Clinical trial NCT05289908: Intrathecal Pemetrexed for Leptomeningeal Metastasis
Official title: Phase I/II Clinical Trial of Intrathecal Pemetrexed as First Line Intrathecal Chemotherapy in Patients With Leptomeningeal Metastasis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Leptomeningeal Metastases
Keywords: Leptomeningeal metastasis
Intrathecal chemotherapy
Pemetrexed
Lead sponsor: The First Hospital of Jilin University
Sponsor class: OTHER
Collaborators: name: Affiliated Hospital of Guangdong Medical University
name: Second Affiliated Hospital of Guangzhou Medical University
name: Guangdong 999 Brain Hospital
name: The Second Hospital of Hebei Medical University
name: Panjin Liaoyou Gem Flower Hospital
name: Wuxi People's Hospital
name: Huizhou Third People's Hospital, Guangzhou Medical University
First posted: 2022-03-22
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: Intrathecal chemotherapy is one of the most important treatment modalities for leptomeningeal metastasis of solid tumors. In the previous study(Intrathecal Pemetrexed for Recurrent Leptomeningeal Metastasis From Non-small Cell Lung Cancer: A Prospective Pilot Clinical Trial. ClinicalTrials.gov identification number: NCT03101579), pemetrexed presented feasibility of intrathecal administration. Pemetrexed at 10 mg dose level on the schedule of 1-2 times per week was recommended as an intrathecal administration agent for patients with refractory leptomeningeal metastases from non-small-cell lung cancer in the previous study. Moreover, the maximum-tolerated dose and recommended dose of intrathecal pemetrexed in the previous study was obtained without vitamin supplementation. Vitamin supplementation has been shown to reduce pemetrexed-induced myelosuppression. In this study, the regimen of intrathecal pemetrexed with folic acid and vitamin B12 supplementation may provide higher safety. Therefore, the purpose of this study is to investigate the maximally tolerated dose and evaluate the safety and effectiveness of intrathecal pemetrexed with vitamin supplementation as the first-line intrathecal chemotherapy in patients with leptomeningeal metastases from malignant solid tumors.

Detailed description: This is a phase I/II clinical trial. The objective of the study is patients with leptomeningeal metastases from solid tumors. Pemetrexed (Alimta, Eli Lilly and Company) is administrated by intrathecal injection, plus dexamethasone 5 mg, twice per week for 2 weeks, followed by once per week for 4 weeks. In phase I study, the initial dose of intrathecal pemetrexed is 15 mg, escalated to 20 mg, and then 25 mg.... A minimum of three patients and a maximum of six are enrolled in each cohort. A dose-limiting toxicity is defined as grade 3 neurological toxicities (e.g., chemical meningitis) or other grade 4 toxicity. If none of the three patients experiences any dose-limiting toxicity, the subsequent three patients are enrolled at the next higher dosage level. If one of three patients experiences a dose-limiting toxicity, up to three more patients are enrolled at the same level. The maximum-tolerated dose is defined as the dose where 0/3 or 1/6 patients experiences a dose-limiting toxicity with at least two patients encountering dose-limiting toxicity at the higher dose. If more than two patients experience a dose-limiting toxicity, that level is considered too toxic. The maximum-tolerated dose is exceeded and an additional three patients should be treated at the next lower dose level. Folic acid 200-400 μg is administered orally once daily, prior to the first intrathecal pemetrexed, until 21 days after the last intrathecal pemetrexed. A single dose of vitamin B12 1000 μg is administered by intramuscular injection before the first intrathecal pemetrexed, once per 3 weeks. In phase II study, the maximum-tolerated dose determined in phase I study is chosen.

Eligibility criteria: Inclusion Criteria:

1. Patients who have been definitely diagnosed as leptomeningeal metastasis according to cerebrospinal fluid cytology or neuroimaging, or patients who got the clinical diagnosis by combining with the history of cancer, clinical manifestation, cerebrospinal fluid examination, neuroimaging etc.;
2. Patients who have been diagnosed as malignant solid tumor according histopathology or cytopathology combined with imaging;
3. No prior intrathecal chemotherapy;
4. Normal liver and kidney function; WBC≥4000/mm3, Plt≥100000/mm3;
5. No other severe chronic diseases;
6. No history of severe nervous system disease;
7. No severe dyscrasia.

Exclusion Criteria:

1. Patients receiving molecularly targeted drugs that are effective in treating leptomeningeal metastases within 2 weeks prior to enrollment;
2. Patients with hydrocephalus or other factors suggestive of cerebrospinal fluid circulation obstruction;
3. patients with serious central nervous system disorders including severe encephalopathy, moderate or severe coma, and Glasgow Coma Score of \<8 points;
4. Patients who have been diagnosed as hematological malignancy or primary central germ cell tumor;
5. Other reasons that were unsuitable for this study, including patients with lethal or extensive systemic diseases with few treatment options,psychiatric illness and poor compliance.

Primary outcomes:
measure: Maximal tolerated dose
timeFrame: From the beginning of the treatment until two months after the treatment.
measure: Incidence of treatment-related adverse events
timeFrame: From the beginning of the treatment until two months after the treatment.
Secondary outcomes:
measure: Overall survival time
timeFrame: The evaluation was performed at least 7 months after leptomeningeal metastasis diagnosis or until death.
Other outcomes:
measure: Clinical response rate
timeFrame: From the beginning of the treatment until two months after the treatment or when patient died.
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
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, 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.