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NCT Number: NCT06762080

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

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.

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Key information

Conditions

Leptomeningeal Metastasis Central Nervous System Neoplasms Meningeal Carcinomatosis Meningeal Neoplasms Neoplasms Neoplasms by Site Nervous System Diseases Nervous System Neoplasms

Age range

21 year–75 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

The Affiliated Huizhou Hospital, Guangzhou Medical University, Huizhou, Guangdong, China

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Histologically or cytologically confirmed diagnosis of solid tumors; Cerebrospinal fluid cytopathology is positive.
  • Male or female aged between 21 and 75 years; Normal liver and kidney function; WBC≥4000/mm3, Plt≥100000/mm3.
  • No history of severe nervous system disease; No severe dyscrasia.

Exclusion criteria

  • Any evidence of nervous system failure, including severe encephalopathy, grade 3 or 4 leukoencephalopathy on imaging, and Glasgow Coma Score less than 11.
  • Any evidence of extensive and lethal progressive systemic diseases without effective treatment.
  • 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.
  • 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.
  • Patients with poor compliance or other reasons that were unsuitable for this study.

Treatment and study plan

Cadonilimab (AK104)

Drug

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.

Pemetrexed (Alimta)

Drug

Pemetrexed was administrated by intrathecal injection, first as induction therapy, twice per week for 2 weeks, followed by consolidation therapy, once per week for 4 weeks, then maintenance therapy, once per month until the patient's death, leptomeningeal metastasis progresses, or intolerable severe adverse events occurred.

Primary outcomes

  1. Recommended Phase II Dose (RP2D)

    Time frame: 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.

  2. Incidence of treatment-related adverse events

    Time frame: 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

Other outcomes

  1. Clinical response rate

    Time frame: Time Frame: 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 response assessment in neuro-oncology criteria (RANO) proposal for response criteria of leptomeningeal metastasis was used to assess the clinical response in this study.

  2. Progression-free survival related to leptomeningeal metastasis (LMPFS)

    Time frame: From date of treatment until the date of first documented leptomeningeal metastasis progression or date of death from any cause, whichever came first, assessed up to 6 months

    LMPFS was defined as time from the start of treatment until leptomeningeal metastasis progression or death. The leptomeningeal metastasis progression was determined based on the RANO proposal evaluation criteria which have been established and published on Neuro Oncol.

  3. Overall survival(OS)

    Time frame: From the enrollment of this study until date of death from any cause, whichever came first, or the last follow-up (at least 6 months)

    Overall survival was recorded since the date of patient enrollment. All patients were followed up until death or the end of the study.

Sponsors and collaborators

Lead sponsor

Guangzhou Medical University

Other

Registry information

Official study title

Intrathecal Administration of PD-1/CTLA-4 Bispecific Antibody Plus Pemetrexed in Patients With Leptomeningeal Metastasis From Solid Tumors: A Phase I/II Study

Important dates

Study start
2025
Primary completion
2026
Study completion
2026
First posted
Jan 7, 2025
Registry last updated
Jul 21, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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