Concurrent Intrathecal-pemetrexed and Involved-field Radiotherapy for Leptomeningeal Metastasis From Solid Tumors

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 retrospective study, it has been proved that concurrent radiotherapy and intrathecal methotrexate for leptomeningeal metastasis from solid tumors with adverse prognostic factors showed great effectiveness and safety. The preliminary results of investigators' current prospective clinical study (Involved-field Radiotherapy Combined With Concurrent Intrathecal-methotrexate Versus Intrathecal-Ara-C for Leptomeningeal Metastases From Solid Tumor: A Randomized Phase II Clinical Trial. ClinicalTrials.gov identification number: NCT03082144) also showed that the regimen of concurrent intrathecal chemotherapy and radiotherapy may serve as an optimal therapeutic option for treatment of leptomeningeal metastases from solid tumors. Pemetrexed is a newer multitargeted antifolate which has shown activity in various tumors. In investigators' current study (Intrathecal Pemetrexed for Recurrent Leptomeningeal Metastasis From Non-small Cell Lung Cancer: A Prospective Pilot Clinical Trial. ClinicalTrials.gov identification number: NCT03101579), the regimen of intrathecal pemetrexed with folic acid and vitamin B12 supplementation may provide higher effectiveness and safety for recurrent leptomeningeal metastasis from non-small cell lung cancer. Therefore, the purpose of the study is to evaluate the tolerability, safety and effectiveness of intrathecal pemetrexed combined with involved-field radiotherapy as the first line treatment in patients with leptomeningeal metastases from malignant solid tumors.

Detailed Description
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This study is a single arm, open clinical trial. Consecutive patients with leptomeningeal metastases from malignant solid tumors are enrolled into this study. Concomitant regimen consisted of intrathecal chemotherapy (via lumbar puncture, pemetrexed 10 mg, plus dexamethasone 5 mg, once per week, 5 to 8 times, 4 to 7 weeks in total) and radiotherapy. Radiotherapy consisted of fractionated, conformal radiation given at a daily dose of 2 Gy. The planning volume consisted of sites of symptomatic disease, bulky disease observed on magnetic resonance imaging(MRI), including the whole brain and basis cranii received 40 Gy in 20 fractions, 4 weeks in total, and/or segment of spinal canal received 40-50 Gy. The RANO proposal for response criteria of leptomeningeal metastasis was used to assess the clinical response in this study.

Official Title
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Intrathecal-pemetrexed Combined With Concurrent Involved-field Radiotherapy for Leptomeningeal Metastasis From Solid Tumor: a Phase I/II Clinical Trial

Conditions
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Leptomeningeal Metastasis

Intervention / Treatment
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* Drug: Pemetrexed
* Drug: Dexamethasone
* Radiation: Radiotherapy


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 (CSF) cytology, or patients who got the clinical diagnosis by combining history of cancer, neuroimaging, clinical manifestation, and CSF examination, etc. Patients who have been diagnosed as malignant solid tumor with definite pathologic type, excluding hematological malignancies (e.g., leukemia and lymphoma) or intracranial germ cell tumors; No severe abnormal liver function; normal kidney function; WBC≥4000/mm3, Plt≥110000/mm3; No other severe chronic diseases; No severe dyscrasia. Exclusion Criteria: Patients with leptomeningeal metastasis from unknown primary tumor; Patients who had received whole brain radiotherapy in the past 10 months; Patients who had accepted systemic chemotherapy within two weeks, or molecular targeted therapy less than two weeks; Patients with poor compliance, or for other reasons, the researchers considered unsuitable to participate in this clinical study.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1,Intra-pemetrexed, radiotherapy<br>The treatment regimen consisted of intrathecal chemotherapy (via lumbar puncture, pemetrexed 10 mg, plus dexamethasone 5 mg, once per week, 5-8 times, 4-7 weeks in total) and radiotherapy. Radiotherapy consisted of fractionated, conformal radiation given at a daily dose of 2 Gy. The planning volume consisted of sites of symptomatic disease, bulky disease observed on magnetic resonance imaging, including the whole brain and basis cranii received 40 Gy in 20 fractions, 4 weeks in total, and/or segment of spinal canal received 40-50 Gy. | Drug: Pemetrexed<br>* Pemetrexed, 10 mg,intrathecal injection, plus dexamethasone 5 mg, once per week, 5 to 8 times, 4 to 7 weeks in total.<br>Drug: Dexamethasone<br>* Dexamethasone, 5 mg, intrathecal injection, simultaneously with pemetrexed, once per week, 5 to 8 times, 4 to 7 weeks in total.<br>Radiation: Radiotherapy<br>* The sites of symptomatic disease, bulky disease observed on MRI, including the whole brain and basis cranii, 40 Gy in 20 fractions;and/or segment of spinal canal received 40-50 Gy in 20-25 fractions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-related adverse events | The incidence of treatment-related adverse events were measured for determing 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. | The evaluation was performed at 3 months after the end of treatment or when patient died. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical response rate | The RANO proposal for response criteria of leptomeningeal metastasis was used to assess the clinical response in this study. | The evaluation was performed at 3 months after the end of treatment or when patient died. | 
| Overall survival | Survival time was recorded since the date of patient enrollment. All patients were followed up until death or the end of the study. | The evaluation was performed at least 7 months after leptomeningeal metastasis diagnosis or until death. | 
| Neurological progression-free survival (NPFS) | NPFS was defined as time from the start of treatment until neurological progression or death. The neurological progression was determined based on the RANO proposal evaluation criteria which have been established and published on Neuro Oncol. | All patients were followed up at least 6 months, and the evaluation of NPFS was performed from the beginning of treatment until the date of first documented neurological progression or date of death from any cause, whichever came first. | 

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