Short RT Versus RCT,Followed by Chemo and Organ Preservation for Interm and High-risk Rectal Cancer Patients (NCT04246684) — Germany Trial Details

Condition(s) studied

Rectal Cancer Stage III

Investigational drug(s) / intervention(s)

Oxaliplatin, 85 mg/m2 →5FU; 2400 mg/m2 →5FU, 250 mg/m2 →5FU, 2400 mg/m2 →Oxaliplatin 50 mg/m2 →Folinic Acid, 400 mg/m2 →Radiotherapy control, 5x5 Gy: 25 GyCapecitabine, 1000 mg/m2 →Oxaliplatin 85 mg/m2 →radiotherapy experimental, 30 x 1,8 Gy: 54 GyCapecitabine, 825 mg/m2 →Oxaliplatin, 130 mg/m2 →

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

5FU; 2400 mg/m2: 2400 mg/m2, 46h-civ, day 22, 36, 50, 64, 78, 92, 106, 120, 134 of therapy for Control arm

5FU, 250 mg/m2: 250 mg/m2 per day, civ, on day 1-14, day 22-35 of radiotherapy;

5FU, 2400 mg/m2: 2400 mg/m2,46h-civ, d64, d78, d92, d106, d120, d134 of therapy

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

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

Radiotherapy control, 5x5 Gy: 25 Gy: Control arm: 5x5 Gy (total: 25 Gy) 5 fractions

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

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

radiotherapy experimental, 30 x 1,8 Gy: 54 Gy: 30 x 1.8 Gy (total: 54 Gy), 5 fractions per week

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

Oxaliplatin, 130 mg/m2: day1every three weeks (optional)

Study 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.

Eligibility

Sex

ALL

Min age

18 Years

Max age

—

Healthy volunteers

No

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 outcome measure(s)

organ preservation — 3 years
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.

Trial sites (75)

Facility	City	Region
Clincal Center Esslingen	Esslingen am Neckar	Baden-Wurttemberg
University Clinic Freiburg	Freiburg im Breisgau	Baden-Wurttemberg
University Clinic Mannheim	Mannheim	Baden-Wurttemberg
Clinic Ostlab, Staufenclinic Schwaeb.Gmuend, Mutlangen	Mutlangen	Baden-Wurttemberg
Pi.Tri-Studien GmbH, Offenburg	Offenburg	Baden-Wurttemberg
Medius Clincal Center Ostfildern-Ruit	Ostfildern	Baden-Wurttemberg
Clinic Stuttgart	Stuttgart	Baden-Wurttemberg
University Clinic for Radioncology Tübingen	Tübingen	Baden-Wurttemberg
University Clinic Ulm	Ulm	Baden-Wurttemberg
Clincal Center "St. Marien" Amberg	Amberg	Bavaria
Clinic Bayreuth GmbH	Bayreuth	Bavaria
Clinical Center Coburg	Coburg	Bavaria
University Clinic Erlangen	Erlangen	Bavaria
Klinikverbund Allgäu	Kempten (Allgäu)	Bavaria
Technical University Clinic Munich	München	Bavaria
Technical University Munich	München	Bavaria
Clincal Center "Bogenhausen" Munich	München	Bavaria
Hospital "Barmherzige Brüder" Regensburg	Regensburg	Bavaria
University Clinic Regensburg	Regensburg	Bavaria
Clinic Nordoberpfalz AG, Clinic Weiden	Weiden	Bavaria
University Clinic Würzburg	Würzburg	Bavaria
Clincal Center Helios Bad Saarrow	Bad Saarow	Brandenburg
Department of Radiooncology	Frankfurt	Frankfurt
Clincal Center Darmstadt	Darmstadt	Hesse
Clinic North West gGmbH Frankfurt	Frankfurt am Main	Hesse
Clinic Fulda	Fulda	Hesse
DRK Clincal Centers North Hessen Kassel	Kassel	Hesse
University Clinic Marburg	Marburg	Hesse
Sana Clinical Center Offenbach	Offenbach	Hesse
Lahn-Dill Clinics Wetzlar	Wetzlar	Hesse
MVZ Oncological Cooperation Harz	Goslar	Lower Saxony
University Clinic Göttingen	Göttingen	Lower Saxony
Hematological-Oncological Practice Dr. Oleg Rubanov, Hameln	Hamelin	Lower Saxony
Medical Project Hannover	Hanover	Lower Saxony
"St. Bernward" Clincal Center Hildesheim	Hildesheim	Lower Saxony
Oncology in Medicinum Hildesheim	Hildesheim	Lower Saxony
Oncology UnterEms, Leer	Leer	Lower Saxony
Pius Hospital, Oldenburg	Oldenburg	Lower Saxony
University Clinic Oldenburg	Oldenburg	Lower Saxony
Clinic Wolfsburg	Wolfsburg	Lower Saxony

+ 35 more sites — see the full list on the official registry below.