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 candidatesfor, fluoropyrimidine, oxaliplatin, irinotecan and anti-angiogenic monoclonalantibody (bevacizumab or aflibercept).

• RAS (codons 12, 13, 59, 61, 117 and 146 of KRAS and NRAS genes) and BRAF (V600Emutation) wt status of primary CRC or related metastasis (local laboratoryassessment).

• Previous first-line anti-EGFR-containing therapy producing at least a partialresponse or a stable disease ≥ 6 months.

• At least 4 months elapsed between the end of first-line anti-EGFR administration andscreening.

• At least one line of therapy between the end of first-line anti-EGFR administrationand 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 (V600Emutation) wt status of ct-DNA at screening (central laboratory assessment by meansof 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 leastone 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), alkalinephosphatase ≤ 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 thebaseline visit. For this trial, women of childbearing potential are defined as allwomen after puberty, unless they are postmenopausal for at least 12 months, aresurgically sterile, or are sexually inactive A postmenopausal state is defined as nomenses for 12 months without an alternative medical cause. A high folliclestimulating hormone (FSH) level in the postmenopausal range may be used to confirm apost-menopausal state in women not using hormonal contraception or hormonalreplacement therapy. However in the absence of 12 months of amenorrhea, a single FSHmeasurement is insufficient.

• Subjects and their partners must be willing to avoid pregnancy during the trial anduntil 8 weeks after the last trial treatment. Male subjects with female partners ofchildbearing 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 hypertensiveencephalopathy.

• Clinically significant (i.e. active) cardiovascular disease for examplecerebrovascular accidents (≤6 months), myocardial infarction (≤6 months), unstableangina, New York Heart Association (NYHA) grade II or greater congestive heartfailure, serious cardiac arrhythmia requiring medication.

• Significant vascular disease (e.g. aortic aneurysm requiring surgical repair orrecent 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 GIbleeding within 6 months prior to the first study treatment.

• Other co-existing malignancies or malignancies diagnosed within the last 5 yearswith the exception of localized basal and squamous cell carcinoma or cervical cancerin situ.

• Lack of physical integrity of the upper gastrointestinal tract, malabsorptionsyndrome, or inability to take oral medication.

• Known hypersensitivity to trial drugs or hypersensitivity to any other component ofthe trial drugs.

• Any concomitant drugs contraindicated for use with the trial drugs according to theproduct information of the pharmaceutical companies.

• Diagnosis of interstitial pneumonitis or pulmonary fibrosis.

• Active uncontrolled infections or other clinically relevant concomitant illnesscontraindicating administration of panitumumab and regorafenib.

• Treatment with any investigational drug within 30 days prior to enrolment or 2investigational agent half-lives (whichever is longer).

• Pregnant or lactating women. Women of childbearing potential with either a positiveor no pregnancy test at baseline. Postmenopausal women must have been amenorrheicfor at least 12 months to be considered of non-childbearing potential. Sexuallyactive males and females (of childbearing potential) unwilling to practicecontraception (barrier contraceptive measure or oral contraception) during the studyand until 8 weeks after the last trial treatment.