Regorafenib With Low-dose Chemotherapies and Aspirin Followed by Standard Chemotherapies in Metastatic Colorectal Cancer

Overview

This study evaluates the interest of regorafenib in combination of metronomic chemotherapies and low-dose aspirin as a 2 months induction therapy before chemotherapy initiation in the second-line metastatic colorectal carcinoma

Eligibility

Inclusion Criteria:

1. Patients with histologically proven metastatic colorectal cancer in progression after a first line of chemotherapy +/- targeted therapy
2. Patients must have been treated for their metastatic disease with one of the following regimens as first-line therapy:
   • FOLFOX (Oxaliplatine, 5-Fluoro-uracil)
   • FOLFIRI (Irinotecan, 5-Fluoro-uracil)
   • FOLFIRINOX (Irinotecan, oxaplipatin, 5-Fluoro-uracil) or FOLFOXIRI (irinotecan, oxaliplatin, 5-Fluoro-uracil)
   • FOLFOX and anti-VEGFA (bevacizumab only)
   • FOLFIRI and anti-VEGFA (bevacizumab only)
   • FOLFIRINOX or FOLFOXIRI and anti-VEGFA (bevacizumab only)
   • FOLFOX and anti-EGFR (Epiderman Growth Factor Recepto)
   • FOLFIRI and anti-EGFR
   • FOLFIRINOX or FOLFOXIRI and anti-EGFR

             Of note, a chemotherapy prescribed for metastases occurring within six months after
             the end of an adjuvant chemotherapy are considered as a second line of therapy.
          3. Patients should have a history of resistance to first line chemotherapy defined by:
               -  Disease progression during the first line of their metastatic disease, less than
                  3 months after the last exposition to chemotherapy (even a chemotherapy regimen
                  mentioned above or a 5-Fluoro-uracil-based maintenance therapy).
               -  Disease relapse within 6 months after the end of an adjuvant FOLFOX based
                  chemotherapy.
               -  Disease relapse within 6 months after the surgical resection of metastases
                  following a first line of chemotherapy.
          4. Life expectancy of at least 3 months
          5. Female or male with age ≥18 years old
          6. Performance status Eastern Cooperative Oncology Group World Health Organization
             (ECOG-WHO) ≤1 (Appendix 1),
          7. Measurable disease defined according to RECIST v1.1 (scanner or MRI)
          8. Molecular status: patients eligible should have microsatellite-stable (MSS) status,
             absence of BRAF V600E (B(Raf gene, val600-to-glu) mutation and a known RAS (Retrovirus
             Associated Sequences) status.
          9. Adequate bone marrow, liver and renal functions.
               -  Haemoglobin ≥ 9 g/dL; absolute neutrophil count (ANC) ≥ 1.5 x 109/L; platelets ≥
                  100 x 109/L
               -  Total serum bilirubin ≤ 1.5 times upper normal value (ULN), serum alkaline
                  phosphatase < 5 times ULN, aminotransferases (AST/ALT) ≤ 3 × ULN in absence of
                  hepatic metastasis or ≤ 5 if presence of hepatic lesions
               -  Cockcroft glomerular filtration rate > 50 ml/min
               -  Proteinuria <2+ (dipstick urinalysis) or ≤1g/24hour
         10. No contraindication to Iodine contrast media injection during CT
         11. For female patients of childbearing potential, negative pregnancy test within 14 days
             before starting the study drug through at 210 days after the last dose of regorafenib.
             Men and women are required to use adequate birth control during the study (when
             applicable),
         12. Signed and dated informed consent,
         13. Ability to comply with the study protocol, in the Investigator's judgment.
         14. Registration in a national health care system (CMU included).
        Exclusion Criteria:
          1. Diagnosis of additional malignancy within 2 years prior to the inclusion (exception of
             curatively treated basal cell carcinoma of the skin and/or curatively resected in situ
             cervical and/or bladder cancer),
          2. Current participation in a study of an investigational agent. Patients might be
             included at least 21 days following the last investigational agent administration.
          3. Any psychological, familial, sociological or geographical condition potentially
             hampering compliance with the study protocol and follow-up schedule; those conditions
             should be discussed with the patient before inclusion in the trial;
          4. Patient under judicial protection (curators, autorship) and/or deprived of freedom,
          5. Planned surgical procedure within the first month of treatment or any procedure that
             might change the timing of regorafenib administration during the first month of
             treatment,
          6. Previous exposure to regorafenib,
          7. Previous exposure to other anti-angiogenic treatment than bevacizumab,
          8. Complete deficit in dihydropyrimidine dehydrogenase (DPD),
          9. Major surgical procedure, open biopsy or significant traumatic injury within 28 days
             before start of study medication,
         10. Pregnant or breast-feeding subjects,
         11. Congestive Heart Failure ≥ New York Heart Association (NYHA) class 2, unstable angina
             (anginal symptomatology at rest),
         12. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3
             months),
         13. Myocardial infarction less than 6 months before start of study drug,
         14. Cardiac arrhythmias requiring anti-arrhythmic therapy (beta-blockers or digoxin are
             permitted),
         15. Uncontrolled hypertension (Systolic blood pressure >150 mmHg and/or diastolic pressure
             >100 mmHg despite optimal medical management), or history of hypertensive crisis, or
             hypertensive encephalopathy
         16. Pleural effusion or ascites that causes respiratory compromise (≥ CTCAE grade 2
             dyspnea),
         17. Ongoing infection >grade 2 CTCAE V5 (Appendix 6 ),
         18. Known History of human immunodeficiency virus (HIV) infection,
         19. Active hepatitis B or C or chronic hepatitis B or C requiring treatment with antiviral
             therapy,
         20. Subjects with seizure disorder requiring medication,
         21. History of organ allograft,
         22. Subjects with evidence or history of any bleeding diathesis, irrespective of severity,
         23. Any haemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of
             study medication,
         24. Serious, Non-healing wound, active ulcer or untreated bone fracture,
         25. History of abdominal fistula, GI perforation, intra-abdominal abscess or active GI
             bleeding within 6 months prior to inclusion,
         26. Dehydration CTCAE v4 grade ≥1,
         27. Known hypersensitivity to any of the study drugs, study drug classes or excipient in
             the formulation,
         28. Interstitial lung disease with ongoing signs or symptoms,
         29. Persistent proteinuria of CTCAE Grade 3 (>3.5 g/24 hours),
         30. Subject unable to swallow oral medications,
         31. Any malabsorption condition, unresolved toxicity higher than CTCAE (V4) Grade 1
             attributed to any prior therapy/procedure excluding alopecia, hypothyroidism and
             oxaliplatin induced neuropathy ≤ Grade 2,
         32. Systemic anticancer therapy including cytotoxic therapy, signal transduction
             inhibitors, immunotherapy, and hormonal therapy during this trial or within 3 weeks,
         33. Treatment with any other investigational medicinal product within 28 days prior to
             study entry, EXCEPT for ASPIRIN,
         34. Co-administration of drugs potentially interacting with regorafenib i.e. CYP3A4 or
             UGT1A9 (UDP-glucuronosyltransferase 1-9) inducers/inhibitors.