E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with a primary rectal cancer without detectable distant
metastasis who after locoregional therapy only, meaning preoperative
radio(chemo)therapy plus surgery have at least a 40% risk of not
having a CRM negative resection or a recurrence, local or distant,
within three years |
Bolniki s primarnim rakom danke brez detektabilnih oddaljenih zasevkov, ki po predoperativni kemo- in radioterapiji imajo vsaj 40% verjetnosti za pozitiven resekcijski rob ali lokalni ali oddaljeni recidiv |
|
E.1.1.1 | Medical condition in easily understood language |
Patients with a locally advanced primary rectal cancer without detectable distant
metastasis |
Bolniki z lokalno vznapredovalim rakom danke brez dokazanih oddaljenih zasevkov |
|
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 |
To increase the disease-free survival after 3 years follow-up. |
Podaljšati preživetje po treh letih sledenja. |
|
E.2.2 | Secondary objectives of the trial |
To describe the toxicity profile of the combined modality treatment in schedule.
To determine the completion rate of the neo-adjuvant treatment.
To determine the fraction of patients with a radical resection (negative CRM).
To determine the pathological complete response rate (pCR).
To determine the postoperative complications.
To describe the local recurrence rate after 3 years follow-up.
To evaluate quality of life.
To evaluate functional outcome.
To increase overall survival after 5 years of follow-up. |
- Ugotoviti toksičnost zdravljenja.
- Ugotoviti delež bolnikov, ki so zaključili neoadjuvantno zdravljenje.
- Ugotoviti delež bolnikov z uspešno zaključenim radikalnim zdravljenjem (negativni resekcijski robovi).
- Ugotoviti delež bolnikov s kompletnim patološkim odgovorm (pCR).
- Ugotoviti postoperativne komplikacije.
- Ugotoviti število bolnikov z lokalnim recidivom po treh letih.
- Oceniti kakovost življenja.
- Oceniti funkcionalno uspešnost zdravljenja.
- Podaljšati skupno preživetje po petih letih sledenja. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Histological proof of newly diagnosed primary adenocarcinoma
of the rectum.
- Locally advanced tumour fulfilling at least one of the following
criteria on pelvic MRI indicating high risk of failing locally and/or
systemically (T4a, i.e. overgrowth to an adjacent organ or structure
like the prostate, urinary bladder, uterus, sacrum, pelvic floor or sidewall
(according to TNM version 5), cT4b, i.e. peritoneal
involvement, extramural vascular invasion (EMVI+). N2, i.e. four or
more lymph nodes in the mesorectum showing morphological signs
on MRI indicating metastatic disease. Four or more nodes, whether
enlarged or not, with a rounded, homogeneous appearance is thus not
sufficient. Positive MRF (previously named CRM), i.e. tumor or
lymph node =< 1 mm from the mesorectal fascia [60]. Enlarged lateral
nodes, > 1 cm (lat LN+).
- Staging done within 4 weeks before randomization.
- No contraindications to chemotherapy, including adequate blood
counts:
white blood count >=4.0 x 109/L
platelet count >=100 x 109/L
clinically acceptable haemoglobin levels
creatinine levels indicating renal clearance of 50 ml/min
bilirubin =<35 μmol/l.
- ECOG performance score =< 1
- Patient is considered to be mentally and physically fit for
chemotherapy as judged by the oncologist.
- Age >= 18 years
- Written informed consent.
- Adequate potential for follow-up. |
- Histološko dokazan, na novo odkrit adenokarcinom danke
- Lokalno vznapredovali rak danke, ki izpolnjuje vsaj en od naslednjih pogojev na MRI posnetku medenice, ki kaže na visoko tveganje za lokalno ali oddaljeno ponovitev bolezni: T4a oz. preraščanje na sosedne organe ali strukture, kot so prostata, mehur, uterus, sakrum, medenično dno ali lateralno med. steno (po TNM klasifikaciji, verzija 5); cT4b oz. prizadetost peritoneja, prisotnost ekstramuralne vaskularne invazije (EMVI+); N2 oz. 4 ali več po MRI kriterijih pozitivnih bezgavk. Štiri ali več vidnih bezgavk, ne glede na velikost, z okroglim, homogenim videzom ne sodijo v to skupino. Prizadeta MRF (prej imenovana CRM), oz. tumor ali LN odaljen < 1 mm od mezorektalne fascije [7]; Povečane lateralne bezgavke, >1cm (lat LN+)
- Staging (določanje stadija) zaključeno znotraj 4 tednov pred randomizacijo
- Brez kontraindikacij za KT, vključno z primernimi lab. izvidi:
Leukociti >=4 x 109/L
Trombociti >=100 x 109/L
Klinično sprejemljiva vrednost hemoglobina
Nivo kreatinina, ki kaže na klirens kreatinina > 50 ml/min
Bilirubin =< 35 µmol/l
- ECOG status < 1
- Po oceni onkologa-internista, bolnik je fizično in mentalno sposoben za KT
- Starost >= 18 let
- Podpisano ozaveščeno soglasje
- Primernost za sledenje |
|
E.4 | Principal exclusion criteria |
- Extensive growth into cranial part of the sacrum (above S3) or the lumbosacral nerve roots indicating that surgery will never be possible even if substantial tumour down-sizing is seen.
- Presence of metastatic disease or recurrent rectal tumour.
- Familial Adenomatosis Polyposis coli (FAP), Hereditary Non-Polyposis Colorectal Cancer (HNPCC), active Crohn’s disease or active ulcerative Colitis.
- Concomitant malignancies, except for adequately treated basocellular carcinoma of the skin or in situ carcinoma of the cervix uteri. Subjects with prior malignancies must be disease-free for at least 5 years.
- Known DPD deficiency.
- Any contraindications to MRI (e.g. patients with pacemakers).
- Medical or psychiatric conditions that compromise the patient’s ability to give informed consent.
- Concurrent uncontrolled medical conditions.
- Any investigational treatment for rectal cancer within the past month.
- Pregnancy or breast feeding.
- Patients with known malabsorption syndromes or a lack of physical integrity of the upper gastrointestinal tract.
- Clinically significant (i.e. active) cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac dysrhythmia, e.g. atrial fibrillation, even if controlled with medication) or myocardial infarction within the past 12 months.
- Patients with symptoms or history of peripheral neuropathy. |
- Ekstenzivno vrtaščanje tumorja v kranialni del sakruma (nad S3) ali lumbosakalne korenine z jasnimi znaki neresektabilnosti tudi po zmanjšanju tumorja po obsevanju
- Prisotnost zasevkov
- FAP, HNPCC, Crohn-ova bolezen ali ulc. kolitis
- Drugi hkratni raki, razen ustrezno zdravljenega bazocel. karcioma kože ali in situ raka materničnega vratu. Od ev. prejšnjih rakov, mora poteči vsaj 5 let.
- Kontraindikacije za MRI (srč. spodb. in podobno)
- Psihične bolezni, ki onemogočajo podajanje ozaveščenega soglasja
- Nosečnost ali dojenje
- Malabs. sindrom
- Resne kardiovask. težave
- Prebolela ali akt. perif. nevropatija |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Disease-free survival after 3 years follow-up is the primary endpoint. |
Preživetje brez bolezni po treh letih sledenja je primarni endpoint. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
Treatment associated toxicity, including surgical morbidity
Completion rate of neo-adjuvant treatment
Negative CRM (margin > 1 mm)
pCR
Postoperative complications
Local recurrence at 3 years
Overall survival
Functional outcome
Quality of life |
Toksičnost in morbiditeta
Zaključeno neoadj. zdravljenje
Negativni resekcijski robovi
Patološki odgovor
Postop. zapleti
Lok. recidiv po treh letih
Skupno preživetje
Funkcionalni izid zdravljenja
Kakovost življenja |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Every six months or by the end of specific procedure |
Vsakih 6 mesecev, oz. po koncu določenih faz. zdravljenja |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
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 | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Canada |
Denmark |
Finland |
Italy |
Luxembourg |
Netherlands |
Norway |
Slovenia |
Spain |
Sweden |
|
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
|
Two year follow up after inclusion of the last
patient |
Dve leti po vključitvi zadnjega bolnika v študijo |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |