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

Primary Purpose

Leptomeningeal Metastases

Status

Completed

Phase

Phase 1

Locations

China

Study Type

Interventional

Intervention

Pemetrexed

Dexamethasone

Folic Acid

Vitamin B12

About this trial

This is an interventional treatment trial for Leptomeningeal Metastases focused on measuring Leptomeningeal metastasis, Recurrence, Intrathecal chemotherapy, Pemetrexed

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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.
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).
No severe abnormal liver and kidney function; WBC≥2500/mm3, Plt≥60000/mm3;
No other severe chronic diseases;
No severe dyscrasia.
Signed informed consent form.

Exclusion Criteria:

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;
Patients with severe nervous system injury related with treatment, such as chemical meningitis;
Patients who had accepted systemic chemotherapy within two weeks, or new molecular targeted therapeutic drug less than one months;
Patients with poor compliance, or for other reasons, the researchers considered unsuitable to participate in this clinical study.

Sites / Locations

The First Hospital of Jilin University

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Intra-pemetrexed

Arm Description

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.

Outcomes

Primary Outcome Measures

Incidence of severe adverse events

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.

Maximal tolerated dose

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

Clinical response rate

The RANO proposal for response criteria of leptomeningeal metastasis was used to assess the clinical response in this study.

Full Information

NCT ID

NCT03101579

First Posted

March 23, 2017

Last Updated

March 16, 2019

Sponsor

The First Hospital of Jilin University

1. Study Identification

Unique Protocol Identification Number

NCT03101579

Brief Title

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

Official Title

Intrathecal Pemetrexed for Recurrent Leptomeningeal Metastasis From Non-small Cell Lung Cancer: A Prospective Pilot Clinical Trial

Study Type

Interventional

2. Study Status

Record Verification Date

March 2019

Overall Recruitment Status

Completed

Study Start Date

March 1, 2017 (Actual)

Primary Completion Date

September 15, 2018 (Actual)

Study Completion Date

January 5, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

The First Hospital of Jilin University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Leptomeningeal Metastases

Keywords

Leptomeningeal metastasis, Recurrence, Intrathecal chemotherapy, Pemetrexed

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

13 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Intra-pemetrexed

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Pemetrexed

Intervention Description

Pemetrexed,10-15 mg, intrathecal injection via lumbar puncture, twice per week for 2 weeks, followed by once per week for 2-4 weeks.

Intervention Type

Drug

Intervention Name(s)

Dexamethasone

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Folic Acid

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Vitamin B12

Intervention Description

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

Primary Outcome Measure Information:

Title

Incidence of severe adverse events

Description

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.

Time Frame

Two months after the treatment.

Title

Maximal tolerated dose

Description

Time Frame

From the beginning of the treatment until two months after the treatment.

Secondary Outcome Measure Information:

Title

Clinical response rate

Description

The RANO proposal for response criteria of leptomeningeal metastasis was used to assess the clinical response in this study.

Time Frame

One month after the treatment.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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. 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). No severe abnormal liver and kidney function; WBC≥2500/mm3, Plt≥60000/mm3; No other severe chronic diseases; No severe dyscrasia. Signed informed consent form. Exclusion Criteria: 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; Patients with severe nervous system injury related with treatment, such as chemical meningitis; Patients who had accepted systemic chemotherapy within two weeks, or new molecular targeted therapeutic drug less than one months; Patients with poor compliance, or for other reasons, the researchers considered unsuitable to participate in this clinical study.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Zhenyu Pan, Professor

Organizational Affiliation

The First Hospital of Jilin University

Official's Role

Principal Investigator

Facility Information:

Facility Name

The First Hospital of Jilin University

City

Changchun

State/Province

Jilin

ZIP/Postal Code

130021

Country

China

12. IPD Sharing Statement

Citations:

PubMed Identifier

9533527

Citation

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Results Reference

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Citation

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Results Reference

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PubMed Identifier

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Citation

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Results Reference

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Citation

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Citation

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Results Reference

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

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