Induction Therapy With Panitumumab + mFOLFOX-6 in Rectal Cancer and Quadruple Wild-type Mutation Before Surgery

Inclusion Criteria:

1. Signed and dated informed consent form, and willingness and ability to comply with the requirements of the protocol;
2. Men or women with rectal cancer, age ≥ 18 and \<75 years;
3. Histologically documented adenocarcinoma of the rectum. All other histologic types are excluded. A biopsy of the rectal primary tumor must be available (between 1-4), with tumor representation \> 50% in each sample. The samples will be sent to Val d'Hebron Institute of Oncology (VHIO) for molecular determination. The blocks of the biopsies will be sent included in paraffin.
4. Rectal cancer candidate for R0 resection with preservation of the rectal sphincter.
5. Tumors with the following characteristics on high-resolution thin-slice (3 mm) MRI:

   1. mrT3
   2. Tumors of the middle third, defined as tumors whose distal edge is ≤ 12 cm of the anal verge or below the peritoneal reflection and above ≥ 2 cm of the anorectal junction.
   3. Absence of MRF invasion, defined as a distance ≥ 1 mm between the tumor and the fascia;
6. Absence of mutations in KRAS (mutations in KRAS exon 2 \[codons 12/13\], exon 3 \[codons 59/61\] and exon 4 \[codon 117/146\], NRAS (NRAS exon 2 \[codons 12/13\], exon 3 \[codons 59/61\] and exon 4 \[codons 117/146\]), BRAF (exon 15 \[codon 600\] and PI3KCA in exons 9 and 20
7. ECOG performance status ≤ 2;
8. Hematological status:

   * Neutrophils (ANC) ≥ 1.5 x 109/L;
   * Platelets ≥ 100 x 109/L;
   * Hemoglobin ≥ 9 g/dL;
9. Adequate renal function: serum creatinine \<1.5 x upper limit of normal (ULN);
10. Adequate liver function:

    * Serum bilirubin ≤ 1.5 x ULN,
    * Alkaline phosphatase \< 5 x ULN,
    * AST/ALT \< 3 x ULN;
11. Regular monitoring feasible;
12. In women of childbearing potential, a negative serum pregnancy test within 1 week (7 days) before the start of study treatment;
13. Women must commit to using reliable and appropriate methods of contraception for up to at least six months after the end of the study treatment (when applicable). Men with a partner of childbearing potential must agree to use a method of contraception and their partners must use another contraceptive method for the duration of the trial. Sexual abstinence will be accepted as a contraception method, with the duration and considerations stablished by the investigator

Exclusion Criteria:

1. Mucinous adenocarcinoma.
2. N2 lymph node involvement, defined as: 4 or more lymph nodes in the mesorectum showing morphological signs of metastatic involvement on MRI. A lymph node is considered malignant when:

   1. Short axis \> 9 mm.
   2. Short axis 5-9 mm and ≥2 of the following criteria:

      i Rounded appearance. ii Heterogeneous margin. iii Heterogeneous signal intensity.
   3. Short axis \< 5 mm AND round shape AND heterogeneous margin AND heterogeneous signal intensity.
3. Extramesorectal lymph node involvement: an involved extramesorectal lymph node is defined as a lymph node in the obturator area with a short axis \> 8 mm, round shape and heterogeneous signal..
4. Prior treatment with panitumumab or cetuximab;
5. Preexisting permanent neuropathy (grade ≥ 2 NCI-CTCAE);
6. Concomitant antitumor treatment not foreseen in the protocol (e.g., chemotherapy, targeted molecular therapy, immunotherapy);
7. Treatment with any other investigational medicinal product within the 28 days prior to study entry;
8. Other simultaneous or prior malignancy, except: i) properly treated uterine cervix carcinoma in situ, ii) basal or squamous cell skin carcinoma, iii) cancer in complete remission for a period \> 5 years;
9. Evidence of metastatic disease in additional studies or in the physical examination;
10. Any other severe and uncontrolled nonmalignant disease, major surgery or traumatic injury in the last 28 days;
11. Pregnant or breastfeeding women;
12. Patients with known allergy to any excipient of the investigational products;
13. Clinically significant cardiovascular disease, including myocardial infarction, unstable angina, symptomatic congestive heart failure or cardiac arrhythmia in the year before randomization in the study.
14. Intestinal occlusion: In the case of intestinal occlusion, patients may be enrolled in the study after performing a derivative stoma.
15. Interstitial Lung Disease