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

NCT ID: NCT05305885

Last Updated: 2022-09-30

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: NA
• Total Enrollment: 100 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-08-19
• Study Completion Date: 2024-07-31

Brief Summary

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.

Detailed Description

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.

Conditions

Leptomeningeal Metastasis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Pemetrexed

Intervention Type: DRUG

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.

Radiotherapy

Intervention Type: RADIATION

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.

Group 2

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.

Group Type: EXPERIMENTAL

Pemetrexed

Intervention Type: DRUG

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.

Interventions

Pemetrexed

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.

Intervention Type: DRUG

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.

Intervention Type: RADIATION

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

The Second Hospital of Hebei Medical University

OTHER

Sponsor Role: collaborator

Second Affiliated Hospital of Guangzhou Medical University

OTHER

Sponsor Role: collaborator

Affiliated Hospital of Guangdong Medical University

OTHER

Sponsor Role: collaborator

Guangdong 999 Brain Hospital

OTHER

Sponsor Role: collaborator

Wuxi People's Hospital

OTHER

Sponsor Role: collaborator

Huizhou Third People's Hospital, Guangzhou Medical University

OTHER

Sponsor Role: collaborator

Panjin Liaoyou Gem Flower Hospital

UNKNOWN

Sponsor Role: collaborator

The First Hospital of Jilin University

OTHER

Sponsor Role: lead

Responsible Party

Zhenyu Pan

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Zhenyu Pan, PhD.

Role: PRINCIPAL_INVESTIGATOR

The First Hospital of Jilin University

Locations

The First Hospital of Jilin University

Changchun, Jilin, China

Site Status: RECRUITING

Countries

China

Central Contacts

Zhenyu Pan, PhD.

Role: CONTACT

dr-zypan@163.com

+8615804302753

Guozi Yang, PhD.

Role: CONTACT

guoziyang_1982@163.com

+8615804302755

Facility Contacts

Zhenyu Pan, Professor

Role: primary

dr-zypan@163.com

+8615804302753

Guozi Yang, Professor

Role: backup

guoziyang_1982@163.com

+8615804302755

References

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.

Reference Type: BACKGROUND

PMID: 32733606 (View on PubMed)

Pan Z, Yang G, He H, Gao P, Jiang T, Chen Y, Zhao G. Identification of Cerebrospinal Fluid MicroRNAs Associated With Leptomeningeal Metastasis From Lung Adenocarcinoma. Front Oncol. 2020 Apr 3;10:387. doi: 10.3389/fonc.2020.00387. eCollection 2020.

Reference Type: BACKGROUND

PMID: 32328453 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 31544065 (View on PubMed)

Other Identifiers

PMRT

Identifier Type: -

Identifier Source: org_study_id