PAnitumumab REchallenge Followed by REgorafenib Versus the Reverse Sequence

Inclusion Criteria:

* Age ≥ 18 years.
* Written informed consent to molecular analyses.
* Histologically proven diagnosis of CRC.
* At least one measurable lesion according to RECIST1.1
* ECOG PS ≤ 1.
* mCRC previously treated for metastatic disease with, or not considered candidates for, fluoropyrimidine, oxaliplatin, irinotecan and anti-angiogenic monoclonal antibody (bevacizumab or aflibercept).
* RAS (codons 12, 13, 59, 61, 117 and 146 of KRAS and NRAS genes) and BRAF (V600E mutation) wt status of primary CRC or related metastasis (local laboratory assessment).
* Previous first-line anti-EGFR-containing therapy producing at least a partial response or a stable disease ≥ 6 months.
* At least 4 months elapsed between the end of first-line anti-EGFR administration and screening.
* At least one line of therapy between the end of first-line anti-EGFR administration and screening.
* Availability of plasma sample for liquid biopsy within 28 days prior enrolment.
* RAS (codons 12, 13, 59, 61, 117 and 146 of KRAS and NRAS genes) and BRAF (V600E mutation) wt status of ct-DNA at screening (central laboratory assessment by means of IdyllaTM ctKRAS-NRAS-BRAF Mutation Test).
* Written informed consent to study treatment and procedures.
* Life expectancy of at least 12 weeks.
* Availability of archival tumour tissue (primary tumour and metastases or at least one of the two) for biomarker analysis.
* Availability of biological samples for translational molecular analyses.
* Neutrophils ≥1.5 x 109/L, Platelets ≥100 x 109/L, Hgb ≥ 9 g/dl.
* Total bilirubin ≤ 1.5 fold the upper-normal limits (UNL), ASAT (SGOT) and/or ALAT (SGPT) ≤ 2.5 x UNL (or \<5 x UNL in the case of liver metastases), alkaline phosphatase ≤ 2.5 x UNL (or \<5 x UNL in case of liver metastases).
* Creatinine clearance ≥ 50 mL/min or serum creatinine ≤1.5 x UNL.
* Women of childbearing potential must have a negative blood pregnancy test at the baseline visit. For this trial, women of childbearing potential are defined as all women after puberty, unless they are postmenopausal for at least 12 months, are surgically sterile, or are sexually inactive A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
* Subjects and their partners must be willing to avoid pregnancy during the trial and until 8 weeks after the last trial treatment. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore, be willing to use adequate contraception as approved by the investigator (barrier contraceptive measure or oral contraception).
* Will and ability to comply with the protocol.

Exclusion Criteria:

* Previous treatment with regorafenib.
* Radiotherapy to any site within 4 weeks before the study.
* Untreated brain metastases or spinal cord compression or primary brain tumours.
* Evidence of bleeding diathesis or coagulopathy.
* Uncontrolled hypertension and prior history of hypertensive crisis or hypertensive encephalopathy.
* Clinically significant (i.e. active) cardiovascular disease for example cerebrovascular accidents (≤6 months), myocardial infarction (≤6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication.
* Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months of study enrolment.
* Any previous venous thromboembolism ≥ NCI CTCAE Grade 4.
* History of abdominal fistula, GI perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to the first study treatment.
* Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of localized basal and squamous cell carcinoma or cervical cancer in situ.
* Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication.
* Known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs.
* Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies.
* Diagnosis of interstitial pneumonitis or pulmonary fibrosis.
* Active uncontrolled infections or other clinically relevant concomitant illness contraindicating administration of panitumumab and regorafenib.
* Treatment with any investigational drug within 30 days prior to enrolment or 2 investigational agent half-lives (whichever is longer).
* Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test at baseline. Postmenopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential. Sexually active males and females (of childbearing potential) unwilling to practice contraception (barrier contraceptive measure or oral contraception) during the study and until 8 weeks after the last trial treatment.