Ivarmacitinib Combined With Camrelizumab and Fruquintinib for Patients With Metastatic Colorectal Cancer After Failure of Second-line or Later Treatment

Condition(s) studied

Investigational drug(s) / intervention(s)

Ivarmacitinib Sulfate Tablets: Ivarmacitinib will be administered orally at a dose of 4 mg once daily for 2 weeks during the lead-in phase. During the combination induction phase, treatment will continue at 4 mg orally once daily. Ivarmacitinib will be discontinued after completion of the combination induction phase, unless earlier discontinuation is required.

Camrelizumab: Camrelizumab will be administered intravenously at a dose of 200 mg once every 3 weeks during the combination induction phase and the maintenance phase. During the maintenance phase, camrelizumab will be administered for 15 cycles. Treatment will be discontinued upon completion of the planned treatment period, disease progression, unacceptable toxicity, or fulfillment of another protocol-defined discontinuation criterion.

Fruquintinib: Fruquintinib will be administered orally at a dose of 5 mg once daily for 14 consecutive days, followed by 7 days off treatment, constituting a 21-day cycle. This regimen will be administered during the combination induction phase and the maintenance phase. Treatment will be discontinued upon completion of the planned treatment period, disease progression, unacceptable toxicity, or fulfillment of another protocol-defined discontinuation criterion.

Study summary

For patients with metastatic colorectal cancer (mCRC) who have failed two or more lines of standard therapy, treatment options are extremely limited, and the prognosis remains poor, with objective response rates (ORRs) generally below 5%. This is particularly challenging for patients with microsatellite-stable (MSS)/proficient mismatch repair (pMMR) tumors, who constitute the vast majority of patients with mCRC. The immunologically "cold" tumor microenvironment (TME) in these patients contributes to widespread primary resistance to PD-1 inhibitor monotherapy. A key mechanism underlying this resistance is the sustained activation of JAK/STAT signaling, which promotes immunosuppression mediated by myeloid-derived suppressor cells (MDSCs) and other immunosuppressive components, thereby limiting T-cell activity and the efficacy of strategies that solely reinvigorate T cells.

To address this challenge, the investigators propose an innovative combination strategy aimed at remodeling the TME and alleviating immunosuppression. The investigators hypothesize that ivarmacitinib, a highly selective JAK1 inhibitor, may attenuate the immunosuppressive TME through modulation of JAK/STAT signaling, potentially converting "cold" tumors into "hot" tumors and enhancing the antitumor activity of camrelizumab, a PD-1 inhibitor, in combination with fruquintinib, a tyrosine kinase inhibitor (TKI). Accordingly, a single-arm, single-center, exploratory phase II clinical study was designed to enroll 33 patients with mCRC who have failed multiple lines of prior therapy. The study aims to evaluate the ORR, survival outcomes, and safety of this combination regimen. The findings are expected to provide preliminary evidence for a potential new therapeutic approach for this heavily pretreated patient population and establish a foundation for subsequent larger confirmatory studies.

Eligibility

Primary outcome measure(s)

• PFS — From the first dose of study treatment through study completion, an average of 1 year
  Progression-free survival (PFS) is defined as the time from the first dose of study treatment to the first documented disease progression, as assessed according to RECIST version 1.1, or death from any cause, whichever occurs first. PFS will be estimated using the Kaplan-Meier method.
• Objective Response Rate (ORR) — Baseline through study completion, an average of 1 year
  Objective response rate (ORR) is defined as the proportion of participants achieving a complete response (CR) or partial response (PR), as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
• Disease Control Rate (DCR) — Baseline through study completion, an average of 1 year
  Disease control rate (DCR) is defined as the proportion of participants achieving a complete response (CR), partial response (PR), or stable disease (SD), as assessed according to RECIST version 1.1.

Trial sites (1)

More Renmin Hospital of Wuhan University trials in China

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