NCT07411781

PIN in Combination With Sintilimab in Previously Treated pMMR/MSS CRC With Hepatic Metastases

Treatment of Pyroptosis-inducible Newcasstle Disease Oncolytic Virus (PIN) Plus Sintilimab (Anti-PD1 Antibody) for Patients With Advanced pMMR/ MSS Colorectal Cancer With Hepatic Metastases:an Open-Label, Randomized,Phase I Study.

• Status: Not Yet Recruiting
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 25 (estimated)
• Sponsor: Chinese PLA General Hospital · Academic / Other
• Sex: All
• Age: 18 Years – 75 Years
• Healthy volunteers: Not accepted

Summary

In this single-center,open-label, phase I study, the safety and efficacy of PIN in combination with anti-programmed cell death -1 (anti-PD1) antibody therapeutic regimen (sintilimab) will be evaluated in patients with advanced proficient mismatch repair/microsatellite stable (pMMR/MSS) colorectal cancer (CRC) with hepatic metastases . A total of 25 to 30 patients are planned to be enrolled and receive PIN plus sintilimab combined treatment. It aims to: 1).assess the safety and antitumor effects of the above combined treatment regimen. 2).detect the dynamic changes and molecular characteristics of PIN induced CD8+ T cells with special phenotype in peripheral blood (PB) and transformation of tumor microenvironment (TME) after the treatment with PIN. 3).evaluate the immunological or clinical predictive biomarkers for toxicity and efficacy.

Detailed description

Over 40% of CRC patients experience liver metastasis during the course of the disease, and up to 50% present with unresectable disease. Without surgical intervention or in cases of postoperative recurrence, survival for patients treated with systemic therapies alone is dismal,especially those with pMMR/MSS (who are almost unresponsive to anti-PD1 antibody treatment). Several clinical studies have found that oncolytic viruses (OVs) can provide clinical benefits to patients with various malignant tumors, including primary and metastatic liver tumors.In recent years, new generations of OVs developed or in clinical stages have shown better safety and stronger anti-tumor capabilities. Through genetic engineering, OVs can express target genes that have anti-tumor effects, such as granulocyte-macrophage colonystimulating factor (GM-CSF), interleukin-12(IL-12),etc, further enhancing their anti-tumor effects. Despite these advances, how to obtain a more durable antitumor immune response and long-term benefits is still an urgent clinical issue. Previous studies have confirmed that the newcastle disease oncolytic virus (NDV) can selectively infect tumor cells while sparing normal cells, demonstrating an acceptable safety profile. In this study, investigators have developed a nove PIN . Preclinical studies and clinical studies conducted in patients with refractory advanced primary hepatocellular carcinoma have both shown that combining PIN with anti-PD1antibody therapy can reverse the immunosuppressive microenvironment and transform "cold" tumors into "hot" tumors, thereby triggering local and systemic anti-tumor immune responses and significantly improving the efficacy of the immune checkpoint inhibitor(ICI). Based on these findings, investigators are conducting this clinical trial to evaluate the safety and anti tumor activity of the PIN and sintilimab combination therapy in patients with advanced pMMR/ MSS CRC with hepatic metastases. In this study, 25 to 30 subjects with advanced pMMR/ MSS CRC with hepatic metastases will be enrolled. The initial dose for the first cycle will be determined as 4e9 or 8e9 viral particles based on the number of injectable lesions, their longest diameter, and the tumor volume capacity. Following the first cycle of treatment, the subsequent dose and injection sites of PIN will be adjusted based on the permissible volume of the injected tumor mass, according to the following principles: PIN injection frequency: day 0 and day 3, per 3 weeks for 8 cycles; unless unavailability of injection lesion, disease progression (PD) or serious intolerable adverse events (AEs). PIN injection dosage: 1. a.For patients with a single injectable lesion with a maximum diameter of \<5 cm, the initial cycle's PIN dose is 4e9 viral particles. Subsequent cycles will maintain this dose of 4e9 or increase it to 8e9 viral particles based on the lesion's capacity to accommodate the injection volume; b. For patients with a single injectable lesion with a maximum diameter of ≥5 cm, the initial cycle's PIN dose is 8e9 viral particles. Subsequent cycles will maintain this dose of 8e9 viral particles based on the lesion's capacity to accommodate the injection volume. 2. a.For patients with two injectable lesions, injections will alternate between the two lesions after two cycles. The initial cycle's PIN dose is 4e9 viral particles, and the second cycle will maintain this dose of 4e9 or increase it to 8e9 viral particles based on the tumor volume's capacity; b.For patients with injectable lesions with a maximum diameter of ≥5 cm, the initial cycle's PIN dose is 8e9 viral particles, and subsequent cycles will maintain this dose of 8e9 or decrease it to 4e9 viral particles based on the lesion's capacity. 3. a.For patients with multiple injectable lesions (≥ 3), after 1-2 cycles of injections in each injectable lesion, injections are alternated between lesions. The initial injection dose for each lesion is determined by the size of the lesion; b.For lesions \<3 cm, the initial cycle's dose is 4e9 viral particles, and the second cycle will maintain this dose of 4e9 or increase it to 8e9 viral particles based on the tumor volume's capacity; c.For lesions ≥3 cm, the initial cycle's injection dose is selected as 8e9 viral particles, and subsequent cycles will maintain this dose of 8e9 or decrease it to 4e9 viral particles based on the tumor volume's capacity. 4. After injections, if the tumor shrinks by 0.5-1 cm in diameter, the injection dose should be adjusted to 2e9 viral particles until the tumor disappears. Anti-PD1 infusion frequency: day -3, per 3 weeks for 8 cycles; until unacceptable toxicity occurred or PD. Objectives: The primary objective are to assess the safety and adverse event profile of the combination regimen. The coprimary objective is immune response, assessed by CD8+T cells with special phenotype by Fluorescence Activating Cell Sorter (FACS). The secondary objectives are to evaluate disease control rate (DCR), objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and quality of life.

Conditions

• Colorectal Cancer
• Adult

Interventions

Type	Name	Description
BIOLOGICAL	PIN+sintilimab	1.Initial treatment phase: PIN injection frequency: day 0 and day 3, per 3 weeks for 8 cycles; PIN injection dosage: Cycle1: 4e9 or 8e9 viral particles based on the number of injectable lesions, their longest diameter, and the tumor volume capacity . Cycle 2\~8: 4e9 or 8e9 viral particles based on the tumor volume's capacity.Sintilimab: day -3, per 3 weeks for 8 cycles; 2.Maintenance treatment phase: No injection lesion: Sintilimab: day 1, per 3 weeks till 2 years unless PD or serious intolerable AEs. Have injection lesion: PIN: 4e9 or 8e9 viral particles based on the tumor volume's capacity, per 6 weeks (within first 24 weeks), then per 8 weeks till 2 years unless unavailability of injection lesion, PD or serious intolerable AEs.Sintilimab: day 1, per 3 weeks till 2 years unless PD or serious intolerable AEs. 3.Salvage treatment phase: Dosage and frequency of administration refer to the initial treatment phase and maintenance treatment phase.

Timeline

• Start date: 2026-03-01
• Primary completion: 2027-03-31
• Completion: 2031-03-01
• First posted: 2026-02-17
• Last updated: 2026-02-17

Locations

1 site across 1 country: China