Intrathecal Dual Checkpoint Inhibitor (PD-1 and CTLA-4) in Combination With Pemetrexed for Leptomeningeal Metastasis

Intrathecal Administration of Dual Checkpoint Inhibitor in Combination With Pemetrexed in Patients With Leptomeningeal Metastasis: a Phase I/II Study

This phase I/II study is to evaluate the recommended dose, safety, feasibility, and therapeutic response of intrathecal dual checkpoint inhibitor (targeting PD-1 and CTLA-4 with QL1706) in combination with pemetrexed in patients with leptomeningeal metastasis.

Study Overview

• Status: Active, not recruiting
• Conditions: Solid Tumors; PD-1 Inhibitor; Leptomeningeal Metastasis; CTLA4; Pemetrexed
• Intervention / Treatment: Drug: QL1706 (bispecific antibody targeting PD-1 and CLTA-4); Drug: Pemetrexed (Alimta)

Detailed Description

This study is a prospective, single-arm, phase I/II clinical trial evaluating intrathecal dual checkpoint inhibitor (targeting PD-1 and CTLA-4 with the bispecific antibody QL1706) in combination with pemetrexed for the treatment of leptomeningeal metastasis.

Intrathecal pemetrexed is administered twice weekly for 2 weeks (induction phase), then weekly for 4 weeks (consolidation phase), and monthly thereafter (maintenance phase). Intrathecal QL1706 (a co-formulation of separate anti-PD-1 and anti-CTLA-4 antibodies) is given every two weeks during the six-week （induction and consolidation phase）, followed by monthly injections in the maintenance phase, until disease progression or death.

The primary objectives are to determine the recommended dose of intrathecal QL1706 in combination with pemetrexed and to assess safety based on the incidence of treatment-related adverse events. Clinical response rate, disease control rate, 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

Study Locations

• China
  • Beijing, China, 101100
    • Beijing Chest Hospital, Capital Medical University
  • Shanghai, China
    • Jinshan Hospital, Fudan University
  • Beijing Municipality
    • Beijing, Beijing Municipality, China
      • Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine
  • Guangdong
    • Huizhou, Guangdong, China, 516000
      • The Affiliated Huizhou Hospital, Guangzhou Medical University
    • Huizhou, Guangdong, China
      • Huizhou First Hospital Affiliated to Guangdong Medical University

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 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. 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. 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: Intrathecal Dual Checkpoint Inhibition in Combination with Pemetrexed; This study is a prospective, single-arm, Phase I/II clinical trial. The primary objectives were to determine the recommended dose of intrathecal dual checkpoint inhibitor (PD-1 and CTLA-4, QL1706) in combination with pemetrexed and safety based on the incidence of treatment-related adverse events. Clinical response rate (CRR), disease control rate (DCR) 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: QL1706 (bispecific antibody targeting PD-1 and CLTA-4); Intrathecal injection of PD-1/CTLA-4 bispecific antibody was administered every 2 weeks for 6 weeks during the induction phase, followed by monthly injections during the maintenance phase, until recurrence or death.; Drug: Pemetrexed (Alimta); Pemetrexed (Alimta, Eli Lilly and Company) 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.
RP2D	The recommended phase II dose. The dose limiting toxicity was defined as ≥ grade 3 neurological toxicities (e.g.,meningitis) or other grade 4 toxicity.	Dose limiting toxicity was assessed during the first 6 weeks after the first intrathecal administration.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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, assessed up to 6 months.
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).	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

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.	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)	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.
Disease control rate (DCR)	Disease control rate was defined as proportion of patients achieving clinical response or stable disease. Clinical response and stable disease were 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 progression or date of death from any cause, whichever came first, assessed up to 6 months.

Collaborators and Investigators

• Sponsor: Guangzhou Medical University
• Investigators: Principal Investigator: Zhenyu Pan, PhD,MD, Jinshan Hospital Fudan University

Study record dates

Study Major Dates

• Study Start (Actual): March 17, 2025
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): September 1, 2027

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 (Actual): September 2, 2026
• Last Update Submitted That Met QC Criteria: August 31, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Leptomeningeal metastasis; pemetrexed; dual checkpoint inhibitor
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms by Site; Neoplasms; Nervous System Neoplasms; Meningeal Neoplasms; Central Nervous System Neoplasms; Meningeal Carcinomatosis; Amino Acids, Peptides, and Proteins; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Guanine; Hypoxanthines; Purinones; Purines; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Dicarboxylic; Pemetrexed
• Other Study ID Numbers: IT-P-QL1706

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