Patients with rectal adenocarcinoma of intermediate risk (defined by magnetic resonance imaging [MRI]), without mutations in KRAS, BRAF, NRAS and PI3KCA, who are candidates for preoperative treatment, will receive a preoperative Induction therapy with 12 weeks of panitumumab with mFOLFOX-6 to evaluate the efficacy in terms of pathologic complete response (pCR)

Phase II, nonrandomized single-arm trial of preoperative treatment with mFOLFOX-6 and panitumumab in an enriched population of patients with rectal adenocarcinoma of intermediate risk, screened by MRI, without mutations in KRAS, BRAF, NRAS and PI3K. All patients enrolled in the study will receive 12 weeks of the investigational product (mFOLFOX-6 with panitumumab) every 14 days for six cycles, unless unacceptable toxicity occurs or progression is detected. After this treatment, response will be evaluated by diffusion-weighted MRI and endoscopy. In the absence of disease progression, patients eligible for R0 resection will undergo total mesorectal excision (TME). After surgery, patients will receive mFOLFOX6 x 6 cycles. In the case of intolerance to FOLFOX-panitumumab, disease progression or ineligibility for R0 resection, patients will receive chemoradiotherapy with capecitabine 825 mg/m2 every 12 hours concomitantly with radiotherapy (RT) with a total dose of 50.4 Gy. At the end of this treatment, patients will undergo TME between 6-8 weeks after finishing the CRT. If a patient has received 4 or more neoadjuvant cycles of FOLFOX-panitumumab before unacceptable toxicity or progression, it will be considered that the neoadjuvant treatment has been completed and the patient will have no additional neoadjuvant treatment but surgery. If the patient has received <4 cycles of neoadjuvant treatment, neoadjuvant CRT will be administered.

If a patient has an acceptable toxicity or disease progression or a R0 surgery is not possible to be performed and the patient received CRT, the patient will be followed up for 24 months, from the enrollment of the last patient in the trial, or until progression occurs, in order to assess progression-free survival and all the data regarding surgery and CRT will be recorded in the eCRF. If a patient withdraws consent and refuses to continue participating in the study, follow-up evaluations must be discontinued.

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