Toripalimab（JS001） as Monotherapy in Participants With POLE or POLD-1 Mutated and Non-MSI-H Advanced Solid Tumors

A Phase II Open Label Study of Toripalimab, a PD-1 Antibody, in Participants With POLE or POLD-1 Mutated and Non-MSI-H Advanced Solid Tumors

The purpose of this study is to evaluate the response of toripalimab (JS001), a PD1 antibody, in participants with POLE or POLD-mutated and non microsatellite instability (non-MSI-H) advanced solid cancers.

Study Overview

• Status: Recruiting
• Conditions: Solid Tumor; Advanced Cancer
• Intervention / Treatment: Drug: Toripalimab

Detailed Description

Immune checkpoint inhibitor (ICI) therapy including antibodies targeting PD-1/PD-L1 or CTLA-4 has greatly advanced the cancer treatments. Recent studies have identified several predictive markers for ICI which includes microsatellite instability (MSI), PD-L1 expression and tumor mutation burden (TMB). DNA polymerase epsilon (POLE) and delta (POLD) are in charge of DNA replication as well as proofreading during DNA replication. Their germline or somatic mutations can lead to DNA repair deficiencies and carcinogenesis. The investigators has found that the POLE or POLD mutation causes an increased TMB in cancer patients and may lead to a better survival to ICI. Therefore, the purpose of this study is to evaluate the efficacy of toripalimab , a PD1 antibody, in participants with POLE or POLD-mutated and non microsatellite instability high (non-MSI-H) advanced solid cancers. This is a Phase II, open label, single arm study. Participants enrolled in this study received toripalimab 240mg, every 3 weeks until disease progress or intolerable toxicity. Primary endpoints is ORR and secondary endpoints are OS, PFS and safety.

• Study Type: Interventional
• Enrollment (Estimated): 35
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Feng Wang, MD, PhD; Phone Number: +862087342635; Email: wangfeng@sysucc.org.cn
• Study Contact Backup: Name: YING JIN, MD; Phone Number: +862087342479; Email: jinying1@sysucc.org.cn

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • Recruiting
      • Cancer center of Sun Yat-sen University
      • Contact: Zhi-da Lv, BS; Phone Number: +862087342635; Email: lvzd@sysucc.org.cn
      • Principal Investigator: Rui-hua Xu, MD, PhD
      • Principal Investigator: Feng Wang, MD, PhD
      • Principal Investigator: Ying Jin, MD
  • Guizhou
    • Guiyang, Guizhou, China
      • Recruiting
      • The Affiliated Hospital of Guizhou Medical University
      • Contact: WeiWei Chen, M.D.; Phone Number: +86 085186512900; Email: 33054905@qq.com
  • Hubei
    • Wuhan, Hubei, China
      • Recruiting
      • Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
      • Contact: Liu Huang, M.D.; Phone Number: 027-69378822; Email: huangliu017@163.com
  • Liaoning
    • Dalian, Liaoning, China
      • Recruiting
      • The Second Affiliated Hospital of Dalian Medical University
      • Contact: Jinghua Sun, M.D.; Phone Number: +86 0411-84671291; Email: sunjinghua2008@hotmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Participants must provide written informed consent to participate
• Adult aged between 18 and 75 years old
• Participants with Histologically- or cytologically- proven advanced solid tumors and not responding to standard therapy
• MSS (microsatellite sability) or MSI-L (microsatellite instability-low) or pMMR status
• Germline mutations or somatic mutations in POLE or POLD (synonymous mutation is excluded)
• Patients refuse any conventional chemotherapy or targeted therapy
• Patients are willing to take biopsy of tumor tissue and take blood samples before treatment (blood samples are also taken at each time of therapeutic evaluation)
• Participants must have at least one measurable site of disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Lesions previously treated with radiotherapy should not be regarded as target lesions unless there is a definite progression of the lesion after radiotherapy.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Estimated life expectancy is greater than 3 months
• Participants can provide more than 10 paraffin sections of tumor tissue
• No history of radiotherapy or received non-targeted radiotherapy outside the target lesions for this study more than 4 weeks ago before the first dose of study treatment
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x (5 x in participants with liver metastasis) upper limit of normal (ULN)
• Albumin ≥ 3 g/dL
• Alkaline phosphatase ≤ 2.5 x ULN.
• Serum bilirubin <1.5 mg/dL
• Creatinine ≤ ULN.
• Absolute neutrophil count ≥ 1.5X10E9/L
• Platelets ≥ 100 x 10E9/L
• Hemoglobin ≥ 90 g/L
• For females of childbearing potential (defined as <2 years after last menstruation or not surgically sterile), a negative serum pregnancy test must be performed within 21 days of the first dose of study treatment.
• For females: agreement to contraception during the study treatment period and for at least 28 days after the last dose of study treatment

Exclusion Criteria:

• Patients with confirmed or suspected brain metastases
• Patients with cancerous meningitis
• Patients without germline mutations or somatic mutations in POLE and POLD
• MSI-H (microsatellite instability-high) or dMMR
• Prior treatment with PD-1 inhibitors, PD-L1 inhibitors or CTLA-4 inhibitors (or other inhibitors in T cell co-stimulatory signals or checkpoint pathways)
• Known history or evidence of cytotoxic drug therapy, biologic drug therapy (such as monoclonal antibodies), immunotherapy (such as interleukin 2 or interferon), or other investigational drugs therapy in the 4 weeks before the first dose of study treatment
• Known history or evidence of significant immunodeficiency (including but not limited to: interstitial pneumonia, uveitis, enteritis, hepatitis, pituitary inflammation, nephritis, hyperthyroidism and hypothyroidism; Patients with vitiligo or asthma completely relieved can be included. Asthma that requires medical intervention cannot be included)
• Patients with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisolone equivalent) or other immunosuppressive medications
• Patients with active tuberculosis. Known history of antituberculosis drugs treatment in 1 year before the first dose of study treatment
• Administration of an anti-infection vaccine (e.g. influenza vaccine, chickenpox vaccine) in the 4 weeks before the first dose of study treatment
• Symptomatic heart failure, coronary heart disease (CHD), myocardial infarction in the 6 months before the first dose of study treatment
• Known allergy to JS001 or its excipients
• Pregnant or breastfeeding females
• Other prior malignancy active within the previous 5 years except for non-melanoma skin cancer
• Persons without legal capacity
• Positive test for HIV or AIDS
• Positive test for HbsAg and HBV-DNA copy numbers (≥ 1000cps/ml)
• Positive test for HCV
• Any medical disorder or condition that, in the opinion of the investigator, may affect the compliance or the signing of informed consent, etc.

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: Toripalimab; Toripalimab, 240mg, every 3 weeks until disease progress or intolerable toxicity	Drug: Toripalimab; Toripalimab, 240mg, every 3 weeks until disease progress or intolerable toxicity

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rates (ORR)	the ratio of patients whose efficiency evaluation is CR or PR	up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	defined as the period from the first dose of study treatment to loss of follow-up or death	up to 2 years
Progression free survival (PFS)	defined as the time from the first dose of study treatment to disease progression	up to 2 years
Adverse Events (AEs)	All treatment-related adverse events (AEs) were categorized according to the National Cancer Institute's Common Terminology Criteria for Adverse Events.	up to 2 years

Collaborators and Investigators

• Sponsor: Sun Yat-sen University
• Investigators: Principal Investigator: Rui-hua Xu, MD, PhD, Sun Yat-sen University Cancer Center; Principal Investigator: FENG WANG, MD,PhD, Sun Yat-sen University Cancer Center; Principal Investigator: Ying Jin, Sun Yat-sen University Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): January 15, 2019
• Primary Completion (Estimated): January 15, 2028
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: January 17, 2019
• First Submitted That Met QC Criteria: January 17, 2019
• First Posted (Actual): January 18, 2019

Study Record Updates

• Last Update Posted (Actual): April 23, 2026
• Last Update Submitted That Met QC Criteria: April 20, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Immune checkpoint inhibitor; POLE/POLD mutation; non-MSI-H
• Additional Relevant MeSH Terms: Neoplasms; toripalimab
• Other Study ID Numbers: PPM

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No