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Intrathecal Pemetrexed for Leptomeningeal Metastasis

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ClinicalTrials.gov Identifier: NCT05289908
Recruitment Status : Recruiting
First Posted : March 22, 2022
Last Update Posted : September 30, 2022
Sponsor:
Collaborators:
The Affiliated Hospital of Guangdong Medical College
Second Affiliated Hospital of Guangzhou Medical University
Guangdong 999 Brain Hospital
The Second Hospital of Hebei Medical University
Panjin Liaoyou Gem Flower Hospital
Wuxi People's Hospital
Huizhou Third People's Hospital, Guangzhou Medical University
Information provided by (Responsible Party):
Zhenyu Pan, The First Hospital of Jilin University

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.

Condition or disease Intervention/treatment Phase
Leptomeningeal Metastases Drug: Pemetrexed (1) Drug: Pemetrexed (2) Drug: Folic Acid Drug: Vitamin B12 Drug: Dexamethasone Phase 1 Phase 2

Detailed Description:
This is a phase I/II clinical trial. The objective of the study is patients with leptomeningeal metastases from solid tumors. 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. In phase I study, 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. A dose-limiting toxicity is defined as grade 3 neurological toxicities (e.g., chemical meningitis) or other grade 4 toxicity. If none of the three patients experiences any dose-limiting toxicity, the subsequent three patients are enrolled at the next higher dosage level. If one of three patients experiences a dose-limiting toxicity, up to three more patients are enrolled at the same level. The maximum-tolerated dose is defined as the dose where 0/3 or 1/6 patients experiences a dose-limiting toxicity with at least two patients encountering dose-limiting toxicity at the higher dose. If more than two patients experience a dose-limiting toxicity, that level is considered too toxic. The maximum-tolerated dose is exceeded and an additional three patients should be treated at the next lower dose level. 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. In phase II study, the maximum-tolerated dose determined in phase I study is chosen.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Clinical Trial of Intrathecal Pemetrexed as First Line Intrathecal Chemotherapy in Patients With Leptomeningeal Metastasis
Actual Study Start Date : February 21, 2022
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : April 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Phase I study
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)
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....

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

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

Drug: Dexamethasone
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.

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

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

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

Drug: Dexamethasone
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.




Primary Outcome Measures :
  1. Maximal tolerated dose [ Time Frame: From the beginning of the treatment until two months after the treatment. ]
    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.


Secondary Outcome Measures :
  1. Incidence of treatment-related adverse events [ Time Frame: From the beginning of the treatment until two months after the treatment. ]
    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.

  2. Clinical response rate [ Time Frame: From the beginning of the treatment until two months after the treatment or when patient died. ]
    The Response Assessment in Neuro-Oncology (RANO) criteria proposal for response criteria of leptomeningeal metastasis was used to assess the clinical response in this study.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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.;
  2. Patients who have been diagnosed as malignant solid tumor according histopathology or cytopathology combined with imaging;
  3. No prior intrathecal chemotherapy;
  4. Normal liver and kidney function; WBC≥4000/mm3, Plt≥100000/mm3;
  5. No other severe chronic diseases;
  6. No history of severe nervous system disease;
  7. No severe dyscrasia.

Exclusion Criteria:

  1. Patients receiving molecularly targeted drugs that are effective in treating leptomeningeal metastases within 2 weeks prior to enrollment;
  2. Patients with hydrocephalus or other factors suggestive of cerebrospinal fluid circulation obstruction;
  3. patients with serious central nervous system disorders including severe encephalopathy, moderate or severe coma, and Glasgow Coma Score of <8 points;
  4. Patients who have been diagnosed as hematological malignancy or primary central germ cell tumor;
  5. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05289908


Contacts
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Contact: Zhenyu Pan +8615804302753 dr-zypan@163.com
Contact: Guozi Yang +8615804302755 guoziyang_1982@163.com

Locations
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China, Jilin
The First Hospital of Jilin University Recruiting
Changchun, Jilin, China, 130021
Contact: Zhenyu Pan, PhD    +8615804302753    dr-zypan@163.com   
Contact: Guozi Yang, PhD    +8615804302755    guoziyang_1982@163.com   
Sponsors and Collaborators
The First Hospital of Jilin University
The Affiliated Hospital of Guangdong Medical College
Second Affiliated Hospital of Guangzhou Medical University
Guangdong 999 Brain Hospital
The Second Hospital of Hebei Medical University
Panjin Liaoyou Gem Flower Hospital
Wuxi People's Hospital
Huizhou Third People's Hospital, Guangzhou Medical University
Investigators
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Principal Investigator: Zhenyu Pan The First Hospital of Jilin University
Publications:
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Responsible Party: Zhenyu Pan, Professor, The First Hospital of Jilin University
ClinicalTrials.gov Identifier: NCT05289908    
Other Study ID Numbers: PMLM
First Posted: March 22, 2022    Key Record Dates
Last Update Posted: September 30, 2022
Last Verified: September 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: All individual participant data that underlie results in a publication will be available to other researchers.
Supporting Materials: 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.

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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.: Yes
Keywords provided by Zhenyu Pan, The First Hospital of Jilin University:
Leptomeningeal metastasis
Intrathecal chemotherapy
Pemetrexed
Additional relevant MeSH terms:
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Neoplasm Metastasis
Meningeal Carcinomatosis
Neoplastic Processes
Neoplasms
Pathologic Processes
Meningeal Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Nervous System Diseases
Folic Acid
Vitamin B 12
Hydroxocobalamin
Dexamethasone
Pemetrexed
Vitamins
Micronutrients
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action