| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with locally advanced rectal or rectosigmoid cancer staged cT3 CRM-negative with MRI |
|
| E.1.1.1 | Medical condition in easily understood language |
| patients with locally advanced rectal or rectsogimoid cancer staged cT3 in MRI |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010036 |
| E.1.2 | Term | Colorectal carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10052360 |
| E.1.2 | Term | Colorectal adenocarcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061451 |
| E.1.2 | Term | Colorectal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
|
| E.2.2 | Secondary objectives of the trial |
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) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 < 16 cm from anal verge as determined by rigid rectoscopy
• MRI criteria:
a. Lower border of tumor below a line defined by promontorium and symphysis, regardless of the criterion “< 16 cm from anal verge as determined by rigid rectoscopy”.
b. No evidence that tumor is adjacent to (defined as within 2 mm of) the mesorectal fascia on MRI (i.e. CRM > 2 mm)
c. Only T3-tumors are included, i.e infiltration into perirectal fat < 10 mm provided CRM > 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 < 3 x ULN
• AST and ALT < 3 x ULN
11. Proteinuria < 2+ (dipstick urinalysis) or ≤ 1 g/24hour or ≤ 500 mg/dl
12. Regular follow-up feasible
13. For female patients of childbearing potential, negative pregnancy test within 1 week (7 Days) prior of starting study treatment
14. Female patients of childbearing potential (i.e. did not undergo surgical sterilization – hysterectomy, bilateral tubal ligation, or bilateral oophorectomy - and is not post-menopausal for at least 24 consecutive months) must commit to using highly effective and appropriate methods of contraception until at least 6 months after the end of study treatment such as combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), vasectomized partner, bilateral tubal occlusion, sexual abstinence. If an oral contraception is used, a barrier method of contraception (e.g. male condom, female condom, cervical cap, diaphragm, contraceptive sponge) has to be applied additionally.
15. Fertile male patients with a partner of childbearing potential must commit to using highly effective and appropriate methods of contraception (details see above) until at least 9 months after the end of study treatment. |
|
| E.4 | Principal 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].
|
|
| E.5 End points |
| E.5.1 | 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At End of Treatment Visit |
|
| E.5.2 | 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 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Various timepoints throughout trial |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 35 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The study will be terminated after the last patient has completed at least 12 months of follow-up or until death, whichever is sooner. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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