Phase II Study of Toripalimab Plus Stereotactic Body Radiotherapy in Colorectal Cancer Patients With Oligometastasis

Phase II Study of Toripalimab (JS001) Plus Stereotactic Body Radiotherapy in Colorectal Cancer Patients With Oligometastasis

Metastatic colorectal cancer is one of the common malignant tumors and the overall prognosis is poor. The introduction of immune-checkpoint inhibition (ICI) has led to a paradigm shift in the treatment of patients with metastatic cancer. Stereotactic body radiation therapy (SBRT) delivers a large dose of radiation to the tumor target with high precision while sparing irradiation of the surrounding normal tissues. It is suggested that SBRT could be the most appropriate radiotherapy modality to be combined with immunotherapy since it induces the expression of a series of cytokines and new tumour-associated antigens (TAAs) and is more likely to cause intense immune response and exert an abscopal effect than conventional radiotherapy.

Thus, this study is to explore the use of SBRT in combination with ICI in colorectal cancer patients with oligometastasis, in order to get better local and systemic tumor control and improve progress-free survival (PFS).

The investigators plan to recruit patients with mCRC, who have received first-line systemic therapy for more than 3 months and achieved PR/SD. Than all the patients will receive SBRT followed by ICI therapy.

Inclusion Criteria:

1. Age：18-75 years old , Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

2. Histologically confirmed CRC , metastatic CRC , subjects have received first-line systemic therapy for more than 3 months and achieved PR/SD, the interval between last systemic therapy and SBRT is≥4 weeks

3. The primary site has been controlled by surgery

4. Patient has at least 1 lesion of measurable metastatic disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and iRECIST , and who can achieve the status of non evidence of disease after local ablative therapy. The number of lesion is ≤ 5, the maximum diameter of the lesion is ≤5cm ,

5. All metastatic lesions are amenable to SBRT with BED≥80Gy in 3 to 5 fractions;

6. Have a life expectancy of at least 6 months

7. Adequate organ function, as defined by the following:

   Hemoglobin ≥ 100 g/L; White blood cell count (WBC) ≥3.5×109/L , Absolute neutrophil count (ANC) ≥ 1.5×109/L; Platelets ≥75×109/L; Serum creatinine ≤ 1.0 x institutional upper limit of normal (ULN) ; Blood Urea Nitrogen(BUN) ≤ 1.0 x institutional (ULN) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 1.5 x institutional ULN ALkaline Phosphatase (ALP) ≤ 1.5 x institutional ULN Serum total bilirubin (TBIL) ≤1.5 x institutional ULN Urine protein is negative , Coagulation function is normal

8. patients and his/her mate must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug；

9. Patient must have the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Serious autoimmune disease at the discretion of the treating attending，subjects with leukodermia，allergic asthma syndrome will not be excluded from the study.

2. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.

3. Has evidence of interstitial lung disease or active, non-infectious pneumonitis requiring systemic steroids.

4. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to study Day 1 of the trial treatment.

5. Has a known additional malignancy，subjects with basal cell carcinoma (BCC)， squamous cell carcinoma of skin and carcinoma in situ of cervix will not be excluded from the study.

6. Has received a vaccine within 30 days prior to study Day 1 of the trial treatment or will receive a vaccine after the trial treatment; active HBV，HCV infection

7. Has received systemic therapy within 4 weeks prior to study Day 1 of the trial treatment or who has not recovered from adverse events due to a previously administered agent.

   Note: Subjects with ≤ Grade 2 neuropathy or myelosuppression are an exception to this criterion and may qualify for the study.

8. Any underlying medical or psychiatric condition: partial endocrine organ deficiencies , serious cardiac，pulmonary，renal disease，active infectious disease.

9. Active diverticulitis, intra-abdominal abscess, Gastrointestinal (GI) obstruction, abdominal carcinomatosis , frequent diarrhea or other known risk factors for bowel perforation.