A Phase II Study of Single-agent Regorafenib in the First Line Treatment of Frail and/or Unfit for Polychemotherapy Patients With Metastatic Colorectal Cancer (mCRC)
1. Signing of the informed consent form.
2. The patient must be able to understand the information and state expressly his or her
desire to take part in the study.
3. Age > 18 years.
4. Patients with histologically or cytologically documented adenocarcinoma of the colon
or rectum who have not been previously treated systemically for advanced disease.
Patients can have received fluoropyrimidine-based adjuvant therapy if the last dose
was taken at least 6 months prior to study entry.
5. Patients who are frail and/or unfit for polychemotherapy owing to the presence of one
or more of the following criteria:
1. Patients with dependence in activities of daily living owing to the presence of
comorbidities other than those resulting from the deterioration caused by the
2. Presence in the patient's medical history of three or more of the following
comorbidities, even if they are under control with proper treatment:
- Congestive heart failure
- Other chronic cardiovascular diseases
- Chronic obstructive pulmonary disease
- Cerebrovascular disease
- Peripheral neuropathy
- Chronic kidney failure
- Diabetes mellitus
- Systemic vasculitis
- Severe arthritis
3. Presence of geriatric syndromes such as age > 85 years, faecal or urinary
incontinence, spontaneous bone fractures, mild and moderate dementia, or
patients who fall repeatedly.
6. Existence of at least one measurable unidimensional lesion using CT or MRI based on
the Response Evaluation Criteria in Solid Tumors criteria (RECIST), version 1.1
7. Overall Eastern Cooperative Oncology Group (ECOG) performance less than or equal to 2
8. Patient's commitment to compliance with the oral medication throughout the duration
of the study
9. Life expectancy of at least 3 months
10. Adequate bone marrow, renal and hepatic function, defined as:
1. Neutrophils > 1500/mm3
2. Platelets > 100,000/mm3
3. Creatinine clearance > 30 ml/min
4. Hemoglobin ≥ 9 gr/dl
5. Bilirubin levels < 2.5 x ULN
6. Aspartate aminotransferase (AST) and alanine transaminase (ALT) levels < 3 x ULN
(if liver metastases < 5 x ULN)
1. Prior treatment with regorafenib.
2. Assignment prior to treatment during this study. Patients who are permanently
withdrawn from participation in the study treatment will not be allowed to return to
3. Prior or concurrent presence of another neoplastic disease that is different in terms
of tumour site and histology of the colorectal cancer in the 5 years prior to the
inclusion of the patient in the study, except in situ cervical cancer, superficial
bladder carcinoma [Ta (non-invasive), Tis (carcinoma in situ) and T1 (tumour invades
lamina propria)] and non-melanoma skin tumours.
4. Presence or history of brain metastases or meningeal tumours.
5. Major surgery, open biopsy or traumatic injury within 28 days prior to the start of
patient treatment with the study medication.
6. Extended-field radiotherapy within 4 weeks prior to randomisation or limited-field
radiotherapy in the previous 2 weeks. Patients must have recovered from all
7. Pregnant or breastfeeding women. Women of childbearing age must use adequate
contraception. Women of childbearing age must have a negative pregnancy test within 7
days prior to starting with the study medication.
8. Women of childbearing age and men who wish to take part in the study must agree to
use adequate contraception from the signing of the informed consent until at least 3
months after stopping the study medication. The investigator or the person designated
by him or her will ensure and advise as to the contraceptive methods that should be
used. Appropriate contraceptive methods include abstinence, oral contraceptives,
transdermal patches and injections of sustained-release progestin (starting at least
4 weeks before administration of the IMP), double-barrier method: condom or female
condom (diaphragm or cervical/vaginal condom) plus spermicide, intrauterine device
(IUD), intrauterine system, implant or vaginal ring (in place at least 4 weeks before
administration of the IMP) or male partner sterilization (vasectomy with
documentation of azoospermia) prior to inclusion of the woman in the trial if he is
the woman's only sexual partner.
9. Active congestive heart failure class 2 or higher on the New York Heart Association
10. Unstable angina (angina symptoms at rest), new-onset angina (having appeared in the
past 3 months) or acute myocardial infarction that has occurred in the 6 months prior
to starting with the study medication.
11. Cardiac arrhythmias that require anti-arrhythmic therapy (only beta blockers and
digoxin would be allowed as concomitant medication for these patients).
12. Uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic blood
pressure > 90 mmHg) despite proper medical management.
13. Patients with phaeochromocytoma.
14. Pleural effusion or ascites that cause breathing difficulties (dyspnoea of grade ≥2
of the CTC).
15. Accidents (including transient ischaemic attacks), deep vein thrombosis or pulmonary
thromboembolism that have occurred in the 6 months prior to starting with the study
16. Active infection > grade 2 based on the NCI CTC, v. 4.0.
17. Human immunodeficiency virus (HIV) infection.
18. Active hepatitis B or C, or hepatitis B or C infection that requires treatment with
19. Patients with severe mental disorders that require medication.
20. Presence or history of brain metastases or meningeal tumours.
21. History of organ transplants.
22. Patients with evidence or history of bleeding diathesis. Any bleeding or bleeding
event > Common Toxicity Criteria for Adverse Effects (CTCAE) grade 3 in the 4 weeks
prior to starting with the study medication.
23. Presence of unhealed wounds, ulcers or bone fractures.
24. Kidney failure requiring haemodialysis or peritoneal dialysis.
25. Dehydration based on NCI CTC criteria, version 4, of > 1.
26. Substance abuse or a history of medical, social or psychological conditions that may
interfere with study participation or compliance with the efficacy and safety
assessments planned in the study.
27. Known hypersensitivity to regorafenib or any of its excipients.
28. Presence of any disease or medical condition that might interfere with patient safety
or may compromise treatment compliance with it.
29. Interstitial lung disease with signs and symptoms present at the time of signing the
30. Patients who are unable to swallow oral medication.
31. Persistent proteinuria > grade 3 based on the NCI CTC, version 4.0 (> 3.5 g/24
32. Intestinal malabsorption syndrome.
33. Close personal relationship with the research staff, such as family members of the
investigator or dependents (e.g. employees or students of the research centre).
34. Unresolved toxicity grade > 1 based on the NCI CTC, version 4.0 (except alopecia),
related to any previous therapy or procedure.