Intrathecal PD-1/VEGF Bispecific Antibody Plus Pemetrexed for Leptomeningeal Metastasis

NCT ID: NCT06809517

Last Updated: 2025-05-20

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 34 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-03-18
• Study Completion Date: 2026-05-01

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 PD-1/VEGF bispecific antibody plus pemetrexed in patients with leptomeningeal metastasis.

Detailed Description

Leptomeningeal metastasis represents a severe complication of advanced malignancies, for which intrathecal chemotherapy remains the mainstay treatment. 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. In recent years, targeted therapy and immunotherapy has been widely used for the treatment of solid tumors. As the world's first PD-1/VEGF bispecific antibody, ivonescimab ((AK112) has shown superior systemic efficacy compared to conventional VEGF targeted therapy combined with immunotherapy, while maintaining a favorable safety profile. The primary objectives are to determine the recommended dose of intrathecal ivonescimab 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.

Conditions

Leptomeningeal Metastasis; Intrathecal Drug Delivery

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Intrathecal PD-1/VEGF Bispecific Antibody plus Pemetrexed

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/VEGF 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.

Group Type: EXPERIMENTAL

AK112

Intervention Type: DRUG

Intrathecal injection of PD-1/VEGF 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)

Intervention Type: 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.

Interventions

AK112

Intrathecal injection of PD-1/VEGF 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.

Intervention Type: DRUG

Pemetrexed (Alimta)

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.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Histologically or cytologically confirmed diagnosis of solid tumors;Cerebrospinal fluid cytopathology is positive.

2. Male or female aged between 21 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. Obvious bleeding tendency; Patients with hemorrhage (NCI-CTCAE v5.0 greater than grade 2), coagulation disorder, hypertensive crisis, and severe arterial thrombosis.

4. 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.

5. 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.

6. Patients with poor compliance or other reasons that were unsuitable for this study.

• Minimum Eligible Age: 21 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Guangzhou Medical University

OTHER

Sponsor Role: lead

Responsible Party

Zhenyu Pan

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Zhenyu Pan, PhD,MD

Role: PRINCIPAL_INVESTIGATOR

The Affiliated HuizhouHospital, Guangzhou Medical University

Locations

The Affiliated Huizhou Hospital, Guangzhou Medical University

Huizhou, Guangdong, China

Site Status: RECRUITING

Countries

China

Central Contacts

Zhenyu Pan, PhD, MD

Role: CONTACT

dr-zypan@163.com

+8618718178286

Guozi Yang, PhD,MD

Role: CONTACT

2023621057@gzhmu.edu.cn

+8615804302755

Facility Contacts

Zhenyu Pan, PhD,MD

Role: primary

dr-zypan@163.com

+8618718178286

Guozi Yang, PhD,MD

Role: backup

2023621057@gzhmu.edu.cn

+8615804302755

Other Identifiers

IT-P-AK112

Identifier Type: -

Identifier Source: org_study_id