Intrathecal Pemetrexed for Leptomeningeal Metastasis

NCT05289908 | Completed Phase 1 DMC

• 1 other identifier: PMLM
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 1

Brief Summary

Intrathecal chemotherapy is one of the most important treatment modalities for leptomeningeal metastasis of solid tumors. In the previous study(Intrathecal Pemetrexed for Recurrent Leptomeningeal Metastasis From Non-small Cell Lung Cancer: A Prospective Pilot Clinical Trial. ClinicalTrials.gov identification number: NCT03101579), pemetrexed presented feasibility of intrathecal administration. Pemetrexed at 10 mg dose level on the schedule of 1-2 times per week was recommended as an intrathecal administration agent for patients with refractory leptomeningeal metastases from non-small-cell lung cancer in the previous study. Moreover, the maximum-tolerated dose and recommended dose of intrathecal pemetrexed in the previous study was obtained without vitamin supplementation. Vitamin supplementation has been shown to reduce pemetrexed-induced myelosuppression. In this study, the regimen of intrathecal pemetrexed with folic acid and vitamin B12 supplementation may provide higher safety. Therefore, the purpose of this study is to investigate the maximally tolerated dose and evaluate the safety and effectiveness of intrathecal pemetrexed with vitamin supplementation as the first-line intrathecal chemotherapy in patients with leptomeningeal metastases from malignant solid tumors.

Conditions

Leptomeningeal Metastases

Keywords

Leptomeningeal metastasis; Intrathecal chemotherapy; Pemetrexed

Outcome Measures

Primary Outcomes (2)

• Maximal tolerated dose

  A dose-limiting toxicity (DLT) was defined as grade 3 neurological toxicities (e.g. chemical meningitis) or other grade 4 toxicity. If more than two patients experienced a DLT, that level was considered too toxic. The maximal tolerated dose (MTD) was exceeded and an additional three patients should be treated at the next lower dose level. The MTD was defined as the dose where 0/3 or 1/6 patients experienced a DLT with at least two patients encountering DLT at the higher dose.

  From the beginning of the treatment until two months after the treatment.

• 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, version 4.03). Events of grade 3-5 are defined as moderate and severe adverse events.

  From the beginning of the treatment until two months after the treatment.

Secondary Outcomes (1)

• Overall survival time

  The evaluation was performed at least 7 months after leptomeningeal metastasis diagnosis or until death.

Other Outcomes (1)

• Clinical response rate

  From the beginning of the treatment until two months after the treatment or when patient died.

Study Arms (2)

Phase I study

EXPERIMENTAL

Pemetrexed (Alimta, Eli Lilly and Company) is administrated by intrathecal injection, plus dexamethasone 5 mg, twice per week for 2 weeks, followed by once per week for 4 weeks. The initial dose of intrathecal pemetrexed is 15 mg, escalated to 20 mg, and then 25 mg.... A minimum of three patients and a maximum of six are enrolled in each cohort. Folic acid 200-400 μg is administered orally once daily, prior to the first intrathecal pemetrexed, until 21 days after the last intrathecal pemetrexed. A single dose of vitamin B12 1000 μg is administered by intramuscular injection before the first intrathecal pemetrexed, once per 3 weeks.

Drug: Pemetrexed (1); Drug: Folic Acid; Drug: Vitamin B12; Drug: Dexamethasone

Phase II study

EXPERIMENTAL

Pemetrexed (Alimta, Eli Lilly and Company) is administrated by intrathecal injection, plus dexamethasone 5 mg, twice per week for 2 weeks, followed by once per week for 4 weeks. The maximum-tolerated dose determined in phase I study is chosen as the treatment dose in phase II study.

Drug: Pemetrexed (2); Drug: Folic Acid; Drug: Vitamin B12; Drug: Dexamethasone

Interventions

Pemetrexed (1) DRUG

Pemetrexed (Alimta, Eli Lilly and Company) is administrated by intrathecal injection, plus dexamethasone, twice per week for 2 weeks, followed by once per week for 4 weeks. The initial dose of intrathecal pemetrexed is 15 mg, escalated to 20 mg, and then 25 mg....

Phase I study

Pemetrexed (2) DRUG

The maximum-tolerated dose determined in phase I study is chosen as the treatment dose in phase II study.

Phase II study

Folic Acid DRUG

Folic acid 200-400 μg is administered orally once daily, prior to the first intrathecal pemetrexed, until 21 days after the last intrathecal pemetrexed.

Phase I study; Phase II study

Vitamin B12 DRUG

A single dose of vitamin B12 1000 μg is administered by intramuscular injection before the first intrathecal pemetrexed, once per 3 weeks.

Phase I study; Phase II study

Dexamethasone DRUG

Dexamethasone, 5 mg, intrathecal injection via lumbar puncture, simultaneously with pemetrexed, twice per week for 2 weeks, followed by once per week for 2-4 weeks.

Phase I study; Phase II study

Eligibility Criteria

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

You may qualify if:

• Patients who have been definitely diagnosed as leptomeningeal metastasis according to cerebrospinal fluid cytology or neuroimaging, or patients who got the clinical diagnosis by combining with the history of cancer, clinical manifestation, cerebrospinal fluid examination, neuroimaging etc.;
• Patients who have been diagnosed as malignant solid tumor according histopathology or cytopathology combined with imaging;
• No prior intrathecal chemotherapy;
• Normal liver and kidney function; WBC≥4000/mm3, Plt≥100000/mm3;
• No other severe chronic diseases;
• No history of severe nervous system disease;
• No severe dyscrasia.

You may not qualify if:

• Patients receiving molecularly targeted drugs that are effective in treating leptomeningeal metastases within 2 weeks prior to enrollment;
• Patients with hydrocephalus or other factors suggestive of cerebrospinal fluid circulation obstruction;
• patients with serious central nervous system disorders including severe encephalopathy, moderate or severe coma, and Glasgow Coma Score of \<8 points;
• Patients who have been diagnosed as hematological malignancy or primary central germ cell tumor;
• Other reasons that were unsuitable for this study, including patients with lethal or extensive systemic diseases with few treatment options,psychiatric illness and poor compliance.

Sponsors & Collaborators

• The First Hospital of Jilin University: lead
• Affiliated Hospital of Guangdong Medical University: collaborator
• Second Affiliated Hospital of Guangzhou Medical University: collaborator
• Guangdong 999 Brain Hospital: collaborator
• The Second Hospital of Hebei Medical University: collaborator
• Panjin Liaoyou Gem Flower Hospital: collaborator
• Wuxi People's Hospital: collaborator
• Huizhou Third People's Hospital, Guangzhou Medical University: collaborator

Study Sites (1)

The First Hospital of Jilin University

Changchun, Jilin, 130021, China

Location

Related Publications (3)

• Pan Z, Yang G, He H, Cui J, Li W, Yuan T, Chen K, Jiang T, Gao P, Sun Y, Cong X, Li Z, Wang Y, Pang X, Song Y, Zhao G. Intrathecal pemetrexed combined with involved-field radiotherapy as a first-line intra-CSF therapy for leptomeningeal metastases from solid tumors: a phase I/II study. Ther Adv Med Oncol. 2020 Jul 17;12:1758835920937953. doi: 10.1177/1758835920937953. eCollection 2020.

  PMID: 32733606 BACKGROUND

• 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

• Pan Z, Ye X, Huang Y, Tai P, Liu M, Sun X, Tang R, Gu A, Wang Z, Shen L, Pang X, Yuan T, Yang G. Intrathecal pemetrexed for newly diagnosed leptomeningeal metastases: a multicenter, open-label, phase I/II study. J Neurooncol. 2025 Nov;175(2):857-868. doi: 10.1007/s11060-025-05160-4. Epub 2025 Jul 23.

  PMID: 40699526 DERIVED

MeSH Terms

Conditions

Meningeal Carcinomatosis

Interventions

Pemetrexed; Folic Acid; Vitamin B 12; Dexamethasone

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; Pterins; Pteridines; Corrinoids; Tetrapyrroles; Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds, 4 or More Rings; Macrocyclic Compounds; Polycyclic Compounds; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Steroids, Fluorinated

Study Officials

• Zhenyu Pan

  The First Hospital of Jilin University

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: March 10, 2022
• First Posted: March 22, 2022
• Study Start: February 21, 2022
• Primary Completion: March 20, 2023
• Study Completion: March 31, 2024
• Last Updated: May 4, 2025

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: Starting 6 months after publication.
• Access Criteria: Individual participant data will be public accessable via contacting with principal investigator by email within 6 months after the trial complete.

Locations

CN (1)