Using toripalimab for advanced solid tumors with specific genetic mutations

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

This study is testing if toripalimab can help people with advanced solid tumors that have certain genetic mutations feel better and live longer.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 35 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: Sun Yat-sen University (other)
• Drugs / interventions: chemotherapy, immunotherapy, toripalimab
• Locations: 4 sites (Guangzhou, Guangdong and 3 other locations)
• Trial ID: NCT03810339 on ClinicalTrials.gov

What this trial studies

This study evaluates the effectiveness of toripalimab, an immune checkpoint inhibitor targeting PD-1, in patients with advanced solid tumors that have mutations in the POLE or POLD genes and are not classified as microsatellite instability-high (non-MSI-H). It is a Phase II, open-label, single-arm trial where participants will receive toripalimab every three weeks until disease progression or intolerable side effects occur. The primary goal is to assess the overall response rate (ORR), while secondary objectives include overall survival (OS), progression-free survival (PFS), and safety assessments.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 to 75 with advanced solid tumors harboring POLE or POLD mutations who have not responded to standard therapies.

Not a fit: Patients with tumors that do not have POLE or POLD mutations or those who are not willing to undergo biopsies may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for patients with specific genetic mutations in advanced solid tumors.

How similar studies have performed: Other studies have shown promising results with immune checkpoint inhibitors in similar patient populations, suggesting potential for success in this approach.

Eligibility criteria

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.

Where this trial is running

Guangzhou, Guangdong and 3 other locations

• Cancer center of Sun Yat-sen University — Guangzhou, Guangdong, China (RECRUITING)
• The Affiliated Hospital of Guizhou Medical University — Guiyang, Guizhou, China (RECRUITING)
• Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology — Wuhan, Hubei, China (RECRUITING)
• The Second Affiliated Hospital of Dalian Medical University — Dalian, Liaoning, China (RECRUITING)

Study contacts

• Principal investigator: Rui-hua Xu, MD, PhD — Sun Yat-Sen University Cancer Center
• Study coordinator: Feng Wang, MD, PhD

Conditions: Solid Tumor, Advanced Cancer, Immune checkpoint inhibitor, POLE/POLD mutation, non-MSI-H