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Intrathecal Pemetrexed for Recurrent Leptomeningeal Metastases From Non-small Cell Lung Cancer

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ClinicalTrials.gov Identifier: NCT03101579
Recruitment Status : Completed
First Posted : April 5, 2017
Last Update Posted : March 19, 2019
Sponsor:
Information provided by (Responsible Party):
Zhenyu Pan, The First Hospital of Jilin University

Brief Summary:
It has been proved that intrathecal chemotherapy is the main treatment strategy for leptomeningeal metastases. At present, the commonly used drugs for intrathecal chemotherapy include methotrexate, cytarabine, and liposomal cytarabine. In recent decades, no new effective drugs have been discovered for intrathecal chemotherapy. The recurrence of leptomeningeal metastases is inevitable even after aggressive treatment. There is no effective treatment for recurrent leptomeningeal metastases after comprehensive treatment which includes intrathecal methotrexate and/or cytarabine, central nervous system radiation therapy, systemic chemotherapy as well as tyrosine-kinase inhibitor drugs. The quality of life is extremely poor, and the patients always die in short time. Pemetrexed is a newer multitargeted antifolate which has shown activity in various tumors. It has higher effectiveness and safety, which has been used as the first-line treatment of non-small cell lung cancer. In animal studies, pemetrexed was demonstrated to suppress tumor growth completely in mice with two types of transplanted human colon xenografts resistant to methotrexate. Therefore, the purpose of the study is to evaluate the safety and feasibility of intrathecal pemetrexed in patients with recurrent leptomeningeal metastases from non-small cell lung cancer.

Condition or disease Intervention/treatment Phase
Leptomeningeal Metastases Drug: Pemetrexed Drug: Dexamethasone Drug: Folic Acid Drug: Vitamin B12 Phase 1

Detailed Description:
This is a single arm clinical trial. The objective of the study is patients with recurrent or progressive leptomeningeal metastases from non-small cell lung cancer after leptomeningeal metastases-related treatment. The regimen of pemetrexed (Alimta, Eli Lilly and Company) is 10/15/20 mg, plus dexamethasone 5 mg, twice per week for 2 weeks, followed by once per week for 2-4 weeks. Pemetrexed and dexamethasone are administrated by intrathecal injection via lumbar puncture. Folic acid and vitamin B12 are administered to reduce the frequency of myelosuppression. 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. To detect the pharmacokinetics of intrathecal pemetrexed, the serum and cerebrospinal fluid samples are collected. These samples would be analyzed by spectrometer for drug concentration.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 13 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Intrathecal Pemetrexed for Recurrent Leptomeningeal Metastasis From Non-small Cell Lung Cancer: A Prospective Pilot Clinical Trial
Actual Study Start Date : March 1, 2017
Actual Primary Completion Date : September 15, 2018
Actual Study Completion Date : January 5, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Intra-pemetrexed
Patients were treated with intrathecal pemetrexed at dose escalation. The regimen of intrathecal pemetrexed is 10/15/20 mg, plus dexamethasone 5 mg, twice per week for 2 weeks, followed by once per week for 2-4 weeks. Pemetrexed is administrated by intrathecal injection via lumbar puncture. 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. To detect the pharmacokinetics of intrathecal pemetrexed, the serum and cerebrospinal fluid samples are collected. These samples would be analyzed by spectrometer for drug concentration.
Drug: Pemetrexed
Pemetrexed,10-15 mg, intrathecal injection via lumbar puncture, twice per week for 2 weeks, followed by once per week for 2-4 weeks.

Drug: Dexamethasone
Dexamethasone, 5 mg, intrathecal injection via lumbar puncture, simultaneously with pemetrexed, twice per week for 2 weeks, followed by once per week for 2-4 weeks.

Drug: Folic Acid
Folic acid, 400 μg, oral, once per day, prior to the first intrathecal pemetrexed, until 21 days after the last intrathecal pemetrexed.

Drug: Vitamin B12
A single dose of vitamin B12 1000 μg, intramuscular injection, before the first intrathecal pemetrexed.




Primary Outcome Measures :
  1. Incidence of severe adverse events [ Time Frame: Two months after the treatment. ]
    Adverse events (AEs) are evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE, version 3.0). Events of grade 3-5 are defined as moderate and severe adverse events.

  2. Maximal tolerated dose [ Time Frame: From the beginning of the treatment until two months after the treatment. ]
    A dose-limiting toxicity (DLT) was defined as grade 3 neurological toxicities (e.g. chemical meningitis) or other grade 4 toxicity. If more than two patients experienced a DLT, that level was considered too toxic. The maximal tolerated dose (MTD) was exceeded and an additional three patients should be treated at the next lower dose level. The MTD was defined as the dose where 0/3 or 1/6 patients experienced a DLT with at least two patients encountering DLT at the higher dose.


Secondary Outcome Measures :
  1. Clinical response rate [ Time Frame: One month after the treatment. ]
    The RANO proposal for response criteria of leptomeningeal metastasis was used to assess the clinical response in this study.



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients diagnosed as leptomeningeal metastases from non-small cell lung cancer had been received comprehensive treatment, including intrathecal methotrexate and/or cytarabine, central nervous system radiation therapy, systemic chemotherapy as well as tyrosine-kinase inhibitor drugs.
  2. Patients diagnosed with recurrent leptomeningeal metastases by positive cerebrospinal fluid cytological examination and persist aggravate symptoms for more than 1 week, or increased intracranial pressure (>300 mmH2O).
  3. No severe abnormal liver and kidney function; WBC≥2500/mm3, Plt≥60000/mm3;
  4. No other severe chronic diseases;
  5. No severe dyscrasia.
  6. Signed informed consent form.

Exclusion Criteria:

  1. Patients with the clinical manifestation of nervous system failure including severe encephalopathy, grade III-IV white matter lesions confirmed by imaging examination, moderate or severe coma, and glasgow coma score less than 9 points;
  2. Patients with severe nervous system injury related with treatment, such as chemical meningitis;
  3. Patients who had accepted systemic chemotherapy within two weeks, or new molecular targeted therapeutic drug less than one months;
  4. Patients with poor compliance, or for other reasons, the researchers considered unsuitable to participate in this clinical study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03101579


Locations
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China, Jilin
The First Hospital of Jilin University
Changchun, Jilin, China, 130021
Sponsors and Collaborators
The First Hospital of Jilin University
Investigators
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Principal Investigator: Zhenyu Pan, Professor The First Hospital of Jilin University
Publications of Results:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Zhenyu Pan, Professor, The First Hospital of Jilin University
ClinicalTrials.gov Identifier: NCT03101579    
Other Study ID Numbers: IPRLM
First Posted: April 5, 2017    Key Record Dates
Last Update Posted: March 19, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Zhenyu Pan, The First Hospital of Jilin University:
Leptomeningeal metastasis
Recurrence
Intrathecal chemotherapy
Pemetrexed
Additional relevant MeSH terms:
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Neoplasm Metastasis
Neoplasms, Second Primary
Meningeal Carcinomatosis
Neoplasms by Site
Neoplasms
Neoplastic Processes
Pathologic Processes
Meningeal Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Nervous System Diseases
Folic Acid
Vitamin B 12
Hydroxocobalamin
Dexamethasone
Pemetrexed
Vitamins
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal