## Protocol Section
### Identification Module
**NCT ID:** 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

#### Organization Study ID Info
**ID:** IPRLM
#### Organization
**Class:** OTHER
**Full Name:** The First Hospital of Jilin University
### Status Module
#### Completion Date
**Date:** 2019-01-05

**Type:** ACTUAL

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2019-03-19

**Type:** ACTUAL

**Last Update Submit Date:** 2019-03-16

**Overall Status:** COMPLETED

#### Primary Completion Date
**Date:** 2018-09-15

**Type:** ACTUAL

#### Start Date
**Date:** 2017-03-01

**Type:** ACTUAL

**Status Verified Date:** 2019-03

#### Study First Post Date
**Date:** 2017-04-05
**Type:** ACTUAL
**Study First Submit Date:** 2017-03-23
**Study First Submit QC Date:** 2017-03-29
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** The First Hospital of Jilin University

#### Responsible Party

**Investigator Affiliation:** The First Hospital of Jilin University

**Investigator Full Name:** Zhenyu Pan

**Investigator Title:** Professor

**Type:** PRINCIPAL_INVESTIGATOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Is US Export:** False

**Oversight Has DMC:** True

### Description Module

**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.

### Conditions Module

**Conditions:**

- Leptomeningeal Metastases

**Keywords:**

- Leptomeningeal metastasis

- Recurrence

- Intrathecal chemotherapy

- Pemetrexed

### Design Module

#### Design Info

**Allocation:** NA

**Intervention Model:** SINGLE_GROUP

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 13

**Type:** ACTUAL

**Phases:**

- PHASE1

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**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.

**Intervention Names:**

- Drug: Pemetrexed

- Drug: Dexamethasone

- Drug: Folic Acid

- Drug: Vitamin B12

**Label:** Intra-pemetrexed

**Type:** EXPERIMENTAL

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Intra-pemetrexed

**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.

**Name:** Pemetrexed

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- Intra-pemetrexed

**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.

**Name:** Dexamethasone

**Type:** DRUG

#### Intervention 3

**Arm Group Labels:**

- Intra-pemetrexed

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

**Name:** Folic Acid

**Type:** DRUG

#### Intervention 4

**Arm Group Labels:**

- Intra-pemetrexed

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

**Name:** Vitamin B12

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**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.

**Measure:** Incidence of severe adverse events

**Time Frame:** Two months after the treatment.

**Description:** 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.

**Measure:** Maximal tolerated dose

**Time Frame:** From the beginning of the treatment until two months after the treatment.

#### Secondary Outcomes

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

**Measure:** Clinical response rate

**Time Frame:** One month after the treatment.

### Eligibility Module

**Eligibility 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.

**Maximum Age:** 75 Years

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Locations

**Location 1:**

**City:** Changchun

**Country:** China

**Facility:** The First Hospital of Jilin University

**State:** Jilin

**Zip:** 130021

#### Overall Officials

**Official 1:**

**Affiliation:** The First Hospital of Jilin University

**Name:** Zhenyu Pan, Professor

**Role:** PRINCIPAL_INVESTIGATOR

### References Module

#### References

**Citation:** McDonald AC, Vasey PA, Adams L, Walling J, Woodworth JR, Abrahams T, McCarthy S, Bailey NP, Siddiqui N, Lind MJ, Calvert AH, Twelves CJ, Cassidy J, Kaye SB. A phase I and pharmacokinetic study of LY231514, the multitargeted antifolate. Clin Cancer Res. 1998 Mar;4(3):605-10.

**PMID:** 9533527

**Citation:** Taylor EC, Kuhnt D, Shih C, Rinzel SM, Grindey GB, Barredo J, Jannatipour M, Moran RG. A dideazatetrahydrofolate analogue lacking a chiral center at C-6, N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5- yl)ethyl]benzoyl]-L-glutamic acid, is an inhibitor of thymidylate synthase. J Med Chem. 1992 Nov 13;35(23):4450-4. doi: 10.1021/jm00101a023.

**PMID:** 1447744

**Citation:** Adjei AA. Pharmacology and mechanism of action of pemetrexed. Clin Lung Cancer. 2004 Apr;5 Suppl 2:S51-5. doi: 10.3816/clc.2004.s.003.

**PMID:** 15117425

**Citation:** Rinaldi DA, Burris HA, Dorr FA, Woodworth JR, Kuhn JG, Eckardt JR, Rodriguez G, Corso SW, Fields SM, Langley C, et al. Initial phase I evaluation of the novel thymidylate synthase inhibitor, LY231514, using the modified continual reassessment method for dose escalation. J Clin Oncol. 1995 Nov;13(11):2842-50. doi: 10.1200/JCO.1995.13.11.2842.

**PMID:** 7595747

**Citation:** Yan J, Zhong N, Liu G, Chen K, Liu X, Su L, Singhal S. Usp9x- and Noxa-mediated Mcl-1 downregulation contributes to pemetrexed-induced apoptosis in human non-small-cell lung cancer cells. Cell Death Dis. 2014 Jul 3;5(7):e1316. doi: 10.1038/cddis.2014.281.

**PMID:** 24991768

**Citation:** Ramirez JM, Ocio EM, San Miguel JF, Pandiella A. Pemetrexed acts as an antimyeloma agent by provoking cell cycle blockade and apoptosis. Leukemia. 2007 Apr;21(4):797-804. doi: 10.1038/sj.leu.2404599. Epub 2007 Feb 22.

**PMID:** 17315026

**Citation:** Pan Z, Yang G, He H, Zhao G, Yuan T, Li Y, Shi W, Gao P, Dong L, Li Y. Concurrent radiotherapy and intrathecal methotrexate for treating leptomeningeal metastasis from solid tumors with adverse prognostic factors: A prospective and single-arm study. Int J Cancer. 2016 Oct 15;139(8):1864-72. doi: 10.1002/ijc.30214. Epub 2016 Jun 30.

**PMID:** 27243238

**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.

**PMID:** 31544065

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000009371

- Term: Neoplasms by Site

- ID: D000009369

- Term: Neoplasms

- ID: D000009385

- Term: Neoplastic Processes

- ID: D000010335

- Term: Pathologic Processes

- ID: D000008577

- Term: Meningeal Neoplasms

- ID: D000016543

- Term: Central Nervous System Neoplasms

- ID: D000009423

- Term: Nervous System Neoplasms

- ID: D000009422

- Term: Nervous System Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC04

- Name: Neoplasms

- Abbrev: BC08

- Name: Respiratory Tract (Lung and Bronchial) Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: BC10

- Name: Nervous System Diseases

### Condition Browse Module - Browse Leaves

- ID: M11172

- Name: Lung Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M5546

- Name: Carcinoma, Non-Small-Cell Lung

- Relevance: LOW

- As Found: Unknown

- ID: M12307

- Name: Neoplasm Metastasis

- Relevance: HIGH

- As Found: Metastases

- ID: M14850

- Name: Recurrence

- Relevance: LOW

- As Found: Unknown

- ID: M28325

- Name: Meningeal Carcinomatosis

- Relevance: HIGH

- As Found: Leptomeningeal Metastasis

- ID: M12330

- Name: Neoplastic Processes

- Relevance: LOW

- As Found: Unknown

- ID: M11560

- Name: Meningeal Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M18937

- Name: Central Nervous System Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M12367

- Name: Nervous System Neoplasms

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000009362

- Term: Neoplasm Metastasis

- ID: D000055756

- Term: Meningeal Carcinomatosis

### Intervention Browse Module - Ancestors

- ID: D000014815

- Term: Vitamins

- ID: D000018977

- Term: Micronutrients

- ID: D000045505

- Term: Physiological Effects of Drugs

- ID: D000000893

- Term: Anti-Inflammatory Agents

- ID: D000000932

- Term: Antiemetics

- ID: D000001337

- Term: Autonomic Agents

- ID: D000018373

- Term: Peripheral Nervous System Agents

- ID: D000005765

- Term: Gastrointestinal Agents

- ID: D000005938

- Term: Glucocorticoids

- ID: D000006728

- Term: Hormones

- ID: D000006730

- Term: Hormones, Hormone Substitutes, and Hormone Antagonists

- ID: D000018931

- Term: Antineoplastic Agents, Hormonal

- ID: D000000970

- Term: Antineoplastic Agents

- ID: D000004791

- Term: Enzyme Inhibitors

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

- ID: D000005493

- Term: Folic Acid Antagonists

- ID: D000019384

- Term: Nucleic Acid Synthesis Inhibitors

- ID: D000006397

- Term: Hematinics

- ID: D000014803

- Term: Vitamin B Complex

### Intervention Browse Module - Browse Branches

- Abbrev: Infl

- Name: Anti-Inflammatory Agents

- Abbrev: ANeo

- Name: Antineoplastic Agents

- Abbrev: AnEm

- Name: Antiemetics

- Abbrev: Gast

- Name: Gastrointestinal Agents

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: Micro

- Name: Micronutrients

- Abbrev: Hemat

- Name: Hematinics

- Abbrev: Vi

- Name: Vitamins

### Intervention Browse Module - Browse Leaves

- ID: M7102

- Name: Dexamethasone

- Relevance: HIGH

- As Found: Children

- ID: M264

- Name: Pemetrexed

- Relevance: HIGH

- As Found: General

- ID: M235549

- Name: Dexamethasone acetate

- Relevance: LOW

- As Found: Unknown

- ID: M8618

- Name: Folic Acid

- Relevance: HIGH

- As Found: Behavioral Therapy

- ID: M17558

- Name: Vitamins

- Relevance: LOW

- As Found: Unknown

- ID: M17546

- Name: Vitamin B Complex

- Relevance: LOW

- As Found: Unknown

- ID: M17548

- Name: Vitamin B 12

- Relevance: HIGH

- As Found: Inclusion criteria

- ID: M9934

- Name: Hydroxocobalamin

- Relevance: LOW

- As Found: Unknown

- ID: M21009

- Name: Micronutrients

- Relevance: LOW

- As Found: Unknown

- ID: M16885

- Name: Trace Elements

- Relevance: LOW

- As Found: Unknown

- ID: M4217

- Name: Anti-Inflammatory Agents

- Relevance: LOW

- As Found: Unknown

- ID: M4251

- Name: Antiemetics

- Relevance: LOW

- As Found: Unknown

- ID: M8881

- Name: Gastrointestinal Agents

- Relevance: LOW

- As Found: Unknown

- ID: M9047

- Name: Glucocorticoids

- Relevance: LOW

- As Found: Unknown

- ID: M9789

- Name: Hormones

- Relevance: LOW

- As Found: Unknown

- ID: M9788

- Name: Hormone Antagonists

- Relevance: LOW

- As Found: Unknown

- ID: M20966

- Name: Antineoplastic Agents, Hormonal

- Relevance: LOW

- As Found: Unknown

- ID: M7951

- Name: Enzyme Inhibitors

- Relevance: LOW

- As Found: Unknown

- ID: M8619

- Name: Folic Acid Antagonists

- Relevance: LOW

- As Found: Unknown

- ID: M9485

- Name: Hematinics

- Relevance: LOW

- As Found: Unknown

- ID: T447

- Name: Folinic Acid

- Relevance: LOW

- As Found: Unknown

- ID: T446

- Name: Folic Acid

- Relevance: HIGH

- As Found: Behavioral Therapy

- ID: T451

- Name: Methylcobalamin

- Relevance: LOW

- As Found: Unknown

- ID: T448

- Name: Folate

- Relevance: LOW

- As Found: Unknown

- ID: T475

- Name: Vitamin B9

- Relevance: LOW

- As Found: Unknown

- ID: T476

- Name: Vitamin B12

- Relevance: HIGH

- As Found: Inclusion criteria

- ID: T441

- Name: Cobalamin

- Relevance: LOW

- As Found: Unknown

- ID: T444

- Name: Cyanocobalamin

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000005492

- Term: Folic Acid

- ID: D000014805

- Term: Vitamin B 12

- ID: D000003907

- Term: Dexamethasone

- ID: D000068437

- Term: Pemetrexed

### Misc Info Module

- Version Holder: 2024-05-24
