Colorectal cancer is one of the most common malignancies in China. Regorafenib is the standard multi-kinase inhibitor for refractory advanced colorectal cancer. In mice, regorafenib combined with anti-PD-1 was shown superior to regorafenib, which has not yet been verified in humans. JS001 is the Chinese anti-PD-1 monoclonal antibody for injection which has been approved for melanoma. This study is the first multi-center, open-label, phase I/II clinical trial to evaluate tolerability, safety and efficacy of JS001 in combination with regorafenib tablet in patients with MSS/MSI-L/pMMR, relapsed or metastatic colorectal cancer who have failed or can not tolerate fluorouracil, oxaliplatin and irinotecan based systemic treatment. The phase I clinical trial is to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of regorafenib tablet in this regimen, and select an acceptable safe dose for the phase II clinical trial to further determine safety and efficacy of this combination regimen in patients with metastatic colorectal cancer.
Colorectal cancer is one of the most common malignancies in China, with incidence and mortality ranking the 3rd and 4th among malignancies in China. Regorafenib is the standard multi-kinase inhibitor for refractory metastatic colorectal cancer, with multiple anti-tumor effects by inhibiting targets related to tumor cell proliferation, tumor metastasis, tumor angiogenesis and tumor immune escape, howerver, its efficacy is limited. Immunotherapy has become standard treatment for mCRC patients with MSI-H/dMMR. Combination of anti-angiogenesis treatment and immunotherapy may have a better anti-tumor effect. In mice, regorafenib combined with anti-PD-1 was shown superior to regorafenib, which has not yet been verified in humans. JS001 is the Chinese anti-PD-1 monoclonal antibody for injection which has been approved for melanoma. This study is the first multi-center, open-label, phase I/II clinical trial to evaluate tolerability, safety and efficacy of JS001 in combination with regorafenib tablet in patients with MSS/MSI-L/pMMR, relapsed or metastatic colorectal cancer who have failed or can not tolerate fluorouracil, oxaliplatin and irinotecan based systemic treatment. The phase I clinical trial is to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of regorafenib tablet in this regimen, and select an acceptable safe dose for the phase II clinical trial to further determine safety and efficacy of this combination regimen in patients with metastatic colorectal cancer.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
44
JS001 3 mg/kg, iv drip, d1, d15, q4w
80/120/160 mg, po, d1-d21, Q4w.
Sun Yat-sen University Cancer Center
Guangzhou, Guangdong, China
Maximum tolerated dose (MTD)
The maximum dose that patients enrolled can tolerate during dose escalation of phase I clinical trial according to mTPI method
Time frame: 28 days after the first dose of JS001 and Regorafenib, assessed up to 8 months
Dose limiting toxicity (DLT)
Severe toxicity that may be related to JS001 or regorafenib during dose escalation of phase I clinical trial according to mTPI method
Time frame: 28 days after the first dose of JS001 and Regorafenib, assessed up to 8 months
Objective response rate (ORR)
The ratio of patients who are evaluated as CR or PR
Time frame: from the initiation date of first cycle to the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years
Progression free survival (PFS)
The Kaplan-Meier survival from the initiation date of first cycle until the date of first documented progression or date of death
Time frame: from the initiation date of first cycle to the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years
Overall survival (OS)
The Kaplan-Meier survival from the initiation date of first cycle until death from any cause or the last follow-up date.
Time frame: from the initiation date of first cycle to the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years
Disease control rate (DCR)
Defined as the proportion of patients whose tumors shrink or remain stable for a certain period of time, including CR, PR and SD.
Time frame: from the initiation date of first cycle to the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years
Duration of response (DOR)
defined as the time between the first assessment of a tumor as PR or CR and the first assessment as PD or any cause of death
Time frame: the first assessment of a tumor as PR or CR and the first assessment as PD or any cause of death or the last follow-up date, assessed up to 2 years.
Severe toxicity
≥ Grade 3 toxicities
Time frame: from the initiation date of first cycle to the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years
cfDNA
The dynamic variation of circulating free DNA or cell free DNA (cfDNA) in immunotherapy efficacy and safety assessment
Time frame: from the initiation date of first cycle to the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years
Intestinal microorganism
The composition of intestinal microorganism pre- and post-treatment tested by intestinal microorganism, the relationship between intestinal flora alpha diversity and beta diversity and immunotherapy response as well as between intestinal microorganism alpha diversity and beta diversity and treatment toxicity and tolerance.
Time frame: from the initiation date of first cycle to the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.