Translational Validation Study to Examine KFO179-1 Biomarker Scores for the Prediction and Prognosis of Advanced Primary Resectable Rectal Cancer Stages UICC II-IV, With a 5-FU-based Standard Radiochemotherapy Followed by Total Mesorectal Excision.
Trial Snapshot
- Phase
- Not Applicable
- Status
- Active, not recruiting
- Sponsor
- Enrollment
- 200
- Locations
- 2
- Primary Endpoint
- Number of patients with histopathologically confirmed complete remission (pCR) (ypT0N0 R0) after preoperative RCTx related to pretherapeutically determined gene expression signature predicting tumor response to RCTx.
Study Overview
Brief Summary
The objective of the TransValid-KFO179/GRCSG-Trial-A is the validation of potential biomarkers. These are predictive (Prediction of probability of response to a certain therapy) / prognostic (predicting long-term outcome) microarray-based gene expression signatures and immunohistochemically evaluated biomarkers. The evaluation was done within the KFO179 (www.kfo179.de) - the validation is implemented in this trial.
Therefore tumor material of patients undergoing standard radiochemotherapy will be analyzed from pretreatment biopsies an residual tissue from the resection specimen after surgery. This validation and the biomaterial asservation will be incorporated into clinical routine in all participating centers as a model for the treatment of solid tumors. The obtained biomarkers with a predictive and prognostic power will be used to develop an algorithm to predict patients at high risk of local and distant cancer recurrence.
Detailed Description
The objective of the TransValid-KFO179/GRCSG-Trial-A is to validate the predictive/prognostic microarray-based gene expression signatures and single gene biomarkers (including 5-Fluorouracil (FU) metabolism, apoptosis, Kirsten Rat Sarcoma (KRAS), CpGCpG island methylation phenotype (CIMP) and TGF-beta pathway), which have been established in patients treated with standard 5-FU based RCT in the GRCSG trials (e.g. the CAO/ARO/AIO-94-, CAO/ARO/AIO-04-phase III trials). This validation will be incorporated into clinical routine in all participating centers as a model for the treatment of solid tumors. If the KFO179 biomarkers are predictive at a satisfactory level in the validation set, we will propose a prediction algorithm to stratify the patient population into a "high"-risk and "low"-risk population to develop local and distant cancer recurrence.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Diagnostic
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 85 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Aged 18 to 85 years, inclusive
- •Histologically confirmed advanced primary rectal cancer localized up to 12 cm above the anocutaneous line (determined with a rigid rectoscope), classified as T3/T4 or N+ carcinomas or with evidence for synchronous, but resectable distant metastases (liver or lung metastases)
- •No specific tumor treatment except colostomy due to tumor stenosis with ileus
- •World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) status ≤2
- •Adequate bone marrow function (WBC >3.0x10^9/L, neutrophils >1.5x10^9/L, thrombocytes >100x10^9/L, hemoglobin ≥10 g/dl)
- •Adequate liver function (bilirubin ≤2.0 mg/dl, SGOT, SGPT, AP, gamma-GT < three point five fold of upper level of normal range
- •serum creatinine < 1.5 mg/dl
- •Written and signed informed consent indicating the understanding of the investigational nature and the study protocol.
Exclusion Criteria
- •Pregnant or lactating women
- •Men and women unwilling or unable to use highly effective methods of contraception (per institutional standard) during treatment and for 6 months (male or female) after the end of treatment
- •Prolonged drug, medication or alcohol abuse
- •Previous chemotherapy (up to 2 years before diagnosis of rectal cancer)
- •Previous radiotherapy to the pelvic area
- •Simultaneous therapy with other anti-cancer drugs
- •Participation in a clinical trial in the period 30 days prior to inclusion
- •Patients (man and woman) who are not able or willing to accept treatment and follow-up care according to trial protocol
- •Patients (man and woman) with uncontrolled, serious physical or mental diseases, e.g.: instable cardiac disease in spite of medical treatment, myocardial infarction during the last 3 months prior to start of trial participation
- •neurological or psychiatric dysfunction including dementia or seizure disorder
- •Disseminated infection or sepsis
- •Disseminated intravascular coagulopathy
- •Symptomatic neuropathy (NCI CTC ≥2)
- •Patients with secondary malignancies except basal cell carcinoma of the skin or carcinoma in situ of the cervix, which have been successfully treated. (The inclusion of patients with other tumors that were successfully treated and no recurrence within the last 3-5 years should be discussed before registration in the trial)
- •Chronic diarrhea (>grade 1 according NCI CTCAE)
- •Allergic reaction to platin-derivates or study medication
- •Simultaneous treatment with sorivudine and analogous
- •Known Dihydropyrimidine dehydrogenase deficiency
Outcomes
Primary Outcomes
Number of patients with histopathologically confirmed complete remission (pCR) (ypT0N0 R0) after preoperative RCTx related to pretherapeutically determined gene expression signature predicting tumor response to RCTx.
Time Frame: 1 year after surgery
The efficacy of the pretherapeutically determined response prediction using a reliable and robust panel of biomarkers (gene expression signature) is assessed by several clinicopathological parameters after preoperative RCTx and TME-surgery that indicate response and toxicity (ypN-status, pCR, tumor regression-grading, R-status, toxicity). Timepoint for measuring the gene expression signature is the time of diagnosis (pretreatment biopsy); several immunohistochemical biomarkers (Thymidylatesynthase, Survivin, HER-2) will be determined in the pretreatment biopsy as well as at the time of resection in the residual tumor tissue.
Secondary Outcomes
- acute and late toxicity of the chemotherapy according to the CommonToxicity Criteria of the National Cancer Institute (CTC) (vs 4.0)(up to 5 years after therapy)
- Cumulative incidence of local relapses and distant metastases(up to 5 years after surgery)
- Quality of TME-surgery according to M.E.R.C.U.R.Y classification(30 days after surgery based on surgical and histopathological findings/reports)
- Overall cancer specific survival (CSS) after 3 and 5 years(up to 5 years after surgery)
- R0-rate of resection(30 days after surgery based on histopathological findings and reports)
- post-operative 30-day mortality(30 days after surgery)
- post-operative late complications (defecation problems, anastomotic, stenoses, loss of sphincter function)(up to 5 years after surgery)
- Disease free survival (DSF) after 2 and 3 years (local and/or distant recurrences)(up to 3 years after surgery)
- post-operative morbidity (esp. rate of anastomotic insufficiencies)(30 days after surgery)
- Quality of life (QL) according to the EORTC-Questionnaire QLQ-30 (3.0)(up to 5 years after surgery)
- Wexner-Score-Questionnaire(up to 5 years after surgery)
Investigators
Torsten Liersch
Prof. Dr. med.
University Medical Center Goettingen