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

Study Overview
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Brief Summary
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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).

Detailed Description
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This is a randomized trial comparing 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. Once it is confirmed that the subjects fulfill the eligibility criteria (MRI-defined high risk RC), and have signed the informed consent, a central review will be requested to confirm clinical stage, and then they will be randomized to receive mFOLFOX6 + Aflibercept or mFOLFOX6 (without Aflibercept). Random assignment of treatment will be stratified by T3 versus T4 stage. All the patients enrolled in the study will receive one cycle of study medication (mFOLFOX6 with or without aflibercept) every 14 days for six cycles, unless unacceptable toxicity or progression is detected. After this treatment, patients will receive standard chemo-radiotherapy (CT/RT) (capecitabine 825 mg/m2 twice daily combined with a total dose of 50.4 Gy in 28 days) followed by surgery, provided they have not progressed. Patients with progression disease during the treatment phase will be withdrawn from the study and will receive their treatment according to the investigator's judgment. If a patient withdraws consent and refuses to receive further treatment, the patient must be followed up for 3 years from randomization or until progression, to evaluate disease-free survival. If a patient withdraws consent and refuses to continue in the study, the follow-up evaluations must be discontinued.

Official Title
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Induction FOLFOX With or Without Aflibercept Followed by Chemoradiation in High Risk Locally Advanced Rectal Cancer. Phase II Randomized, Multicenter, Open Label Trial

Conditions
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Rectal Cancer

Intervention / Treatment
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* Drug: Aflibercept
* Drug: 5-Fluoruracil
* Drug: Oxaliplatin
* Drug: Leucovorin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated informed consent, and willing and able to comply with protocol requirement; Male or female subjects with rectal cancer ≥18 and <70 years of age; 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 Extramural vascular invasion (EMVI) positive Extramural extension > 5 mms into perirectal fat 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. Histologically confirmed adenocarcinoma of the rectum. All other histological types are excluded; Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤1; Hematological status: neutrophils (ANC) ≥1.5x109/L; platelets ≥100x109/L; hemoglobin ≥9g/dL; Adequate renal function: serum creatinine level <1.5 x upper limit of normality (ULN); Adequate liver function: serum bilirubin ≤1.5 x ULN, alkaline phosphatase <5x ULN, AST/ALT < 3 x ULN; Proteinuria <2+ (dipstick urinalysis) or ≤1g/24hour; Regular follow-up feasible; For female patients of childbearing potential, negative serum pregnancy test within 1 week (7 days) prior to starting study treatment; 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: Prior treatment with aflibercept; History or evidence upon physical examination of metastasis; Uncontrolled hypercalcemia; Pre-existing permanent neuropathy (NCI grade ≥2); Uncontrolled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg), or history of hypertensive crisis, or hypertensive encephalopathy; Concomitant protocol unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy); Treatment with any other investigational medicinal product within 28 days prior to study entry; 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; Any other serious and uncontrolled non-malignant disease, major surgery or traumatic injury within the last 28 days; Pregnant or breastfeeding women; Patients with known allergy to any excipient to study drugs; 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. Bowel obstruction.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 69 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: mFOLFOX6 + Aflibercept<br>- mFOLFOX-6 scheme: 5-Fluoruracil [5-FU], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². - Aflibercept, will be administered intravenously (I.V.) at doses of 4 mg/Kg on Day 1 every 14 days. Aflibercept will be supplied to sites by the study Sponsor as 4 ml vials at a concentration of 25 mg/ml. Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. | Drug: Aflibercept<br>* 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<br>* Other names: ZALTRAP;Drug: 5-Fluoruracil<br>* Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2<br>* Other names: 5-FU;Drug: Oxaliplatin<br>* Once every 14 days. Day 1: 85 mg/m2 I.V. infusion in 250-500 mL, over two hours, followed by 5-FU<br>* Other names: Any marketed;Drug: Leucovorin<br>* Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU<br>* Other names: Any marketed;|
| Active Comparator: mFOLFOX6<br>- mFOLFOX-6 scheme: 5-Fluoruracil [5-FU], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. | Drug: 5-Fluoruracil<br>* Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2<br>* Other names: 5-FU;Drug: Oxaliplatin<br>* Once every 14 days. Day 1: 85 mg/m2 I.V. infusion in 250-500 mL, over two hours, followed by 5-FU<br>* Other names: Any marketed;Drug: Leucovorin<br>* Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU<br>* Other names: Any marketed;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Achieving Pathologic Complete Response (pCR). | The number of patients achieving pCR after induction therapy with mFOLFOX6 +/- aflibercept followed by chemotherapy (CT)/radiotherapy (RT). pCR will be defined as the absence of viable tumor cells in the primary tumor and in the lymph nodes (T0N0) | From baseline until 2 years and 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Achieving Pathological Parameters of Efficacy: R0 Resection, Tumor Regression Grade, and Circular Radial Margin Rate | R0 resection is defined as complete tumor removal, and correlates with good prognosis. Tumor regression grade (TRG) is defined as presence of residual tumor after preoperative therapy. This was assessed by magnetic resonance imaging (MRI) according to the 5-point regression grading scale established by Mandard: TRG1 (complete response with no residual cancer), TRG2 (rare residual cancer), TRG3 (fibrosis outgrowing residual cancer), TRG4 (residual cancer outgrowing fibrosis) and TRG5 (absence of regression). Circular Radial Margin (CRM) is defined as the distance from the margin of normal tissue to the edge of tumor tissue in the resected primary tumor the measured by histopathology study after surgery. A margin of ≤1 mm is considered to be a negative prognostic factor for local recurrence. | From baseline until 2 years and 2 months | 
| Number of Participants With Significant MRI Changes Post Intervention, as Defined by T Downstaging | Tumor size is assessed by MRI to determine the T stage. T Downstaging: defined as a lower pathologic T stage compared to pre-treatment T stage. | From baseline until 2 years and 2 months | 
| Number of Patients Reporting Adverse Events (AEs) | The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data. AEs were coded and evaluated using the NCI-CTCAE v4.0 toxicity criteria (if NCI-CTCAE are not applicable, MedDRA was used). | From baseline until 2 years and 2 months | 
| Number of Patients Reporting Surgical Complications | Surgical complications will be assessed by means of AEs reported during 30 days post surgery. | From surgical intervention up to 30 days post-surgery, within a general time frame of 2 years and 2 months per study protocol | 
| Disease Free Survival (DFS) Rate at 3 Years | DFS rate is defined as the percentage of participants without local recurrences at 3-years post study treatment. Here we report the DFS rate at 3-years after completing the Study treatment. | At 3 years after study treatment completion, within a general time frame of 5 years and two months |