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

Rectal Cancer Stage III Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04246684
• Other study ID #: ACO/ARO/AIO-18.1
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: October 15, 2020
• Est. completion date: October 14, 2028

Study information

• Verified date: December 2022
• Source: Goethe University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 702
• Est. completion date: October 14, 2028
• Est. primary completion date: October 14, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Rectal Cancer Stage III
• Rectal Neoplasms

Intervention

Drug:
• 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

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

Drug:
• 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

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

Drug:
• 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)

Locations

Country	Name	City	State
Germany	Clincal Center "St. Marien" Amberg	Amberg	Bavaria
Germany	Clincal Center Helios Bad Saarrow	Bad Saarow	Brandenburg
Germany	Clinic Bayreuth GmbH	Bayreuth	Bavaria
Germany	Clincal Center Helios Berlin Buch	Berlin
Germany	Ev. Waldkrankenhaus, Spandau,	Berlin
Germany	Helios Klinikum Berlin Emil von Behring	Berlin
Germany	Vivantes Clincial Center in Friedrichshain	Berlin
Germany	Franziskus Hospital Bielefeld	Bielefeld	North Rhine-Westphalia
Germany	Klinikum Bielefeld	Bielefeld
Germany	Hospital Bochum	Bochum	North Rhine-Westphalia
Germany	St. Josef Hospital of the catholic clinic Bochum	Bochum	North Rhine Westphalia
Germany	Clincal Center Chemnitz	Chemnitz	Saxony
Germany	Clinical Center Coburg	Coburg	Bavaria
Germany	Clincal Center Darmstadt	Darmstadt	Hessen
Germany	Onkologische Schwerpunktpraxis	Darmstadt
Germany	Clinic Lippe GmbH (Lemgo/Detmold)	Detmold	North Rhine-Westphalia
Germany	Oncology Practice Dresden	Dresden	Saxony
Germany	Radiotherapy Practice Dr. A. Schreiber, Dresden	Dresden	Saxony
Germany	University Clinic Erlangen	Erlangen	Bavaria
Germany	Clinical Center "Essen Mitte"	Essen	North Rhine-Westphalia
Germany	University Clinic Essen	Essen	North Rhine-Westphalia
Germany	Clincal Center Esslingen	Esslingen	Baden-Wuerttemberg
Germany	Department of Radiooncology	Frankfurt
Germany	Clinic North West gGmbH Frankfurt	Frankfurt am Main	Hessen
Germany	University Clinic Freiburg	Freiburg	Baden-Wuerttemberg
Germany	Clinic Fulda	Fulda	Hessen
Germany	Praxis für Hämatologie und Onkologie	Gießen
Germany	MVZ Oncological Cooperation Harz	Goslar	Lower Saxony
Germany	University Clinic Göttingen	Göttingen	Lower Saxony
Germany	Universitätsklinikum Halle	Halle (Saale)
Germany	Hematological-Oncological Practice Dr. Oleg Rubanov, Hameln	Hameln	Lower Saxony
Germany	Medical Project Hannover	Hannover	Lower Saxony
Germany	"St. Bernward" Clincal Center Hildesheim	Hildesheim	Lower Saxony
Germany	Oncology in Medicinum Hildesheim	Hildesheim	Lower Saxony
Germany	DRK Clincal Centers North Hessen Kassel	Kassel	Hessen
Germany	Klinikverbund Allgäu	Kempten	Bavaria
Germany	University Clinic Kiel	Kiel	Schleswig-Holstein
Germany	Alexianer Krefeld GmbH / Maria Hilf Krankenhaus	Krefeld
Germany	Oncology UnterEms, Leer	Leer	Lower Saxony
Germany	Clinic Sankt Georg gGmbH, Leipzig	Leipzig	Saxony
Germany	University Clinic Leipzig	Leipzig	Saxony
Germany	Uniklinik Schleswig Holstein	Luebeck
Germany	University Clinic Magdeburg	Magdeburg	Saxony-Anhalt
Germany	University Clinic Mainz	Mainz	Rhineland-Palantine
Germany	University Clinic Mannheim	Mannheim	Baden-Wuerttemberg
Germany	University Clinic Marburg	Marburg	Hessen
Germany	Clinic Maria Hilf GmbH	Mönchengladbach	North Rhine-Westphalia
Germany	Clincal Center "Bogenhausen" Munich	München	Bavaria
Germany	Technical University Clinic Munich	München	Bavaria
Germany	Technical University Munich	München	Bavaria
Germany	Clinic Ostlab, Staufenclinic Schwaeb.Gmuend, Mutlangen	Mutlangen	Baden-Wuerttemberg
Germany	Dietrich Bonhoeffer Klinik	Neubrandenburg
Germany	Sana Clinical Center Offenbach	Offenbach	Hessen
Germany	Pi.Tri-Studien GmbH, Offenburg	Offenburg	Baden-Wuerttemberg
Germany	Pius Hospital, Oldenburg	Oldenburg	Lower Saxony
Germany	University Clinic Oldenburg	Oldenburg	Lower Saxony
Germany	Medius Clincal Center Ostfildern-Ruit	Ostfildern	Baden-Wuerttemberg
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	Hospital "Barmherzige Brüder" Regensburg	Regensburg	Bavaria
Germany	University Clinic Regensburg	Regensburg	Bavaria
Germany	Mathias-Spital, Rheine	Rheine	North Rhine-Westphalia
Germany	University Clinic Rostock	Rostock	Mecklenburg Western Pomerania
Germany	CaritasClinic Saarbrücken	Saarbrücken	Saarland
Germany	Med. Statistik Saarbrücken GgR	Saarbruecken
Germany	Clinic Stuttgart	Stuttgart	Baden-Wuerttemberg
Germany	Clinical Center "Mutterhaus" Trier	Trier	Rhineland-Palatinate
Germany	University Clinic for Radioncology Tübingen	Tübingen	Baden-Wuerttemberg
Germany	University Clinic Ulm	Ulm	Baden-Wuerttemberg
Germany	Schwarzwald-Baar-Kliniken	Villingen-Schwenningen
Germany	Clinic Nordoberpfalz AG, Clinic Weiden	Weiden	Bavaria
Germany	Evangelical Clinic Wesel	Wesel	North Rhine Westphalia
Germany	Lahn-Dill Clinics Wetzlar	Wetzlar	Hessen
Germany	Clinic Wolfsburg	Wolfsburg	Lower Saxony
Germany	University Clinic Würzburg	Würzburg	Bavaria

Sponsors (1)

Lead Sponsor	Collaborator
Prof. Dr. med. Claus Rödel

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Disease-free survival	Disease-free survival	3 years
Secondary	Rate of clinical complete response after TNT:	TNT total neoadjuvant therapy	3 years
Secondary	Rate of immediate TME after TNT	TNT total neoadjuvant therapy TME total mesorectal excision	3 years
Secondary	Cumulative incidence of locoregional regrowth after cCR	cCR clinical complete response	3 years
Secondary	Rate of salvage surgery (LE/TME with or APR/stoma) after locoregional regrowth APR/stoma) after locoregional regrowth	LE local Exision; TME: Transanale endoscopic Mikrochirurgie; APR Abdomino perineal Rectum exstirpation	3 years
Secondary	Cumulative incidence of local recurrence after (salvage) surgery surgery	Cumulative incidence of local recurrence after (salvage) surgery	3 years
Secondary	Postoperative complications of (salvage) surgery	Postoperative complications of (salvage) surgery	3 years
Secondary	Rate of sphincter-sparing (salvage) surgery	Rate of sphincter-sparing (salvage) surgery	3 years
Secondary	Pathological TNM-staging	Pathological tumor evaluations;TNM tumor staging	3 years
Secondary	R0 resection rate; negative circumferential resection rate	R0 Removal of the tumor in healthy tissue	3 years
Secondary	Tumor regression grading according to Dworak	pathological response from scale 1-4 poor to very good ascending	3 years
Secondary	Neoadjuvant rectal score	Neoadjuvant rectal score from low to high values means good to poor	3 years
Secondary	Quality of TME according to MERCURY	Tumor response using MRI scale 1-5 from good to poor descending	3 years
Secondary	Acute and late toxicity assessment according to NCI CTCAE V.5.0) CTCAE V.5.0)	CTCAE V.5.0	3 Yeears
Secondary	Quality of life C30 based on treatment arm and surgical procedures/organ preservation	Quality of life based on EORTC-QLQs-C30	3 years
Secondary	functional outcome based on treatment arm and surgical procedures/organ preservation	functional outcome based on Wexner score	3 years
Secondary	Quality of life CR29 based on treatment arm and surgical procedures/organ preservation	Quality of life based on EORTC-QLQs-CR29	3 years
Secondary	Quality of life CPIN 20 based on treatment arm and surgical procedures/organ preservation	Quality of life based on EORTC-QLQs-CPIN20 Quality of life based on EORTC-QLQs-CPIN20	3 years
Secondary	Cumulative incidence of distant metastases	Cumulative incidence of distant metastases	3 Years
Secondary	Overall survival	Overall survival	3 years
Secondary	Translational / biomarker studies	The translational research program will include proteomics, genomics and immune profile assessment in primary tumor samples as well as peripheral bloods samples (liquid biopsy).; Tumor tissue samples and blood will be collected, processed and stored using protocols.; Primary tumor tissue with either fresh tissue or formalin-fixed, paraffin-embedded (FFPE) tissue will be collected at two different time points: i) preoperative biopsy; ii) before/during surgical resection. Peripheral blood samples will be stored at three different time points: i) immediately before initiation of preoperative treatment (day 1); ii) during therapy assessment at week 22-24 and iii) at the time point of the first follow up.	3 years