| Eligibility |
Inclusion Criteria:
1. Histologically confirmed diagnosis of colorectal adenocarcinoma
2. Any RAS mutation that prevent treatment with anti-EGFR antibodies
3. Stage IV
4. Measurable disease according to RECIST v. 1.1
5. Disease progression during or following a treatment with fluoropyrimidine, oxaliplatin
and bevacizumab, and a treatment with irinotecan is not considered immediately
mandatory by the Investigator
6. Age = 18 years
7. ECOG Performance Status 0-1
8. Neutrophils > 1500 / mm3, platelets > 100,000 / mm3, and hemoglobin > 9 g/dL without
transfusion or granulocyte-colony stimulating factor (G-CSF) and other hematopoietic
growth factors.
9. Bilirubin level < 1.5 x ULN
10. Glomerular filtration rate > 30 mL/min/1.73 m2 according to the Modified Diet in Renal
Disease abbreviated formula
11. AST (SGOT) and ALT (SGPT) = 3.0 x ULN (= 5 x ULN if liver metastasis are present)
12. Alkaline phosphatase = 2.5 x ULN (= 5 x ULN if liver metastasis are present)
13. Serum creatinine < 1.5 x ULN
14. Amylase and lipase = 1.5 x ULN
15. INR and aPTT = 1.5 x ULN. Subjects who are therapeutically treated with an agent such
as warfarin or heparin will be allowed to participate if no underlying abnormality in
coagulation parameters exists per medical history.
16. Understand, be willing to give consent, and sign the written informed consent form
(ICF) prior to undergoing any study-specific procedure.
17. If female and of childbearing potential, have a negative result on a pregnancy test
performed a maximum of 7 days before initiation of study treatment.
18. If potentially childbearing female, or if male, agree to use adequate contraception
(eg, abstinence, intrauterine device, oral contraceptive, or double-barrier method)
from the date on which the ICF is signed until 8 weeks after the last dose of study
drug.
19. Life expectancy of greater than 3 months
Exclusion Criteria:
1. Previous treatment with regorafenib or irinotecan
2. Are taking strong cytochrome P (CYP) CYP3A4 inhibitors (eg, clarithromycin, indinavir,
itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir,
saquinavir, telithromycin, voriconazole) or strong CYP3A4 inducers (eg, carbamazepine,
phenobarbital, phenytoin, rifampin, St. John's Wort)
3. Have had a major surgical procedure, open biopsy, or significant traumatic injury
within 28 days prior to initiation of study treatment
4. Have congestive heart failure classified as New York Heart Association Class 2 or
higher
5. Have had unstable angina (angina symptoms at rest) or new-onset angina < 3 months
prior to screening.
6. Have had a myocardial infarction < 6 months prior to initiation of study treatment.
7. Have cardiac arrhythmias requiring anti-arrhythmic therapy, with the exception of beta
blockers or digoxin.
8. Have had arterial or venous thrombotic or embolic events such as cerebrovascular
accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary
embolism within 6 months prior to the initiation of study treatment
9. Symptomatic brain metastases or meningeal tumors
10. Patients with evidence or history of bleeding diathesis
11. Uncontrolled hypertension (systolic blood pressure [SBP] >140 mmHg or diastolic blood
pressure [DBP] > 90 mmHg)
12. Have interstitial lung disease with ongoing signs and symptoms at the time informed
consent is obtained
13. Have persistent proteinuria > 3.5 g/24 hours measured by urine protein creatinine
ratio from a random urine sample (< Grade 3, CTCAE v 4.0).
14. Have unresolved toxicity higher than National Cancer Institute-Common Terminology for
Adverse Events version 4.0 (CTCAE v 4.0) Grade 1 attributed to any prior
therapy/procedure, excluding alopecia and/or oxaliplatin-induced neurotoxicity = Grade
2 and hemoglobin = 9 g/dL as per inclusion criteria
15. Patients who cannot take oral medication, who require intravenous alimentation, have
had prior surgical procedures affecting absorption, or have active peptic ulcer
disease
16. Pregnant or lactating women
17. Any other malignancies within 5 years (except for adequately treated carcinoma in situ
of the cervix or non melanoma skin cancer)
18. Any unstable systemic disease (including active infections, any significant hepatic,
renal or metabolic disease), metabolic dysfunction, physical examination finding, or
clinical laboratory finding that contraindicates the use of regorafenib or render the
patient at high risk for treatment complications
19. Sexually active males and females (of childbearing potential) unwilling to practice
contraception during the study.
20. Have any other serious or unstable illness, or medical, psychological, or social
condition, that could jeopardize the safety of the subject and/or his/her compliance
with study procedures, or may interfere with the subject's participation in the study
or evaluation of the study results.
21. Have a known hypersensitivity to any of the study drugs, study drug classes, or
excipients in the formulation of the study drugs.
22. Have a close affiliation with the investigational site (eg, be a close relative of the
investigator) or be a dependent person (eg, be an employee or student working at the
investigational site).
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