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Efficacy And Safety Of Xeliri + Avastin Followed By Xelox + Avastin Or Reverse Sequence In Metastatic Colorectal Cancer

ABSTRACT: Since its introduction, 5-fluorouracil (5-FU) has been the cornerstone of treatment for metastatic colorectal cancer (mCRC). Meanwhile the oral 5FU pro-drug Capecitabine (Xeloda) proved equivalence to 5-FU and is a well tolerated alternative combination partner for Irinotecan (XELIRI) or Oxaliplatin (XELOX) which are widely used for first line treatment of mCRC. Recent advances in molecular biology have resulted in the development of an inhibitor of the vascular endothelial growth factor (VEGF) by the monoclonal humanized antibody bevacizumab (Avastin). XELOX or XELIRI +bevacizumab have been investigated in several trials, but not in an approach with clearly defined cross-wise XELIRI-XELOX change criteria. This trial investigates two different sequential treatment options with XELIRI/ XELOX in first and second line with the addition of bevacizumab and tries to give answer to the question if there is an optimal sequence for the benefit of the patient. This is a prospective, randomized, open-label, 2-arm pilot trial in patients with mCRC who did not receive systemic treatment for their metastatic disease. The study is designed to evaluate the efficacy of XELIRI followed by XELOX and XELOX followed by XELIRI + bevacizumab in terms of Duration of Disease Control (DDC). Patients will be treated with an established first line therapy consisting of either XELOX or XELIRI + bevacizumab. The chemotherapy treatment will be given for 6 months except prior disease progression, unacceptable toxicity or patient refusal. Bevacizumab will be given until disease progression, unacceptable toxicity or patient refusal. Capecitabine can be given in addition at the investigators’ discretion until disease progression, unacceptable toxicity or patient refusal. If serious side effects occur despite adequate dose reduction, Oxaliplatin or Irinotecan should be discontinued. In case of Oxaliplatin or Irinotecan-related discontinuation Capecitabine and Bevacizumab should be continued. If Capecitabine also has to be discontinued in first line treatment bevacizumab should be continued. In case of permanent discontinuation of bevacizumab for toxicities, chemotherapy should be continued. Upon completion of first line chemotherapy patients with disease control will receive bevacizumab maintenance treatment. On investigators decision patients can receive Capecitabine as additional maintenance treatment. The primary endpoint is to determine the efficacy of a modified XELIRI + bevacizumab followed by XELOX + bevacizumab scheme at progression in comparison with the reverse sequence based on DDC. Secondary endpoints are first line progression-free survival (PFS), second line PFS, overall response rate, time to response, duration of response, overall survival, tumor assessments (based on RECIST criteria) using CT scans, MRI scans, X-ray, bone scan, clinical examination.

DISEASE(S): Metastatic Colorectal Cancer,Colorectal Neoplasms

PROVIDER: 2165111 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Objective: Insights about differences in tumor vasculature and how it reacts to VEGF inhibition is limited, but nevertheless of major relevance to anti-angiogenic therapy. In this study we therefore characterize the effect of bevacizumab combined with chemoradiotherapy (CRT), and explore molecular and genetic markers for response prediction to this combination treatment. Material and Methods: In an academic multicentric randomized phase II study, patients with advanced rectal cancer have been treated with bevacizumab (5mg/kg) in combination with capecitabine (1650mg/m2/day) and radiotherapy (45Gy; 1.8Gy/day) with (50mg/m2) or without oxaliplatin prior to surgery. Of 59 patients, tumor tissue and blood samples were collected before treatment and after the first loading dose of bevacizumab but before CRT (week 3). First, cDNA micro-arrays were performed on the biopsies to investigate differences in gene expression of tumors from patients with and without a pathological complete response (pCR) before start of treatment and to identify biological processes affected by bevacizumab delivery. The paraffin embedded tissue was stained for blood vessels (CD31/CD34) combined with Î±-SMA (pericytes) and CA-IX (hypoxia). To explore candidate blood-based biomarkers ELISAâs were performed for PDGF-AA, PDGF-BB, THBS-1, IL-8, CYR61 and Ang-2. The expression of all markers was correlated with the pathological response of the patients. Results: Differences in tumoral gene expression are observed between patients with and without a pCR, with the first response group presenting a more angiogenic phenotype before start of treatment and changes in angiogenic processes after bevacizumab delivery. One dose of bevacizumab leads to a decrease in the number of pericyte covered blood vessels, a decrease in circulating PDGF-AA, PDGF-BB and Thrombospondin-1. Patients showing a pCR having less pericyte covered blood vessels, more hypoxia, and less circulating PDGF-BB compared to patients who did not have a pCR after bevacizumab treatment with chemoradiation and bevacizumab. Conclusions: The translational data demonstrate that tumors with an angiogenic expression profile respond better to bevacizumab combined with CRT and points towards a possible role for PDGF, CA-IX and pericyte covered blood vessels for the early response prediction to this treatment. Our findings suggest a role for mural cell recruitment and vessel maturation for the susceptibility of the tumor vasculature to bevacizumab treatment. Further validation of our biological observations and hypothesis generating data in randomized trials is needed. This study involves samples of patients enrolled in the AXEbeam trail that were analysed by Primeview microarray (Affymetrix). Biopsies were taken at two different timepoints: before treatment (tumor and normal mucosa) and after the first loading dose of bevacizumab but before chemoradiation (only tumor, week 3). Patients were classified into two groups: with a complete pathological response at time of surgery (Responders=R) or non-responders (NR). For the responders, we collected 21 samples in total (7 tumor samples and 8 normal mucosa samples taken before treatment and 6 tumor samples collected at week 3). From the non-responders we had 26 samples in total (9 tumor and 10 mucosa samples before treatment and 7 tumor samples at week 3 after a single dose of bevacizumab). Microarrays were run in two batches (15xxx versus 16xxx CEL file samples; indicated in the description field). Three samples (NJ 04/003 T1, RVS 09/002 M and NJ 04/003 W3) were put twice on the array (15897+16789; 15893+16790; 15898+16791) to verify and exclude batch effects. Please note that, due to these three technical repeats the total number of microarray CEL files is 50 (21 Responders, 26 Non-responders and 3 repeats).

Project description:KRAS mutation is a negative predictive factor for treatment with anti-epidermal growth factor receptor (EGFR) antibodies in metastatic colorectal cancer (mCRC). Novel predictive markers are required to further improve the selection of patients for this treatment. Here, we assessed the influence of modification of KRAS by gene copy number aberration (CNA) and microRNAs (miRNAs) in correlation to clinical outcome in mCRC patients treated with cetuximab in combination with chemotherapy and bevacizumab. Formalin-fixed paraffin-embedded primary tumour tissue was used from 34 mCRC patients in a phase III trial, who were selected based upon their good (n=17) or poor (n=17) progression-free survival (PFS) upon treatment with cetuximab in combination with capecitabine, oxaliplatin, and bevacizumab. Gene copy number at the KRAS locus was assessed using high resolution genome-wide array CGH and the expression levels of 17 miRNAs targeting KRAS were determined by real-time PCR. Good response was associated with 12p12.1 copy number loss, even in patients with a KRAS mutation, while copy number gain in wild-type KRAS patients was correlated with a poor response. In KRAS mutated tumours increased miR-200b and decreased miR-143 expression were associated with a good response. In wild-type KRAS patients, miRNA expression did not predict response in a multivariate model. Thus, assessment of KRAS CNA and miRNAs targeting KRAS might further optimize the selection of patients eligible for anti-EGFR therapy. Copy number detection was performed using NimbleScan and Nexus software Formalin-fixed paraffin-embedded primary tumour tissue was used from 34 metastisized colorectal cancer patients in a phase III trial (CKTO 2005-02; ClinTrials.gov NCT00208546) of the Dutch Colorectal Cancer Group (DCCG), who were selected based upon their good (n=17) or poor (n=17) progression-free survival (PFS) upon treatment with cetuximab in combination with capecitabine, oxaliplatin, and bevacizumab.

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Efficacy And Safety Of Xeliri + Avastin Followed By Xelox + Avastin Or Reverse Sequence In Metastatic Colorectal Cancer

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