Regorafenib and Nivolumab in Treating Regorafenib and Nivolumab in Mismatch Repair (MMR) Proficient Advanced Refractory Colorectal Cancer

Status: Active


This phase I trial studies the side effects and best dose of regorafenib when given with nivolumab in treating patients with mismatch repair proficient colorectal cancer that has spread to other places in the body (advanced) and does not respond to treatment (refractory). Regorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving regorafenib and nivolumab may work better in treating colorectal cancer.

Eligibility Criteria

Inclusion Criteria

  • Histologically confirmed diagnosis of colorectal adenocarcinoma
  • Proficient deoxyribonucleic acid (DNA) mismatch repair (MMR) or stable microsatellite disease confirmed by immunohistochemical staining or polymerase chain reaction (PCR)
  • Patients with the presence of at least one lesion with measurable disease as defined by 10 mm in longest diameter for a soft tissue lesions or 15 mm in short axis for a lymph node by RECIST 1.1 for response assessment
  • Patients must have received and progressed through or become intolerant to fluoropyrimidine, irinotecan, oxaliplatin, and bevacizumab, and if K-ras wild type, cetuximab or panitumumab containing therapies. Prior TAS 102 is allowed
  • Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1
  • Estimated life expectancy > 3 months
  • Hemoglobin > 8.0 g/dl
  • Absolute neutrophil count (ANC) > 1,000/mm3 independent of growth factor support
  • Platelet count > 100,000/mm3
  • Total bilirubin < 1.5 times upper limit of normal (ULN) unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin
  • Aspartate aminotransferase (AST), alanine aminotransferase (ALT) =< 2.5 times the ULN (=< 5 x ULN for patients with liver involvement)
  • Alkaline phosphatase =< 2.5 times the ULN (=< 5 x ULN for patients with liver involvement)
  • Creatinine clearance, calculated according to the Cockroft-Gault formula, must be >= 30 ml/min
  • Patients must not have had chemotherapy, major surgery, monoclonal antibody therapy or experimental therapy within the 21 days prior to the start of regorafenib and nivolumab administration
  • Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) performed within 24 hours prior to the start of study drug and then every 4 weeks. Post-menopausal women (defined as no menses for at least 1 year) and surgically sterilized women are not required to undergo a pregnancy test
  • Subjects (men and women) of childbearing potential must agree to use adequate contraception beginning at the signing of the informed consent form (ICF) until at least 5 months for females and 7 months for males after the last dose of study drug
  • Subjects must be able to understand and be willing to sign the written informed consent form. A signed informed consent form must be appropriately obtained prior to the conduct of any trial-specific procedure. Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other study requirements

Exclusion Criteria

  • Subjects with active central nervous system (CNS) metastases. If CNS metastases are treated and subjects are at neurologic baseline for at least 2 weeks prior to enrollment, they will be eligible but will need a brain magnetic resonance imaging (MRI) prior to enrollment
  • Uncontrolled hypertension (systolic pressure > 140 mm Hg or diastolic pressure > 90 mm Hg [National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0] on repeated measurement) despite optimal medical management
  • Active or clinically significant cardiac disease including: * Congestive heart failure – New York Heart Association (NYHA) > class II * Active coronary artery disease * Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin * Unstable angina (angina symptoms at rest), new-onset angina within 3 months, or myocardial infarction within 6 months
  • Women who are pregnant or breast-feeding
  • Prior therapy with regorafenib, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways)
  • Previous or concurrent cancer within 3 years prior to treatment start EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder tumors (Ta [non-invasive tumor], Tis [carcinoma in situ] and T1 [tumor invades lamina propria])
  • Active autoimmune disease (active defined as having autoimmune disease related symptoms and detectable autoantibodies) that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
  • Ascites, pleural effusion, or pericardial fluid requiring drainage in the last 4 weeks
  • Patients with phaeochromocytoma
  • Ongoing infection > grade 2 NCI-CTCAE v5.0
  • Presence of a non-healing wound, or bone fracture
  • Renal failure requiring hemo-or peritoneal dialysis
  • Patients with seizure disorder requiring medication
  • Interstitial lung disease with ongoing signs and symptoms at the time of informed consent
  • Pleural effusion or ascites that causes respiratory compromise (>= NCI-CTCAE version 5.0 grade 2 dyspnea)
  • Any condition which, in the investigator’s opinion, makes the subject unsuitable for trial participation
  • Known or suspected allergy or hypersensitivity to any of the study drugs, study drug classes, or excipients of the formulations given during the course of this trial
  • Persistent proteinuria >= grade 3 NCI-CTCAE v5.0 (> 3.5 g/24 hours [hrs], measured by urine protein:creatinine ratio on a random urine sample)
  • History of organ allograft
  • Subjects requiring warfarin or equivalent vitamin K antagonists (e.g. phenprocoumon)
  • Subjects with a condition requiring a strong CYP3A4 inhibitors or strong CYP3A4 inducers
  • Unresolved toxicity higher than CTCAE grade 1 attributed to any prior therapy or procedure, excluding alopecia
  • Any hemorrhage or bleeding event >= NCI CTCAE grade 3 within 4 weeks prior to start of study medication
  • Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results
  • Subjects with an arterial thrombotic or thromboembolic event within 6 months of informed consent
  • Known history of human immunodeficiency virus (HIV) infection or current chronic or active hepatitis B or C infection
  • Child-Pugh B cirrhosis (or worse) or a history of hepatic encephalopathy
  • History of stroke or intracranial hemorrhage within 6 months prior to enrollment
  • Major surgery or a wound that has not fully healed within 4 weeks of enrollment
  • Subjects requiring concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, or tumor embolization) other than study treatment
  • Subjects requiring hormonal therapy during the study or within 2 weeks of first study enrollment

Locations & Contacts


Moffitt Cancer Center
Status: Active
Contact: Dae Won Kim
Phone: 813-745-6898

Trial Objectives and Outline


I. To assess safety and tolerability, describe the dose-limiting toxicities (DLTs), and determine the maximum tolerated dose (MTD) or the highest protocol-defined dose level in the absence of establishing an MTD of regorafenib in combination with nivolumab in subjects with advanced, refractory colorectal cancers.


I. To assess response rate using Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

II. To assess overall survival.

III. To further evaluate the frequency and severity of adverse events and tolerability of the combination regimen.


I. To explore potential correlation of biomarkers to predict clinical response of the combination therapy.

OUTLINE: This is a dose-escalation study of regorafenib.

Patients receive regorafenib (PO) daily on days 1-21 and nivolumab intravenously (IV) over 60 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 100 days, then every 12 weeks thereafter.

Trial Phase & Type

Trial Phase

Phase I

Trial Type


Lead Organization

Lead Organization
Moffitt Cancer Center

Principal Investigator
Dae Won Kim

Trial IDs

Primary ID MCC-19581
Secondary IDs NCI-2018-02506 ID NCT03712943