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

Phase 1

Recruiting

• Conditions: Leptomeningeal Metastasis
• Interventions: Drug: Cadonilimab (AK104); Drug: Pemetrexed (Alimta)

• Registration Number: NCT06762080
• Lead Sponsor: Guangzhou Medical University

Brief Summary

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 phase I/II study is to evaluate the recommended dose, safety, feasibility, and therapeutic response of intrathecal Programmed Death-1 (PD-1)/Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4) bispecific antibodies combined with pemetrexed in patients with leptomeningeal metastasis.

Detailed Description

Leptomeningeal metastasis is a severe complication of advanced cancer, traditionally managed with intrathecal chemotherapy. Recently, immunotherapy has emerged as a promising treatment for solid tumors. The preliminary results from our previous study on PD-1 combined with pemetrexed intrathecal administration showed safety and feasibility for leptomeningeal metastasis from solid tumors with potential activity. Currently, a clinical trial in Switzerland is evaluating the efficacy of dual immunotherapy (PD-1 plus CTLA-4 inhibitors) administered intrathecally for leptomeningeal metastasis. Cadonilimab, the world's first PD-1/CTLA-4 bispecific antibody, has shown favorable safety and efficacy in clinical practice, further supporting its potential in this setting. The primary objectives are to determine the recommended dose of intrathecal cadonilimab in combination with pemetrexed and to assess safety based on the incidence of treatment-related adverse events. Clinical response rate, progression-free survival related to leptomeningeal metastasis, and overall survival are also evaluated. Patients undergo cerebrospinal fluid and blood specimen collection to evaluate potential clinical, molecular, and/or immune predictors of treatment efficacy and safety.

Study Timeline

• Study First Submitted: 2025-01-01
• Study First Submitted QC: 2025-01-01
• Study First Posted: 2025-01-07
• Status Verified: 2025-03
• Study Start: 2025-03-07
• Last Update Submitted: 2025-05-15
• Last Update Posted: 2025-05-20
• Primary Completion: 2026-01-01
• Study Completion: 2026-06-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 36

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 leptomeningeal 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
PD-1/CTLA-4 Bispecific Antibody with Pemetrexed	Cadonilimab (AK104)	This study is a prospective, single-arm, Phase I/II clinical trial. The primary objective is to determine the recommended Phase II dose (RP2D) for the intrathecal combination of PD-1/CTLA-4 bispecific antibody with pemetrexed and and safety based on the incidence of treatment-related adverse events. Clinical response rate (CRR), progression-free survival related to leptomeningeal metastasis (LMPFS) and overall survival (OS) are also evaluated. Patients will have cerebrospinal fluid (CSF) and blood specimen collection for the evaluation of predictors (clinical, molecular, and/or immune) of the efficacy and safety of this regimen.
PD-1/CTLA-4 Bispecific Antibody with Pemetrexed	Pemetrexed (Alimta)	This study is a prospective, single-arm, Phase I/II clinical trial. The primary objective is to determine the recommended Phase II dose (RP2D) for the intrathecal combination of PD-1/CTLA-4 bispecific antibody with pemetrexed and and safety based on the incidence of treatment-related adverse events. Clinical response rate (CRR), progression-free survival related to leptomeningeal metastasis (LMPFS) and overall survival (OS) are also evaluated. Patients will have cerebrospinal fluid (CSF) and blood specimen collection for the evaluation of predictors (clinical, molecular, and/or immune) of the efficacy and safety of this regimen.

Primary Outcome Measures

Name	Time	Method
Recommended Phase II Dose (RP2D)	From date of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months	The recommended phase II dose. The dose limiting toxicity was defined as ≥ grade 3 neurological toxicities (e.g., chemical meningitis) or other grade 4 toxicity.
Incidence of treatment-related adverse events	From date of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months	The incidence of treatment-related adverse events were measured for determining tolerability and safety. Adverse events (AEs) are evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE). Events of grade 3-5 are defined as moderate and severe adverse events

Trial Locations

Locations (1)

The Affiliated Huizhou Hospital, Guangzhou Medical University; 🇨🇳 Huizhou, Guangdong, China