## Protocol Section
### Identification Module
**NCT ID:** NCT06431685

**Brief Title:** Safety and Efficacy of Whole Brain LDRT+ICI+Intrathecal Chemotherapy in Refractory Meningeal Metastasis of Lung Cancer

**Official Title:** Phase I Study of Whole Brain Low Dose Radiotherapy Combined With ICI and Intrathecal Chemotherapy for Treatment of Refractory Meningeal Metastasis of Lung Cancer

#### Organization Study ID Info
**ID:** LM-001
#### Organization
**Class:** OTHER
**Full Name:** Sichuan University
### Status Module
#### Completion Date
**Date:** 2026-12

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-28

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-27

**Overall Status:** RECRUITING

#### Primary Completion Date
**Date:** 2026-05

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-04-25

**Type:** ACTUAL

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-28
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-19
**Study First Submit QC Date:** 2024-05-27
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** Sichuan University

#### Responsible Party

**Investigator Affiliation:** Sichuan University

**Investigator Full Name:** You Lu

**Investigator Title:** Chair of Department of Thoracic Cancer

**Type:** PRINCIPAL_INVESTIGATOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

### Description Module

**Brief Summary:** This phase I study aims to investigate the safety and efficacy of whole brain low dose radiotherapy (WB-LDRT) combined with ICI and intrathecal chemotherapy for treatment of refractory meningeal metastasis of lung cancer.

**Detailed Description:** This exploratory phase I study will be conducted in West China Hospital, Sichuan University. Three cohorts of whole brain low dose radiotherapy (3 patients per cohort) will be enrolled to determine the safety and efficacy of whole brain low dose radiotherapy combined with ICI and intrathecal chemotherapy for treatment of refractory meningeal metastasis of lung cancer.

Subjects who fulfil all the inclusion criteria and none of the exclusion criteria will be enrolled and receive treatment with WB-LDRT at same dose (4 Gy/2f) with diffent cycles (decried as below), PD-1 inhibitor, pemetrexed chemotherapy, and intrathecal pemetrexed every 3 weeks (Q3w) for 4 cycles.

Patients will receive WB-LDRT at 3 cohorts with increasing dose fractions: 4 Gy/2f of one cycle in group 1; 4 Gy/2f of two cycles in group 2; 4 Gy/2f of four cycles in group 3.

### Conditions Module

**Conditions:**

- NSCLC

- Low Dose Radiotherapy

- PD-1 Inhibitor

- Leptomeningeal Metastasis

### Design Module

#### Design Info

**Allocation:** NA

**Intervention Model:** SINGLE_GROUP

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 10

**Type:** ESTIMATED

**Phases:**

- PHASE1

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** The treatment regimen consisted of intrathecal chemotherapy (via lumbar puncture, pemetrexed 30 mg, once per three weeks, 4 cycles in total), PD-1 inhibitor (Sintilimab, via intravenous infusion, once per three weeks, 4 cycles in total)), pemetrexed chemotherapy (via intravenous infusion, once per three weeks, 4 cycles in total) and radiotherapy. Whole brain LDRT will be administered at 3 cohorts with increasing dose fractions: 4 Gy/2f of 2 fraction (administered a daily dose of 2 Gy for two days) in group 1; 4 Gy/2f of 4 fractions (administered a daily dose of 2 Gy for two days, once per three weeks, 2 cycles in total) in group 2; 4 Gy/2f of 8 fractions (administered a daily dose of 2 Gy for two days, once per three weeks, 4 cycles in total) in group 3.

**Intervention Names:**

- Radiation: Whole Brain Low Dose Radiotherapy

- Drug: Pemetrexed

- Drug: Sintilimab

- Drug: Chemotherapy

**Label:** whole brain LDRT + ICI + intrathecal chemotherapy

**Type:** EXPERIMENTAL

### Interventions

#### Intervention 1

**Arm Group Labels:**

- whole brain LDRT + ICI + intrathecal chemotherapy

**Description:** Whole brain LDRT will be administered at 3 cohorts with increasing dose fractions: Group 1: 4 Gy/2f of one cycle; Group 2: 4 Gy/2f of two cycles (Q3w); Group 3: 4 Gy/2f of three cycles (Q3w). WB-LDRT will be administered in a 4 Gy of 2 fractions over two days, starting from Day 1 in the first cycle (a daily dose of 2 Gy, 4 Gy/2f for one cycle, once per three weeks, at minmum in one cycle and maximum in four cycles in total).

**Name:** Whole Brain Low Dose Radiotherapy

**Other Names:**

- WB-LDRT

**Type:** RADIATION

#### Intervention 2

**Arm Group Labels:**

- whole brain LDRT + ICI + intrathecal chemotherapy

**Description:** Pemetrexed, 30 mg, intrathecal injection, once per three weeks, 4 cycles in total

**Name:** Pemetrexed

**Other Names:**

- Intrathecal Chemotherapy

**Type:** DRUG

#### Intervention 3

**Arm Group Labels:**

- whole brain LDRT + ICI + intrathecal chemotherapy

**Description:** PD-1 inhibitor (Sintilimab, dose as recommended in the instruction manual), intravenous infusion, once per three weeks, 4 cycles in total

**Name:** Sintilimab

**Other Names:**

- PD-1 Inhibitor

**Type:** DRUG

#### Intervention 4

**Arm Group Labels:**

- whole brain LDRT + ICI + intrathecal chemotherapy

**Description:** Pemetrexed at a dose of 500 mg/m\^2, intravenous infusion, once per three weeks, 4 cycles in total

**Name:** Chemotherapy

**Other Names:**

- One of the standard chemotherapy regimens

**Type:** DRUG

### Outcomes Module

#### Primary 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:** 48 months

**Description:** The incidence of treatment-related adverse events were measured for determing tolerability and safety. Adverse events (AEs) are evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). Events of grade 3-5 are defined as moderate and severe adverse events.

**Measure:** Incidence of treatment-related adverse events

**Time Frame:** 48 months

#### Secondary Outcomes

**Description:** NPFS was defined as time from the start of treatment until neurological progression or death. The neurological progression was determined based on the RANO proposal evaluation criteria which have been established and published on Neuro Oncol.

**Measure:** Neurological progression-free survival (NPFS)

**Time Frame:** 48 months

**Description:** Survival time was recorded since the date of patient enrollment. All patients were followed up until death or the end of the study.

**Measure:** Overall survival

**Time Frame:** 48 months

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

1. ≥ 18 years old and ≤ 75 years old;
2. Patients with a definite diagnosis of leptomeningeal metastasis by cerebrospinal fluid cytology, or patients with clinical diagnosis combined with tumor history, neuroimaging, clinical manifestations, cerebrospinal fluid examination, etc.;
3. Patients with a clear history of lung carcinoma, including histopathological diagnosis or a combination of cytopathology and imaging, and failure of standard treatment;
4. Efficacy of extracranial lesions SD;
5. Patients with no contraindications to craniocranial radiotherapy were judged by radiotherapy doctors. Subjects who agree to receive immunotherapy, Lumbar puncture, intrathecal chemotherapy, and radiotherapy;
6. Expected survival ≥3 months, PS score ≤3;
7. Agree to provide cerebrospinal fluid, blood and tissue samples for biomarker testing;
8. The main organs function normally, no serious blood, heart, lung, liver, kidney, bone marrow and other functional abnormalities and immune deficiency diseases;
9. One week before enrollment, bone marrow and liver and kidney function met the following criteria:

   ① Hemoglobin ≥80 g/L, neutrophils ≥1.5×10\^9/L and platelets ≥70×10\^9/L;

   ② Renal function: Cr≤ULN (upper limit of normal) × 1.5, endogenous creatinine clearance (Ccr)≥55 ml/min; Liver function: total bilirubin ≤ULN × 1.5; ALT, AST≤ULN × 2.5; (In case of liver metastasis, total bilirubin should not be higher than 3 times the upper normal limit, and transaminase should not be higher than 5 times the upper normal limit);
10. The fertile women agreed to use contraception during the study period and for 6 months after the study ended; Patients who tested negative for a serum or urine pregnancy test within 7 days prior to joining the study and were not breastfed; Men who agreed to use contraception during the study period and for 6 months after the study ended

Exclusion Criteria:

1. Active autoimmune disease or history of autoimmune diseases;
2. Congenital or acquired immunodeficiency;
3. Uncontrolled cardiac clinical symptoms or diseases;
4. Severe infection or severe comorbidities, such as bleeding peptic ulcer, ileus, heart failure, renal failure, or poorly controlled diabetes;
5. History of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation;
6. Other systemic malignancies within the last 5 years;
7. Allergy to any test drug;
8. Uncontrolled epilepsy, neurological failure, or severe treatment-related neurological impairment, uncontrollable psychosis, and other conditions deemed unsuitable for inclusion by the investigator;
9. Pregnant and lactating women, subjects with reproductive capacity are unwilling to take effective contraceptive measures.

**Maximum Age:** 75 Years

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** radyoulu@hotmali.com

**Name:** You Lu, MD

**Phone:** 18980601763

**Phone Ext:** +86

**Role:** CONTACT

**Contact 2:**

**Email:** lishaxiang@foxmail.com

**Name:** Lisha Xiang, MD

**Phone:** 13320943069

**Phone Ext:** +86

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Chengdu

**Contacts:**

***Contact 1:***

- **Email:** lishaxiang@foxmail.com

- **Name:** Lisha Xiang, MD

- **Phone:** 13320943069

- **Phone Ext:** +86

- **Role:** CONTACT

**Country:** China

**Facility:** West China Hospital, Sichuan University

**State:** Sichuan

**Status:** RECRUITING

**Zip:** 610041

#### Overall Officials

**Official 1:**

**Affiliation:** West China Hospital

**Name:** You Lu, MD

**Role:** PRINCIPAL_INVESTIGATOR

### IPD Sharing Statement Module

**IPD Sharing:** NO

### References Module

#### References

**Citation:** Cao M, Chen W. Epidemiology of lung cancer in China. Thorac Cancer. 2019 Jan;10(1):3-7. doi: 10.1111/1759-7714.12916. Epub 2018 Nov 28.

**PMID:** 30485694

**Citation:** Clarke JL, Perez HR, Jacks LM, Panageas KS, Deangelis LM. Leptomeningeal metastases in the MRI era. Neurology. 2010 May 4;74(18):1449-54. doi: 10.1212/WNL.0b013e3181dc1a69.

**PMID:** 20439847

**Citation:** Remon J, Le Rhun E, Besse B. Leptomeningeal carcinomatosis in non-small cell lung cancer patients: A continuing challenge in the personalized treatment era. Cancer Treat Rev. 2017 Feb;53:128-137. doi: 10.1016/j.ctrv.2016.12.006. Epub 2016 Dec 30.

**PMID:** 28110254

**Citation:** Gleissner B, Chamberlain MC. Neoplastic meningitis. Lancet Neurol. 2006 May;5(5):443-52. doi: 10.1016/S1474-4422(06)70443-4.

**PMID:** 16632315

**Citation:** Cheng H, Perez-Soler R. Leptomeningeal metastases in non-small-cell lung cancer. Lancet Oncol. 2018 Jan;19(1):e43-e55. doi: 10.1016/S1470-2045(17)30689-7.

**PMID:** 29304362

**Citation:** Le Rhun E, Weller M, van den Bent M, Brandsma D, Furtner J, Ruda R, Schadendorf D, Seoane J, Tonn JC, Wesseling P, Wick W, Minniti G, Peters S, Curigliano G, Preusser M; EANO Guidelines Committee and ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Leptomeningeal metastasis from solid tumours: EANO-ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. ESMO Open. 2023 Oct;8(5):101624. doi: 10.1016/j.esmoop.2023.101624. Epub 2023 Sep 19.

**PMID:** 37863528

**Citation:** Chamberlain M, Junck L, Brandsma D, Soffietti R, Ruda R, Raizer J, Boogerd W, Taillibert S, Groves MD, Le Rhun E, Walker J, van den Bent M, Wen PY, Jaeckle KA. Leptomeningeal metastases: a RANO proposal for response criteria. Neuro Oncol. 2017 Apr 1;19(4):484-492. doi: 10.1093/neuonc/now183.

**PMID:** 28039364

**Citation:** Yin K, Li YS, Zheng MM, Jiang BY, Li WF, Yang JJ, Tu HY, Zhou Q, Zhong WZ, Yang XN, Chen HJ, Yan HH, Li LL, Wu YL, Zhang XC. A molecular graded prognostic assessment (molGPA) model specific for estimating survival in lung cancer patients with leptomeningeal metastases. Lung Cancer. 2019 May;131:134-138. doi: 10.1016/j.lungcan.2019.03.015. Epub 2019 Mar 18.

**PMID:** 31027690

**Citation:** Wang Y, Yang X, Li NJ, Xue JX. Leptomeningeal metastases in non-small cell lung cancer: Diagnosis and treatment. Lung Cancer. 2022 Dec;174:1-13. doi: 10.1016/j.lungcan.2022.09.013. Epub 2022 Oct 1.

**PMID:** 36206679

**Citation:** Thai K, Prat A. CNS therapeutics: Immune cells break the barriers. Sci Transl Med. 2023 Nov 8;15(721):eadh1150. doi: 10.1126/scitranslmed.adh1150. Epub 2023 Nov 8.

**PMID:** 37939159

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000009385

- Term: Neoplastic Processes

- ID: D000009369

- Term: Neoplasms

- ID: D000010335

- Term: Pathologic Processes

### Condition Browse Module - Browse Branches

- Abbrev: BC04

- Name: Neoplasms

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: All

- Name: All Conditions

- Abbrev: BC08

- Name: Respiratory Tract (Lung and Bronchial) Diseases

### Condition Browse Module - Browse Leaves

- ID: M12307

- Name: Neoplasm Metastasis

- Relevance: HIGH

- As Found: Metastases

- ID: M11172

- Name: Lung Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M12330

- Name: Neoplastic Processes

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000009362

- Term: Neoplasm Metastasis

### Intervention Browse Module - Ancestors

- 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: D000074322

- Term: Antineoplastic Agents, Immunological

### Intervention Browse Module - Browse Branches

- Abbrev: ANeo

- Name: Antineoplastic 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: M264

- Name: Pemetrexed

- Relevance: HIGH

- As Found: Strategies

- ID: M2342

- Name: Immune Checkpoint Inhibitors

- Relevance: HIGH

- As Found: Obstruction

- ID: M7951

- Name: Enzyme Inhibitors

- Relevance: LOW

- As Found: Unknown

- ID: M8618

- Name: Folic Acid

- Relevance: LOW

- As Found: Unknown

- ID: M17546

- Name: Vitamin B Complex

- Relevance: LOW

- As Found: Unknown

- ID: M8619

- Name: Folic Acid Antagonists

- Relevance: LOW

- As Found: Unknown

- ID: M1346

- Name: Antineoplastic Agents, Immunological

- Relevance: LOW

- As Found: Unknown

- ID: T447

- Name: Folinic Acid

- Relevance: LOW

- As Found: Unknown

- ID: T446

- Name: Folic Acid

- Relevance: LOW

- As Found: Unknown

- ID: T448

- Name: Folate

- Relevance: LOW

- As Found: Unknown

- ID: T475

- Name: Vitamin B9

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000068437

- Term: Pemetrexed

- ID: D000082082

- Term: Immune Checkpoint Inhibitors

### Misc Info Module

- Version Holder: 2024-05-31
