Intra-pemetrexed Alone or Combined With Concurrent Radiotherapy for Leptomeningeal Metastasis

Study Purpose

Intrathecal chemotherapy is one of the mainstay treatment options for leptomeningeal metastases. Owing to the limited number of agents available for intrathecal chemotherapy, it is crucial to find a novel agent with efficacy and safety. In our phase 1 study, intrathecal pemetrexed showed controllable toxicities and potential promising efficacy for refractory leptomeningeal metastases from non-small-cell lung cancer patients. In our further study, intrathecal pemetrexed combined with involved-field radiation therapy was administered as the first-line intrathecal chemotherapy for leptomeningeal metastases from solid tumors. In this study, intrathecal pemetrexed combined with involved-field radiation therapy showed feasibility and controllable adverse events. It has been proved that pemetrexed as a novel intrathecal drug exhibited promising antitumor effects in cerebrospinal fluid. Moreover, the concomitant therapeutic modality is an optimal treatment option for leptomeningeal metastases from solid tumors. Central nervous system radiotherapy is a part of the specific treatment of leptomeningeal metastases. Radiotherapy has been proved to improve neurologic function and control of parenchymal brain metastases in leptomeningeal metastases treatment. Additionally, radiotherapy is revealed to improve the efficacy and attenuate toxicity of intrathecal chemotherapy as a result of normal cerebrospinal fluid reestablishing. However, it is still controversial whether radiotherapy can improve the overall survival. We conduct this study to further demonstrate the efficacy and safety of intrathecal pemetrexed administration for patients with leptomeningeal metastases from solid tumors by multicenter study. Furthermore, the study of effective treatment modality is of great significance. The safety and antitumor activity of intrathecal pemetrexed combined with involved-field radiation therapy and intrathecal pemetrexed alone were also compared to confirm an optimized therapeutic regimen.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years - 75 Years
Gender	All

More Inclusion & Exclusion Criteria

Inclusion Criteria:

1. Patients with a confirmed or probable diagnosis of leptomeningeal metastasis according to European Association of Neuro-Oncology-European Society for Medical Oncology (EANO-ESMO) guidelines；Patients who have been definitely diagnosed as leptomeningeal metastasis according to cerebrospinal fluid cytology, or patients who got the clinical diagnosis by combining with neuroimaging, history of cancer, clinical manifestation, cerebrospinal fluid examination, etc. 2. Participants with histologically or cytologically confirmed disease from solid tumors; 3. No history of whole brain radiotherapy; 4. Normal liver and kidney function; WBC≥4000/mm3, Plt≥100000/mm3.

Exclusion Criteria:

1. Patients with primary tumor of hematological tumors or primary central germ cell tumors; 2. Patients administrated with new molecular targeted therapy which is effective for leptomeningeal metastasis in 2 weeks; 3. Patients with hydrocephalus or other factors suggestive of cerebrospinal fluid circulation obstruction; 4. Patients with severe encephalopathy, grade 3 leukoencephalopathy, Glasgow Coma Scale less than 8 score; 5. Patients with extensive and lethal systemic diseases with few treatment options; 6. Patients with poor compliance, or for other reasons, the researchers considered unsuitable to participate in this clinical study.

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT05305885
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	N/A
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	The First Hospital of Jilin University
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Zhenyu Pan, PhD.
Principal Investigator Affiliation	The First Hospital of Jilin University
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Recruiting
Countries	China
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Leptomeningeal Metastasis

Additional Details

In this randomized, open-label, multicenter clinical trial, we aim to compare the efficacy and safety of intrathecal pemetrexed combined with concomitant involved-field radiation therapy and intrathecal pemetrexed alone for leptomeningeal metastasis patients from solid tumor. Patients were randomly divided into two arms willing to receive involved-field radiation therapy combined with concurrent intrathecal pemetrexed and intrathecal pemetrexed alone, respectively. In concomitant therapy group, participants received induction intrathecal pemetrexed first. Then concomitant intrathecal pemetrexed and involved-field radiation therapy were given. In intrathecal pemetrexed alone group, participants received induction intrathecal pemetrexed and consolidation intrathecal pemetrexed. Pemetrexed was administrated by intrathecal injection via intraventricular administration or lumbar puncture. Induction intrathecal pemetrexed was given twice per week for 2 weeks to all participants first. Then consolidation/concomitant intrathecal pemetrexed was given once per week for 4 weeks. Involved-field radiation therapy was administrated with a total dose of 40 Gy in 20 fractions for 4 weeks to the concomitant therapy group participants. Primary endpoints were clinical response and treatment-related adverse events. Secondary endpoints were overall survival and neurological progression-free survival.

Arms & Interventions

Arms

Experimental: Group 1

Intrathecal administration, intraventricular administration or via lumbar puncture, pemetrexed plus dexamethasone, first induction intra-cerebrospinal fluid chemotherapy twice per week for 2 weeks, then once per week for 4 times, 6 weeks in total. Concurrent 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 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 Gy.

Experimental: Group 2

Interventions

Drug: - Pemetrexed

Radiation: - Radiotherapy

Concurrent 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 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 Gy.

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International Sites

The First Hospital of Jilin University, Changchun, Jilin, China

Status

Recruiting

Address

The First Hospital of Jilin University

Changchun, Jilin, 130021

Site Contact

Zhenyu Pan, Professor

[email protected]

+8615804302753

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