Patients with locally advanced rectal or rectosigmoid cancer staged cT3 CRM-negative with MRI MedDRA version: 20.0 Level: LLT Classification code 10010036 Term: Colorectal carcinoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.0 Level: PT Classification code 10052360 Term: Colorectal adenocarcinoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.0 Leve
Conditions
Sponsors
AIO-Studien-gGmbH
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Age = 18 years on day of signing informed consent 2. Signed and dated informed consent, and willing and able to comply with protocol requirements 3. WHO/ECOG Performance Status (PS) 0-1 4. Diagnosis of rectal adenocarcinoma 5. Candidate for sphincter-sparing surgical resection prior to neoadjuvant therapy according to the primary surgeon, i.e. no patient will be included for whom surgeon indicates need for abdomino-perineal resection (APR) at baseline. 6. Clinical staging is based on the combination of the following assessments: • Physical examination by the primary surgeon • CT scan of the chest/abdomen • Pelvic MRI • Rigid rectoscopy / endoscopic ultrasound (ERUS). • Both examinations (MRI + ERUS) are mandatory. 7. The tumor has to fulfill the following criteria: • No symptomatic bowel obstruction • Locally advanced rectal and rectosigmoid cancer, i.e. lower border of tumor > 5 cm and 2 mm) c. Only T3-tumors are included, i.e infiltration into perirectal fat 2 mm d. Note: MRI criteria are used for the definition of T3 tumor (i.e. exclusion of T2 and T4 situation). 8. Hematological status: • Neutrophils (ANC) = 2 x 10^9/L • Platelets = 100 x 10^9/L • Hemoglobin = 9 g/dL (previous transfusion of packed blood cells allowed) 9. Adequate renal function: • Serum creatinine level = 1.5 x upper limit normal (ULN) or = 1.5 mg/dl • Creatinine clearance = 30 ml/min 10. Adequate liver function: • Serum bilirubin = 1.5 x upper limit normal (ULN) • Alkaline phosphatase =65 years) yes F.1.3.1 Number of subjects for this age range 59
Exclusion criteria
Exclusion criteria: 1. Distant metastases (CT scans of thorax and abdomen are mandatory) 2. cT2 and cT4 tumors (defined by MRI criteria) 3. Exclusion of potentially compromised CRM as defined by MRI criteria (i.e. > 2 mm distance from CRM) 4. Prior antineoplastic therapy for rectal cancer 5. History or evidence upon physical examination of CNS metastasis 6. Uncontrolled hypercalcemia 7. Pre-existing permanent neuropathy (NCI-CTCAE grade = 2) 8. Uncontrolled hypertension (defined as systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg), or history of hypertensive crisis, or hypertensive encephalopathy 9. Concomitant protocol unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy, radiotherapy) 10. Treatment with any other investigational medicinal product within 28 days prior to study entry 11. Known dihydropyrimidine dehydrogenase (DPD) deficiency 12. Treatment with CYP3A4 inducers unless discontinued > 7 Days prior to randomization 13. Any of the following in 3 months prior to inclusion: • Grade 3-4 gastrointestinal bleeding • Treatment resistant peptic ulcer disease • Erosive esophagitis or gastritis • Infectious or inflammatory bowel disease • Diverticulitis 14. Any active infection within 2 weeks prior to study inclusion 15. Vaccination with a live, attenuated vaccine within 4 weeks prior to the first administration of the study medication 16. Other concomitant or previous malignancy, except: • Adequately treated in-situ carcinoma of the uterine cervix • Basal or squamous cell carcinoma of the skin • Cancer in complete remission for > 5 years 17. Any other serious and uncontrolled non-malignant disease, major surgery or traumatic injury within the last 28 days prior to study entry 18. Pregnant or breastfeeding women 19. Patients with known allergy to any constituent to study drugs 20. History of myocardial infarction and/or stroke within 6 months prior to randomization, NYHA class III and IV congestive heart failure 21. Severe renal insufficiency (creatinin clearance < 30 ml/min) 22. Bowel obstruction 23. Contra-indication to the assessment by MRI 24. Involvement in the planning and/or conduct of the study (applies to both Sanofi staff and/or staff of Sponsor and study site) 25. Patient who might be dependent on the sponsor, site or the investigator 26. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG. 27. Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To investigate the pathological tumor response based on central pathologic review of the mFOLFOX6/aflibercept combination as compared to mFOLFOX6 alone in patients with locally advanced rectal cancer staged cT3 CRM-negative with MRI.;Secondary Objective: To compare the treatment arms with respect to: Safety - Dose intensities of study medication - Type, incidence and severity of AEs and SAEs - Laboratory parameters Efficacy - Survival, disease-free survival, relapse-free survival - Downstaging and downsizing using a standardized regression grading (Dworak regression grading) Surgical morbidity and mortality - Perioperative in-hospital morbidity and mortality within 28 days after surgery Others - Vital signs, Physical examination, WHO/ECOG The following secondary/exploratory objectives will be considered beyond the clinical study report: Quality assurance of MRI (central read) - Comparison of the local read of: o T, N, M Staging o Heigh localization o Distance to circumferential resection margin (CRM);Primary end point(s): Pathologic complete response (pCR) rate, defined by the number of patients with a pCR finding divided by the number of patients in the analysis set. The pCR will be assessed in a standardized manner independently by a central pathology.;Timepoint(s) of evaluation of this end point: At End of Treatment Visit | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Safety • Dose intensities of study medication • Type, incidence and severity of AEs, SAEs • Dose reduction or discontinuation of study drug due to adverse events • Rate of treatment discontination due to toxicity • Type, incidence and severity of laboratory abnormalities Efficacy • Rate of R0-wide, R0-close (according to CRM definitions in S3-guideline Version 1.1 August 2014), R1 and locoregional R2 resection • Disease-free survival (DFS) rate • Relapse-free survival (RFS) in resected patients • Overall survival (OS) • Downstaging and downsizing using a standardized regression grading (Dworak regression grading) Surgical morbidity and mortality • Type, incidence and severity of perioperativ medical events • Mortality within 28 days after surgery Others • Vital signs • Physical examination • WHO/ECOG;Timepoint(s) of evaluation of this end point: Various timepoints throughout trial | — |
Countries
Austria, Germany
Contacts
Public ContactDr. Aysun Karatas
AIO-Studien-gGmbH
Outcome results
None listed