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

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ClinicalTrials.gov Identifier: NCT04246684
Recruitment Status : Recruiting
First Posted : January 29, 2020
Last Update Posted : June 16, 2021
Sponsor:
Information provided by (Responsible Party):
Prof. Dr. med. Claus Rödel, Goethe University

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 702 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Investigator-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 : October 15, 2020
Estimated Primary Completion Date : October 14, 2025
Estimated Study Completion Date : October 14, 2028

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 Name: 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 Name: 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 Name: Experimental arm: 5-FU

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

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




Primary Outcome Measures :
  1. disease-free survival (DFS) [ Time Frame: 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 :
  1. Acute and late toxicity, Incidence of Treatment-Emergent Adverse Events assessment according to NCICTCAE V.5.0 [ Time Frame: 3 years ]
  2. Surgical morbidity and complications [ Time Frame: 3 years ]
  3. Rate of sphincter-sparing surgery [ Time Frame: 3 years ]
  4. Pathological TNM-staging, Number of participants with histologically complete response [ Time Frame: 3 years ]
  5. R0 resection rate; negative circumferential resection rate [ Time Frame: 3 years ]
  6. Tumor regression grading according to Dworak [ Time Frame: 3 years ]
  7. Quality of TME according to MERCURY [ Time Frame: 3 years ]
    Pathological tumor evaluations

  8. Rate of W&W with or without local regrowth [ Time Frame: 3 years ]
  9. Cumulative incidence of local and distant recurrences [ Time Frame: 3 years ]
  10. Overall survival [ Time Frame: 3 years ]
  11. Quality of life arm and surgical procedures [ Time Frame: 3 years ]
    QLQ C30, CR29

  12. Translational study with FACS analyses [ Time Frame: 3 years ]
  13. functional outcome based on Treatment, Wexner-Vaizey-Score [ Time Frame: 3 years ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Male and female patients with histologically confirmed diagnosis of rectal adenocarcinoma localised 0 - 12 cm from the anocutaneous line as measured by rigid rectoscopy
Accepts Healthy Volunteers:   No
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.
  • 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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04246684


Contacts
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Contact: Claus Roedel, Prof. Dr. 0049-69-6301 ext 5130 claus.roedel@kgu.de
Contact: Emmanouil Fokas, Prof. Dr. 0049-69-6301 ext 5130 emmanouil.fokas@kgu.de

Locations
Show Show 65 study locations
Sponsors and Collaborators
Prof. Dr. med. Claus Rödel
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Responsible Party: Prof. Dr. med. Claus Rödel, Prof. Dr. med., Goethe University
ClinicalTrials.gov Identifier: NCT04246684    
Other Study ID Numbers: ACO/ARO/AIO-18.1
First Posted: January 29, 2020    Key Record Dates
Last Update Posted: June 16, 2021
Last Verified: June 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases
Leucovorin
Folic Acid
Capecitabine
Fluorouracil
Oxaliplatin
Levoleucovorin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antidotes
Protective Agents
Vitamin B Complex
Vitamins
Micronutrients
Hematinics