ABOUT THIS STUDY
1. Histologically and/or cytologically confirmed and radiographically evaluable refractory metastatic colorectal adenocarcinoma for which regorafenib would be considered a therapeutic option.
2. Disease must be measurable by RECIST 1.1 criteria (see Appendix 1).
3. Age ≥ 18 years.
4. ECOG 0 or 1.
5. Life expectancy of at least 3 months.
6. Adequate bone marrow function as shown by:
1. ANC ≥ 1.5 x 109
2. Platelets ≥ 100 x 109/L
3. Hemoglobin ≥ 9 g/dL; Erythropoietin and transfusion support is permitted provided treatments are not required more than every 8 weeks. Hemoglobin must be stable above or equal to 9 g/dL for at least 2 weeks prior to day 1of study drug without blood transfusion to maintain hemoglobin level.
7. Adequate liver function as shown by:
1. serum bilirubin ≤ 1.5x ULN
2. PT/PTT/INR ≤ 1.5x ULN
3. ALT and AST ≤ 2.5x ULN
8. Adequate renal function: creatinine clearance (estimated) ≥ 50 cc/min by Cockroft Gault or 24 hour urine (see Appendix 6).
9. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days from day 1 of study drug; both men and women must be willing to use two methods of contraception, one of them being a barrier method during the study and for 6 months after last study drug administration.
10. Signed informed consent.
11. Presence of an archived tumor sample (no size requirements).
1. Prior regorafenib use with disease progression (expanded cohort only).
2. Prior failure to tolerate regorafenib at 120 mg/day.
3. Patients currently receiving anticancer therapies or who have received anticancer
therapies within 28 days from day 1 of study drug (including investigational agents,
chemotherapy, radiation therapy, antibody based therapy, etc.)
4. Patients who:
1. Have had a major surgery or significant traumatic injury within 4 weeks from day
1 of study drug,
2. Have not recovered from the side effects of any major surgery (defined as
requiring general anesthesia) or
3. Are anticipated to require major surgery during the course of the study.
5. Patients who have exhibited hypersensitivity reactions to regorafenib and/or a
structural compound, biological agent, or formulation (eg sorafenib).
6. Grade 3-4 AE associated with prior anti-VEGF therapy. Grade 3 hypertension that was
readily managed will be permitted.
7. History of grade 3 or higher hypersensitivity reactions/anaphylaxis attributed to
humanized and/or chimeric monoclonal antibodies or other such proteins.
Hypersensitivity reactions that are clearly related to cetuximab may be permitted at
the discretion of the principal investigator.
8. Patients receiving chronic, systemic treatment with corticosteroids or another
immunosuppressive agent with the following exceptions:
1. Intermittent steroids (not to exceed 4 mg every day) may be used on an as-needed
basis (e.g. treatment for chemotherapy-related nausea, anorexia and fatigue.)
2. Patients on physiologic replacement doses of steroids due to adrenal
insufficiency for any reason may remain on these medications.
3. Topical, inhaled or intra-articular corticosteroids
9. Active brain or leptomeningeal metastases, including patients who continue to require
glucocorticoids for brain or leptomeningeal metastases. Treated, asymptomatic
metastases are permitted provided the patient has been off steroids for at least 1
month prior to day 1 of study drug.
10. Severe chronic obstructive or other pulmonary disease with hypoxemia (requires
supplementary oxygen, symptoms due to hypoxemia or O2 saturation <90% by pulse
oximetry after a 2 minute walk or in the opinion of the investigator any physiological
state likely to cause systemic or regional hypoxemia.
11. Presence of poorly controlled atrial fibrillation (ventricular heart rate >100 bpm)
12. Previous history of CVA, TIA, angina pectoris, acute MI or history of recent
re-perfusion procedures (e.g. PTCA), pulmonary embolus or untreated deep vein
thrombosis (DVT) within 6 months from day 1 of study drug. NOTE: Subjects with recent
DVT who have been therapeutically anti-coagulated for at least 6 weeks are eligible.
13. Known significant or active CAD or PVD or CVD defined as abnormal stress test,
symptoms, or requiring medication for the prevention of symptoms.
14. Congestive heart failure (New York Heart Association (NYHA classification, see
Appendix 4 functional classification III-IV).
15. Proteinuria at screening demonstrated by urine analysis (UA) > 1+ and 24 hour urine
protein ≥ 1 gram/24 hours.
16. Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study as so judged by the
treating physician. Examples include but are not limited to:
1. Severely impaired lung function (e.g. use of home O2, history of Idiopathic Lung
Disease (ILD), any evidence of ILD on scan.
2. Active (acute or chronic) severe infections requiring treatment with I.V.
3. Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent
4. Poorly controlled hypertension [defined as systolic blood pressure (SBP of >140
mmHg or diastolic blood pressure (DBP) of >90 mmHg] NOTE: Initiation or
adjustment of antihypertensive medication(s) is permitted prior to study entry.
Following antihypertensive medication initiation or adjustment, blood pressure
(BP) must be re-assessed three times at approximately 2-minute intervals. At
least 24 hours must have elapsed between anti-hypertensive medication initiation
or adjustment and BP measurement. These three values should be averaged to obtain
the mean diastolic blood pressure and the mean systolic blood pressure. The mean
SBP/DBP ratio must be <140/90 mmHg in order for a subject to be eligible for the
17. Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of oral medications (e.g., ulcerative disease,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel
18. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
recent peripheral arterial thrombosis) within 6 months prior to day 1 of study drug
19. History of hemoptysis (greater than or equal to 1/2 teaspoon of bright red blood per
episode) or other significant spontaneous bleeding event within 1 month prior to day 1
of study drug or at any time on a prior VEGF inhibitor.
20. History of abdominal fistula or gastrointestinal perforation at any point within 6
months prior to day 1 of study drug, unless surgically repaired.
21. Active peptic ulcer disease, inflammatory bowel disease (e.g. ulcerative colitis,
Crohn's disease), or other gastrointestinal conditions with increased risk of
perforation or gastrointestinal bleeding.
22. Use or need for full dose anticoagulation other than low molecular weight heparin and
Factor Xa inhibitors (e.g. Lovenox, Fondaparinux) and no other bleeding risk.
23. Serious, non-healing wound, active ulcer, or untreated bone fracture as judged by
24. Active bleeding diathesis.
25. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that
increase the risk of pulmonary hemorrhage.
26. Known history of HIV or Hepatitis B or C seropositivity.
27. Female patients who are pregnant or breast feeding, or adults of reproductive
potential who are not using effective birth control methods. Two acceptable forms of
contraceptives must be continued throughout the trial by either sex and for 2 months
(60 days) following last dose of either drug. Hormonal contraceptives are not
acceptable as a sole method of contraception. (Women of childbearing potential must
have a negative serum pregnancy test within 7 days prior to day 1 of study drug).
28. Concomitant use of CYP3A4 strong inducers and strong inhibitors. (See Appendix 7).
29. Corrected QTc interval > 500 msec. If QTc interval is > 500 msec, then 2 additional
ECGs should be obtained over a brief period of time (e.g., within 15-20 minutes) to
confirm the abnormality. The average QTc interval will be determined from the 3 ECG
tracings by manual evaluation and will be used to determine if the subject will be
excluded from the study. The same method of QTc determination must be used throughout
the subject's participation in the trial.
30. History of Osler-Weber-Rendu syndrome or Hereditary Hemorrhagic Telangiectasia
31. Patients unwilling to or unable to comply with the protocol.
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