A Prospective Single Arm Phase II Exploratory Study on the Combination of Whole Brain Radiotherapy, Thiotepa Intrathecal Injection and Systemic Treatment of Primary Diseases in the Treatment of Solid Tumor Leptomeningeal Metastasis

A Prospective Single Arm Phase II Exploratory Study on the Combination of Whole Brain Radiotherapy and Thiotepa Intrathecal Injection for Systemic Treatment of Primary Diseases in the Treatment of Solid Tumor Leptomeningeal Metastasis

The goal of this prospective, single-arm exploratory clinical study is to explore the safty and efficacy of whole-brain radiotherapy combined with Thiotepa intrathecal injection combined with systemic therapy for the primary disease in the treatment of leptoeningeal metastases in solid tumors

How works well was the combined therapy？ How safe was combined therapy？ Participants will continue systemic treatment, receive HA-WBRT combined with intrathecal injection of Thiotepa. Evaluate the efficacy and safety every 6 cycles.

Researchers will evaluate whether this combination treatment is safe and whether it is more effective than previous studies.

Study Overview

• Status: Completed
• Conditions: Solid Tumor Leptomeningeal Metastasis
• Intervention / Treatment: Drug: Intrathecal Injection of Thiotepa+Radiation+Systemic Treatment of Primary Diseases

Detailed Description

Participants will receive a comprehensive treatment plan consisting mainly of HA-WBRT combined with intrathecal injection of Thiotepa. All eligible patients received intrathecal injection of Thiotepa twice a week for 1 week as induction treatment for 3 weeks, followed by once every week as consolidation therapy for 6 week and then once monthly as maintenance therapy, until progressive disease was observed or intolerance or adverse events (AEs) developed. The injection was administered by qualified individuals (certified personnel in the radiotherapy department of our hospital) . Thiotepa was injected 10mg each time, mixed with cerebrospinal fluid, and then injected slowly for 5-10 minutes. Evaluate the efficacy and safety every 6 cycles according to RANO-LM criteria.

• Study Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310000
      • The Second Affiliated Hospital of Zhejiang University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 1) Voluntary participation in clinical research: fully understand and be informed of this study, and sign an informed consent form in writing; Willing to follow and capable of completing all experimental procedures.

  2) Age: ≥ 18 years old, both male and female. 3) Solid tumor patients diagnosed with meningeal metastasis according to the EANO-ESMO guidelines 4) Whole brain 6MX X-ray PTV D95/30Gy/10F regimen radiotherapy has been performed 5) CNS IPI ≥ 4. 6) An increase in serum LDH or involvement of more than one extranodal site. 7) ECOG score ≤ 2. 8) Expected survival time is at least 3 months. 9) Adequate organ and bone marrow function, without severe hematopoietic dysfunction, heart, lung, liver, kidney dysfunction, and immune deficiency (no blood transfusion, granulocyte colony-stimulating factor, or other related medical support received within 14 days prior to the use of the study drug):

  1. Blood routine: Absolute neutrophil count (ANC) ≥ 1.5'109/L (1500/mm3), platelet count ≥ 75'109/L, hemoglobin count ≥ 9 g/dL (if bone marrow is involved, platelet count ≥ 50'109/L, ANC ≥ 1.0'109/L, hemoglobin count ≥ 8 g/dL).
  2. Liver function: Serum bilirubin ≤ 1.5 times the upper limit of normal value, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 1.5 times the upper limit of normal value (if liver involvement occurs, AST is allowed, ALT ≤ 5 times the upper limit of normal value).
  3. Renal function: Serum creatinine ≤ 1.5 times the upper limit of normal value.

  4. Coagulation function: INR ≤ 1.5 times the upper limit of normal value; PT and APTT ≤ 1.5 times the upper limit of normal values (unless the subject is receiving anticoagulant treatment and PT and APTT are within the expected range of anticoagulant treatment during screening).

     10) Left ventricular ejection fraction (LVEF) ≥ 50% in cardiac function examination.

     11) The serum pregnancy test is negative, and effective contraceptive measures are taken within 6 months from the signing of the informed consent form until the use of the last chemotherapy.

     12) Thyroid stimulating hormone (TSH), free thyroxine (FT4), or free triiodothyronine (FT3) are all within the normal range of ± 10%.

     13) Ophthalmic examination: including dilated pupil fundus examination, slit lamp examination, and fundus color photography.

     Exclusion Criteria:

• 1) Participating in other clinical studies, or the first study drug administration is less than 4 weeks after the end of the previous clinical study treatment.

  2) Has suffered from other malignant tumors within the past 5 years. 3) Patients who have received CNS guided treatment and prevention. 4) Patients with a known history of human immunodeficiency virus (HIV) infection and/or acquired immunodeficiency syndrome.

  5) Patients with active autoimmune diseases or a history of hematological autoimmune diseases with a high risk of recurrence, including but not limited to immune related neuropathy, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain's syndrome, myasthenia gravis, systemic lupus erythematosus, connective tissue disease, scleroderma, inflammatory bowel cancer (including Crohn's disease and ulcerative colitis), autoimmune hepatitis Toxic epidermal necrolysis or Stevens Johnson syndrome.

  6) Patients with active chronic hepatitis B or active hepatitis C. Patients with positive hepatitis B B surface antigen or hepatitis C virus antibody in screening period must further pass the hepatitis B virus DNA drop test (not more than 1000 iu/ml) and HCV RNA test (not more than the lower limit of the test method), and can be included in the test only after the active hepatitis B or hepatitis C infection requiring treatment is excluded. Hepatitis B virus carriers, hepatitis B patients who are stable after drug treatment and cured hepatitis C patients can be included in the group.

  7) Suffer from active pulmonary tuberculosis. 8) Currently, there is interstitial lung disease or infectious pneumonia. 9) Active infections that require systematic anti infective treatment, including but not limited to bacterial, fungal, or viral infections.

  10) Screening for heart failure classified as Grade III or IV according to the New York Heart Association (NYHA) functional classification within the first 6 months, unstable angina, severe uncontrolled ventricular arrhythmias, and electrocardiograms showing acute ischemia or myocardial infarction.

  11) QTcF interval>480msec, unless secondary to bundle branch block. 12) Suffering from uncontrollable comorbidities, including but not limited to uncontrollable hypertension, active peptic ulcers, or hemorrhagic diseases.

  13) Individuals with a history of mental illness; Individuals with no or limited capacity for behavior.

  14) According to the researchers, the patient's underlying condition may increase their risk of receiving treatment with the investigational drug, or may cause confusion regarding the occurrence of toxic reactions and their judgment.

  15) Other researchers believe that patients who are not suitable to participate in this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Interventional arm; Participants will receive a comprehensive treatment plan consisting mainly of whole brain 30Gy/10F radiotherapy combined with intrathecal injection of Thiotepa twice a week for a total of 4 weeks.

Drug: Intrathecal Injection of Thiotepa+Radiation+Systemic Treatment of Primary Diseases; Participants will receive a comprehensive treatment plan consisting mainly of whole brain 30Gy/10F radiotherapy combined with intrathecal injection of Thiotepa. The injection was administered by qualified individuals (certified personnel in the radiotherapy department of our hospital). Thiotepa was injected 10mg each time, mixed with cerebrospinal fluid, and then injected slowly for 5-10 minutes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The objective response rate (ORR)	The proportion of responsive patients according to RANO-LM criteria	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS	progression free survival	2 years
OS	overall survival	2 years
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]	The primary safety analysis will be conducted based on subjects who experience toxicity (as defined by CTCAE standards). CTCAE version 5.0 will be used to evaluate safety through reported adverse events.	2 years
3-month OS	3-month overall survival	3 months
6-month OS	6-month overall survival	6 months
9-month OS	9-month overall survival	9 months
12-month OS	12-month overall survival	12 months
The disease control rate(DCR)	The proportion of patients who, according to RANO-LM criteria, achieve response and stable disease (SD) after treatment.	2 years
Mean total score on FACT-G	Quality of life (QOL) was evaluated as a secondary endpoint using the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire. The score of FACT-G will be compared before and after treatment. The FACT-G is a 27-item questionnaire that covers four HR-QOL sub-domains: physical, social, emotional, and functional well-being. Each of the questions will be scored on a scale from 0 (Not at all) to 4 (Very much) using a manual scoring template in which some items are reverse scored. The minimally important difference (MID) is 5 points for the FACT-G questionnaire. In other words, five points is the most minimal difference between the control group and treatment group scores that would indicate a clinically meaningful change. A positive change in points indicates better QOL.	2 year

Collaborators and Investigators

• Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University

Study record dates

Study Major Dates

• Study Start (Actual): January 6, 2024
• Primary Completion (Actual): September 1, 2025
• Study Completion (Actual): September 1, 2025

Study Registration Dates

• First Submitted: February 27, 2024
• First Submitted That Met QC Criteria: April 16, 2024
• First Posted (Actual): April 19, 2024

Study Record Updates

• Last Update Posted (Actual): May 18, 2026
• Last Update Submitted That Met QC Criteria: May 12, 2026
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplastic Processes; Neoplasm Metastasis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Thiotepa
• Other Study ID Numbers: Y2024-0106

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No