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

NCT ID: NCT04246684

Last Updated: 2024-09-19

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 702 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-11-05
• Study Completion Date: 2028-09-15

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.

Conditions

Rectal Cancer Stage III

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Control arm

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.

Group Type: ACTIVE_COMPARATOR

Oxaliplatin, 85 mg/m2

Intervention Type: DRUG

85 mg/m2,2h-civ, day 22, 36, 50, 64, 78, 92, 106, 120, and 134 of therapy

5FU; 2400 mg/m2

Intervention Type: DRUG

2400 mg/m2, 46h-civ, day 22, 36, 50, 64, 78, 92, 106, 120, 134 of therapy for Control arm

Folinic Acid, 400 mg/m2

Intervention Type: 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

Radiotherapy control, 5x5 Gy: 25 Gy

Intervention Type: RADIATION

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

Capecitabine, 1000 mg/m2

Intervention Type: DRUG

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

Oxaliplatin, 130 mg/m2

Intervention Type: DRUG

day1every three weeks (optional)

Experimental arm

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.

Group Type: EXPERIMENTAL

5FU, 250 mg/m2

Intervention Type: DRUG

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

5FU, 2400 mg/m2

Intervention Type: DRUG

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

Oxaliplatin 50 mg/m2

Intervention Type: DRUG

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

Folinic Acid, 400 mg/m2

Intervention Type: 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

Capecitabine, 1000 mg/m2

Intervention Type: DRUG

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

Oxaliplatin 85 mg/m2

Intervention Type: DRUG

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

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

Intervention Type: RADIATION

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

Capecitabine, 825 mg/m2

Intervention Type: DRUG

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

Oxaliplatin, 130 mg/m2

Intervention Type: DRUG

day1every three weeks (optional)

Interventions

Oxaliplatin, 85 mg/m2

85 mg/m2,2h-civ, day 22, 36, 50, 64, 78, 92, 106, 120, and 134 of therapy

Intervention Type: DRUG

5FU; 2400 mg/m2

2400 mg/m2, 46h-civ, day 22, 36, 50, 64, 78, 92, 106, 120, 134 of therapy for Control arm

Intervention Type: DRUG

5FU, 250 mg/m2

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

Intervention Type: DRUG

5FU, 2400 mg/m2

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

Intervention Type: DRUG

Oxaliplatin 50 mg/m2

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

Intervention Type: DRUG

Folinic Acid, 400 mg/m2

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

Intervention Type: DRUG

Radiotherapy control, 5x5 Gy: 25 Gy

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

Intervention Type: RADIATION

Capecitabine, 1000 mg/m2

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

Intervention Type: DRUG

Oxaliplatin 85 mg/m2

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

Intervention Type: DRUG

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

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

Intervention Type: RADIATION

Capecitabine, 825 mg/m2

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

Intervention Type: DRUG

Oxaliplatin, 130 mg/m2

day1every three weeks (optional)

Intervention Type: DRUG

Other Intervention Names

Control arm; 5-FU, control arm; Experimental arm: 5-FU; experimental arm; Experimental arm; Folinic Acid; Capecitabine; experimental arm; Capecitabine; Oxaliplatin

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.
• 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).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Prof. Dr. med. Claus Rödel

OTHER

Sponsor Role: lead

Responsible Party

Prof. Dr. med. Claus Rödel

Prof. Dr. med.

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Claus Roedel, Prof. Dr.

Role: STUDY_DIRECTOR

clinic for radiotherapy

Locations

Clincal Center Esslingen

Esslingen am Neckar, Baden-Wurttemberg, Germany

University Clinic Freiburg

Freiburg im Breisgau, Baden-Wurttemberg, Germany

University Clinic Mannheim

Mannheim, Baden-Wurttemberg, Germany

Clinic Ostlab, Staufenclinic Schwaeb.Gmuend, Mutlangen

Mutlangen, Baden-Wurttemberg, Germany

Pi.Tri-Studien GmbH, Offenburg

Offenburg, Baden-Wurttemberg, Germany

Medius Clincal Center Ostfildern-Ruit

Ostfildern, Baden-Wurttemberg, Germany

Clinic Stuttgart

Stuttgart, Baden-Wurttemberg, Germany

University Clinic for Radioncology Tübingen

Tübingen, Baden-Wurttemberg, Germany

University Clinic Ulm

Ulm, Baden-Wurttemberg, Germany

Clincal Center "St. Marien" Amberg

Amberg, Bavaria, Germany

Clinic Bayreuth GmbH

Bayreuth, Bavaria, Germany

Clinical Center Coburg

Coburg, Bavaria, Germany

University Clinic Erlangen

Erlangen, Bavaria, Germany

Klinikverbund Allgäu

Kempten (Allgäu), Bavaria, Germany

Technical University Clinic Munich

München, Bavaria, Germany

Technical University Munich

München, Bavaria, Germany

Clincal Center "Bogenhausen" Munich

München, Bavaria, Germany

Hospital "Barmherzige Brüder" Regensburg

Regensburg, Bavaria, Germany

University Clinic Regensburg

Regensburg, Bavaria, Germany

Clinic Nordoberpfalz AG, Clinic Weiden

Weiden, Bavaria, Germany

University Clinic Würzburg

Würzburg, Bavaria, Germany

Clincal Center Helios Bad Saarrow

Bad Saarow, Brandenburg, Germany

Clincal Center Darmstadt

Darmstadt, Hesse, Germany

Clinic North West gGmbH Frankfurt

Frankfurt am Main, Hesse, Germany

Clinic Fulda

Fulda, Hesse, Germany

DRK Clincal Centers North Hessen Kassel

Kassel, Hesse, Germany

University Clinic Marburg

Marburg, Hesse, Germany

Sana Clinical Center Offenbach

Offenbach, Hesse, Germany

Lahn-Dill Clinics Wetzlar

Wetzlar, Hesse, Germany

MVZ Oncological Cooperation Harz

Goslar, Lower Saxony, Germany

University Clinic Göttingen

Göttingen, Lower Saxony, Germany

Hematological-Oncological Practice Dr. Oleg Rubanov, Hameln

Hamelin, Lower Saxony, Germany

Medical Project Hannover

Hanover, Lower Saxony, Germany

"St. Bernward" Clincal Center Hildesheim

Hildesheim, Lower Saxony, Germany

Oncology in Medicinum Hildesheim

Hildesheim, Lower Saxony, Germany

Oncology UnterEms, Leer

Leer, Lower Saxony, Germany

Pius Hospital, Oldenburg

Oldenburg, Lower Saxony, Germany

University Clinic Oldenburg

Oldenburg, Lower Saxony, Germany

Clinic Wolfsburg

Wolfsburg, Lower Saxony, Germany

University Clinic Rostock

Rostock, Mecklenburg-Vorpommern, Germany

Franziskus Hospital Bielefeld

Bielefeld, North Rhine-Westphalia, Germany

St. Josef Hospital of the catholic clinic Bochum

Bochum, North Rhine-Westphalia, Germany

Hospital Bochum

Bochum, North Rhine-Westphalia, Germany

Clinic Lippe GmbH (Lemgo/Detmold)

Detmold, North Rhine-Westphalia, Germany

University Clinic Essen

Essen, North Rhine-Westphalia, Germany

Clinical Center "Essen Mitte"

Essen, North Rhine-Westphalia, Germany

Clinic Maria Hilf GmbH

Mönchengladbach, North Rhine-Westphalia, Germany

Brother clinic St. Josef, Paderborn

Paderborn, North Rhine-Westphalia, Germany

St. Vincenz Hospital Paderborn

Paderborn, North Rhine-Westphalia, Germany

Prosper Hospital Recklinghausen

Recklinghausen, North Rhine-Westphalia, Germany

Mathias-Spital, Rheine

Rheine, North Rhine-Westphalia, Germany

Evangelical Clinic Wesel

Wesel, North Rhine-Westphalia, Germany

University Clinic Mainz

Mainz, Rhineland-Palantine, Germany

Clinical Center "Mutterhaus" Trier

Trier, Rhineland-Palatinate, Germany

CaritasClinic Saarbrücken

Saarbrücken, Saarland, Germany

Clincal Center Chemnitz

Chemnitz, Saxony, Germany

Radiotherapy Practice Dr. A. Schreiber, Dresden

Dresden, Saxony, Germany

Oncology Practice Dresden

Dresden, Saxony, Germany

University Clinic Leipzig

Leipzig, Saxony, Germany

Clinic Sankt Georg gGmbH, Leipzig

Leipzig, Saxony, Germany

University Clinic Magdeburg

Magdeburg, Saxony-Anhalt, Germany

University Clinic Kiel

Kiel, Schleswig-Holstein, Germany

Vivantes Clincial Center in Friedrichshain

Berlin, , Germany

Clincal Center Helios Berlin Buch

Berlin, , Germany

Ev. Waldkrankenhaus, Spandau,

Berlin, , Germany

Helios Klinikum Berlin Emil von Behring

Berlin, , Germany

Klinikum Bielefeld

Bielefeld, , Germany

Onkologische Schwerpunktpraxis

Darmstadt, , Germany

Department of Radiooncology

Frankfurt, , Germany

Praxis für Hämatologie und Onkologie

Giessen, , Germany

Universitätsklinikum Halle

Halle, , Germany

Alexianer Krefeld GmbH / Maria Hilf Krankenhaus

Krefeld, , Germany

Uniklinik Schleswig Holstein

Lübeck, , Germany

Dietrich Bonhoeffer Klinik

Neubrandenburg, , Germany

Med. Statistik Saarbrücken GgR

Saarbrücken, , Germany

Schwarzwald-Baar-Kliniken

Villingen-Schwenningen, , Germany

Countries

Germany

Other Identifiers

ACO/ARO/AIO-18.1

Identifier Type: -

Identifier Source: org_study_id