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

Phase 2

• Conditions: Metastatic Colorectal Cancer
• Interventions: Drug: Toripalimab; Radiation: Stereotactic Body Radiotherapy

• Registration Number: NCT03927898
• Lead Sponsor: Chinese Academy of Medical Sciences

Brief Summary

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).

Detailed Description

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.

Study Timeline

• Study Start: 2019-03-01
• Status Verified: 2019-04
• Study First Submitted: 2019-04-09
• Study First Submitted QC: 2019-04-23
• Last Update Submitted: 2019-04-23
• Study First Posted: 2019-04-25
• Last Update Posted: 2019-04-25
• Primary Completion: 2021-03-01
• Study Completion: 2021-09-01

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 40

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
SBRT+Toripalimab	Toripalimab	Participants received SBRT (BED\>80Gy) to oligometastatic lesions and then receive Toripalimab (240mg)/q3w till progression of disease.
SBRT+Toripalimab	Stereotactic Body Radiotherapy	Participants received SBRT (BED\>80Gy) to oligometastatic lesions and then receive Toripalimab (240mg)/q3w till progression of disease.

Primary Outcome Measures

Name	Time	Method
1 year Progression-Free-Survival (PFS)	1 year	1 year PFS

Secondary Outcome Measures

Name	Time	Method
Grade 3-5 acute adverse events	6 months since last treatment of Toripalimab	Grade 3-5 acute adverse events
2 year local control rate	2 year	2 year local control rate
2 year overall survival	2 year	2 year overall survival
T cell receptor repertoire and T cell clones in peripheral blood	At the end of 6 cycles of Toripalimab (each cycle is 21 days)	Change of T cell receptor repertoire and T cell clones in peripheral blood
Expression of PD-1, ki-67 on T cell	At the end of 6 cycles of Toripalimab (each cycle is 21 days)	Change of expression of PD-1, ki-67 on T cell
Objective response rate	At the end of 4 cycles of Toripalimab (each cycle is 21 days)	Objective response rate
Expression of PD-L1 on Exosomes in peripheral blood	At the end of 6 cycles of Toripalimab (each cycle is 21 days)	Change of expression of PD-L1 on Exosomes in peripheral blood
Expression of PD-L1 on circulation tumor cell	At the end of 6 cycles of Toripalimab (each cycle is 21 days)	Change of expression of PD-L1 on circulation tumor cell

Trial Locations

Locations (1)

Department of Radiation Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College; 🇨🇳 Beijing, China