Short RT Versus RCT,Followed by Chemo.and Organ Preservation for Interm and High-risk Rectal Cancer Patients
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| ClinicalTrials.gov Identifier: NCT04246684 |
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Recruitment Status :
Recruiting
First Posted : January 29, 2020
Last Update Posted : December 16, 2022
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Sponsor:
Prof. Dr. med. Claus Rödel
Information provided by (Responsible Party):
Prof. Dr. med. Claus Rödel, Goethe University
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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 |
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.
| 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 |
|---|---|
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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.
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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
Other Name: Folinic Acid 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
Other Name: Capecitabine Drug: Oxaliplatin, 130 mg/m2 day1every three weeks (optional)
Other Name: Oxaliplatin |
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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.
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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
Other Name: Folinic Acid Drug: Capecitabine, 1000 mg/m2 1000 mg/m2 (twice daily) day1-14 every three weeks instead of 5FU optional
Other Name: Capecitabine 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
Other Name: Capecitabine Drug: Oxaliplatin, 130 mg/m2 day1every three weeks (optional)
Other Name: Oxaliplatin |
Primary Outcome Measures :
- organ preservation [ Time Frame: 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.
Secondary Outcome Measures :
- Disease-free survival [ Time Frame: 3 years ]Disease-free survival
- Rate of clinical complete response after TNT: [ Time Frame: 3 years ]TNT total neoadjuvant therapy
- Rate of immediate TME after TNT [ Time Frame: 3 years ]TNT total neoadjuvant therapy TME total mesorectal excision
- Cumulative incidence of locoregional regrowth after cCR [ Time Frame: 3 years ]cCR clinical complete response
- Rate of salvage surgery (LE/TME with or APR/stoma) after locoregional regrowth APR/stoma) after locoregional regrowth [ Time Frame: 3 years ]LE local Exision; TME: Transanale endoscopic Mikrochirurgie; APR Abdomino perineal Rectum exstirpation
- Cumulative incidence of local recurrence after (salvage) surgery surgery [ Time Frame: 3 years ]Cumulative incidence of local recurrence after (salvage) surgery
- Postoperative complications of (salvage) surgery [ Time Frame: 3 years ]Postoperative complications of (salvage) surgery
- Rate of sphincter-sparing (salvage) surgery [ Time Frame: 3 years ]Rate of sphincter-sparing (salvage) surgery
- Pathological TNM-staging [ Time Frame: 3 years ]Pathological tumor evaluations;TNM tumor staging
- R0 resection rate; negative circumferential resection rate [ Time Frame: 3 years ]R0 Removal of the tumor in healthy tissue
- Tumor regression grading according to Dworak [ Time Frame: 3 years ]pathological response from scale 1-4 poor to very good ascending
- Neoadjuvant rectal score [ Time Frame: 3 years ]Neoadjuvant rectal score from low to high values means good to poor
- Quality of TME according to MERCURY [ Time Frame: 3 years ]Tumor response using MRI scale 1-5 from good to poor descending
- Acute and late toxicity assessment according to NCI CTCAE V.5.0) CTCAE V.5.0) [ Time Frame: 3 Yeears ]CTCAE V.5.0
- Quality of life C30 based on treatment arm and surgical procedures/organ preservation [ Time Frame: 3 years ]Quality of life based on EORTC-QLQs-C30
- functional outcome based on treatment arm and surgical procedures/organ preservation [ Time Frame: 3 years ]functional outcome based on Wexner score
- Quality of life CR29 based on treatment arm and surgical procedures/organ preservation [ Time Frame: 3 years ]Quality of life based on EORTC-QLQs-CR29
- Quality of life CPIN 20 based on treatment arm and surgical procedures/organ preservation [ Time Frame: 3 years ]Quality of life based on EORTC-QLQs-CPIN20 Quality of life based on EORTC-QLQs-CPIN20
- Cumulative incidence of distant metastases [ Time Frame: 3 Years ]Cumulative incidence of distant metastases
- Overall survival [ Time Frame: 3 years ]Overall survival
- Translational / biomarker studies [ Time Frame: 3 years ]
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.
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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
- 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).
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
| 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 76 study locations
Sponsors and Collaborators
Prof. Dr. med. Claus Rödel
Investigators
| Study Director: | Claus Roedel, Prof. Dr. | clinic for radiotherapy |
| 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: | December 16, 2022 |
| Last Verified: | December 2022 |
| 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 |