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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Leptomeningeal Metastasis
• Intervention / Treatment: Drug: Cadonilimab (AK104); Drug: Pemetrexed (Alimta)

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 Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Zhenyu Pan, PhD, MD; Phone Number: +8618718178286; Email: dr-zypan@163.com
• Study Contact Backup: Name: Guozi Yang, PhD, MD; Phone Number: +8615804302755; Email: 2023621057@gzhmu.edu.cn

Study Locations

• China
  • Guangdong
    • Huizhou, Guangdong, China, 516000
      • Recruiting
      • The Affiliated Huizhou Hospital, Guangzhou Medical University
      • Contact: Zhenyu Pan, PhD, MD; Phone Number: +8618718178286; Email: dr-zypan@163.com
      • Contact: Guozi Yang, PhD, MD; Phone Number: +8615804302755; Email: 2023621057@gzhmu.edu.cn

Participation Criteria

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 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 Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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

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 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	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
Recommended Phase II Dose (RP2D)	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)	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)	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
Overall survival(OS)	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 (at least 6 months)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical response rate	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.	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
Progression-free survival related to leptomeningeal metastasis (LMPFS)	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
Overall survival(OS)	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 (at least 6 months)

Collaborators and Investigators

• Sponsor: Guangzhou Medical University
• Investigators: Principal Investigator: Zhenyu Pan, PhD, MD, The Affiliated Huizhou Hospital, Guangzhou Medical University

Publications and helpful links

General Publications

• Pan Z, Yang G, Cui J, Li W, Li Y, Gao P, Jiang T, Sun Y, Dong L, Song Y, Zhao G. A Pilot Phase 1 Study of Intrathecal Pemetrexed for Refractory Leptomeningeal Metastases From Non-small-cell Lung Cancer. Front Oncol. 2019 Aug 30;9:838. doi: 10.3389/fonc.2019.00838. eCollection 2019.
• Glitza Oliva IC, Ferguson SD, Bassett R Jr, Foster AP, John I, Hennegan TD, Rohlfs M, Richard J, Iqbal M, Dett T, Lacey C, Jackson N, Rodgers T, Phillips S, Duncan S, Haydu L, Lin R, Amaria RN, Wong MK, Diab A, Yee C, Patel SP, McQuade JL, Fischer GM, McCutcheon IE, O'Brien BJ, Tummala S, Debnam M, Guha-Thakurta N, Wargo JA, Carapeto FCL, Hudgens CW, Huse JT, Tetzlaff MT, Burton EM, Tawbi HA, Davies MA. Concurrent intrathecal and intravenous nivolumab in leptomeningeal disease: phase 1 trial interim results. Nat Med. 2023 Apr;29(4):898-905. doi: 10.1038/s41591-022-02170-x. Epub 2023 Mar 30. Erratum In: Nat Med. 2024 Jun;30(6):1787. doi: 10.1038/s41591-024-02998-5.

Study record dates

Study Major Dates

• Study Start (Actual): March 7, 2025
• Primary Completion (Estimated): January 1, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: January 1, 2025
• First Submitted That Met QC Criteria: January 1, 2025
• First Posted (Actual): January 7, 2025

Study Record Updates

• Last Update Posted (Estimated): May 20, 2025
• Last Update Submitted That Met QC Criteria: May 15, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Pemetrexed; Leptomeningeal Metastasis; Intrathecal; Cadonilimab; PD-1/CTLA-4
• Additional Relevant MeSH Terms: Nervous System Diseases; Pathologic Processes; Neoplasms by Site; Neoplasms; Neoplastic Processes; Nervous System Neoplasms; Meningeal Neoplasms; Central Nervous System Neoplasms; Neoplasm Metastasis; Meningeal Carcinomatosis; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Folic Acid Antagonists; Nucleic Acid Synthesis Inhibitors; Pemetrexed
• Other Study ID Numbers: IMPACT

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