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Analysis of 2nd line panitumumab + FOLFIRI efficacy in wild type RAS converted subjects from initially mutated RAS subjects with metastatic colorectal cancer treated in 1st line with standard FOLFOX + bevacizumab treatment.

ABSTRACT: Primary objectives: To estimate progression-free survival (PFS) in second- line treatment with panitumumab + FOLFIRI in wild type RAS mCRC patients who had mutant RAS at initiation of the first-line (standard FOLFOX + bevacizumab treatment) Primary endpoints: PFS defined as the time from second-line initiation to progression or death.

DISEASE(S): Wild-type Ras Metastatic Colorectal Cancer (mcrc),Colorectal Cancer Metastatic,Cáncer Colorrectal Metastásico (ccrm) Con Ras No Mutado

PROVIDER: 2537270 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Second-line FOLFIRI + Panitumumab in Subjects With Wild Type RAS Metastatic Colorectal

Project description:To estimate progression-free-survival at 6 months in subjects treated in first-line with panitumumab and FOLFOX and with wild type RAS mCRC (metastatic colorectal cancer) confirmed in liquid biopsies before starting second line treatment will be screened for this trial and who have interrupted panitumumab for <3 months (panitumumab continuation). Control arm of subjects treated with FOLFIRI alone will be included. The combinations of 5-fluorouracil (5-FU) with oxaliplatin (FOLFOX)are considered the backbone chemotherapy for mCRC. Clinical trials have shown the benefit of adding monoclonal antibodies to subjects without mutations in RAS, directed against the epidermal growth factor receptor (EGFR) (cetuximab and panitumumab) to conventional chemotherapy as first-line treatment of mCRC. This trial purposes to study the treatment beyond progression with panitumumab in subjects treated in first-line with an anti-EGFR monoclonal antibody, or rather,the re-introduction of the same targeted therapy after progression to first line. The clinical hypothesis of this study is that the second-line regimen FOLFIRI + panitumumab, is sufficiently active (defined as a 6-months PFS higher than 30% [based on prior results with second-line FOLFIRI alone] and of at least 50%), justifying further study in this population.

| 2290288 | ecrin-mdr-crc

First-line durvalumab and tremelimumab with chemotherapy in RAS-mutated metastatic colorectal cancer: a phase 1b/2 trial [RNA-Seq]

Project description:While patients with microsatellite instable, metastatic colorectal cancer (CRC) benefit from immune checkpoint blockade, chemotherapy with targeted therapies remains the only therapeutic option for microsatellite stable (MSS) tumors. The single arm, phase IB/II MEDITREME trial evaluates safety and efficacy of durvalumab plus tremelimumab in combination with mFOLFOX6 chemotherapy in first line, in 57 patients with RAS-mutant unresectable mCRC. Safety was primary objective of phase IB and no safety issue was observed. The primary objective of phase II was efficacy in terms of 3-month PFS in MSS patients, which was met with a 3 month PFS of 90.7% [95% CI: 79.2-96%]. For secondary objective, response rate was 64.5%, median PFS was 8.2 months [95% CI: 5.9–8.6] and overall survival was not reached in MSS patients. Higher tumor mutational burden and a lower degree of genomic instability in responder patients. Integrated transcriptomic analysis underlined that high immune signature, and low epithelio-mesenchymal transition were associated with better outcome. Immunomonitoring showed induction of neoantigen and NY-ESO1 and TERT blood tumor specific T cell response associated with better PFS. The combination of durvalumab-tremelimumab with mFOLFOX6 was tolerable with promising clinical activity in MSS mCRC.

2023-07-05 | GSE235919 | GEO

First-line durvalumab and tremelimumab with chemotherapy in RAS-mutated metastatic colorectal cancer: a phase 1b/2 trial [scRNA-Seq]

2023-07-05 | GSE235917 | GEO

RAS Pathway–Mutated Chronic Myelomonocytic Leukemia at the Single Cell Level

Project description:RAS pathway mutations, which are present in 30% of patients with chronic myelomonocytic leukemia (CMML) at diagnosis, confer a high risk of resistance to and progression after hypomethylating agent (HMA) therapy, the current standard of care for the disease. Using single-cell, multi-omics technologies, we sought to dissect the biological mechanisms underlying the initiation and progression of RAS pathway–mutated CMML. We found that RAS pathway mutations induced the transcriptional reprogramming of hematopoietic stem and progenitor cells (HSPCs), which underwent proliferation and monocytic differentiation in response to cell-intrinsic and -extrinsic inflammatory signaling that also impaired immune cells’ functions. HSPCs expanded at disease progression and relied on the NF-KB pathway effector MCL1 to maintain their survival, which explains why patients with RAS pathway–mutated CMML do not benefit from BCL2 inhibitors such as venetoclax. Our study has implications for developing therapies to improve the survival of patients with RAS pathway–mutated CMML.

2024-04-21 | GSE218390 | GEO

Optimal strategy in K-ras wild type metastatic colorectal cancer patients: cetuximab plus FOLFIRI followed by FOLFOX+/- cetuximab (GOIM multicenter program)

Project description:Primary objectives: The primary objective of first line treatment is:- Evaluation of efficacy (in terms of PFS) of ongoing FOLFIRI + Cetuximab as first line treatment in wild type (WT) K-ras metastatic colorectal cancer patients. the primary objective of second line treatment is:- evaluation of efficacy (in terms of PFS) of ongoing cetuximab as second line tretment in combination with chemotherapy after progerssion of first line treatment with FOLFIRI plus cetuximab in wild type (WT) K-ras metastatic colorectal cancer patients. Primary endpoints: The primary objective of first line treatment is:- Evaluation of efficacy (in terms of PFS) of ongoing FOLFIRI + Cetuximab as first line treatment in wild type (WT) K-ras metastatic colorectal cancer patients. the primary objective of second line treatment is:- evaluation of efficacy (in terms of PFS) of ongoing cetuximab as second line tretment in combination with chemotherapy after progerssion of first line treatment with FOLFIRI plus cetuximab in wild type (WT) K-ras metastatic colorectal cancer patients

| 2526788 | ecrin-mdr-crc

Transcription profiling of C. elegans with activated let-60 Ras

Project description:In Caenorhabditis elegans, let-60 Ras controls many cellular processes, such as differentiation of vulval epithelial cells, function of chemosensory neurons, and meiotic progression in the germ line. Although much is known about the let-60 Ras signaling pathway, relatively little is understood about the target genes induced by let-60 Ras signaling that carry out terminal effector functions leading to morphological change. We have used DNA microarrays to identify 708 genes that change expression in response to activated let-60 Ras.

2005-07-13 | E-SMDB-1398 | biostudies-arrayexpress

Gene expression changes induced by K-ras oncogene in the human pancreatic duct epithelial cell line (H6c7)

Project description:k-ras oncogene was transduced into the HPV16-E6E7 immortalized normal human pancreatic duct epithelial cell line (H6c7) to generate a stable K-ras oncogene-expressing cell line (H6c7-Kr). The gene expression profile of the H6c7-Kr cells was compared to that of H6c7 cells. We have excluded (subtracted) genes that were deregulated by transduction of the construct used for K-ras oncogene expression. Keywords: parallel sample

2005-01-11 | GSE1955 | GEO

Downstream targets of let-60 Ras in Caenorhabditis elegans

2005-07-22 | GSE2974 | GEO

Downstream targets of let-60 Ras in Caenorhabditis elegans

2005-07-22 | E-GEOD-2974 | biostudies-arrayexpress

A Multicenter single arm Phase II clinical trial of the second-line treatment with FOLFIRI plus panitumumab after failure of the first-line treatment with FOLFOX plus panitumumab for advanced and/or recurrent RAS wild-type colorectal cancer with special reference to the changes in biomarker expression examined by a liquid biopsy and its effect on the refractory tumor

Project description:Interventions: Second-line treatment with FOLFIRI plus panitumumab after failure of the first-line treatment with FOLFOX plus panitumumab for advanced and/or recurrent RAS wild-type colorectal cancer with special reference to the changes in biomarker expression examined by a liquid biopsy and its effect on the refractory tumor Primary outcome(s): 6-month progression-free survival (PFS) rate * Study Design: Single arm Non-randomized

| 2642034 | ecrin-mdr-crc

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