-1. Median prior chemotherapies for stage IV NSCLC were two. Median follow-up was 9.4 (range: 1.3-32.2) months. Eight-week DCRs by histology were 59.1%, 57.1%, and 55.6% for adenocarcinomas, squamous cell carcinomas and other histologies respectively. Patients with tumors harboring EGFR mutations had significantly lower 8-week DCR compared to patients with wild-type tumors (23.1% vs. 64.2%, P=0.0119), and patients with tumors harboring K-RAS mutations had the highest 8-week DCR (67%). Most commonly reported treatment-related adverse events include hand-foot syndrome (59.6%), fatigue (42.3%), rash (40.4%), diarrhea (38.5%), and weight loss (38.5%). Conclusion: 8-week DCR was better in patients treated with sorafenib who had EGFR wild-type tumors (including those with K-RAS mutations) when compared to those who had EGFR mutations. Additional analyses are warranted to further explore the biology of these tumors and related patient outcomes with sorafenib treatment. ClinicalTrials.gov number, NCT00411671.
2012-06-18 | GSE32036 | GEO
Project description:Sitravatinib is an immunomodulatory tyrosine kinase inhibitor that can improve responses when combined with immune checkpoint therapy (ICT). We conducted a phase I trial to determine the optimal dose of triplet therapy with sitravatinib plus nivolumab plus ipilimumab in 22 previously untreated patients with advanced clear cell renal cell carcinoma (ccRCC). The primary endpoint was safety. The addition of even a low sitravatinib dose of 35 mg daily to nivolumab 3 mg/kg and ipilimumab 1 mg/kg resulted in high frequency of immune-related adverse events (irAEs). Subsequent dose reduction of ipilimumab to 0.7 mg/kg in combination with nivolumab 3 mg/kg allowed safe escalation of sitravatinib up to 100 mg daily. Key secondary endpoints were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Overall, the triplet combination in the dose-finding setting achieved an ORR of 45.5%, DCR of 86.4%, and a median PFS of 14.5 months with 72.7% of patients alive after a median follow-up of 15.7 months. Single-cell RNA-seq performed in longitudinally collected tumor biopsies from 12 patients treated with the triplet therapy identified a tumor cell-specific epithelial-mesenchymal transition (EMT)-like program associated with treatment resistance and poor outcomes in patients of this trial and in patients of the TCGA ccRCC cohort. Within the tumor microenvironment (TME), the emergence of treatment resistance was characterized by a transition from cytotoxic to exhausted T cell state and enrichment for M2-like myeloid cells. The observed changes in gene expression dynamics and cellular states in tumor cell and TME may help inform future strategies to optimize ICT efficacy.
2024-11-26 | GSE264586 | GEO