NCT04483219

Tyrosine Kinase Inhibitor (TKI) + Anti-PD-1 Antibody in TKI-responded Microsatellite Stability/Proficient Mismatch Repair (MSS/pMMR) Metastatic Colorectal Adenocarcinoma.

A Single-arm, Multicenter Phase II Clinical Study to Evaluate the Efficacy and Safety of Tyrosine Kinase Inhibitor (TKI) in Combination With Anti-PD-1 Antibody in TKI-responded Microsatellite Stability/Proficient Mismatch Repair (MSS/pMMR) Metastatic Colorectal Adenocarcinoma.

• Status: Unknown
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 53 (estimated)
• Sponsor: China Medical University, China · Academic / Other
• Sex: All
• Age: 18 Years – 75 Years
• Healthy volunteers: Not accepted

Summary

The purpose of this study is to evaluate the efficacy and safety of fruquintinib or regorafenib in combination with anti-PD-1 antibody in TKI (fruquintinib or regorafenib)-responded MSS/pMMR metastatic colorectal adenocarcinoma.

Detailed description

At present, the later-line treatment of metastatic colorectal cancer (mCRC) can bring benefits to subjects. However, the overall efficacy of treatment is still low. The programmed cell death protein 1 (PD-1) blockade alone in MSS/pMMR mCRC is inefficiency, highlighting a need for strategies that converse the immunity suppressive to immunity supportive microenvironment. Fruquintinib and regorafenib are multi-target TKI mainly for angiogenesis, which has the following characteristics: cause tumor necrosis and release a lot of new antigens, improve the microenvironment of immunosuppression, and induce tumor vascular normalization. In addition to killing tumor cells, fruquintinib and regorafenib could also converse the immunity suppressive to immunity supportive microenvironment, which could sensitize PD-1 blockade, ultimately improve the prognosis of patients with MSS/pMMR mCRC. This prospective study is a single-arm, multicenter phase II clinical study to evaluate the efficacy and safety of fruquintinib or regorafenib in combination with anti-PD-1 antibody in TKI (fruquintinib or regorafenib)-responded MSS/pMMR metastatic colorectal cancer. In this prospective study, the 9-month PFS rate in subjects receiving TKI followed by TKI in combination with anti-PD-1 antibody, will be used as primary outcome measures and 53 subjects will be recruited. After fully informed and signed the informed consent, the subjects will receive one cycle of TKI (fruquintinib or regorafenib) treatment after enrollment. According to response to TKI, the subjects will be divided into three arms. The definition of response to TKI are as follows: (1) obvious response to TKI (arm A)：effective imaging changes, including reduction of target lesion diameter to CR, PR or shrunken SD (based on response evaluation criteria in solid tumors, RECIST v 1.1), or cavitation in metastatic lung lesions, or decrease in the density of liver metastatic target lesions ≥15%; (2) general response to TKI (arm B): enlarged SD (based on RECIST v 1.1); (3) poor response to TKI (arm C): PD (based on RECIST v 1.1). TKI in combination with anti-PD-1 antibody will be administered in arm A. The subjects in arm C will exit the study. The subjects in arm B will continue to take TKI for another one cycle. After that, the obvious response subjects will be entered group A, the general response subjects will keep in arm B and continue the TKI monotherapy, and the poor response subjects will exit the study. The administration of arm A or B will be last until disease progression or intolerable toxicity，anti-PD-1 antibody can be applied for up to 2 years. The first two imaging evaluations would be performed every 4 weeks after the beginning of treatment to evaluate TKI response, and then once every 6 weeks, until the end of treatment, withdrawal of informed consent or death. The TKI response would be assessed according to RECIST v1.1 criteria and effective imaging changes (cavitation in metastatic lung lesions, or decrease in the density of liver metastatic target lesions ≥15%). The efficacy of TKI followed by TKI in combination with anti-PD-1 antibody would be evaluated based on immune-related RECIST (iRECIST) v1.1 criteria. PD-1/PD-L1 expression, T lymphocyte infiltration, T lymphocyte subsets in peripheral blood, granulocyte to lymphocyte ratio, tumor mutant burden (TMB), circulating tumor DNA (ctDNA), exosomes，etc.，will be measured and monitored during the treatment. In addition，the safety evaluation will be carried out according to the standard of adverse reaction classification (Common Terminology Criteria for Adverse Events, CTCAE v5.0)

Conditions

• MSS
• pMMR
• Metastatic Colorectal Adenocarcinoma

Interventions

Type	Name	Description
DRUG	TKI ± anti-PD-1 antibody	After one cycle of TKI, evaluations would be performed according to RECIST v 1.1. (1) obvious response (A): CR, PR or shrunken SD, or cavitation in metastatic lung lesions, or decrease in the density of liver metastatic targets ≥15%; (2) general response (B): enlarged SD; (3) poor response (C): PD. TKI ＋ anti-PD-1 antibody will be administered in group A. The subjects in group C will exit the study. The subjects in group B will continue TKI for another one cycle, the obvious response subjects will entered group A, the general response subjects will keep in arm B and continue the TKI monotherapy, and the poor response subjects will exit the study. 1. Fruquintinib 5mg or regorafenib 120mg, qd po, 3 weeks, Q4w. (The investigators decide to choose fruquintinib or regorafenib) 2. Toripalimab injection 240mg, Q3w, until the disease progresses or lasts for two years.

Timeline

• Start date: 2020-07-24
• Primary completion: 2022-07-31
• Completion: 2022-07-31
• First posted: 2020-07-23
• Last updated: 2021-10-05

Locations

1 site across 1 country: China