Intrathecal Combination of Programmed Death-1 (PD-1)/Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4) Bispecific Antibody and Pemetrexed for Leptomeningeal Metastasis

Study Purpose

Leptomeningeal metastasis, characterized by tumor cells infiltrating and proliferating in the subarachnoid space, represents a distinct pattern of central nervous system involvement and is a fatal complication of malignant tumors. This study is a prospective, single-arm phase I/II clinical trial aimed at evaluating the safety and efficacy of intrathecal Programmed Death-1 (PD-1)/Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4) bispecific antibodies combined with pemetrexed in treating leptomeningeal metastases from solid tumors, with the goal of identifying more effective treatment options.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years - 75 Years
Gender	All

More Inclusion & Exclusion Criteria

Inclusion Criteria:

1. Histologically or cytologically confirmed diagnosis of solid tumors; Cerebrospinal fluid cytopathology is positive. 2. Male or female aged between 18 and 75 years; Normal liver and kidney function; WBC≥4000/mm3, Plt≥100000/mm3. 3. No history of severe nervous system disease; No severe dyscrasia.

Exclusion Criteria:

1. Any evidence of nervous system failure, including severe encephalopathy, grade 3 or 4 leukoencephalopathy on imaging, and Glasgow Coma Score less than 11. 2. Any evidence of extensive and lethal progressive systemic diseases without effective treatment. 3. A history of HIV or AIDS, acute or chronic hepatitis B or C infection, previous anti-PD1 therapy-induced pneumonitis, or have ongoing >Grade 2 adverse events of such therapy; or ongoing autoimmune disease that required systemic treatment in the past 2 years. 4. The first month to treatment, as well as during induction and consolidation therapy, new drugs effective against meningeal metastases were used, excluding those previously administered. These primarily included small molecule targeted therapies, such as EGFR-TKI/ALK-TKI drugs like Osimertinib and Lorlatinib. 5. Patients with poor compliance or other reasons that were unsuitable for this study.

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT06762080
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 1/Phase 2
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	Guangzhou Medical University
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Zhenyu Pan, PhD, MD
Principal Investigator Affiliation	The Affiliated Huizhou Hospital, Guangzhou Medical University
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Recruiting
Countries	China
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Leptomeningeal Metastasis

Additional Details

Leptomeningeal metastasis is a severe form of tumor metastasis, primarily treated with intrathecal chemotherapy. Recently, immunotherapy has been applied to various solid tumors. Previous studies have demonstrated that combining PD-1 monoclonal antibody immunotherapy with intrathecal pemetrexed is both safe and effective. Currently, a clinical study in Switzerland is investigating the use of combined PD-1 and CTLA-4 dual immunotherapy with intrathecal administration for treating leptomeningeal metastasis. Cadonilimab, the world's first PD-1/CTLA-4 bispecific antibody, is widely used in clinical settings, showing good safety and efficacy. This prospective, single-arm Phase I/II clinical study aims to evaluate the safety and efficacy of intrathecal Cadonilimab (PD-1/CTLA-4) combined with pemetrexed in treating leptomeningeal metastasis from solid tumors, seeking more effective treatment options.

Arms & Interventions

Arms

Experimental: PD-1/CTLA-4 Bispecific Antibody with Pemetrexed

This study is a prospective, single-arm, Phase I/II clinical trial. The primary objective of the Phase I study is to determine the maximum tolerated dose (MTD) and the recommended Phase II dose (RP2D) for the intrathecal combination of PD-1/CTLA-4 bispecific antibody with pemetrexed.The primary endpoint of the Phase II study is to assess the safety and clinical response rate of intrathecal combination of PD-1/CTLA-4 bispecific antibody with pemetrexed under PR2D. The secondary endpoints include overall survival, progression-free survival in the nervous system (covering both leptomeningeal and parenchymal lesions), and progression-free survival related to leptomeningeal metastasis

Interventions

Drug: - Cadonilimab (AK104)

Intrathecal injection of PD-1/CTLA-4 bispecific antibody was administered every two weeks for six weeks during the induction phase, followed by monthly injections during the maintenance phase, until recurrence or death.

Drug: - Pemetrexed (Alimta)

Pemetrexed intrathecal chemotherapy is administered by intracerebroventricular or lumbar puncture. Pemetrexed intrathecal chemotherapy is divided into induction, consolidation and maintenance phases. Induction therapy was first performed with a single dose of 15 mg twice a week for 2 weeks for a total of 4 doses. This was followed by consolidation therapy, 1 time per week for 4 consecutive weeks for a total of 4 times.

Contact a Trial Team

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International Sites

Huizhou, Guangdong, China

Status

Recruiting

Address

The Affiliated Huizhou Hospital, Guangzhou Medical University

Huizhou, Guangdong, 516000

Site Contact

Zhenyu Pan, PhD, MD

[email protected]

+8618718178286

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