Trial document




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  DRKS00020770

Trial Description

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Title

Preoperative Oxaliplatin-based Chemoradiotherapy and Consolidation Chemotherapy Versus Fluorouracil-based Chemoradiotherapy for MRIdefined Intermediate and High-risk Rectal Cancer Patients

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Trial Acronym

ACO/ARO/AIO-18.1

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URL of the Trial

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Brief Summary in Lay Language

Preoperative 5-FU-based chemoradiotherapy (CRT) and total mesorectal excision (TME) surgery 6
weeks thereafter with optional adjuvant chemotherapy is at present a standard of care for
patients with UICC II and III rectal cancer and used as control arm. With this, pathological
complete response rates (pCR) are in the range of 10%, 3 year-local failure rates in the
range of 5%, distant recurrences occur in 25-30% of patients, and 3 years disease-free
survival (DFS) amounts to 70%. The hereby proposed ACO/ARO/AIO-18.1 randomized trial aims to
improve standard treatment by incorporating several novel and innovative aspects, partly
established by our preceding CAO/ARO/AIO-04 and CAO/ARO/AIO-12 randomized trials:

1. patient selection is based on strict MRI features of intermediate and high-risk
characteristics

2. the CRT and chemotherapy(CT) regimens incorporate 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 and interval of CRT, CT, and surgery adopts the innovative total
neoadjuvant treatment (TNT) approach as established by our CAO/ARO/AIO-12 trial

4. surgical stratification allows for watch & wait (W&W) management for strictly selected
patients

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Brief Summary in Scientific Language

The current standard of care for rectal cancer patients with stage II and III UICC is preoperative 5-fluorouracil (5-FU) -based chemoradiation therapy (RCT) followed by total mesorectal excision 6-8 weeks later. The meaning of adjuvant chemotherapy is unclear, it is used optionally. With this therapy concept, which serves as a control arm in this study, the rates for complete pathological remission (pCR) are around 10%, local recurrences occur in around 5%, distant metastases in around 25-30% of the patients, and 3-year disease-free survival is approximately 70%.
The randomized study ACO / ARO / AIO-18.1 presented here tries to improve the current therapy standard by integrating innovative aspects that were partially established in the preliminary studies CAO / ARO / AIO-04 and CAO / ARO / AIO-12. This includes (1) the better selection of patients with MRI-defined, intermediate and high-risk characteristics, (2) the use of a 5-FU / oxaliplatin-based RCT analogous to the regime established in the CAO / ARO / AIO-04 study , (3) the optimization of the sequence RCT, CT, OP as well as the time interval between RCT and OP in terms of a total neoadjuvant therapy (TNT), as could be established by the CAO / ARO / AIO-12 study, and finally ( 4) the option of organ preservation for patients with complete clinical remission after neoadjuvant intended therapy (watch & wait strategy instead of radical surgery).

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Do you plan to share individual participant data with other researchers?

No

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Description IPD sharing plan:

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Organizational Data

  •   DRKS00020770
  •   2020/02/07
  •   2020/01/23
  •   yes
  •   Approved
  •   19-414-AMG, Ethikkommission des Fachbereichs Humanmedizin der Johann-Wolfgang-Goethe-Universität Frankfurt am Main
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Secondary IDs

  •   2018-000876-14 
  •   NCT04246684  (ClinicalTrials.gov)
  •   ACO/ARO/AIO-18.1  (Prof. Dr. med. Claus Rödel)
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Health Condition or Problem studied

  •   C20 -  Malignant neoplasm of rectum
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Interventions/Observational Groups

  •   5 fluorouracil: during chemotherapy 2400 mg / m ^ 2; during chemoradiation: 250 mg / m ^ 2;
    oxaliplatin; during chemoradiation: 50 mg / m ^ 2; during chemotherapy: 100mg / m ^ 2
    Calcium folinate: during chemotherapy: 400mg / m ^ 2
    Radiotherapy: during chemoradiation
    28 x 1.8 Gy (50.4 Gy)
  •   5 fluorouracil: during chemotherapy) 400 mg / m ^ 2; during chemoradiation
    225 mg / m ^ 2,
    Calcium folinate during chemotherapy: 200mg / m ^ 2
    Radiotherapy: during chemoradiotherapy
    28 x 1.8 Gy (50.4 Gy)
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Blinded
  •   investigator/therapist
  •   Active control (effective treament of control group)
  •   Treatment
  •   Parallel
  •   III
  •   No
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Primary Outcome

- 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.

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Secondary Outcome

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

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

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Recruitment

  •   Planned
  •   2020/03/01
  •   822
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional 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-
- Adequate bone marrow, liver, kidney function:
- leukocytes> ≥ 3,000 / mm ^ 3
- Neutrophils> 1,500 / mm ^ 3
Platelets> 100,000 / mm ^ 3
- Hemoglobin ≥ 9 g / dl
- Bilirubin ≤ 2.0 mg / dl, SGOT (ASAT), SGPT (ALAT), alkaline phosphatase ≤ 3 x upper limit of normal value
-Adequate serum creatinine ≤ 1.5 x upper limit of normal value
• Patient's written consent

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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).

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Addresses

  • start of 1:1-Block address primary-sponsor
    • Klinik für Strahlentherapie Universitätsklinikum Frankfurt/M
    • Mr.  Prof. Dr. med.  Claus  Rödel 
    • Theodor-Stern-Kai 7
    • 60590  Frankfurt
    • Germany
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    • Klinik für Strahlentherapie Universitätsklinikum Frankfurt/M
    • Mr.  Prof. Dr. med.  Claus  Rödel 
    • Theodor-Stern-Kai 7
    • 60590  Frankfurt/M
    • Germany
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    • Klinik für StrahlentherapieUniversitätsklinik Frankfurt/M
    • Mr.  Prof. Dr. med.  Claus  Rödel 
    • Theodor-Stern-Kai 7
    • 60590  Frankfurt/M
    • Germany
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Sources of Monetary or Material Support

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    • Deutsche Krebshilfe
    • Ms.  Dr.  Laura  Planko 
    • Buschstr. 32
    • 53113   Bonn
    • Germany
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Status

  •   Recruiting planned
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Trial Publications, Results and other Documents

  •   Ethikvotum
  •   Prüfplan
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* This entry means the parameter is not applicable or has not been set.