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

September 29, 2022 updated by: Zhenyu Pan, The First Hospital of Jilin University

An Open-label, Randomized, Multicenter Trial of Intrathecal-pemetrexed Combined With Concurrent Involved-field Radiotherapy and Intrathecal-pemetrexed Alone in Patients With Leptomeningeal Metastasis From Solid Tumors

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Anticipated)

100

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • China
    • Jilin
      • Changchun, Jilin, China, 130021
        • Recruiting
        • The First Hospital of Jilin University
        • Contact:
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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.
Drug: 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.
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.
EXPERIMENTAL: 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.
Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Clinical response rate
Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months.
The response assessment in neuro-oncology criteria (RANO) proposal for response criteria of leptomeningeal metastasis was used to assess the clinical response in this study.
From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months.
Incidence of treatment-related adverse events
Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months.
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 date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall survival
Time Frame: From the enrollment of this study until date of death from any cause, whichever came first, or the last follow-up (at least 7 months).
Survival time was recorded since the date of patient enrollment. All patients were followed up until death or the end of the study.
From the enrollment of this study until date of death from any cause, whichever came first, or the last follow-up (at least 7 months).
Neurological progression-free survival (NPFS)
Time Frame: From date of randomization until the date of first documented neurological progression or date of death from any cause, whichever came first, assessed up to 6 months.
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.
From date of randomization until the date of first documented neurological progression or date of death from any cause, whichever came first, assessed up to 6 months.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The First Hospital of Jilin University

Collaborators

The Second Hospital of Hebei Medical University
Second Affiliated Hospital of Guangzhou Medical University
Wuxi People's Hospital
The Affiliated Hospital of Guangdong Medical College
Guangdong 999 Brain Hospital
Panjin Liaoyou Gem Flower Hospital
Huizhou Third People's Hospital, Guangzhou Medical University

Investigators

  • Principal Investigator: Zhenyu Pan, PhD., The First Hospital of Jilin University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

August 19, 2022

Primary Completion (ANTICIPATED)

October 1, 2023

Study Completion (ANTICIPATED)

July 1, 2024

Study Registration Dates

First Submitted

March 14, 2022

First Submitted That Met QC Criteria

March 23, 2022

First Posted (ACTUAL)

March 31, 2022

Study Record Updates

Last Update Posted (ACTUAL)

September 30, 2022

Last Update Submitted That Met QC Criteria

September 29, 2022

Last Verified

September 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PMRT

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

All individual participant data that underlie results in a publication will be available to other researchers.

IPD Sharing Time Frame

Starting 6 months after publication.

IPD Sharing Access Criteria

Individual participant data will be public accessable via contacting with principal investigator by email within 6 months after the trial complete.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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