Summary

This phase II trial investigates how well regorafenib and anti-EGFR therapy (cetuximab or panitumumab) works for the treatment of patients with colorectal cancer that cannot be removed by surgery (unresectable), has spread to nearby tissue or lymph nodes (locally advanced), or has spread to other places in the body (metastatic). Regorafenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cetuximab or panitumumab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as irinotecan, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. The purpose of this research study is to compare the effects, good and/or bad, of taking regorafenib follow by cetuximab or panitumumab, to those that receive cetuximab or panitumumab before regorafenib.

Objectives

PRIMARY OBJECTIVE:
I. To compare the overall survival between evaluable patients who were randomized to receive regorafenib followed by anti-EGFR monoclonal antibody therapy compared to those that receive anti-EGFR monoclonal antibody followed by regorafenib.

SECONDARY OBJECTIVES:
I. To compare the first progression free survival (PFS1) of patients between evaluable patients who were randomized to receive regorafenib followed by anti-EGFR monoclonal antibody therapy compared to those that receive anti-EGFR monoclonal antibody followed by regorafenib.
II. To compare the second progression free survival (PFS2) of patients between evaluable patients who were randomized to receive regorafenib followed by anti-EGFR monoclonal antibody therapy compared to those that receive anti-EGFR monoclonal antibody followed by regorafenib.
III. To compare the sequential treatment progression free survival (stPFS) of patients between evaluable patients who were randomized to receive regorafenib followed by anti-EGFR monoclonal antibody therapy compared to those that receive anti-EGFR monoclonal antibody followed by regorafenib.
IV. To assess the frequency and severity of adverse events between evaluable patients who were randomized to receive regorafenib followed by anti-EGFR monoclonal antibody therapy compared to those that receive anti-EGFR monoclonal antibody followed by regorafenib.
V. To compare the objective response rate (ORR), while on initial treatment, between evaluable patients who were randomized to receive regorafenib followed by anti-EGFR monoclonal antibody therapy compared to those that receive anti-EGFR monoclonal antibody followed by regorafenib.
VI. To compare the objective response rate (ORR), while on sequential treatment, between evaluable patients who were randomized to receive regorafenib followed by anti-EGFR monoclonal antibody therapy compared to those that receive anti-EGFR monoclonal antibody prior to regorafenib.

CORRELATIVE RESEARCH OBJECTIVES:
I. To assess plasma pharmacodynamics biomarkers of response and resistance to therapy.
II. To explore any correlation between tissue and blood based biomarkers and clinical outcomes.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive regorafenib orally (PO) once daily (QD) on days 1-21. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Per the treating physician's discretion, patients who experience disease progression may initiate a treatment regimen consisting of cetuximab or panitumumab intravenously (IV) over 30-90 minutes on days 1 and 15. Patients may also receive irinotecan IV on days 1 and 15 as determined by the study doctor. Cycles repeat every 28 days until disease progression or unacceptable toxicity.

ARM B: Patients receive cetuximab or panitumumab IV over 30-90 minutes on days 1 and 15. Patients may also receive irinotecan IV on days 1 and 15 as determined by the study doctor. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Per the treating physician's discretion, patients who experience disease progression may initiate a treatment regimen consisting of regorafenib PO QD on days 1-21. Cycles repeat every 28 days until disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, and then every 3 months for up to 3 years after randomization.

Eligibility

1. Histologically proven, unresectable distant metastatic or locally advanced colorectal adenocarcinoma
2. KRAS, NRAS wild type
3. BRAF v600E wildtype
4. Measurable disease
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2
6. Life expectancy of >= 3 months per estimation of treating physician
7. Absolute neutrophil count (ANC) >= 1200/mm^3 (obtained =< 7 days prior to randomization)
8. Platelet count >= 75,000/mm^3 (obtained =< 7 days prior to randomization)
9. Hemoglobin >= 9.0 g/dL (obtained =< 7 days prior to randomization)
10. Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 7 days prior to randomization)
11. Alanine aminotransferase (ALT) and aspartate amino-transferase (AST) =< 2.5 x ULN (=< 5 x ULN for subjects with liver involvement of their cancer) (obtained =< 7 days prior to randomization)
12. Serum creatinine =< 1.5 x ULN (obtained =< 7 days prior to randomization)
13. International normalized ratio (INR)/partial thromboplastin time (PTT) =< 1.5 x ULN (obtained =< 7 days prior to randomization) * NOTE: Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists. Close monitoring of at least weekly evaluations will be performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care
14. Alkaline phosphatase limit =< 2.5 x ULN (=< 5 x ULN for patients with liver involvement of their cancer) (obtained =< 7 days prior to randomization)
15. Negative serum pregnancy test done =< 7 days prior to randomization for women of childbearing potential only. * NOTE: Post-menopausal women (defined as no menses for at least 1 year) and surgically sterilized women are not required to undergo a pregnancy test. The definition of adequate contraception will be based on the judgment of the treating physician
16. Provide informed written consent
17. Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
18. Disease progression on or intolerable to any of the following: fluoropyrimidine, oxaliplatin and irinotecan
19. Able to swallow and retain oral medication
20. Willing to provide tissue and blood samples for correlative research purposes
21. Willing to allow transfer of tissue and blood samples, clinical information, and outcome data collected from this trial for future research