Forschung

TransValid-B

Translational Validation Trial-B (add-on phase I/II study to the Clinical Research Unit) KFO179-2: Preoperative rasiochemotherapy (RCT) combined with 5- fluorouracil (5-FU) and oxaliplatin followed by 3 cycles of FOLFOX chemotherapy ant total mesorectal excision (TME surgery) in advanced rectal cancer (clinically staged as UICC stages II, III or IV) accompanied by molecular and cell biological (translational) analysis.

Study typ: Investigator-initiated, open label, non-randomized, prospective, exploratory multicenter feasibility study (phase I/II trial)

Study population: Patients with advanced but resectable rectal cancer (clinically staged as rectal cancers of the UICC stages II, III or IV)

Aims:
The aim of this study is to establish the feasibility and to receive first data on the efficacy of an innovative sequential combination of established pre-operative intensified RCT (5-FU+Oxaliplatin) with consecutively intensive but shortened preoperative FOLFOX-chemotherapy (5-FU+Oxaliplatin) followed by TME-surgery.
Primary Objectives:
- The primary objectives for this evaluation will be toxicity, histopathologically confirmed complete tumor remission (pCR), residual metastases in mesorectal lymph nodes (ypN-status) and resection status (R0 resection, circumferential resection margins).
- The data will be compared exploratively to the separate TransValid-KFO179/GRCSG-Trial-A (validation study, n=200 patients) and to expectations derived from historical data (e.g. the large CAO/AIO/ARO-94 as well as -04 trial of the GRCSG and others).

Secondary Objectives:

Safety of the respective combination sequences (Toxicity assessment according to NCI CTCAE V.3)

- Surgical morbidity and complications

- Pathological staging, tumor downstaging; tumor regression grading according to established methods

- R0 resection rate, circumferential resection margins, resection status

- residual metastases in mesorectal lymph nodes (ypN-status)

- Rate of sphincter-sparing surgery

- Clinical response (rates of von complete remission [CR]/partial remission [PR]/ stable disease[SD]/ progressive disease [PD]) after preoperative (neoadjuvant) treatment, both after the first and second treatment step)

- Relapse-free survival (local / distant / overall)

- Cancer-specific overall survival

- Translational / biomarker studies:
     o    to re-evaluate the prognostic relevance of the KFO179 scores [as assessed during the KFO179-1 funding period as predictive/ prognostic microarray-based gene expression signatures and single gene biomarkers in patients treated with standard 5-FU based RCT in the CAO/ARO/AIO-94- and CAO/ARO/AIO-04-phase III trials of the GRCSG as well as in the separately ongoing TransValid-KFO179/ GRCSG -Trial-A (validation study)] and as well as the primary clinicopathological parameters/biomarkers in long term follow-up by recording the data (i.e. disease free and/or overall survival, occurrence of local and distant metastases, long-term [chronic] toxicity) of all patients in the trial.

o   to develop an improved 5-FU dose adjustment by measuring 5-FU blood levels during intensified preoperative RCT and CTx (feasibility study). The results will be used in planned studies of the GRCSG (e.g. the CAO/AIO/ ARO-12 Trial, a randomized multicentric phase IIb trial).

Inclusion criteria:
- Histologically confirmed resectable advanced primary rectal cancer of the lower thirds of the rectum (localized within 0 to 12 cm above the anocutaneous verge as measured by rigid rectoscopy), clinically (c) classified as cT3/cT4 or cN+ carcinomas or with evidence for syn- chronous, but resectable distant metastases (liver metastases, cM+)
- Staging requirements: 
      o   Transrectal endoscopic ultrasound is the mandatory local staging procedure,
      o   Additional high-resolution, thin-sliced (i.e. 3 mm) magnetic resonance imaging (MRI) of the pelvis to classify infiltration depth and/or cN+ status or extramural venous cancer invasion (based on MRI-criteria)
      o   abdominal sonography and chest x-ray /or contrast-enhanced computed tomography scan of the thorax and abdomen (and pelvis, if EUS and/or MRI are not available) to complete UICC staging classification
- Aged 18 to 80 years, inclusive
- WHO/ECOG status ≤2
- Life expectancy ≤ weeks
- Adequate bone marrow function: WBC >3.0x10⁹/L, neutrophils >1.5x10⁹/L, thrombocytes >100x10⁹/L, hemoglobin ≥10 g/dl
- Adequate liver function: bilirubin
- Creatinine clearance > 50ml/min, serum creatinine ≤2.0 mg/dl, SGOT, SGPT, AP, gamma-GT < threefold of upper level of normal range ≤1.5 mg/dl
- Written and signed informed consent of competent patient 

Exclusion criteria:
- Prior or concurrent malignancy (≤3 years prior to enrolment in study) except non-melanoma skin cancer or cervical carcinoma FIGO stage 0-1 if the patient is continuously disease-free patients with other tumors that have been successfully treated and have not reappeared during the last 3 years, may be included at the principal investigator’s discretion
- Simultaneous therapy with other anti-cancer drugs
- Major surgery at the pelvic region 2-3 weeks prior to inclusion
- Previous multimodal treatment of rectal cancer
- Chronic colonic diseases
- Chronic diarrhea (>grade 1 according NCI CTCAE)
- Allergic reaction to platin-derivates or study medication
- Symptomatic neuropathia (NCI CTC ≥2) 
- Simultaneous treatment with sorivudin and analogous
- Known Dihydropyrimidine dehydrogenase (DPD) deficiency
- Cardiac infarction/failure within 3 months before start of multimodal therapy
- Disseminated infection or sepsis
- Activated disseminated intravasal coagulopathia
- Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment
- 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 (adequate: oral contraceptives, intrauterine device or barrier method in conjunction with spermicidal jelly)
- Participation in an AMG-clinical trial in the period 30 days prior to inclusion
- Current drug abuse 
- Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule (these conditions should be discussed with the patient before registration in the trial)
- Insufficient compliance of the patient

Recruting start: November 2013

Status: Active

Zentrum im UCT Universitätsklinikum Frankfurt

Prüfer: Prof. Dr. med. Claus Rödel

Stellvertretender Prüfer: Dr. med. Detlef Imhoff
Studiensekretariat:
Atefeh Nateghian

Margarita Diaz

Universitätsklinikum Frankfurt/Main

Zentrum für Radiologie und Strahlentherapie

Theodor-Stern Kai 7

60590 Frankfurt am Main

Tel: +49 (0)69 6301-4655/ 3742

E-Mail: atefeh.nateghian@unimedizin-ffm.de
margarita.diazmaguina@unimedizin-ffm.de

 

Ansprechpartner Leiter der klinischen Prüfung
Priv. Doz. Dr. T. Liersch
Abt. Allgemein- und Viszeralchirurgie
Universitätsmedizin Göttingen
Robert-Koch-Str. 40
37075 Göttingen
E-Mail: tliersc@gwdg.de