Induction FOLFOX With or Without Aflibercept Followed by Chemoradiation in High Risk Locally Advanced Rectal Cancer (RIA)

This is an interventional treatment trial for Rectal Cancer Read More

Inclusion Criteria:

1. Signed and dated informed consent, and willing and able to comply with protocol requirement;
2. Male or female subjects with rectal cancer ≥18 and <70 years of age;

3. High risk MRI-defined operable rectal cancer (with an inferior margin no more than 12 cm above the anal verge as assessed by MRI). Presence of at least 1 of the following on high resolution, thin-slice MRI (3 mm):

   Middle Third Tumors

   • mr T3

     1. Extramural vascular invasion (EMVI) positive
     2. Extramural extension > 5 mms into perirectal fat
     3. Mesorectal fascia (MRF) threatened or involved*
   • mr T4***

   Distal Third Tumors (≤5 cm from anal verge)

   • mr T3 tumor at or below levators

   • T4 as above N2**

     • tumor or lymph node < 1 mm from the mesorectal fascia **≥4 lymph nodes in the mesorectum showing morphological signs on MRI indicating metastatic disease. ≥4 nodes, whether enlarged or not, with a rounded, homogeneous appearance is thus not sufficient.

       • T4a: overgrowth to an adjacent organ or structure or T4b: peritoneal involvement.
4. Histologically confirmed adenocarcinoma of the rectum. All other histological types are excluded;
5. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤1;
6. Hematological status: neutrophils (ANC) ≥1.5x109/L; platelets ≥100x109/L; hemoglobin ≥9g/dL;
7. Adequate renal function: serum creatinine level <1.5 x upper limit of normality (ULN);
8. Adequate liver function: serum bilirubin ≤1.5 x ULN, alkaline phosphatase <5x ULN, AST/ALT < 3 x ULN;
9. Proteinuria <2+ (dipstick urinalysis) or ≤1g/24hour;
10. Regular follow-up feasible;
11. For female patients of childbearing potential, negative serum pregnancy test within 1 week (7 days) prior to starting study treatment;
12. Female patients must commit to using reliable and appropriate methods of contraception until at least three months after the end of study treatment (when applicable). Male patients with a partner of childbearing potential must agree to use contraception in addition to having their partner use another contraceptive method during the trial.

Exclusion Criteria:

1. Prior treatment with aflibercept;
2. History or evidence upon physical examination of metastasis;
3. Uncontrolled hypercalcemia;
4. Pre-existing permanent neuropathy (NCI grade ≥2);
5. Uncontrolled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg), or history of hypertensive crisis, or hypertensive encephalopathy;
6. Concomitant protocol unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy);
7. Treatment with any other investigational medicinal product within 28 days prior to study entry;
8. Other concomitant or previous malignancy, except: i/ adequately treated in-situ carcinoma of the uterine cervix, ii/ basal or squamous cell carcinoma of the skin, iii/ cancer in complete remission for >5 years;
9. Any other serious and uncontrolled non-malignant disease, major surgery or traumatic injury within the last 28 days;
10. Pregnant or breastfeeding women;
11. Patients with known allergy to any excipient to study drugs;
12. History of myocardial infarction and/or stroke within 6 months prior to randomization; Previous history of stable angina, uncontrolled arrhythmia, and acute coronary syndrome even if controlled with medication or with myocardial infarction within the last 12 months.
13. Bowel obstruction.