| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Patients with advanced but resectable rectal cancer (clinically staged as
rectal cancers of the UICC stages II, III or IV) |
|
| E.1.1.1 | Medical condition in easily understood language |
Patients with advanced but resectable rectal cancer (clinically staged as
rectal cancers of the UICC stages II, III or IV) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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 FOLFOXchemotherapy
(5-FU+Oxaliplatin) followed by TME-surgery.
Primary Objectives:
- The primary objectives for this evaluation will be toxicity and
histopathologically confirmed complete tumor remission (pCR).
- 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 German Rectal Cancer Study Group [GRCSG]
and others). |
|
| E.2.2 | Secondary objectives of the trial |
-R0-rate of resection, CRM, resection status
-Rate of sphincter-sparing surgery
-Clinical response after each treatment step
-TRG
-residual tumor infiltration depth
-residual lymph node status incl. residual metastases in mesorectal
lymph nodes
-post-operative 30-day mortality, morbidity and late complications
-quality of TME-surgery
-acute and late toxicity of the RCT and CTx according to the CTC/ NCI
-DFS after 2 and 3 ys
-cumulative incidence of local relapses and/or distant metastases
-overall cancer-specific survival (CSS) after 3 and 5 ys
-Quality of life
-Translational/biomarker trial: Re-evaluate the prognostic relevance of
the KFO179 scores [A predictive microarray-based gene expression
signatures and single gene biomarkers in patients treated with 5-FU
based RCT] + primary clinicopathological parameters/biomarkers in a
follow-up. Developing an improved 5-FU dose adjustment by measuring 5-FU blood levels during preoperative RCT and CTx. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 synchronous,
but resectable distant metastases (liver metastases, cM+)
Staging requirements:
--Transrectal endoscopic ultrasound is the mandatory local staging
procedure,
--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)
--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 ≤2.0 mg/dl, SGOT, SGPT, AP, gamma-
GT < threefold of upper level of normal range
-Creatinine clearance > 50ml/min, serum creatinine ≤1.5 mg/dl
-Written and signed informed consent of competent patient |
|
| E.4 | Principal 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 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1) toxicity
2) histopathologically confirmed complete remission (pCR)
These data will be compared exploratively to the TransValid-KFO179/
GRCSG-A-Trial (validation study, n=200 patients), conducted in parallel,
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). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1: during RCT D1,15,29,43, during CTx D57,D71,D85 + one week before
surgery, one week after surgery, foru weeks after surgery, each followup
visit
2: pathology assessement (after surgery) |
|
| E.5.2 | Secondary end point(s) |
1) R0-rate of resection, circumferential resection margin, resection
status
2) tumor regression grading
3) residual tumor infiltration depth (ypT-status)
4) residual lymph node status (ypN-status)
5) post-operative 30-day mortality
6) post-operative morbidity (esp. rate of anastomotic insufficiencies)
7) post-operative late complications (defecation problems, anastomotic,
stenoses, loss of sphincter function)
8) quality of TME-surgery
9) acute and late toxicity of the chemotherapy according to the Common
Toxicity Criteria of the National Cancer Institute (vs 4.0)
10) Disease-fee survival (DFS) after 2 and 3 years (local and/or distant
recurrences)
11) cumulative incidence of local relapses and distant metastases
12) overall cancer-specific survival (CSS) after 3 and 5 years
13) quality of life according to the EORTC-Questionnaire QLQ-30 (3.0)
and Wexner-Score
14) Translational / biomarker studies:
14a) to re-evaluate the prognostic relevance of the KFO179 scores
identified during the KFO179-1 funding period (as predictive/prognostic
microarray-based gene expression signatures and single gene
biomarkers [see KFO 179-2 application, pp 32-228, Appendix 21]). The
identified biomarkers will be compared with results from patients
treated with standard 5-FU based RCT in the CAO/ARO/AIO-94- and
CAO/ARO/AIO-04-trials of the GRCSG, in the TransValid-
KFO179/GRCSG-A-Trial (validation study, n=200 patients)], and with
primary clinicopathological parameters/biomarkers in long term followup
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.
14b) to evaluate a proof-of-concept multimodal treatment selection by
risk stratification on the basis of the KFO179 biomarkers (as re-validated
within the TransValid-KFO179/GRCSG-A-Trial (validation study).
14c) to develop an improved 5-FU dose adjustment by measuring 5-FU
blood levels during intensified preoperative RCT and CTx (feasibility
study).
Note: The data will be compared exploratively to the TransValid-
KFO179/ GRCSG-A-Trial (validation study,), conducted in parallel, 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), and will be used to
design future studies. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-4,8: at pathology assessment
5-7: 4 weeks after surgery
9: before and during treatment D1,15,29,57,71,85, one week before and
after surgery, 4 weeks after surgery, each visit of follow-up
10-12: each visit of follow-up
13: at recruitment, end of therapy and follow-up
14a-b: during the trial
14c: during the chemotherapy |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last visit of last enrolled Trial subject |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
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