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

May 15, 2025 updated by: Zhenyu Pan, Guangzhou Medical University

A Phase I/II Clinical Study of Intrathecal Combination Therapy With the PD-1/VEGF 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 PD-1/VEGF bispecific antibody plus pemetrexed in patients with leptomeningeal metastasis.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

34

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Zhenyu Pan, PhD, MD
  • Phone Number: +8618718178286
  • Email: dr-zypan@163.com

Study Contact Backup

Study Locations

  • China
    • Guangdong
      • Huizhou, Guangdong, China, 516000
        • Recruiting
        • The Affiliated Huizhou Hospital, Guangzhou Medical University
        • Contact:
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 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.
Drug: 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.
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
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.
PR2D
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.
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

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Neurological progression-free survival (NPFS)
Time Frame: From date of treatment until the date of first documented neurological progression or date of death from any cause, whichever came first, assessed up to 6 months
NPFS was defined as time from the start of treatment until neurological progression or death (covering both leptomeningeal and parenchymal lesions).
From date of treatment until the date of first documented neurological progression or date of death from any cause, whichever came first, assessed up to 6 months
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.
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

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
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
Clinical response rate
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.
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
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，assessed up to 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.
From the enrollment of this study until date of death from any cause, whichever came first, or the last follow-up，assessed up to 6 months.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Guangzhou Medical University

Investigators

  • Principal Investigator: Zhenyu Pan, PhD,MD, The Affiliated HuizhouHospital, Guangzhou Medical University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 18, 2025

Primary Completion (Estimated)

March 1, 2026

Study Completion (Estimated)

May 1, 2026

Study Registration Dates

First Submitted

January 26, 2025

First Submitted That Met QC Criteria

February 1, 2025

First Posted (Actual)

February 5, 2025

Study Record Updates

Last Update Posted (Estimated)

May 20, 2025

Last Update Submitted That Met QC Criteria

May 15, 2025

Last Verified

January 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IT-P-AK112

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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