Clinical trial NCT04246684: Short RT Versus RCT,Followed by Chemo.and Organ Preservation for Interm and High-risk Rectal Cancer Patients
Official title: Short-course Radiotherapy Versus Chemoradiotherapy, Followed by Consolidation Chemotherapy, and Selective Organ Preservation for MRI-defined Intermediate and High-risk Rectal Cancer Patients
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Rectal Cancer Stage III
Lead sponsor: Goethe University
Sponsor class: OTHER
First posted: 2020-01-29
Enrollment: 702
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Investigator-driven
Primary purpose: TREATMENT

Brief summary: The hereby proposed ACO/ARO/AIO-18.1 randomized trial aims to directly compare the newly established TNT concepts applying either short-course RT according to RAPIDO, or CRT according to CAO/ARO/AIO-04/-12, both followed by consolidation chemotherapy, and surgery or a watch\&wait (W\&W) approach for patients with clinical complete response (cCR).

The ACO/ARO/AIO-18.1 study incorporates several novel and innovative aspects to further optimize multimodal rectal cancer treatment, partly established by our preceding CAO/ARO/AIO-04 and CAO/ARO/AIO-12 randomized trials: (1) patient selection is based on strict, quality controlled MRI features of intermediate and high-risk characteristics (and, thus, complementary to our ACO/ARO/AIO-18.2 trial in "low-risk" rectal cancer), (2) the CRT regimens incorporates 5-FU/oxaliplatin with doses and intensities shown to be effective and well-tolerated without compromising treatment compliance in CAO/ARO/AIO-04, (3) the sequence of CRT, CT, and surgery/W\&W adopts the TNT approach as established by our CAO/ARO/AIO-12 and OPRA trial, (4) surgical stratification allows for W\&W management for strictly selected patients with clinical complete response (cCR). Thus, we hypothesize that TNT with 5-FU/oxaliplatin-CRT followed by consolidation chemotherapy may increase organ preservation while maintaining DFS as compared to RAPIDO-like short-course RT followed by consolidation chemotherapy.

Detailed description: The primary endpoint of this trial, organ preservation, is defined as follows: survival with rectum intact, no major surgery, no stoma. Accordingly, the primary endpoint, organ preservation, will not be reached if any of the following occurs: (1) death, (2) any major surgery other than local excision (R0) performed after randomization, during TNT, at re-staging scheduled 22-24 weeks after start of TNT due to clinical non-cCR, or for any locoregional regrowth after initial cCR requiring salvage-TME, (3) any locoregional regrowth not amenable to salvage surgery, or (4) any stoma (non-re-converted protective stoma within 6 months after completion of TNT, or any stoma needed for toxicity or poor function), whichever occurs first. We hypothesized that the 3-year organ preservation rate will improve from 30% in the control arm to 40% in the investigational arm (hazard ratio of 0.76). With a power of 90% and a two-sided type I error of 5%, the sample size required to obtain a statistically significant difference is 702 patients (564 events) in total.

Eligibility criteria: Inclusion Criteria:

* diagnosis of rectal adenocarcinoma localised 0 - 12 cm from the anocutaneous line as measured by rigid rectoscopy (i.e. lower and middle third of the rectum)
* Staging requirements: High-resolution, thin-sliced (i.e. 3mm) magnetic resonance imaging (MRI) of the pelvis is the mandatory local staging procedure.
* MRI-defined inclusion criteria: presence of at least one of the following high-risk conditions:
* any cT3 if the distal extent of the tumor is \< 6 cm from the anocutaneous line, or
* cT3c/d in the middle third of the rectum (≥ 6-12 cm) with MRI evidence of extramural tumor spread into the mesorectal fat of more than 5 mm (\>cT3b), or
* cT3 with clear cN+ based on strict MRI-criteria
* cT4 tumors, or
* Tany middle/low third of rectum with clear MRI criteria for N+
* mrCRM+ (\< 1mm), or
* Extramural venous invasion (EMVI+)
* Trans-rectal endoscopic ultrasound (EUS) is additionally used when MRI is not definitive to exclude early cT1/T2 disease in the lower third of the rectum or early cT3a/b tumors in the middle third of the rectum.
* Spiral-CT of the abdomen and chest to exclude distant metastases.
* Aged at least 18 years. No upper age limit.
* WHO/ECOG Performance Status 0-1
* Adequate haematological, hepatic, renal and metabolic function parameters:
* Leukocytes ≥ 3.000/mm\^3, ANC ≥ 1.500/mm\^3, platelets ≥ 100.000/mm\^3, Hb \> 9 g/dl
* Serum creatinine ≤ 1.5 x upper limit of normal
* Bilirubin ≤ 2.0 mg/dl, SGOT-SGPT, and AP ≤ 3 x upper limit of normal • Informed consent of the patient

Exclusion Criteria:

* Lower border of the tumor localised more than 12 cm from the anocutaneous line as measured by rigid rectoscopy
* Distant metastases (to be excluded by CT scan of the thorax and abdomen)
* Prior antineoplastic therapy for rectal cancer
* Prior radiotherapy of the pelvic region
* Major surgery within the last 4 weeks prior to inclusion
* Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment.
* Subject (male or female) is not willing to use highly effective methods of Contraception during treatment and for 6 months after the end of treatment.
* On-treatment participation in a clinical study in the period 30 days prior to inclusion
* Previous or current drug abuse
* Other concomitant antineoplastic therapy
* Serious concurrent diseases, including neurologic or psychiatric disorders (incl. dementia and uncontrolled seizures), active, uncontrolled infections, active, disseminated coagulation disorder
* Clinically significant cardiovascular disease in (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) \< 6 months before enrolment
* Prior or concurrent malignancy \< 3 years prior to enrolment in study (Exception: non-melanoma Skin cancer or cervical carcinoma FIGO stage 0-1), if the patient is continuously disease-free
* Known allergic reactions on study medication
* Known dihydropyrimidine dehydrogenase deficiency
* 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).

Primary outcomes:
measure: organ preservation
timeFrame: 3 years
Secondary outcomes:
measure: Disease-free survival
timeFrame: 3 years
measure: Rate of clinical complete response after TNT:
timeFrame: 3 years
measure: Rate of immediate TME after TNT
timeFrame: 3 years
measure: Cumulative incidence of locoregional regrowth after cCR
timeFrame: 3 years
measure: Rate of salvage surgery (LE/TME with or APR/stoma) after locoregional regrowth APR/stoma) after locoregional regrowth
timeFrame: 3 years
measure: Cumulative incidence of local recurrence after (salvage) surgery surgery
timeFrame: 3 years
measure: Postoperative complications of (salvage) surgery
timeFrame: 3 years
measure: Rate of sphincter-sparing (salvage) surgery
timeFrame: 3 years
measure: Pathological TNM-staging
timeFrame: 3 years
measure: R0 resection rate; negative circumferential resection rate
timeFrame: 3 years
measure: Tumor regression grading according to Dworak
timeFrame: 3 years
measure: Neoadjuvant rectal score
timeFrame: 3 years
measure: Quality of TME according to MERCURY
timeFrame: 3 years
measure: Acute and late toxicity assessment according to NCI CTCAE V.5.0) CTCAE V.5.0)
timeFrame: 3 Yeears
measure: Quality of life C30 based on treatment arm and surgical procedures/organ preservation
timeFrame: 3 years
measure: functional outcome based on treatment arm and surgical procedures/organ preservation
timeFrame: 3 years
measure: Quality of life CR29 based on treatment arm and surgical procedures/organ preservation
timeFrame: 3 years
measure: Quality of life CPIN 20 based on treatment arm and surgical procedures/organ preservation
timeFrame: 3 years
measure: Cumulative incidence of distant metastases
timeFrame: 3 Years
measure: Overall survival
timeFrame: 3 years
measure: Translational / biomarker studies
timeFrame: 3 years
Other outcomes:
Locations:
city: Esslingen
country: Germany
facility: Clincal Center Esslingen
state: Baden-Wuerttemberg
city: Freiburg
country: Germany
facility: University Clinic Freiburg
state: Baden-Wuerttemberg
city: Mannheim
country: Germany
facility: University Clinic Mannheim
state: Baden-Wuerttemberg
city: Mutlangen
country: Germany
facility: Clinic Ostlab, Staufenclinic Schwaeb.Gmuend, Mutlangen
state: Baden-Wuerttemberg
city: Offenburg
country: Germany
facility: Pi.Tri-Studien GmbH, Offenburg
state: Baden-Wuerttemberg
city: Ostfildern
country: Germany
facility: Medius Clincal Center Ostfildern-Ruit
state: Baden-Wuerttemberg
city: Stuttgart
country: Germany
facility: Clinic Stuttgart
state: Baden-Wuerttemberg
city: Tübingen
country: Germany
facility: University Clinic for Radioncology Tübingen
state: Baden-Wuerttemberg
city: Ulm
country: Germany
facility: University Clinic Ulm
state: Baden-Wuerttemberg
city: Amberg
country: Germany
facility: Clincal Center "St. Marien" Amberg
state: Bavaria
city: Bayreuth
country: Germany
facility: Clinic Bayreuth GmbH
state: Bavaria
city: Coburg
country: Germany
facility: Clinical Center Coburg
state: Bavaria
city: Erlangen
country: Germany
facility: University Clinic Erlangen
state: Bavaria
city: Kempten
country: Germany
facility: Klinikverbund Allgäu
state: Bavaria
city: München
country: Germany
facility: Technical University Clinic Munich
state: Bavaria
city: München
country: Germany
facility: Technical University Munich
state: Bavaria
city: München
country: Germany
facility: Clincal Center "Bogenhausen" Munich
state: Bavaria
city: Regensburg
country: Germany
facility: Hospital "Barmherzige Brüder" Regensburg
state: Bavaria
city: Regensburg
country: Germany
facility: University Clinic Regensburg
state: Bavaria
city: Weiden
country: Germany
facility: Clinic Nordoberpfalz AG, Clinic Weiden
state: Bavaria
city: Würzburg
country: Germany
facility: University Clinic Würzburg
state: Bavaria
city: Bad Saarow
country: Germany
facility: Clincal Center Helios Bad Saarrow
state: Brandenburg
city: Darmstadt
country: Germany
facility: Clincal Center Darmstadt
state: Hessen
city: Frankfurt am Main
country: Germany
facility: Clinic North West gGmbH Frankfurt
state: Hessen
city: Fulda
country: Germany
facility: Clinic Fulda
state: Hessen
city: Kassel
country: Germany
facility: DRK Clincal Centers North Hessen Kassel
state: Hessen
city: Marburg
country: Germany
facility: University Clinic Marburg
state: Hessen
city: Offenbach
country: Germany
facility: Sana Clinical Center Offenbach
state: Hessen
city: Wetzlar
country: Germany
facility: Lahn-Dill Clinics Wetzlar
state: Hessen
city: Goslar
country: Germany
facility: MVZ Oncological Cooperation Harz
state: Lower Saxony
city: Göttingen
country: Germany
facility: University Clinic Göttingen
state: Lower Saxony
city: Hameln
country: Germany
facility: Hematological-Oncological Practice Dr. Oleg Rubanov, Hameln
state: Lower Saxony
city: Hannover
country: Germany
facility: Medical Project Hannover
state: Lower Saxony
city: Hildesheim
country: Germany
facility: "St. Bernward" Clincal Center Hildesheim
state: Lower Saxony
city: Hildesheim
country: Germany
facility: Oncology in Medicinum Hildesheim
state: Lower Saxony
city: Leer
country: Germany
facility: Oncology UnterEms, Leer
state: Lower Saxony
city: Oldenburg
country: Germany
facility: Pius Hospital, Oldenburg
state: Lower Saxony
city: Oldenburg
country: Germany
facility: University Clinic Oldenburg
state: Lower Saxony
city: Wolfsburg
country: Germany
facility: Clinic Wolfsburg
state: Lower Saxony
city: Rostock
country: Germany
facility: University Clinic Rostock
state: Mecklenburg Western Pomerania
city: Bochum
country: Germany
facility: St. Josef Hospital of the catholic clinic Bochum
state: North Rhine Westphalia
city: Paderborn
country: Germany
facility: Brother clinic St. Josef, Paderborn
state: North Rhine Westphalia
city: Wesel
country: Germany
facility: Evangelical Clinic Wesel
state: North Rhine Westphalia
city: Bielefeld
country: Germany
facility: Franziskus Hospital Bielefeld
state: North Rhine-Westphalia
city: Bochum
country: Germany
facility: Hospital Bochum
state: North Rhine-Westphalia
city: Detmold
country: Germany
facility: Clinic Lippe GmbH (Lemgo/Detmold)
state: North Rhine-Westphalia
city: Essen
country: Germany
facility: University Clinic Essen
state: North Rhine-Westphalia
city: Essen
country: Germany
facility: Clinical Center "Essen Mitte"
state: North Rhine-Westphalia
city: Mönchengladbach
country: Germany
facility: Clinic Maria Hilf GmbH
state: North Rhine-Westphalia
city: Paderborn
country: Germany
facility: St. Vincenz Hospital Paderborn
state: North Rhine-Westphalia
city: Recklinghausen
country: Germany
facility: Prosper Hospital Recklinghausen
state: North Rhine-Westphalia
city: Rheine
country: Germany
facility: Mathias-Spital, Rheine
state: North Rhine-Westphalia
city: Mainz
country: Germany
facility: University Clinic Mainz
state: Rhineland-Palantine
city: Trier
country: Germany
facility: Clinical Center "Mutterhaus" Trier
state: Rhineland-Palatinate
city: Saarbrücken
country: Germany
facility: CaritasClinic Saarbrücken
state: Saarland
city: Magdeburg
country: Germany
facility: University Clinic Magdeburg
state: Saxony-Anhalt
city: Chemnitz
country: Germany
facility: Clincal Center Chemnitz
state: Saxony
city: Dresden
country: Germany
facility: Radiotherapy Practice Dr. A. Schreiber, Dresden
state: Saxony
city: Dresden
country: Germany
facility: Oncology Practice Dresden
state: Saxony
city: Leipzig
country: Germany
facility: University Clinic Leipzig
state: Saxony
city: Leipzig
country: Germany
facility: Clinic Sankt Georg gGmbH, Leipzig
state: Saxony
city: Kiel
country: Germany
facility: University Clinic Kiel
state: Schleswig-Holstein
city: Berlin
country: Germany
facility: Vivantes Clincial Center in Friedrichshain
city: Berlin
country: Germany
facility: Clincal Center Helios Berlin Buch
city: Berlin
country: Germany
facility: Ev. Waldkrankenhaus, Spandau,
city: Berlin
country: Germany
facility: Helios Klinikum Berlin Emil von Behring
city: Bielefeld
country: Germany
facility: Klinikum Bielefeld
city: Darmstadt
country: Germany
facility: Onkologische Schwerpunktpraxis
city: Frankfurt
country: Germany
facility: Department of Radiooncology
city: Gießen
country: Germany
facility: Praxis für Hämatologie und Onkologie
city: Halle (Saale)
country: Germany
facility: Universitätsklinikum Halle
city: Krefeld
country: Germany
facility: Alexianer Krefeld GmbH / Maria Hilf Krankenhaus
city: Luebeck
country: Germany
facility: Uniklinik Schleswig Holstein
city: Neubrandenburg
country: Germany
facility: Dietrich Bonhoeffer Klinik
city: Saarbruecken
country: Germany
facility: Med. Statistik Saarbrücken GgR
city: Villingen-Schwenningen
country: Germany
facility: Schwarzwald-Baar-Kliniken
Study officials:
affiliation: clinic for radiotherapy
name: Claus Roedel, Prof. Dr.
role: STUDY_DIRECTOR
References: