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

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.

• QL1706 (bispecific antibody targeting PD-1 and CLTA-4) (Drug): 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.
• Pemetrexed (Alimta) (Drug): 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.

Primary outcomes

• RP2D [Dose limiting toxicity was assessed during the first 6 weeks after the first intrathecal administration.]: The recommended phase II dose. The dose limiting toxicity was defined as ≥ grade 3 neurological toxicities (e.g.,meningitis) or other grade 4 toxicity.
• Incidence of treatment-related 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.]: 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.

Other outcomes

• Clinical response rate [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.
• Disease control rate (DCR) [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.]: 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.
• Overall survival(OS) [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.

Sex: All, ages: 21 Years to 75 Years

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.

• Zhenyu Pan, PhD,MD, Principal investigator, Jinshan Hospital Fudan University