Refractory Colorectal Adenocarcinoma Clinical Trial
Official title:
A Phase II Trial Evaluating the Activity of caBozantinib in Pre-treated pAtients With Metastatic COlorectal Cancer (mCRC). ABACO Trial.
This is a phase II non-randomised and non-comparative study, in pretreated mCRC patients, progressed after at least 2 lines of prior chemotherapy for metastatic disease. Treatment plan: - First Stage: A total of 22 patients will be enrolled in the first stage to detect at least 3 patients free of progression at 16 weeks - Second Stage: If at least 3 patients will be free of progression at 16 weeks, an additional cohort of 11 patients will be enrolled in the second stage
The prognosis of patients diagnosed with metastatic colorectal cancer (mCRC) remains poor despite significant progress made in the treatment efficacy and tolerability. The introduction of cytotoxic drugs (i.e. oxaliplatin, irinotecan, and trifluridine/tipiracil) and molecular targeted agents (i.e. bevacizumab, cetuximab, panitumumab, aflibercept, and regorafenib), has dramatically improved patients outcomes with an increase in median overall survival from 6 months with best supportive care only, to more than 30 months with new treatment strategies. The recent advances in genomic technologies have provided further insight into the profound complexity and molecular heterogeneity of colorectal cancer. According to the recent Consensus on CRC Molecular Subtypes (CMS) four biologically distinct subtypes have been identified. CMS1 (14%) occurring more often in older age, female patients, is characterized by right-sided tumors, hypermutated, enriched for MSI and BRAF mutant and with immune pathway activation. CMS2 (37%) shows epithelial phenotype, left-sided location, chromosomal instability (CIN), microsatellites stable (MSS), TP53 mutation, WNT/MYC pathway activation, and Epidermal Growth Factor Receptor (EGFR) upregulation and is associated with better survival rates; CMS3(13%), also expressing epithelial phenotype, is highly heterogeneous in CIN/MSI status and KRAS and PIK3CA mutant; CMS4 (23%) is defined by mesenchymal phenotype, increased TGF-β and AXL signalling, younger age at diagnosis, invasive phenotype, NOTCH3/VEGFR2 overexpression, and worse survival outcomes. This knowledge cannot be immediately translated into clinical practice, since CMS is not yet used to stratify patients for anti-cancer treatment. However, a better understanding of the complex molecular landscape in CRC will contribute to new treatment strategies. Cabozantinib is an oral, small-molecule inhibitor of tyrosine kinases, including MET, VEGF receptor 2 (VEGFR2), AXL and RET, currently approved for the treatment of patients with progressive, metastatic medullary thyroid cancer; treatment-naïve patients with renal cell carcinoma with intermediate or poor risk disease or previously treated with a vascular endothelial growth factor (VEGF)-inhibitor; hepatocellular carcinoma (HCC) previously treated with sorafenib. Angiogenesis is a crucial mechanism in CRC development and progression Moreover, AXL and MET signalling pathways are implicated in CRC invasion and metastasis and are involved in drug resistance occurrence . Cabozantinib has shown antitumor activity in preclinical CRC patient-derived tumor xenograft (PDTX) model leading to a decrease in the phosphorylation of Tie2, VEGFR2 (pro-angiogenic factors) and the MET, RET and AXL receptors (oncogenic pathways). ;
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