Study Comparing Pathological Responses Observed on Colorectal Cancer Metastases Resected After Preoperative Treatment Combining Cetuximab With FOLFOX or FOLFIRI in RAS and B-RAF WT Tumors

Overview

To analyze the pathological tumor response on resected colorectal cancer metastases after preoperative treatment with cetuximab combined with FOLFOX or FOLFIRI regimen in a prospective cohort (RAS and B-RAF WT tumors) and to correlate this response with patient's outcome.

Full Title of Study: “Randomised Phase 2 Study Comparing Pathological Responses Observed on Colorectal Cancer Metastases Resected After Preoperative Treatment Combining Cetuximab With FOLFOX or FOLFIRI in RAS and B-RAF WT Tumors”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: November 2015

Detailed Description

This is a phase II , openlabel, randomized study in patients with confirmed diagnosis of potentially or borderline resectable metastatic colorectal adenocarcinoma (RAS and B-RAF WT tumors ), who have not received prior chemotherapy for their metastatic disease. The study is designed to compare pathological responses observed after pre-operative chemotherapy cetuximab with FOLFOX or FOLFIRI.

Interventions

  • Procedure: Metastases Resection ( multiple steep surgery possible)
    • Metastases resection will be process by surgery, after a randomized chemotherapy (FOLFOX or FOLFIRI) + Target therapy (Cetuximab). The surgery will allow to compare the pathological response on the resected metastases by the chemotherapy + target therapy type.
  • Drug: 5-Fluorouracile
    • 5-FU bolus 400 mg/m2, IV bolus every 2 weeks 5-FU continuous infusion 2400 mg/m2, 46-hour cont. IV infusion every 2 weeks
  • Drug: leucovorin L
    • Leucovorin L (levoleucovorin) 200 mg/m2 (or folinic acid 400 mg/m²) in 250 ml glucose 5%, 2-hour IV infusion
  • Drug: Oxaliplatin
    • Oxaliplatin 85 mg/m² in 150 ml NaCl 0.9%, 2-hour IV infusion every 2 weeks
  • Drug: Irinotecan
    • Irinotecan 180 mg/m² in 150 ml NaCl 0.9%, 1.30-hour IV infusion every 2 weeks
  • Drug: Cetuximab
    • Cetuximab 400 mg/m² in 100 ml NaCl 0.9% 2-hour IV infusion for 1rst cycle and after the 1rst cycle 250 mg/m² in 100 ml NaCl 0.9% 1-hour IV infusion

Arms, Groups and Cohorts

  • Active Comparator: oxaliplatin +leucovorin L+5FU+ cetuximab
    • oxaliplatin +leucovorinL+5-Fluorouracile +cetuximab+’Metastases Resection ( multiple steep surgery possible)
  • Active Comparator: Irinotecan+ + leucovorinL +5-Fluorouracil +cetuximab
    • Irinotecan+ + leucovorinL +5-Fluorouracile + cetuximab +’Metastases Resection ( multiple steep surgery possible)

Clinical Trial Outcome Measures

Primary Measures

  • Major Pathological Response Rate
    • Time Frame: Average 3 months (after resection of metastases)
    • Major pathological response rate (MPRR) is defined as the proportion of patients presenting a major pathological response. Pathologic response will be evaluated according the Rubbia-Brandt Tumor Regression Grade classification .For patients with multiple colorectal metastases the global pathological response will be categorized based on the mean TRG of all metastases.: a major response is defined as a mean TRG < 3, a partial response is defined for patient presenting a mean TRG ≥3 and <4, and a no response for patient with a mean TRG ≥4.

Secondary Measures

  • progression free survival
    • Time Frame: at 6 months and at 12 months after randomization
    • -Progression Free Survival (PFS) is defined as the time from randomization to the time of first event (relapse of the original mCRC, development of a new colorectal cancer or death due to any cause). Patients without any such event at the time of data analysis will be censored at the last date they were known to be event-free. PFS analysis will be based on tumour assessments and survival follow-up assessments.
  • Overall survival
    • Time Frame: At the end of the study
    • The overall survival will be analyzed at the end of study (3 year of recruitment and one year of follow-up).
  • Clinical response rate
    • Time Frame: at time of surgery –
    • Clinical response rate at time of surgery: Clinical tumour response will be measured according to the RECIST 1.1 criteria
  • Metabolic response rate
    • Time Frame: At time of surgery – average 3 months
    • Metabolic response rate at time of surgery (in selected centres only, optional): Metabolic tumour response will be measured according to the EORTC criteria . PET-Scan evaluation remains optional to selected centres only.
  • post operative complications
    • Time Frame: one month after surgery
    • . Severe pre- or postoperative complications within 30 days of surgery: surgery-associated bleeding requiring replacement with > 4 units of erythrocyte concentrates, wound infection, intra-abdominal infection, severe sepsis (American College of Chest physicians/Society of Critical Care Medicine, 1992), impaired wound healing, subphrenic or perihepatic abscess requiring drainage during hospital stay or within 30 days after the operation, re-laparotomy connected with the resection, a biliary fistula for more than 10 days with a discharge of > 100 mL/day, transient liver failure (bilirubin > 10 mg/dL lasting > 3 days), renal failure requiring dialysis, respiratory failure with renewed necessary mechanical ventilation, venous thromboembolism, cardiac failure, death of the patient as a result of the operation.
  • Curative resection rate
    • Time Frame: At time of surgery
    • Curative resection rate (R0 resection) is defined by the surgical clearance (+/- radiofrequency ablation) of all detectable hepatic lesions with tumor-free margins at histo-pathological evaluation.
  • Chemotherapy-associated hepatotoxicity:
    • Time Frame: at time of surgery
    • Systemic neo-adjuvant chemotherapy in mCRC frequently causes morphological lesions involving hepatic microvasculature . Sinusoidal obstruction, complicated by perisinusoidal fibrosis and veno-occlusive lesion of the non tumoral liver, should be included in the list of the adverse side-effects of colorectal systemic chemotherapy, in particular related to the use of oxaliplatin.

Participating in This Clinical Trial

Inclusion Criteria

1. Female or male patients with at least 18 years at the time the informed consent is signed 2. ECOG performance status 0 or 1 3. Histological or cytological confirmed diagnostic of adenocarcinoma of the colon or rectum, with or without primary tumour in situ. Wild-type RAS and B-RAF tumor status. 4. Patients with potentially resectable metastatic disease at diagnosis and for whom a chemotherapy first in a curative intent is recommended . Resectability could be planed in one or multiple stage if indicated. As commonly admitted, resectability means the surgical clearance (+/- radiofrequency ablation) of all detectable (liver) lesions with tumor-free margins and compatible with an adequate hepatic reserve. Practically, bilateral tumor location, number and location of lesions, and inadequate hepatic reserve remain the main decisional factors. 5. Partial and minor resection of metastatic disease is allowed within 3 months before inclusion if patient has never received chemotherapy for mCRC. 6. Extra hepatic metastatic location is limited to 1 site. 7. Patients may have received adjuvant chemotherapy or (neo-) adjuvant chemo-radiotherapy to the pelvis, provided the last dose of chemotherapy was administered at least 6 months prior to inclusion (12 months for oxaliplatin). Previous radiotherapy to the pelvis is not an exclusion criterion. 8. Adequate haematological, renal and hepatic function as follows: Haematological: haemoglobin >9g/dl Neutrophils > 1.5 x 109/L Platelets > 100 x 109/L Renal: Creatinine< 1.5 x ULN (Upper Limit of Normal) Hepatic: Bilirubin < or equal 1.5 X ULN AST (Aspartate Aminotransferase),and ALT (Alanine Aminotransferase)< or equal 5 x ULN, Phos Alc< or equal 5 x ULN 9. Female patients must either be postmenopausal, sterile (surgically or radiation- or chemically-induced), or if sexually active using an acceptable method of contraception. 10. Male patients must be surgically sterile or if sexually active and having a pre-menopausal partner must be using an acceptable method of contraception. 11. Life expectancy of at least 3 months without any active treatment. Exclusion Criteria:

  • 1.Definitively non resectable mCRC at diagnosis – 2.Prior chemotherapy or systemic therapy for mCRC. Adjuvant chemotherapy for colorectal cancer is not an exclusion criterion provided that it was completed more than 6 months prior to inclusion. Oxaliplatin-based chemotherapy must be completed more than 1 year prior to inclusion. – 3.Prior utilization of cetuximab, panitumumab (or other anti-EGFR (epidermal growth factor receptor)therapy). – 4.Previous radiotherapy delivered to the upper abdomen. – 5 Non mesurable disease( RECIST 1.1 criteria) – 6.Evidence of ascites, cirrhosis, portal hypertension, main portal venous tumour involvement or thrombosis as determined by clinical or radiologic assessment. – 7.Prior major liver resection: remnant liver < 50% of the initial liver volume. – 8.Non-malignant disease that would render the patient unsuitable for treatment according to this protocol. – 9.Concurrent central nervous systems metastases – 10.Peripheric neuropathy ≥ grade 2. – 11.Interstitial lung disease – 12.Pregnant or breast feeding. – 13.The patient has previous or concomitant malignancies, except: Invasive malignancies in remission for more than 5 years and non melanoma skin cancer or carcinoma in situ of the cervix.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Cliniques universitaires Saint-Luc- Université Catholique de Louvain
  • Collaborator
    • Grand Hôpital de Charleroi
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Marc Van den Eynde, MD, Principal Investigator, Cliniques universitaires Saint-Luc – UCL
    • Javier Carrasco, MD PhD, Principal Investigator, Grand Hôpital de Charleroi

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Tesniere A, Apetoh L, Ghiringhelli F, Joza N, Panaretakis T, Kepp O, Schlemmer F, Zitvogel L, Kroemer G. Immunogenic cancer cell death: a key-lock paradigm. Curr Opin Immunol. 2008 Oct;20(5):504-11. doi: 10.1016/j.coi.2008.05.007. Epub 2008 Jun 23.

Ghiringhelli F, Menard C, Puig PE, Ladoire S, Roux S, Martin F, Solary E, Le Cesne A, Zitvogel L, Chauffert B. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother. 2007 May;56(5):641-8. doi: 10.1007/s00262-006-0225-8. Epub 2006 Sep 8.

Machiels JP, Reilly RT, Emens LA, Ercolini AM, Lei RY, Weintraub D, Okoye FI, Jaffee EM. Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice. Cancer Res. 2001 May 1;61(9):3689-97.

Mlecnik B, Tosolini M, Charoentong P, Kirilovsky A, Bindea G, Berger A, Camus M, Gillard M, Bruneval P, Fridman WH, Pages F, Trajanoski Z, Galon J. Biomolecular network reconstruction identifies T-cell homing factors associated with survival in colorectal cancer. Gastroenterology. 2010 Apr;138(4):1429-40. doi: 10.1053/j.gastro.2009.10.057. Epub 2009 Nov 10.

Branford S. Chronic myeloid leukemia: molecular monitoring in clinical practice. Hematology Am Soc Hematol Educ Program. 2007:376-83. doi: 10.1182/asheducation-2007.1.376.

Campbell PJ, Stephens PJ, Pleasance ED, O'Meara S, Li H, Santarius T, Stebbings LA, Leroy C, Edkins S, Hardy C, Teague JW, Menzies A, Goodhead I, Turner DJ, Clee CM, Quail MA, Cox A, Brown C, Durbin R, Hurles ME, Edwards PA, Bignell GR, Stratton MR, Futreal PA. Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nat Genet. 2008 Jun;40(6):722-9. doi: 10.1038/ng.128. Epub 2008 Apr 27.

Diehl F, Schmidt K, Choti MA, Romans K, Goodman S, Li M, Thornton K, Agrawal N, Sokoll L, Szabo SA, Kinzler KW, Vogelstein B, Diaz LA Jr. Circulating mutant DNA to assess tumor dynamics. Nat Med. 2008 Sep;14(9):985-90. doi: 10.1038/nm.1789. Epub 2007 Jul 31.

Yung TK, Chan KC, Mok TS, Tong J, To KF, Lo YM. Single-molecule detection of epidermal growth factor receptor mutations in plasma by microfluidics digital PCR in non-small cell lung cancer patients. Clin Cancer Res. 2009 Mar 15;15(6):2076-84. doi: 10.1158/1078-0432.CCR-08-2622. Epub 2009 Mar 10.

Leary RJ, Kinde I, Diehl F, Schmidt K, Clouser C, Duncan C, Antipova A, Lee C, McKernan K, De La Vega FM, Kinzler KW, Vogelstein B, Diaz LA Jr, Velculescu VE. Development of personalized tumor biomarkers using massively parallel sequencing. Sci Transl Med. 2010 Feb 24;2(20):20ra14. doi: 10.1126/scitranslmed.3000702.

McBride DJ, Orpana AK, Sotiriou C, Joensuu H, Stephens PJ, Mudie LJ, Hamalainen E, Stebbings LA, Andersson LC, Flanagan AM, Durbecq V, Ignatiadis M, Kallioniemi O, Heckman CA, Alitalo K, Edgren H, Futreal PA, Stratton MR, Campbell PJ. Use of cancer-specific genomic rearrangements to quantify disease burden in plasma from patients with solid tumors. Genes Chromosomes Cancer. 2010 Nov;49(11):1062-9. doi: 10.1002/gcc.20815.

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