Induction FOLFOX With or Without Aflibercept Followed by Chemoradiation in High Risk Locally Advanced Rectal Cancer
Condition: Rectal Cancer
MeSH terms: Rectal Neoplasms
Intervention: Aflibercept; 5-Fluoruracil; Oxaliplatin; Leucovorin
Intervention description: Administered I.V. at doses of 4 mg/Kg on Day 1 every 14 days. It will be supplied to sites by Sponsor as 4 ml vials at a concentration of 25 mg/ml; Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2; Once every 14 days. Day 1: 85 mg/m2 I.V. infusion in 250-500 mL, over two hours, followed by 5-FU; Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU
Intervention MeSH terms: Leucovorin; Oxaliplatin; Aflibercept; Fluorouracil
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 180.0
Sex: All
Minimum age: 18 Years
Maximum age: 69 Years
Healthy volunteers: No

Summary:

      This trial compares induction treatment with FOLFOX with or without aflibercept in a high
      risk population selected by MRI, prior to receiving standard chemoradiation (capecitabine
      combined with 50.4 Gy in 28 days) and surgery, in order to evaluate the efficacy in terms of
      pathologic complete response (pCR).
    

Eligibility criteria:

        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.