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

NCT06762080 | Recruiting Phase 1 DMC

• 1 other identifier: IMPACT
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

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.

Conditions

Leptomeningeal Metastasis

Keywords

Cadonilimab; PD-1/CTLA-4; Pemetrexed; Intrathecal; Leptomeningeal Metastasis

Outcome Measures

Primary Outcomes (2)

• 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

• 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

Other Outcomes (3)

• 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

• Progression-free survival related to leptomeningeal metastasis (LMPFS)

  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)

  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)

Study Arms (1)

PD-1/CTLA-4 Bispecific Antibody with Pemetrexed

EXPERIMENTAL

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); Drug: Pemetrexed (Alimta)

Interventions

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.

PD-1/CTLA-4 Bispecific Antibody with Pemetrexed

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.

PD-1/CTLA-4 Bispecific Antibody with Pemetrexed

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically or cytologically confirmed diagnosis of solid tumors; Cerebrospinal fluid cytopathology is positive.
• Male or female aged between 18 and 75 years; Normal liver and kidney function; WBC≥4000/mm3, Plt≥100000/mm3.
• No history of severe nervous system disease; No severe dyscrasia.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Guangzhou Medical University: lead

Study Sites (1)

The Affiliated Huizhou Hospital, Guangzhou Medical University

Huizhou, Guangdong, 516000, China

RECRUITING

Related Publications (2)

• 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.

  PMID: 31544065 BACKGROUND

• 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.

  PMID: 36997799 BACKGROUND

MeSH Terms

Conditions

Meningeal Carcinomatosis

Interventions

Pemetrexed

Condition Hierarchy (Ancestors)

Meningeal Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Dicarboxylic

Study Officials

• Zhenyu Pan, PhD, MD

  The Affiliated Huizhou Hospital, Guangzhou Medical University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Zhenyu Pan, PhD, MD

CONTACT

+8618718178286; dr-zypan@163.com

Guozi Yang, PhD, MD

CONTACT

+8615804302755; 2023621057@gzhmu.edu.cn

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: January 1, 2025
• First Posted: January 7, 2025
• Study Start: March 7, 2025
• Primary Completion: January 1, 2026
• Study Completion (Estimated): June 1, 2026
• Last Updated: May 20, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)