Short-course Radiotherapy Versus Chemoradiotherapy, Followed by Consolidation Chemotherapy, and Selective Organ Preservation for MRI-defined Intermediate and High-risk Rectal Cancer Patients

Sponsor

Prof. Dr. med. Claus Rödel (Other)

Overall Status

Recruiting

CT.gov ID

NCT04246684

Collaborator

(none)

702

Enrollment

Locations

Arms

Anticipated Duration (Months)

10.8

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Rectal Cancer Stage III	Drug: Oxaliplatin, 85 mg/m2 Drug: 5FU; 2400 mg/m2 Drug: 5FU, 250 mg/m2 Drug: 5FU, 2400 mg/m2 Drug: Oxaliplatin 50 mg/m2 Drug: Folinic Acid, 400 mg/m2 Radiation: Radiotherapy control, 5x5 Gy: 25 Gy 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	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

702 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Investigator-drivenInvestigator-driven

Masking:

Single (Investigator)

Masking Description:

multicentre, open-labeled, Phase III study

Primary Purpose:

Treatment

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

Actual Study Start Date :

Oct 15, 2020

Anticipated Primary Completion Date :

Oct 14, 2025

Anticipated Study Completion Date :

Oct 14, 2028

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 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.	Drug: Oxaliplatin, 85 mg/m2 85 mg/m2,2h-civ, day 22, 36, 50, 64, 78, 92, 106, 120, and 134 of therapy Other Names: Control arm 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 Other Names: 5-FU, control arm 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 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 Drug: Oxaliplatin, 130 mg/m2 day1every three weeks (optional)
Experimental: 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.	Drug: 5FU, 250 mg/m2 250 mg/m2 per day, civ, on day 1-14, day 22-35 of radiotherapy; Other Names: Experimental arm: 5-FU Drug: 5FU, 2400 mg/m2 2400 mg/m2,46h-civ, d64, d78, d92, d106, d120, d134 of therapy Other Names: experimental arm Drug: Oxaliplatin 50 mg/m2 50 mg/m2, 2h-civ, d1, d8, d21, d29 of radiotherapy and Other Names: Experimental arm 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 Drug: Capecitabine, 1000 mg/m2 1000 mg/m2 (twice daily) day1-14 every three weeks instead of 5FU optional Drug: Oxaliplatin 85 mg/m2 85 mg/m2, 2h-civ, d64, d78, d92, d106, d120, d134 of therapy Other Names: experimental arm 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 Drug: Oxaliplatin, 130 mg/m2 day1every three weeks (optional)

Arm

Intervention/Treatment

Active Comparator: 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.

Drug: Oxaliplatin, 85 mg/m2

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

Other Names:

Control arm

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

Other Names:

5-FU, control arm

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

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

Drug: Oxaliplatin, 130 mg/m2

day1every three weeks (optional)

Experimental: 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.

Drug: 5FU, 250 mg/m2

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

Other Names:

Experimental arm: 5-FU

Drug: 5FU, 2400 mg/m2

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

Other Names:

experimental arm

Drug: Oxaliplatin 50 mg/m2

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

Other Names:

Experimental arm

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

Drug: Capecitabine, 1000 mg/m2

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

Drug: Oxaliplatin 85 mg/m2

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

Other Names:

experimental arm

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

Drug: Oxaliplatin, 130 mg/m2

day1every three weeks (optional)

Outcome Measures

Primary Outcome Measures

disease-free survival (DFS) [the 3 years DFS survival]
this is defined as the time from randomisation to one of the following events: no resection of primary tumor due to progression, nonradical surgery of the primary tumor (R2 resection), locoregional recurrence after R0/1 resection of the primary tumor, nonsalvageable local regrowth in case of W&W management (no salvage operation or R2 resection), metastatic disease before, at, or after surgery or W&W management, second primary colorectal or other cancer, or death (all cause), whichever occurs first.

Secondary Outcome Measures

Acute and late toxicity, Incidence of Treatment-Emergent Adverse Events assessment according to NCICTCAE V.5.0 [3 years]
Surgical morbidity and complications [3 years]
Rate of sphincter-sparing surgery [3 years]
Pathological TNM-staging, Number of participants with histologically complete response [3 years]
R0 resection rate; negative circumferential resection rate [3 years]
Tumor regression grading according to Dworak [3 years]
Quality of TME according to MERCURY [3 years]
Pathological tumor evaluations
Rate of W&W with or without local regrowth [3 years]
Cumulative incidence of local and distant recurrences [3 years]
Overall survival [3 years]
Quality of life arm and surgical procedures [3 years]
QLQ C30, CR29
Translational study with FACS analyses [3 years]
functional outcome based on Treatment, Wexner-Vaizey-Score [3 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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
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

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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Clincal Center Esslingen	Esslingen	Baden-Wuerttemberg	Germany	73730
2	University Clinic Freiburg	Freiburg	Baden-Wuerttemberg	Germany	79106
3	University Clinic Mannheim	Mannheim	Baden-Wuerttemberg	Germany	68167
4	Clinic Ostlab, Staufenclinic Schwaeb.Gmuend, Mutlangen	Mutlangen	Baden-Wuerttemberg	Germany	73557
5	Pi.Tri-Studien GmbH, Offenburg	Offenburg	Baden-Wuerttemberg	Germany	77654
6	Medius Clincal Center Ostfildern-Ruit	Ostfildern	Baden-Wuerttemberg	Germany	73760
7	Clinic Stuttgart	Stuttgart	Baden-Wuerttemberg	Germany	70174
8	University Clinic for Radioncology Tübingen	Tübingen	Baden-Wuerttemberg	Germany	72076
9	University Clinic Ulm	Ulm	Baden-Wuerttemberg	Germany	89081
10	Clincal Center "St. Marien" Amberg	Amberg	Bavaria	Germany	92224
11	Clinic Bayreuth GmbH	Bayreuth	Bavaria	Germany	95445
12	Clinical Center Coburg	Coburg	Bavaria	Germany	96450
13	University Clinic Erlangen	Erlangen	Bavaria	Germany	91054
14	Klinikverbund Allgäu	Kempten	Bavaria	Germany	87439
15	Technical University Clinic Munich	München	Bavaria	Germany	81675
16	Technical University Munich	München	Bavaria	Germany	81675
17	Clincal Center "Bogenhausen" Munich	München	Bavaria	Germany	81925
18	Hospital "Barmherzige Brüder" Regensburg	Regensburg	Bavaria	Germany	93046
19	University Clinic Regensburg	Regensburg	Bavaria	Germany	93053
20	Clinic Nordoberpfalz AG, Clinic Weiden	Weiden	Bavaria	Germany	92637
21	University Clinic Würzburg	Würzburg	Bavaria	Germany	97080
22	Clincal Center Helios Bad Saarrow	Bad Saarow	Brandenburg	Germany	15526
23	Clincal Center Darmstadt	Darmstadt	Hessen	Germany	64283
24	Clinic North West gGmbH Frankfurt	Frankfurt am Main	Hessen	Germany	60488
25	Clinic Fulda	Fulda	Hessen	Germany	36043
26	DRK Clincal Centers North Hessen Kassel	Kassel	Hessen	Germany	34121
27	University Clinic Marburg	Marburg	Hessen	Germany	35043
28	Sana Clinical Center Offenbach	Offenbach	Hessen	Germany	63069
29	Lahn-Dill Clinics Wetzlar	Wetzlar	Hessen	Germany	35578
30	MVZ Oncological Cooperation Harz	Goslar	Lower Saxony	Germany	38642
31	University Clinic Göttingen	Göttingen	Lower Saxony	Germany	37075
32	Hematological-Oncological Practice Dr. Oleg Rubanov, Hameln	Hameln	Lower Saxony	Germany	31785
33	Medical Project Hannover	Hannover	Lower Saxony	Germany	30171
34	"St. Bernward" Clincal Center Hildesheim	Hildesheim	Lower Saxony	Germany	31134
35	Oncology in Medicinum Hildesheim	Hildesheim	Lower Saxony	Germany	31135
36	Oncology UnterEms, Leer	Leer	Lower Saxony	Germany	26789
37	Pius Hospital, Oldenburg	Oldenburg	Lower Saxony	Germany	25121
38	University Clinic Oldenburg	Oldenburg	Lower Saxony	Germany	26133
39	Clinic Wolfsburg	Wolfsburg	Lower Saxony	Germany	38440
40	University Clinic Rostock	Rostock	Mecklenburg Western Pomerania	Germany	18059
41	St. Josef Hospital of the catholic clinic Bochum	Bochum	North Rhine Westphalia	Germany	44791
42	Brother clinic St. Josef, Paderborn	Paderborn	North Rhine Westphalia	Germany	33098
43	Evangelical Clinic Wesel	Wesel	North Rhine Westphalia	Germany	46485
44	Franziskus Hospital Bielefeld	Bielefeld	North Rhine-Westphalia	Germany	33615
45	Hospital Bochum	Bochum	North Rhine-Westphalia	Germany	44892
46	Clinic Lippe GmbH (Lemgo/Detmold)	Detmold	North Rhine-Westphalia	Germany	32756
47	University Clinic Essen	Essen	North Rhine-Westphalia	Germany	45122
48	Clinical Center "Essen Mitte"	Essen	North Rhine-Westphalia	Germany	45136
49	Clinic Maria Hilf GmbH	Mönchengladbach	North Rhine-Westphalia	Germany	41063
50	St. Vincenz Hospital Paderborn	Paderborn	North Rhine-Westphalia	Germany	33098
51	Prosper Hospital Recklinghausen	Recklinghausen	North Rhine-Westphalia	Germany	45659
52	Mathias-Spital, Rheine	Rheine	North Rhine-Westphalia	Germany	48431
53	University Clinic Mainz	Mainz	Rhineland-Palantine	Germany	55116
54	Clinical Center "Mutterhaus" Trier	Trier	Rhineland-Palatinate	Germany	54290
55	CaritasClinic Saarbrücken	Saarbrücken	Saarland	Germany	66113
56	University Clinic Magdeburg	Magdeburg	Saxony-Anhalt	Germany	39120
57	Clincal Center Chemnitz	Chemnitz	Saxony	Germany	09113
58	Radiotherapy Practice Dr. A. Schreiber, Dresden	Dresden	Saxony	Germany	01067
59	Oncology Practice Dresden	Dresden	Saxony	Germany	01307
60	University Clinic Leipzig	Leipzig	Saxony	Germany	04103
61	Clinic Sankt Georg gGmbH, Leipzig	Leipzig	Saxony	Germany	04129
62	University Clinic Kiel	Kiel	Schleswig-Holstein	Germany	24105
63	Vivantes Clincial Center in Friedrichshain	Berlin		Germany	10249
64	Clincal Center Helios Berlin Buch	Berlin		Germany	13125
65	Department of Radiooncology	Frankfurt		Germany	60590