AN OPEN-LABEL, MULTICENTER, RANDOMIZED PHASE III STUDY OF SECOND-LINE CHEMOTHERAPY WITH OR WITHOUT BEVACIZUMAB IN METASTATIC COLORECTAL CANCER PATIENTS WHO HAVE RECEIVED FIRST-LINE CHEMOTHERAPY PLUS BEVACIZUMAB
Ontology highlight
ABSTRACT:
DISEASE(S): Metastatic Colorectal Cancer Patients,Colorectal Cancer Metastatic
PROVIDER: 2542918 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Purpose: This phase II study evaluated the efficacy and tolerability of onvansertib, a polo-like kinase 1 (PLK1) inhibitor, combined with FOLFIRI + bevacizumab for the second-line treatment of KRAS-mutant metastatic colorectal cancer (mCRC). Patients and Methods: This multicenter, open-label, single-arm study enrolled KRAS-mutated mCRC patients previously treated with oxaliplatin and 5-fluorouracil with or without bevacizumab. Patients received onvansertib 15 mg/m2 (days 1-5 and 15-19 of a 28-day cycle) and FOLFIRI + bevacizumab (days 1 and 15). The primary endpoint was the objective response rate (ORR), and secondary endpoints included progression-free survival (PFS), duration of response (DOR), and tolerability. Translational and preclinical studies were conducted in KRAS-mutant CRC. Results: Among the 53 patients treated, the confirmed ORR was 26.4% (95% CI, 15.3 to 40.3). The median DOR was 11.7 months (95% CI, 9.4 to not reached). Grade 3/4 adverse events were reported in 62% of patients. A post hoc analysis revealed that patients with no prior bevacizumab treatment had a significantly higher ORR and longer PFS compared to patients with prior bevacizumab treatment: ORR of 76.9% versus 10.0% (odds ratio of 30.0, p<0.001) and median PFS of 14.9 months versus 6.6 months (hazard ratio of 0.16, p<0.001). Our translational findings support that prior bevacizumab exposure contributes to onvansertib resistance. Preclinically, we showed that onvansertib inhibited the hypoxia pathway and exhibited robust antitumor activity in combination with bevacizumab through the inhibition of angiogenesis. Conclusion: Onvansertib combined with FOLFIRI + bevacizumab showed significant activity in the second-line treatment of KRAS-mutant mCRC patients, particularly in patients with no prior bevacizumab treatment. These findings led to the evaluation of the combination in the first line setting (ClinicalTrails.gov identifier: NCT06106308).
2025-11-25 | GSE273769 | GEO
Project description:<p>Neoadjuvant chemotherapy (NAC) for breast cancer is widely employed. We performed genome-wide association studies (GWAS) to determine if germline genetic variability was associated with benefits, in terms of pathological complete response (pCR), disease-free survival (DFS), and overall survival (OS), in patients entered on the NSABP B-40 NAC (National Surgical Adjuvant Breast and Bowel Project, B-40, Neoadjuvant Chemotherapy) trial where some patients were randomized to receive bevacizumab, in addition to chemotherapy. </p>
| phs001365 | dbGaP
Project description:Background. Bevacizumab, an antibody neutralizing Vascular Endothelial Growth Factor (VEGF), is licensed for the management of patients with advanced colon cancer. However, tumor biomarkers identifying the molecular tumor subsets most amenable to angiogenesis modulation are lacking. Patients and Methods. We profiled expession of 24526 genes by means of whole genome 24K DASL (c-DNA-mediated, Annealing, Selection and Ligation) arrays, (Illumina, CA) in 16 bevacizumab-treated patients with advanced colon cancer (Test set). Genes with correlation to 8-month Progression-free status were studied by means of qPCR in two independent colon cancer cohorts: 49 patients treated with bevacizumab+chemotherapy (Bevacizumab qPCR set) and 72 patients treated with chemotherapy only (Control qPCR set). Endpoints were best tumor response before metastasectomy (ORR) and progression-free survival (PFS). Results. Five genes were significantly correlated to 8-month progression-free status in the Test set: overexpression of KLF12 and downregulation of AGR2, ALDH6A1, MCM5, TFF2. In the two independent datasets, irinotecan- or oxaliplatin-based chemotherapy was administered as first-line treatment and metastasectomies were subsequently applied in 8-14% of patients. No prognostically significant gene classifier encompassing all five genes could be validated in the Bevacizumab or Control qPCR sets. The complex gene expression profile of all-low tumor (ALDH6A1+TFF2+MCM5) was strongly associated with ORR in the Bevacizumab qPCR set (ORR 85.7%, p=0.007), but not in the Control set (ORR 36.4%, p=0.747). The Odds Ratio for response for the all-low tumor (ALDH6A1+TFF2+MCM5) profile versus any other ALDH6A1+TFF2+MCM5 profile was 15 (p=0.018) in the Bevacizumab qPCR set but only 0.72 (p=0.63) in the Control set. The tumor expression profile of (KLF12-high+TFF2-low) was significantly associated with PFS only in the Bevacizumab qPCR set: bevacizumab-treated patients with (KLF12-high + TFF2-low) tumors had superior PFS (median 14 months, 95% CI 2-21) compared to patients with any other (KLF12+TFF2) expression profile (median PFS 7 months, 95% CI 5-10, p=0.021). The Hazard Ratio for disease progression for (KLF12-high + TFF2-low) versus any other KLF12+TFF2 expression profile was 2.92 (p=0.03) in the Validation and 1.29 (p=0.39) in the Control set. Conclusions. Our <three-stage> hypothesis-generating study failed to validate the prognostic significance of a five-gene classifier in mCRC patients. Exploratory analyses suggest two gene signatures that are potentially associated with bevazicumab benefit in patients with advanced colon cancer. 18 tumor tissue samples were analysed, no replicates
2013-12-18 | E-GEOD-53127 | biostudies-arrayexpress
Project description:Background. Bevacizumab, an antibody neutralizing Vascular Endothelial Growth Factor (VEGF), is licensed for the management of patients with advanced colon cancer. However, tumor biomarkers identifying the molecular tumor subsets most amenable to angiogenesis modulation are lacking. Patients and Methods. We profiled expession of 24526 genes by means of whole genome 24K DASL (c-DNA-mediated, Annealing, Selection and Ligation) arrays, (Illumina, CA) in 16 bevacizumab-treated patients with advanced colon cancer (Test set). Genes with correlation to 8-month Progression-free status were studied by means of qPCR in two independent colon cancer cohorts: 49 patients treated with bevacizumab+chemotherapy (Bevacizumab qPCR set) and 72 patients treated with chemotherapy only (Control qPCR set). Endpoints were best tumor response before metastasectomy (ORR) and progression-free survival (PFS). Results. Five genes were significantly correlated to 8-month progression-free status in the Test set: overexpression of KLF12 and downregulation of AGR2, ALDH6A1, MCM5, TFF2. In the two independent datasets, irinotecan- or oxaliplatin-based chemotherapy was administered as first-line treatment and metastasectomies were subsequently applied in 8-14% of patients. No prognostically significant gene classifier encompassing all five genes could be validated in the Bevacizumab or Control qPCR sets. The complex gene expression profile of all-low tumor (ALDH6A1+TFF2+MCM5) was strongly associated with ORR in the Bevacizumab qPCR set (ORR 85.7%, p=0.007), but not in the Control set (ORR 36.4%, p=0.747). The Odds Ratio for response for the all-low tumor (ALDH6A1+TFF2+MCM5) profile versus any other ALDH6A1+TFF2+MCM5 profile was 15 (p=0.018) in the Bevacizumab qPCR set but only 0.72 (p=0.63) in the Control set. The tumor expression profile of (KLF12-high+TFF2-low) was significantly associated with PFS only in the Bevacizumab qPCR set: bevacizumab-treated patients with (KLF12-high + TFF2-low) tumors had superior PFS (median 14 months, 95% CI 2-21) compared to patients with any other (KLF12+TFF2) expression profile (median PFS 7 months, 95% CI 5-10, p=0.021). The Hazard Ratio for disease progression for (KLF12-high + TFF2-low) versus any other KLF12+TFF2 expression profile was 2.92 (p=0.03) in the Validation and 1.29 (p=0.39) in the Control set. Conclusions. Our <three-stage> hypothesis-generating study failed to validate the prognostic significance of a five-gene classifier in mCRC patients. Exploratory analyses suggest two gene signatures that are potentially associated with bevazicumab benefit in patients with advanced colon cancer.
2013-12-18 | GSE53127 | GEO
Project description:The AVAglio and RTOG-0825 randomized, placebo-controlled phase III trials in newly diagnosed glioblastoma reported prolonged progression-free survival (PFS), but not overall survival (OS), with the addition of bevacizumab to radiotherapy/temozolomide. To establish whether certain patient subgroups derived OS benefit from the addition of bevacizumab to first-line standard-of-care therapy, AVAglio patients were retrospectively evaluated for molecular subtype, and bevacizumab efficacy assessed for each patient subgroup. A multivariate analysis accounting for prognostic covariates revealed that bevacizumab conferred a significant OS advantage versus placebo for patients with Proneural IDH1 wild-type tumors (17.1 v 12.8 months, respectively; hazard ratio, 0.43; 95% CI, 0.26 to 0.73; P = .002). This analysis also revealed an interaction between the Proneural subtype biomarker and treatment arm (P = .023). The group of patients with Mesenchymal and Proneural tumors derived a PFS benefit from bevacizumab, compared with placebo; however, this translated to an OS benefit in the Proneural subset only. Retrospective analysis of AVAglio data suggests that patients with IDH1 wild-type Proneural glioblastoma may derive OS benefit from first-line bevacizumab treatment. The predictive value of the Proneural subtype observed in AVAglio should be validated in an independent dataset.
2016-07-06 | GSE84010 | GEO
Project description:The patients who underwent surgery for primary lesions were examined. All patients had metastatic or recurrent CRC and received bevacizumab therapy as first line or second line treatment. Responders and nonresponders were determined based on RECIST and confirmed by CT or MRI. Gene-expression profiles of primary CRC were determined using Human Genome GeneChip arrays U133.
2013-01-03 | GSE19862 | GEO
Project description:A Cartes d'Identite des Tumeurs (CIT) project from the French National League Against Cancer (http://cit.ligue-cancer.net ) 25 glioblastoma multiforme tumors hybridized on Illumina SNP and Affymetrix gene expression arrays. Project leader : François DUCRAY (francois.ducray@chu-lyon.fr). CIT Analysis : Julien LAFFAIRE (laffairej@ligue-cancer.net). Note: PFS : progression-free survival, OS: Overall Survival,BCNU : Carmustine (chemotherapy agent). RESPONDER: if the patient has shown or not shown a response to the treatment (Bevacizumab (Avastin) plus Irinotecan). Progression during : If the disease has progressed (cancer relapse or patient's death); otherwise (patient is alive without relapse).
2013-01-15 | E-MTAB-951 | biostudies-arrayexpress
Project description:The patients who underwent surgery for primary lesions were examined. All patients had metastatic or recurrent CRC and received bevacizumab therapy as first line or second line treatment. Responders and nonresponders were determined based on RECIST and confirmed by CT or MRI. Gene-expression profiles of primary CRC were determined using Human Genome GeneChip arrays U133. Colorectal cancer patients who had undergone surgical resection of colorectal cancer were studied. To identify molecular signatures to predict response to bevacizumab, gene expression profiles were compared between Reponder and Non-responder.
2013-01-03 | E-GEOD-19862 | biostudies-arrayexpress
Project description:The combination of bevacizumab with temozolomide and radiotherapy was shown to prolong progression-free survival in newly diagnosed glioblastoma patients, and this emphasizes the potential of bevacizumab as a glioma treatment. However, while bevacizumab effectively inhibits angiogenesis, it has also been reported to induce invasive proliferation. This study examined gene expression in glioma cells to investigate the mechanisms of bevacizumab-induced invasion. We made a human glioma U87ΔEGFR cell xenograft model by stereotactically injecting glioma cells into the brain of animals. We administered bevacizumab intraperitoneally three times per week. At 18 days after tumor implantation, the brains were removed for histopathology and mRNA was extracted. In vivo, bevacizumab treatment increased glioma cell invasion. qRT-PCR array analysis were perfomed.
2019-02-07 | GSE126168 | GEO
Project description:The AVAglio and RTOG-0825 randomized, placebo-controlled phase III trials in newly diagnosed glioblastoma reported prolonged progression-free survival (PFS), but not overall survival (OS), with the addition of bevacizumab to radiotherapy/temozolomide. To establish whether certain patient subgroups derived OS benefit from the addition of bevacizumab to first-line standard-of-care therapy, AVAglio patients were retrospectively evaluated for molecular subtype, and bevacizumab efficacy assessed for each patient subgroup. A multivariate analysis accounting for prognostic covariates revealed that bevacizumab conferred a significant OS advantage versus placebo for patients with Proneural IDH1 wild-type tumors (17.1 v 12.8 months, respectively; hazard ratio, 0.43; 95% CI, 0.26 to 0.73; P = .002). This analysis also revealed an interaction between the Proneural subtype biomarker and treatment arm (P = .023). The group of patients with Mesenchymal and Proneural tumors derived a PFS benefit from bevacizumab, compared with placebo; however, this translated to an OS benefit in the Proneural subset only. Retrospective analysis of AVAglio data suggests that patients with IDH1 wild-type Proneural glioblastoma may derive OS benefit from first-line bevacizumab treatment. The predictive value of the Proneural subtype observed in AVAglio should be validated in an independent dataset. A total of 349 (bevacizumab arm, n = 171; placebo arm, n = 178) pretreatment specimens from AVAglio patients (total n = 921) were available for biomarker analysis. Samples were profiled for gene expression and isocitrate dehydrogenase 1 (IDH1) mutation status and classified into previously identified molecular subtypes. PFS and OS were assessed within each subtype.
2016-07-06 | E-GEOD-84010 | biostudies-arrayexpress