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-Fluorouracil-based Standard Radiochemotherapy Followed by Total Mesorectal Excision.

NCT03034473 | Unknown

• 3 other identifiers: TransValid-KFO179/GRCSG-ADRKS00003659UTN U1111-1131-9971
• Study Type: interventional
• Target: 200
• Locations: 1 country
• Sites: 1

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.

Conditions

Locally Advanced Rectal Cancer

Keywords

locally advanced rectal cancer; translational research; Biomarker

Outcome Measures

Primary Outcomes (1)

• 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.

  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.

  1 year after surgery

Secondary Outcomes (11)

• 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 morbidity (esp. rate of anastomotic insufficiencies)

  30 days after surgery

• post-operative late complications (defecation problems, anastomotic, stenoses, loss of sphincter function)

  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

Study Arms (1)

Blood and tissue samples during therapy

OTHER

Collection of blood and tissue samples during preoperative multimodal treatment (Radiochemotherapy (RCTx) followed by total mesorectal excision (TME) and Chemotherapy (CT)) in rectal cancer.

Other: Translational Research and multimodal treatment

Interventions

Translational Research and multimodal treatment OTHER

Blood/biopsy samples (tumor \& mucosa) are taken pretherapeutically. Blood samples (serum \& plasma) are drawn at 11 time points during RCTx (e.g. for analysis of 5-FU metabolism, genomic DNA extraction). After pathohistological workup of the TME specimen, the formalin-fixed material will be transferred to the central biobank of KFO179. Blood samples (plasma \& serum) will be drawn during 5y-follow-up. Treatment (based on CAO/ARO/AIO-94- and CAO/ARO/AIO-04-phase-III trials of the GRCSG): Preoperative RCT: 28x1.8 Gy (total: 50.4 Gy, 5 fractions per week on d1-d38) combined with 5-FU (1000 mg/m2/d) as 120 h civ during 1st and 5th week. TME-surgery is performed 6 weeks after RCTx. 4 to 8 weeks after surgery, patients receive either 4 cycles 5-FU (500 mg 5-FU/m2 iv, d1-5, repeat d 29-33) or 3 cycles (6 single appl.) of FOLFOX regimen \[(400 mg FA/m2, 2-h civ, d 1; 100 mg oxaliplatin/m2, 2-h civ in 500 ml Glucose 5%, d 1; 2400 mg 5-FU/m2 as 46-h civ) on d1+d15, d30+d45 and d60+d75\].

Blood and tissue samples during therapy

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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
• 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)
• Chronic diarrhea (\>grade 1 according NCI CTCAE)
• Allergic reaction to platin-derivates or study medication
• Simultaneous treatment with sorivudine and analogous

Sponsors & Collaborators

• University Medical Center Goettingen: lead
• German Research Foundation: collaborator

Study Sites (1)

University Medical Center Goettingen

Göttingen, Lower Saxony, 37075, Germany

Location

Related Publications (62)

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• Jakob C, Liersch T, Meyer W, Baretton GB, Hausler P, Schwabe W, Becker H, Aust DE. Immunohistochemical analysis of thymidylate synthase, thymidine phosphorylase, and dihydropyrimidine dehydrogenase in rectal cancer (cUICC II/III): correlation with histopathologic tumor regression after 5-fluorouracil-based long-term neoadjuvant chemoradiotherapy. Am J Surg Pathol. 2005 Oct;29(10):1304-9. doi: 10.1097/01.pas.0000170346.55304.88.

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• Liersch T, Meller J, Bittrich M, Kulle B, Becker H, Goldenberg DM. Update of carcinoembryonic antigen radioimmunotherapy with (131)I-labetuzumab after salvage resection of colorectal liver metastases: comparison of outcome to a contemporaneous control group. Ann Surg Oncol. 2007 Sep;14(9):2577-90. doi: 10.1245/s10434-006-9328-x. Epub 2007 Jun 15.

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• Fokas E, Conradi L, Weiss C, Sprenger T, Middel P, Rau T, Dellas K, Kitz J, Rodel F, Sauer R, Ruschoff J, Beissbarth T, Arnold D, Ghadimi BM, Rodel C, Liersch T. Preoperative chemoradiation therapy with capecitabine/oxaliplatin and cetuximab in rectal cancer: long-term results of a prospective phase 1/2 study. Int J Radiat Oncol Biol Phys. 2013 Dec 1;87(5):992-9. doi: 10.1016/j.ijrobp.2013.09.011. Epub 2013 Oct 24.

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• Quack H, Erpenbeck L, Wolff HA, Sprenger T, Seitz CS, Schon MP, Neumann S, Stanek K, Ghadimi BM, Michels B, Middel P, Schaefer IM, Liersch T, Conradi LC. Oxaliplatin-Induced Leukocytoclastic Vasculitis under Adjuvant Chemotherapy for Colorectal Cancer: Two Cases of a Rare Adverse Event. Case Rep Oncol. 2013 Dec 11;6(3):609-15. doi: 10.1159/000357166. eCollection 2013 Sep.

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• Folprecht G, Gruenberger T, Bechstein W, Raab HR, Weitz J, Lordick F, Hartmann JT, Stoehlmacher-Williams J, Lang H, Trarbach T, Liersch T, Ockert D, Jaeger D, Steger U, Suedhoff T, Rentsch A, Kohne CH. Survival of patients with initially unresectable colorectal liver metastases treated with FOLFOX/cetuximab or FOLFIRI/cetuximab in a multidisciplinary concept (CELIM study). Ann Oncol. 2014 May;25(5):1018-25. doi: 10.1093/annonc/mdu088. Epub 2014 Feb 27.

  PMID: 24585720 BACKGROUND

• Fokas E, Liersch T, Fietkau R, Hohenberger W, Beissbarth T, Hess C, Becker H, Ghadimi M, Mrak K, Merkel S, Raab HR, Sauer R, Wittekind C, Rodel C. Tumor regression grading after preoperative chemoradiotherapy for locally advanced rectal carcinoma revisited: updated results of the CAO/ARO/AIO-94 trial. J Clin Oncol. 2014 May 20;32(15):1554-62. doi: 10.1200/JCO.2013.54.3769. Epub 2014 Apr 21.

  PMID: 24752056 BACKGROUND

• Homayounfar K, Bleckmann A, Helms HJ, Lordick F, Ruschoff J, Conradi LC, Sprenger T, Ghadimi M, Liersch T. Discrepancies between medical oncologists and surgeons in assessment of resectability and indication for chemotherapy in patients with colorectal liver metastases. Br J Surg. 2014 Apr;101(5):550-7. doi: 10.1002/bjs.9436. Epub 2014 Feb 20.

  PMID: 24756914 BACKGROUND

• Ilgen P, Stoldt S, Conradi LC, Wurm CA, Ruschoff J, Ghadimi BM, Liersch T, Jakobs S. STED super-resolution microscopy of clinical paraffin-embedded human rectal cancer tissue. PLoS One. 2014 Jul 15;9(7):e101563. doi: 10.1371/journal.pone.0101563. eCollection 2014.

  PMID: 25025184 BACKGROUND

• Fokas E, Liersch T, Fietkau R, Hohenberger W, Hess C, Becker H, Sauer R, Wittekind C, Rodel C. Downstage migration after neoadjuvant chemoradiotherapy for rectal cancer: the reverse of the Will Rogers phenomenon? Cancer. 2015 Jun 1;121(11):1724-7. doi: 10.1002/cncr.29260. Epub 2015 Jan 21.

  PMID: 25611452 BACKGROUND

• Scheel AH, Reineke RA, Sprenger T, Lokka S, Kitz J, Ghadimi BM, Ruschoff J, Liersch T, Middel P. Comprehensive lymph node morphometry in rectal cancer using acetone compression. J Clin Pathol. 2015 Jun;68(6):458-64. doi: 10.1136/jclinpath-2014-202555. Epub 2015 Mar 16.

  PMID: 25779094 BACKGROUND

• Styczen H, Nagelmeier I, Beissbarth T, Nietert M, Homayounfar K, Sprenger T, Boczek U, Stanek K, Kitz J, Wolff HA, Ghadimi BM, Middel P, Liersch T, Ruschoff J, Conradi LC. HER-2 and HER-3 expression in liver metastases of patients with colorectal cancer. Oncotarget. 2015 Jun 20;6(17):15065-76. doi: 10.18632/oncotarget.3527.

  PMID: 25915155 BACKGROUND

• Poschau M, Dickreuter E, Singh-Muller J, Zscheppang K, Eke I, Liersch T, Cordes N. EGFR and beta1-integrin targeting differentially affect colorectal carcinoma cell radiosensitivity and invasion. Radiother Oncol. 2015 Sep;116(3):510-6. doi: 10.1016/j.radonc.2015.06.005. Epub 2015 Jun 18.

  PMID: 26096850 BACKGROUND

• Rodel C, Graeven U, Fietkau R, Hohenberger W, Hothorn T, Arnold D, Hofheinz RD, Ghadimi M, Wolff HA, Lang-Welzenbach M, Raab HR, Wittekind C, Strobel P, Staib L, Wilhelm M, Grabenbauer GG, Hoffmanns H, Lindemann F, Schlenska-Lange A, Folprecht G, Sauer R, Liersch T; German Rectal Cancer Study Group. Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2015 Aug;16(8):979-89. doi: 10.1016/S1470-2045(15)00159-X. Epub 2015 Jul 15.

  PMID: 26189067 BACKGROUND

• Bleckmann A, Conradi LC, Menck K, Schmick NA, Schubert A, Rietkotter E, Arackal J, Middel P, Schambony A, Liersch T, Homayounfar K, Beissbarth T, Klemm F, Binder C, Pukrop T. beta-catenin-independent WNT signaling and Ki67 in contrast to the estrogen receptor status are prognostic and associated with poor prognosis in breast cancer liver metastases. Clin Exp Metastasis. 2016 Apr;33(4):309-23. doi: 10.1007/s10585-016-9780-3. Epub 2016 Feb 9.

  PMID: 26862065 BACKGROUND

• Sprenger T, Rothe H, Conradi LC, Beissbarth T, Kauffels A, Kitz J, Homayounfar K, Wolff H, Strobel P, Ghadimi M, Wittekind C, Sauer R, Rodel C, Liersch T. Stage-Dependent Frequency of Lymph Node Metastases in Patients With Rectal Carcinoma After Preoperative Chemoradiation: Results from the CAO/ARO/AIO-94 Trial and From a Comparative Prospective Evaluation With Extensive Pathological Workup. Dis Colon Rectum. 2016 May;59(5):377-85. doi: 10.1097/DCR.0000000000000570.

  PMID: 27050599 BACKGROUND

• Jo P, Nietert M, Gusky L, Kitz J, Conradi LC, Muller-Dornieden A, Schuler P, Wolff HA, Ruschoff J, Strobel P, Grade M, Liersch T, Beissbarth T, Ghadimi MB, Sax U, Gaedcke J. Neoadjuvant Therapy in Rectal Cancer - Biobanking of Preoperative Tumor Biopsies. Sci Rep. 2016 Oct 18;6:35589. doi: 10.1038/srep35589.

  PMID: 27752113 BACKGROUND

• Sahlmann CO, Homayounfar K, Niessner M, Dyczkowski J, Conradi LC, Braulke F, Meller B, Beissbarth T, Ghadimi BM, Meller J, Goldenberg DM, Liersch T. Repeated adjuvant anti-CEA radioimmunotherapy after resection of colorectal liver metastases: Safety, feasibility, and long-term efficacy results of a prospective phase 2 study. Cancer. 2017 Feb 15;123(4):638-649. doi: 10.1002/cncr.30390. Epub 2016 Oct 20.

  PMID: 27763687 BACKGROUND

MeSH Terms

Interventions

Combined Modality Therapy

Intervention Hierarchy (Ancestors)

Therapeutics

Study Officials

• Torsten Liersch, MD, Prof.

  University Medical Center Goettingen

  PRINCIPAL INVESTIGATOR

• Michael Ghadimi, MD, Prof.

  University Medical Center Goettingen

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr. med.

Study Record Dates

• First Submitted: January 13, 2017
• First Posted: January 27, 2017
• Study Start: August 1, 2011
• Primary Completion: August 1, 2024
• Study Completion: August 1, 2024
• Last Updated: December 28, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)