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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.
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 PD-1/CTLA-4 bispecific antibody) is given every two weeks during the six-week induction 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, 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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Intrathecal Dual Checkpoint Inhibition in Combination with Pemetrexed | Experimental | 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), 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| PR2D | 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. |
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| 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 |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Zhenyu Pan | Contact | +8618718178286 | dr-zypan@163.com | |
| Guozi Yang, PhD,MD | Contact | +8615804302755 | 2023621057@gzhmu.edu.cn |
| Name | Affiliation | Role |
|---|---|---|
| Zhenyu Pan, PhD,MD | The Affiliated HuizhouHospital, Guangzhou Medical University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Affiliated Huizhou Hospital, Guangzhou Medical University | Recruiting | Huizhou | Guangdong | 516000 | China | |
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| 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. |
|
| 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. |
| The Affiliated Huizhou Hospital, Guangzhou Medical University |
| Recruiting |
| Huizhou |
| Guangdong |
| 516000 |
| China |
|
| ID | Term |
|---|---|
| D055756 | Meningeal Carcinomatosis |
| ID | Term |
|---|---|
| D008577 | Meningeal Neoplasms |
| D016543 | Central Nervous System Neoplasms |
| D009423 | Nervous System Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D000068437 | Pemetrexed |
| ID | Term |
|---|---|
| D006147 | Guanine |
| D007042 | Hypoxanthines |
| D011688 | Purinones |
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D005971 | Glutamates |
| D024342 | Amino Acids, Acidic |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
| D000600 | Amino Acids, Dicarboxylic |
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