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.

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Colorectal Cancer; Adult
• Intervention / Treatment: Biological: PIN+sintilimab

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.

• Study Type: Interventional
• Enrollment (Estimated): 25
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Weidong Han, Ph.D; Phone Number: +86 010-66937231; Email: hanwdrsw@sina.com
• Study Contact Backup: Name: Yang Liu, M.D; Phone Number: +86 010-66939460; Email: liuyang301blood@163.com

Study Locations

• China
  • Beijing Municipality
    • Beijing, Beijing Municipality, China, 100853
      • Biotherapeutic Department and Hematology Department of Chinese PLA General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age 18-75 (inclusive).
2. Eastern Cooperative Oncology Group (ECOG) performance status ≤2 and Estimated life expectancy of more than 3 months.
3. Histologically confirmed diagnosis of unresectable locally advanced, recurrent or metastatic CRC with hepatic metastases have failed at least two lines of prior treatment.
4. Tumor tissues were identified as pMMR by immunohistochemistry (IHC) method or MSS by polymerase chain reaction (PCR).
5. At least one measurable lesion at baseline according to investigators Response Evaluation Criteria in Solid Tumours 1.1 (RECIST 1.1).
6. Patients with injectable lesions (those suitable for direct injection or injection with the assistance of medical imaging) in the liver metastatic lesions, defined as follows: at least one injectable lesion in the skin, mucous membrane, subcutaneous tissue, lymph node or visceral organ with a longest diameter ≥10 mm.
7. Subjects are willing to accept tumor rebiopsy in the process of this study.

8. Adequate organ function as defined by the following criteria:

   • Absolute neutrophil count (ANC) ≥ 1 x 10^9/L, Platelet count ≥50 x 10^9/ L, hemoglobin (Hgb) ≥ 80g/L ;
   • Serum creatinine≤1.5 upper limit of normal (ULN) or creatinine clearance (as estimated by Cockcroft Gault) ≥60 mL/min;
   • Serum aspartate amino transferase (AST) and alanine aminotransferase (ALT), ≤5 x ULN ; Total serum bilirubin ≤3 x ULN);
   • Cardiac ejection fraction ≥ 50%, no evidence of pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings;
   • International Normalized Ratio (INR) ≤ 1.5 times the upper limit of normal (ULN), and Activated Partial Thromboplastin Time (APTT) ≤ 1.5 times ULN;
   • Baseline oxygen saturation >91% on room air.
9. Previous treatments must be completed for more than 4 weeks prior to the enrollment of this study, and subjects have recovered to <= grade 1 toxicity (except for hematological toxicities and clinically non-significant toxicities such as alopecia).
10. Pregnancy tests for women of childbearing age shall be negative; Both men and women agreed to use effective contraception during treatment and during the subsequent 1 year.
11. Voluntarily participate in this clinical trial and sign an informed consent form.

Exclusion Criteria:

1. Participants with DNA mismatch repair-deficient or microsatellite instability-high (dMMR /MSI-H) CRC.
2. Advanced CRC without hepatic metastases.
3. Subjects are being treated with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment.
4. Active central nervous system disease involvement (but allow patients with prior brain metastases treated at least 4 weeks prior to enrollment that are clinically stable and do not require intervention), or prior history of Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥3 drug-related Central Nervous System (CNS) toxicity.
5. Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous (IV) antimicrobials for management.
6. Any serious underlying medical (eg, pulmonary, renal, hepatic,gastrointestinal, or neurological) or psychiatric condition or any issue that would limit compliance with study requirements.
7. Major surgery or trauma occurred within 28 days prior to enrollment, or major side effects have not been recovered.
8. Received cytotoxic chemicals, monoclonal antibodies, immunotherapy or other intervene within 4 weeks or 5 half-lives before enrollment.
9. Received radiotherapy within 3 months before enrollment.
10. Patients with primary immunodeficiency or autoimmune diseases requiring immunosuppressive therapy.
11. The presence of uncontrollable serous membrane fluid, such as massive pleural effusion or ascites.
12. Previous or concurrent cancer within 3 years prior to treatment start except for curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)].
13. Known positive test result for human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS).
14. Prior organ allograft transplantations or allogeneic hematopoietic stem cell transplantation.
15. History of allergy or intolerance to study drug components.
16. Pregnant or breast-feeding. Women of childbearing potential must have a pregnancy test performed within 7 days before the enrollment, and a negative result must be documented.
17. Being participating any other trials or withdraw within 4 weeks.
18. Researchers believe that other reasons are not suitable for clinical trials.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: PIN+sintilimab; Initial treatment phase:The combined treatment of PIN and sintilimab will be administered for 8 cycles; Unless PD or serious intolerable AEs.; Maintenance treatment phase:For patients who completed 8 cycles treatment and obtained effective disease control, if residual tumor lesions are still accessible for local injection, combination therapy will be continued. If no injectable lesion, sintilimab will be administrated per 3 weeks till 2 years unless PD or serious intolerable AEs.; Salvage treatment phase: For patients who experience disease recurrence or progression 16 weeks after ceasing PIN injection, if there are accessible lesions available for PIN injection, combination therapy will be resumed. If specific T cells induced by PIN can be detected in PB when there is no injectable lesion, then the specific T cells are amplified and transfused for salvage therapy.

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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of treatment-related AEs.	Treatment-related AEs are defined as any adverse medical events occurring since the initiation of treatment and grading these toxicities by Common Terminology Criteria for Adverse Events (CTCAE) V5.0.	Up to 12 months since the initiation of treatment.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DOR	DOR is defined as the date of their first CR or PR (which is subsequently confirmed) to PD assessed by investigators, or death regardless of cause.	Up to 5 years since the initiation of treatment.
PFS	PFS is defined as the time from the initiation of treatment to the date of PD assessed by investigators, or death any cause. Participants not meeting the criteria for progression by the analysis data cutoff date were censored at their last evaluable disease assessment date.	Up to 5 years since the initiation of treatment.
OS	OS is defined as the time from the initiation of treatment to the date of death. Subjects who have not died by the analysis data cutoff date will be censored at their last contact date.	Up to 5 years since the initiation of treatment.
DCR	DCR includes complete response (CR) ,partial response (PR) and stable disease (SD) defined by investigators according to Immune Response Evaluation Criteria in Solid Tumours (iRECIST) criteria or modified Response Evaluation Criteria in Solid Tumours (mRECIST) criteria.	Up to 2 years since the initiation of treatment.
ORR	ORR includes CR and PR defined by investigators according to iRECIST or mRECIST criteria.	Up to 2 years since the initiation of treatment.
Quality of Life Assessment.	Quality of life will be evaluated by European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-Core 30 (C30) a core scale for all cancer patients, with a total of 30 items. Among them, items 29 and 30 are divided into seven levels. Based on the responses of the subjects, they are scored from 1 to 7 points. Other items are divided into four levels: never, a little, quite a bit, and a lot. When scoring, directly assign a score from 1 to 4 points.The researchers will assess changes in quality of life by calculating total scores.	Every 6 weeks up to 2 years since the initiation of treatment.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immunological response.	Dynamics and molecular characteristics of CD8+ T cells with special phenotypes induced by PIN injection and its association with the treatment outcome. The relationship between the number of the CD8+ T cells and its anti-tumor effect was analyzed. To analyze the number and function of the CD8+ T cells in PB of patients with primary or acquired resistance after PIN injection and to summarize the key cellular and molecular mechanisms of resistance.	PB samples are collected at least on day 0 (before PIN injection), 3 (before PIN injection) and 6 during each treatment cycle ( each cycle is 21 days)
The level of cytokines and anti-PIN antibodies in serum .	The cytokines mainly include interleukin-1beta (IL-1β ) (pg / ml), IL-2(U/ml), IL-6(pg / ml),IL-10(pg / ml), tumor necrosis factor-α (TNF-α)(pg / ml), et al.	PB samples are collected at least on day 0 (before PIN injection), 3 (before PIN injection) and 6 during each treatment cycle ( each cycle is 21 days)

Collaborators and Investigators

• Sponsor: Chinese PLA General Hospital
• Collaborators: Changping Laboratory
• Investigators: Study Director: Lilin Ye, Ph.D, Department of Tumor Immunology, Changping Laboratory; Study Director: Weidong Han, Ph.D, Biotherapeutic Department, Chinese PLA General Hospital; Study Director: Guanghua Rong, Ph.D, Biotherapeutic Department, the Fifth Medical Center of the PLA General Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2026
• Primary Completion (Estimated): March 31, 2027
• Study Completion (Estimated): March 1, 2031

Study Registration Dates

• First Submitted: February 9, 2026
• First Submitted That Met QC Criteria: February 9, 2026
• First Posted (Actual): February 17, 2026

Study Record Updates

• Last Update Posted (Actual): February 17, 2026
• Last Update Submitted That Met QC Criteria: February 9, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: PD-1; oncolytic viruses
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms
• Other Study ID Numbers: CHN-PLAGH-BT-098

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No