Short RT Versus RCT,Followed by Chemo.and Organ Preservation for Interm and High-risk Rectal Cancer Patients

NCT04246684 | Active Not Recruiting Phase 3 DMC

• 1 other identifier: ACO/ARO/AIO-18.1
• Study Type: interventional
• Target: 702
• Locations: 1 country
• Sites: 76

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.

Conditions

Rectal Cancer Stage III

Outcome Measures

Primary Outcomes (1)

• organ preservation

  it 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.

  3 years

Secondary Outcomes (21)

• Disease-free survival

  3 years

• Rate of clinical complete response after TNT:

  3 years

• Rate of immediate TME after TNT

  3 years

• Cumulative incidence of locoregional regrowth after cCR

  3 years

• Rate of salvage surgery (LE/TME with or APR/stoma) after locoregional regrowth APR/stoma) after locoregional regrowth

  3 years

Study Arms (2)

Control arm

ACTIVE COMPARATOR

In the control arm patients receive 5x5 Gy followed by 9 cycles of consolidation chemotherapy mFOLFOX6 or alternatively 6 cycles of CAPOX, followed by re-staging at week 22-24 as established as new preferred neoadjuvant regimen by the RAPIDO trial.

Drug: Oxaliplatin, 85 mg/m2; Drug: 5FU; 2400 mg/m2; Drug: Folinic Acid, 400 mg/m2; Radiation: Radiotherapy control, 5x5 Gy: 25 Gy; Drug: Capecitabine, 1000 mg/m2; Drug: Oxaliplatin, 130 mg/m2

Experimental arm

EXPERIMENTAL

The experimental arm starts with Fluoropyrimidin/Oxaliplatin-based CRT (1.8 Gy to 45 Gy to the primary tumor and pelvic lymph nodes; followed by sequential boost of 9 Gy to the gross tumor volume) followed by consolidation chemotherapy with 6 cycles mFOLFOX6 or alternatively 4 cycles CAPOX, followed by re-staging at week 22-24. In both arms, for patients achieving a clinical complete response (cCR), as strictly assessed by clinical investigation, endoscopy and MRI, a W\&W option with close follow-up is scheduled. In case of non-complete response, immediate TME surgery is performed.

Drug: 5FU, 250 mg/m2; Drug: 5FU, 2400 mg/m2; Drug: Oxaliplatin 50 mg/m2; Drug: Folinic Acid, 400 mg/m2; Drug: Capecitabine, 1000 mg/m2; Drug: Oxaliplatin 85 mg/m2; Radiation: radiotherapy experimental, 30 x 1,8 Gy: 54 Gy; Drug: Capecitabine, 825 mg/m2; Drug: Oxaliplatin, 130 mg/m2

Interventions

Oxaliplatin 85 mg/m2 DRUG

85 mg/m2, 2h-civ, d64, d78, d92, d106, d120, d134 of therapy

Also known as: experimental arm

Experimental arm

5FU, 2400 mg/m2 DRUG

2400 mg/m2,46h-civ, d64, d78, d92, d106, d120, d134 of therapy

Also known as: experimental arm

Experimental arm

5FU, 250 mg/m2 DRUG

250 mg/m2 per day, civ, on day 1-14, day 22-35 of radiotherapy;

Also known as: Experimental arm: 5-FU

Experimental arm

Oxaliplatin 50 mg/m2 DRUG

50 mg/m2, 2h-civ, d1, d8, d21, d29 of radiotherapy and

Also known as: Experimental arm

Experimental arm

Folinic Acid, 400 mg/m2 DRUG

2h-civ day 22, 36, 50, 64, 78, 92, 106, 120, and 134 of therapyfor Control arm; 400 mg/m2, 2h-civ d 64, d78, d92, d106, d120, d134 of therapy for experimental arm

Also known as: Folinic Acid

Control arm; Experimental arm

Radiotherapy control, 5x5 Gy: 25 Gy RADIATION

Control arm: 5x5 Gy (total: 25 Gy) 5 fractions

Control arm

Capecitabine, 1000 mg/m2 DRUG

1000 mg/m2 (twice daily) day1-14 every three weeks instead of 5FU optional

Also known as: Capecitabine

Control arm; Experimental arm

radiotherapy experimental, 30 x 1,8 Gy: 54 Gy RADIATION

30 x 1.8 Gy (total: 54 Gy), 5 fractions per week

Experimental arm

Capecitabine, 825 mg/m2 DRUG

825 mg/m2 bid, per os, on day 1-14, 22-35 of RT instead of 5FU optional

Also known as: Capecitabine

Experimental arm

Oxaliplatin, 130 mg/m2 DRUG

day1every three weeks (optional)

Also known as: Oxaliplatin

Control arm; Experimental arm

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: Male and female patients with histologically confirmed diagnosis of rectal adenocarcinoma localised 0 - 12 cm from the anocutaneous line as measured by rigid rectoscopy
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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

You may not qualify if:

• 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
• 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.
• 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).

Sponsors & Collaborators

• Prof. Dr. med. Claus Rödel: lead

Study Sites (76)

Clincal Center Esslingen

Esslingen am Neckar, Baden-Wurttemberg, 73730, Germany

Location

University Clinic Freiburg

Freiburg im Breisgau, Baden-Wurttemberg, 79106, Germany

Location

University Clinic Mannheim

Mannheim, Baden-Wurttemberg, 68167, Germany

Location

Clinic Ostlab, Staufenclinic Schwaeb.Gmuend, Mutlangen

Mutlangen, Baden-Wurttemberg, 73557, Germany

Location

Pi.Tri-Studien GmbH, Offenburg

Offenburg, Baden-Wurttemberg, 77654, Germany

Location

Medius Clincal Center Ostfildern-Ruit

Ostfildern, Baden-Wurttemberg, 73760, Germany

Location

Clinic Stuttgart

Stuttgart, Baden-Wurttemberg, 70174, Germany

Location

University Clinic for Radioncology Tübingen

Tübingen, Baden-Wurttemberg, 72076, Germany

Location

University Clinic Ulm

Ulm, Baden-Wurttemberg, 89081, Germany

Location

Clincal Center "St. Marien" Amberg

Amberg, Bavaria, 92224, Germany

Location

Clinic Bayreuth GmbH

Bayreuth, Bavaria, 95445, Germany

Location

Clinical Center Coburg

Coburg, Bavaria, 96450, Germany

Location

University Clinic Erlangen

Erlangen, Bavaria, 91054, Germany

Location

Klinikverbund Allgäu

Kempten (Allgäu), Bavaria, 87439, Germany

Location

Technical University Clinic Munich

München, Bavaria, 81675, Germany

Location

Technical University Munich

München, Bavaria, 81675, Germany

Location

Clincal Center "Bogenhausen" Munich

München, Bavaria, 81925, Germany

Location

Hospital "Barmherzige Brüder" Regensburg

Regensburg, Bavaria, 93046, Germany

Location

University Clinic Regensburg

Regensburg, Bavaria, 93053, Germany

Location

Clinic Nordoberpfalz AG, Clinic Weiden

Weiden, Bavaria, 92637, Germany

Location

University Clinic Würzburg

Würzburg, Bavaria, 97080, Germany

Location

Clincal Center Helios Bad Saarrow

Bad Saarow, Brandenburg, 15526, Germany

Location

Clincal Center Darmstadt

Darmstadt, Hesse, 64283, Germany

Location

Clinic North West gGmbH Frankfurt

Frankfurt am Main, Hesse, 60488, Germany

Location

Clinic Fulda

Fulda, Hesse, 36043, Germany

Location

DRK Clincal Centers North Hessen Kassel

Kassel, Hesse, 34121, Germany

Location

University Clinic Marburg

Marburg, Hesse, 35043, Germany

Location

Sana Clinical Center Offenbach

Offenbach, Hesse, 63069, Germany

Location

Lahn-Dill Clinics Wetzlar

Wetzlar, Hesse, 35578, Germany

Location

MVZ Oncological Cooperation Harz

Goslar, Lower Saxony, 38642, Germany

Location

University Clinic Göttingen

Göttingen, Lower Saxony, 37075, Germany

Location

Hematological-Oncological Practice Dr. Oleg Rubanov, Hameln

Hamelin, Lower Saxony, 31785, Germany

Location

Medical Project Hannover

Hanover, Lower Saxony, 30171, Germany

Location

"St. Bernward" Clincal Center Hildesheim

Hildesheim, Lower Saxony, 31134, Germany

Location

Oncology in Medicinum Hildesheim

Hildesheim, Lower Saxony, 31135, Germany

Location

Oncology UnterEms, Leer

Leer, Lower Saxony, 26789, Germany

Location

Pius Hospital, Oldenburg

Oldenburg, Lower Saxony, 25121, Germany

Location

University Clinic Oldenburg

Oldenburg, Lower Saxony, 26133, Germany

Location

Clinic Wolfsburg

Wolfsburg, Lower Saxony, 38440, Germany

Location

University Clinic Rostock

Rostock, Mecklenburg-Vorpommern, 18059, Germany

Location

Franziskus Hospital Bielefeld

Bielefeld, North Rhine-Westphalia, 33615, Germany

Location

St. Josef Hospital of the catholic clinic Bochum

Bochum, North Rhine-Westphalia, 44791, Germany

Location

Hospital Bochum

Bochum, North Rhine-Westphalia, 44892, Germany

Location

Clinic Lippe GmbH (Lemgo/Detmold)

Detmold, North Rhine-Westphalia, 32756, Germany

Location

University Clinic Essen

Essen, North Rhine-Westphalia, 45122, Germany

Location

Clinical Center "Essen Mitte"

Essen, North Rhine-Westphalia, 45136, Germany

Location

Clinic Maria Hilf GmbH

Mönchengladbach, North Rhine-Westphalia, 41063, Germany

Location

Brother clinic St. Josef, Paderborn

Paderborn, North Rhine-Westphalia, 33098, Germany

Location

St. Vincenz Hospital Paderborn

Paderborn, North Rhine-Westphalia, 33098, Germany

Location

Prosper Hospital Recklinghausen

Recklinghausen, North Rhine-Westphalia, 45659, Germany

Location

Mathias-Spital, Rheine

Rheine, North Rhine-Westphalia, 48431, Germany

Location

Evangelical Clinic Wesel

Wesel, North Rhine-Westphalia, 46485, Germany

Location

University Clinic Mainz

Mainz, Rhineland-Palantine, 55116, Germany

Location

Clinical Center "Mutterhaus" Trier

Trier, Rhineland-Palatinate, 54290, Germany

Location

CaritasClinic Saarbrücken

Saarbrücken, Saarland, 66113, Germany

Location

Clincal Center Chemnitz

Chemnitz, Saxony, 09113, Germany

Location

Radiotherapy Practice Dr. A. Schreiber, Dresden

Dresden, Saxony, 01067, Germany

Location

Oncology Practice Dresden

Dresden, Saxony, 01307, Germany

Location

University Clinic Leipzig

Leipzig, Saxony, 04103, Germany

Location

Clinic Sankt Georg gGmbH, Leipzig

Leipzig, Saxony, 04129, Germany

Location

University Clinic Magdeburg

Magdeburg, Saxony-Anhalt, 39120, Germany

Location

University Clinic Kiel

Kiel, Schleswig-Holstein, 24105, Germany

Location

Vivantes Clincial Center in Friedrichshain

Berlin, 10249, Germany

Location

Clincal Center Helios Berlin Buch

Berlin, 13125, Germany

Location

Ev. Waldkrankenhaus, Spandau,

Berlin, 13589, Germany

Location

Helios Klinikum Berlin Emil von Behring

Berlin, 14650, Germany

Location

Klinikum Bielefeld

Bielefeld, 33604, Germany

Location

Onkologische Schwerpunktpraxis

Darmstadt, 64287, Germany

Location

Department of Radiooncology

Frankfurt, 60590, Germany

Location

Praxis für Hämatologie und Onkologie

Giessen, 35392, Germany

Location

Universitätsklinikum Halle

Halle, 06120, Germany

Location

Alexianer Krefeld GmbH / Maria Hilf Krankenhaus

Krefeld, 47805, Germany

Location

Uniklinik Schleswig Holstein

Lübeck, 23538, Germany

Location

Dietrich Bonhoeffer Klinik

Neubrandenburg, 17036, Germany

Location

Med. Statistik Saarbrücken GgR

Saarbrücken, 66113, Germany

Location

Schwarzwald-Baar-Kliniken

Villingen-Schwenningen, 78052, Germany

Location

MeSH Terms

Conditions

Rectal Neoplasms

Interventions

Oxaliplatin; Fluorouracil; Leucovorin; Capecitabine

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Claus Roedel, Prof. Dr.

  clinic for radiotherapy

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: INVESTIGATOR
• Masking Details: multicentre, open-labeled, Phase III study
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prof. Dr. med.

Model Details: Investigator-driven

Study Record Dates

• First Submitted: January 23, 2020
• First Posted: January 29, 2020
• Study Start: November 5, 2020
• Primary Completion: September 15, 2023
• Study Completion (Estimated): September 15, 2028
• Last Updated: September 19, 2024

Record last verified: 2024-09

Locations

DE (76)