Locally advanced rectal adenocarcinoma localized 0 - 16 cm from the anal verge with low risk of local failure MedDRA version: 20.0 Level: LLT Classification code 10038052 Term: Rectal carcinoma System Organ Class: 100000004864
Conditions
Interventions
Product Name: 5-Fluorouracil
Pharmaceutical Form: Solution for injection
INN or Proposed INN: 5-fluorouracil
Other descriptive name: FLUOROURACIL
Trade Name: Oxaliplatin
Product Name: Oxaliplatin
Pha
Sponsors
University of Heidelberg
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male and female patients* with histologically confirmed diagnosis of rectal adenocarcinoma localized 0 – 16 cm from the anal verge as measured by rigid rectoscopy (i.e. lower, middle and upper third of the rectum), depending on MRI-defined inclusion criteria (see below). 2. Staging requirements: High-resolution, thin-sliced (i.e. 3mm) magnetic resonance imaging (MRI) of the pelvis is the mandatory local staging procedure. 3. Transrectal endoscopic ultrasound (EUS) is mandatory and used to help discriminate between T1/2 and early T3 tumors. 4. MRI-defined inclusion criteria: i) Lower third (0-6 cm): cT1/2 with clear cN+ based on defined MRI criteria, provided CRM- and EMVI-** ii) Middle third (= 6-12 cm): cT1/2 with clear cN+ provided CRM- and EMVI-**; cT3 with maximum infiltration of 10mm in the perirectal fat, provided no evidence that tumor is adjacent to (defined as within 2 mm of) the mesorectal fascia on MRI (i.e. CRM > 2 mm), N0 or N1, EMVI-** iii) Upper third (= 12-16 cm): cT1/2 with clear cN+, irrespective of CRM and EMVI; any cT3-4 irrespective of nodal status, CRM and EMVI. 5. Spiral-CT of the abdomen and chest to exclude distant metastases. 6. Aged at least 18 years. No upper age limit. 7. WHO/ECOG Performance Status =1. 8. Adequate hematological, hepatic, renal and metabolic function parameters: 9. Leukocytes = 3.000/mm³, ANC = 2.000/mm³, platelets = 100.000/mm³, Hb > 9 g/dl 10. Serum creatinine = 1.5 x upper limit of normal 11. Bilirubin = 2.0 mg/dl, SGOT-SGPT, and AP = 3 x upper limit of normal. 12. QTc interval (Bazett***) = 440 ms 13. Informed consent of the patient. * Thera are no data that indicate special gender distribution. Therefore, patients will be enrolled in the study gender-independently. ** defined as MRI-EMVI score 0-3; see SOP in chapter 12 of the appendix *** Formula for QTc interval calculation (Bazett): QTc= ((QT) ¯" (ms)" )/v(RR (sec))= ((QT) ¯" (ms)" )/v(60/(Frequenz (1/min))) Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 275 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 275
Exclusion criteria
Exclusion criteria: 1. Distant metastases (to be excluded by CT scan of the thorax and abdomen). 2. Prior antineoplastic therapy for rectal cancer. 3. Prior radiotherapy of the pelvic region. 4. Major surgery within the last 4 weeks prior to inclusion. 5. Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment. 6. Subject (male or female) is not willing to use highly effective**** methods of contraception during treatment and for 6 months (male or female) after the end of treatment. Male patients treated with Oxaliplatin should take legal advice concerning sperm conservation before start of therapy and should additionally use a condom during treatment period. Their female partner of childbearing potential should also use an appropriate contraceptive measure. 7. On-treatment participation in a clinical study in the period 30 days prior to inclusion. 8. Previous or current drug abuse. 9. Other concomitant antineoplastic therapy. 10. Serious concurrent diseases, including neurologic or psychiatric disorders (incl. dementia and uncontrolled seizures), active, uncontrolled infections, active, disseminated coagulation disorder. 11. Clinically significant cardiovascular disease (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) = 6 months before enrolment. 12. Chronic diarrhea (> grade 1 according NCI CTCAE). 13. 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. 14. Known allergic reactions or hypersensitivity on study medication or to any of the other excipients. 15. Evidence of peripheral sensory neuropathy > grade 1 according to CTCAE version 5.0 (see appendix). 16. Severe kidney dysfunction (creatinine clearance < 30 ml/min). 17. Recent or concurrent treatment with brivudine. 18. Pernicious or other megaloblastic anaemia caused by vitamin B12 deficiency. 19. Known dihydropyrimidine dehydrogenase deficiency (activity score < 1,5 after genetic testing of DPYD variants). 20. 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). ****highly effective (i.e. failure rate of <1% per year when used consistently and correctly) methods: intravaginal and transdermal combined (estrogen and progestogen containing) hormonal contraception; injectable and implantable progestogen-only hormonal contraception; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomized partner; sexual abstinence (complete abstinence is defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary endpoint of this trial is disease-free survival, defined as the time from randomisation to one of the following events: no surgery or non-radical (R2) surgery of the primary tumour, locoregional recurrence after R0/1 resection of the primary tumour, second primary colorectal or other cancer, metastatic disease or progression, or death from any cause, whichever occurred first. We hypothesize that the 3-year DFS probability would improve from 76% in the standard arm to 85% in the investigational arm (hazard ratio of 0.6). With a power of 90% at a two-sided significance level of 5%, the sample size required to obtain a statistically significant difference is 550 patients (161 events) in total. ;Secondary Objective: •Acute and late toxicity assessment according to NCI CTCAE version 5.0 •Compliance (completion rate) of chemotherapy •Surgical morbidity and complications •Pathological UICC-staging, including pCR (ypT0N0) rate •R0 resection rate; negative circumferential resection rate (CRM > 1mm) •Tumor regression grading according to Dworak in the experimental arm •Rate of sphincter-sparing surgery •Rate of W&W with or without local regrowth •Cumulative incidence of local and distant recurrences •Overall survival •Quality of life and functional outcome based on treatment arm, and surgical procedures ;Primary end point(s): The primary endpoint of this trial is disease-free survival, defined as the time from randomisation to one of the following events: no surgery or non-radical (R2) surgery of the primary tumour, locoregional recurrence after R0/1 resection of the primary tumour, second primary colorectal or other cancer, metastatic disease or progression, or death from any cause, whichever occurred first.;Timepoint(s) of evaluation of this end point: End of treatment of last patient | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Acute and late toxicity assessment according to NCI CTCAE version 5.0 • Compliance (completion rate) of chemotherapy • Surgical morbidity and complications • Pathological UICC-staging, including pCR (ypT0N0) rate • R0 resection rate; negative circumferential resection rate (CRM > 1mm) • Tumor regression grading according to Dworak in the experimental arm • Rate of sphincter-sparing surgery • Rate of W&W with or without local regrowth • Cumulative incidence of local and distant recurrences • Overall survival • Quality of life and functional outcome based on treatment arm, and surgical procedures ;Timepoint(s) of evaluation of this end point: End of study | — |
Countries
Germany
Contacts
Public ContactProject Management
Institut für Klinische Krebsforschung IKF GmbH
Outcome results
None listed