REGONIVO is a Phase Ib study to explore the efficacy and safety of regorafenib in combination with nivolumab in the treatment of gastric cancer and colorectal cancer with MSS. The study enrolled 50 patients with advanced disease, including 25 cases of gastric cancer, 25 cases of colorectal cancer, except for one case of colorectal cancer with MSI-H, and others were MSS type. The results of the study showed that patients with colorectal cancer had an objective response rate (ORR) of 36% and a progression-free survival (PFS) of 6.3 months.

Based on the preliminary results of the REGONIVO study, the aim of this phase 2 study is to explore the safety and efficacy of regorafenib and PD-1 antibody with or without radiotherapy in previously treated metastatic colorectal cancer patients with pMMR/MSS.

Inclusion Criteria:

• Histological or cytological documentation of adenocarcinoma of the colon or rectum. All other histological types are excluded.

• Subjects with metastatic colorectal cancer(CRC) (Stage IV).

• Subjects must have failed at least two lines of prior treatment.

• Tumor tissues were identified as mismatch repair-proficient (pMMR) by immunohistochemistry (IHC) method or microsatellite stability (MSS) by polymerase chain reaction (PCR).

• Progression during or within 3 months following the last administration of approved standard therapies which must include a fluoropyrimidine, oxaliplatin and irinotecan.

  • Subjects treated with oxaliplatin in an adjuvant setting should have progressed during or within 6 months of completion of adjuvant therapy.
  • Subjects who progress more than 6 months after completion of oxaliplatin containing adjuvant treatment must be retreated with oxaliplatin-based therapy to be eligible.
  • Subjects who have withdrawn from standard treatment due to unacceptable toxicity warranting discontinuation of treatment and precluding retreatment with the same agent prior to progression of disease will also be allowed into the study.
  • Subjects may have received prior treatment with Avastin (bevacizumab) and/or Erbitux (cetuximab)/Vectibix (panitumumab) (if KRAS WT)

• Metastatic CRC subjects must have measurable or non measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, version 1.1.

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 1.

• Life expectancy of at least 3 months.

• Adequate bone marrow, liver and renal function as assessed by the laboratory required by protocol.

Exclusion Criteria:

• Prior treatment with Regorafenib.
• Previously received anti-programmed death-1 (PD-1) or its ligand (PD-L1) antibody, anti-cytotoxic T lymphocyte-associated antigen 4 (cytotoxic T-lymphocyte-associated Protein 4, CTLA-4) antibody or other drug/antibody that acts on T cell costimulation or checkpoint pathways.
• Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer within 5 years prior to randomization EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)].
• Extended field radiotherapy within 4 weeks or limited field radiotherapy within 2 weeks prior to randomization.
• Cardiological disease including Congestive heart failure, Unstable angina, Myocardial infarction, Cardiac arrhythmias requiring anti-arrhythmic therapy.
• Uncontrolled hypertension. (Systolic blood pressure 150 mmHg or diastolic pressure 90 mmHg despite optimal medical management).
• Pleural effusion or ascites that causes respiratory compromise.
• Arterial or venous thrombotic or embolic events.
• Any history of or currently known brain metastases.
• Interstitial lung disease with ongoing signs and symptoms at the time of informed consent.
• Systemic anticancer therapy including cytotoxic therapy, signal transduction inhibitors, immunotherapy, and hormonal therapy during this trial or within 4 week.