Clinical trial NCT05305885: Intra-pemetrexed Alone or Combined With Concurrent Radiotherapy for Leptomeningeal Metastasis
Official title: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Leptomeningeal Metastasis
Keywords: Leptomeningeal metastasis
Malignant solid tumors
Pemetrexed
Intrathecal chemotherapy
Radiotherapy
Lead sponsor: The First Hospital of Jilin University
Sponsor class: OTHER
Collaborators: name: The Second Hospital of Hebei Medical University
name: Second Affiliated Hospital of Guangzhou Medical University
name: Affiliated Hospital of Guangdong Medical University
name: Guangdong 999 Brain Hospital
name: Wuxi People's Hospital
name: Huizhou Third People's Hospital, Guangzhou Medical University
name: Panjin Liaoyou Gem Flower Hospital
First posted: 2022-03-31
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Clinical response rate
timeFrame: 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.
measure: Incidence of treatment-related adverse events
timeFrame: 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 outcomes:
measure: Overall survival
timeFrame: 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).
measure: Neurological progression-free survival (NPFS)
timeFrame: 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.
Other outcomes:
Locations:
city: Changchun
country: China
facility: The First Hospital of Jilin University
state: Jilin
Study officials:
affiliation: The First Hospital of Jilin University
name: Zhenyu Pan, PhD.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.