Clinical Trials /

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



The main purpose of this study is to test the safety, tolerable side effects, and determine the highest tolerable dose of the combination of Regorafenib and Nivolumab. Researchers want to find out if this combination of Regorafenib and Nivolumab can help people with metastatic colorectal cancer with mismatch repair (MMR) proficiency.

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Active, not recruiting


Phase 1

Trial Eligibility



  • Brief Title: Regorafenib and Nivolumab in Mismatch Repair (MMR) Refractory Colorectal Cancer
  • Official Title: Phase I Study of Regorafenib and Nivolumab in Mismatch Repair (MMR) Proficient Advanced Refractory Colorectal Cancer

Clinical Trial IDs

  • ORG STUDY ID: MCC-19581
  • NCT ID: NCT03712943


  • Colorectal Cancer
  • Metastatic Colorectal Cancer
  • Colon Cancer


RegorafenibStivargaRegorafenib and Nivolumab Combination - Escalation
NivolumabOPDIVORegorafenib and Nivolumab Combination - Escalation


The main purpose of this study is to test the safety, tolerable side effects, and determine the highest tolerable dose of the combination of Regorafenib and Nivolumab. Researchers want to find out if this combination of Regorafenib and Nivolumab can help people with metastatic colorectal cancer with mismatch repair (MMR) proficiency.

Trial Arms

Regorafenib and Nivolumab Combination - EscalationExperimentalDose Escalation: To find the dose of regorafenib that can be safely given with nivolumab in patients with advanced, refractory colorectal cancers.
  • Regorafenib
  • Nivolumab
Regorafenib and Nivolumab Combination - ExpansionExperimentalDose Expansion: To find the effect on tumor of the combination of regorafenib and nivolumab.
  • Regorafenib
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically confirmed diagnosis of colorectal adenocarcinoma

          -  Proficient DNA mismatch repair (MMR) or stable microsatellite disease.

          -  Participants with the presence of at least one lesion with measurable disease as
             defined by 10mm in longest diameter for a soft tissue lesions or 15mm in short axis
             for a lymph node by RECIST 1.1 for response assessment.

          -  Participants 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. Exceptions may apply.

          -  Eastern Cooperative Oncology Group (ECOG) Performance Score 0 or 1

          -  Estimated life expectancy over 3 months.

          -  Adequate bone marrow, liver and renal function.

          -  Participants 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 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.

          -  Participants (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

          -  Participants must be able to understand and be willing to sign the written informed
             consent form and be willing and able to comply with scheduled visits, treatment
             schedule, laboratory testing, and other study requirements.

        Exclusion Criteria:

          -  Participants with active Central Nervous System (CNS) metastases If CNS metastases are
             treated and participants are at neurologic baseline for at least 2 weeks prior to
             enrollment, they will be eligible but will need a Brain MRI prior to enrollment.

          -  Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic pressure > 90 mm
             Hg [NCI-CTCAE v5.0] on repeated measurement) despite optimal medical management.

          -  Active or clinically significant cardiac disease.

          -  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 that has required systemic treatment in the past 2 years.
             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

          -  Participants with phaeochromocytoma

          -  Ongoing infection > Grade 2

          -  Presence of a non-healing wound, or bone fracture.

          -  Renal failure requiring hemo-or peritoneal dialysis.

          -  Seizure disorder requiring medication.

          -  Interstitial lung disease with ongoing signs and symptoms at the time of informed

          -  Pleural effusion or ascites that causes respiratory compromise.

          -  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

          -  History of organ allograft

          -  Participants requiring warfarin or equivalent vitamin K antagonists (e.g.

          -  Participants with a condition requiring a strong CYP3A4 inhibitors or strong CYP3A4

          -  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.

          -  Participants 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.

          -  Participants requiring concurrent anti-cancer therapy other than study treatment.

          -  Participants requiring hormonal therapy during the study or within 2 weeks of first
             study enrollment.
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose
Time Frame:Up to 12 months
Safety Issue:
Description:To determine the maximum tolerated dose of Regorafenib in combination with Nivolumab in advanced, refractory colorectal cancers.

Secondary Outcome Measures

Measure:Response Rate
Time Frame:Every 2nd cycle (Cycles are 28 days) up to 12 months
Safety Issue:
Description:To access response rate using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
Measure:Overall Survival (OS)
Time Frame:Up to 24 months after conclusion of treatment
Safety Issue:
Description:Occurrence of Overall Survival
Measure:Frequency and Severity of Adverse Events
Time Frame:Up to 12 months
Safety Issue:
Description:To evaluate the frequency and severity of adverse events and tolerability of the combination regimen.


Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:H. Lee Moffitt Cancer Center and Research Institute

Trial Keywords

  • colon cancer
  • colorectal
  • MMR
  • Mismatch Repair

Last Updated

July 13, 2021