Intrathecal Pemetrexed for Leptomeningeal Metastasis

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Phase I/II Clinical Trial of Intrathecal Pemetrexed as First Line Intrathecal Chemotherapy in Patients With Leptomeningeal Metastasis

Conditions
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Leptomeningeal Metastases

Intervention / Treatment
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* Drug: Pemetrexed (1)
* Drug: Pemetrexed (2)
* Drug: Folic Acid
* Drug: Vitamin B12
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I study<br>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)<br>* 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....<br>Drug: Folic Acid<br>* Folic acid 200-400 μg is administered orally once daily, prior to the first intrathecal pemetrexed, until 21 days after the last intrathecal pemetrexed.<br>Drug: Vitamin B12<br>* A single dose of vitamin B12 1000 μg is administered by intramuscular injection before the first intrathecal pemetrexed, once per 3 weeks.<br>Drug: Dexamethasone<br>* 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.<br>|
| Experimental: Phase II study<br>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)<br>* The maximum-tolerated dose determined in phase I study is chosen as the treatment dose in phase II study.<br>Drug: Folic Acid<br>* Folic acid 200-400 μg is administered orally once daily, prior to the first intrathecal pemetrexed, until 21 days after the last intrathecal pemetrexed.<br>Drug: Vitamin B12<br>* A single dose of vitamin B12 1000 μg is administered by intramuscular injection before the first intrathecal pemetrexed, once per 3 weeks.<br>Drug: Dexamethasone<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 

Secondary 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, 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. | 
| Clinical response rate | 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. | From the beginning of the treatment until two months after the treatment or when patient died. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leptomeningeal metastasis, Intrathecal chemotherapy, Pemetrexed