Combined Intrathecal and Systemic Therapy With Trastuzumab Rezetecan for Leptomeningeal Metastases

Phase 2Not Yet RecruitingNCT07833657

Jiuda Zhao28 enrolled

Overview

This phase II clinical study enrolls patients with leptomeningeal metastases from solid tumors. Participants will receive intrathecal and systemic administration of Trastuzumab Rezetecan. The study aims to obtain clinical evidence about the efficacy and safety of this antibody-drug conjugate (ADC) given via intrathecal plus systemic routes. It hopes to offer a new treatment option for these patients with hard-to-manage disease and provide scientific support for optimizing treatment strategies for solid tumor patients with leptomeningeal metastases.

This is a prospective, multicenter, single-arm, dual-cohort phase II clinical trial. It is designed to evaluate the efficacy and safety of combined intravenous and intrathecal Trastuzumab Rezetecan in adult patients with leptomeningeal metastases (LMD) from solid tumors.Participants are stratified into two cohorts based on HER2 expression and mutation status. All enrolled patients receive dualroute treatment with intravenous plus intrathecal Trastuzumab Rezetecan. The systemic intravenous dose is 4.8 mg/kg administered every 3 weeks, with a 21-day treatment cycle. The intrathecal dose is set at 20% of the single systemic dose. In terms of administration schedule, intrathecal injection is performed once weekly during Cycle 1 and Cycle 2, and once per treatment cycle starting from Cycle 3.The primary endpoint is the 3-month overall survival (OS) rate. Secondary endpoints cover intracranial tumor response and survival outcomes, cerebrospinal fluid tumor cell clearance rate, and extracranial tumor response. This study also evaluates treatment-related adverse events according to NCI-CTCAE v5.0 and assesses patients' quality of life using the EORTC QLQ-C30 questionnaire.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Aged ≥ 18 years of any gender; histologically confirmed solid tumor; signed informed consent form. 2. Patients with Type I LMD (defined as positive cerebrospinal fluid cytology or positive leptomeningeal biopsy) or Type II LMD (diagnosed based on clinical manifestations and neuroimaging alone) according to the European Association of Neuro-Oncology (EANO)-European Society for Medical Oncology (ESMO) clinical practice guidelines;patients with treatment-naive LMD or recurrent LMD after radiotherapy. 3. Investigators assess that immediate radiotherapy for leptomeningeal lesions is not required, or the patient declines radiotherapy. 4. Expected survival ≥ 6 weeks. 5. Left ventricular ejection fraction (LVEF) ≥ 50% measured by echocardiogram; adequate organ and bone marrow function. 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-4. 7. All enrolled subjects will be stratified into 2 predefined cohorts based on tumor HER2 status: Cohort 1: Patients with leptomeningeal disease secondary to solid tumors without HER2 protein overexpression and without HER2-activating mutations; Cohort 2: Patients with leptomeningeal disease secondary to solid tumors with HER2 protein overexpression or harboring HER2-activating mutations. Exclusion Criteria: 1. Presence of severe central nervous system (CNS) complications, such as progressive cerebral edema; recurrent seizures refractory to standardized antiepileptic therapy. Note: "refractory recurrent seizures" refers to persistent clinical seizures despite adequate standardized antiepileptic treatment. Subjects with a prior history of epilepsy with long-term seizure control on medication are not excluded by this criterion. 2. Receipt of whole-brain radiotherapy or other intrathecal therapies within the recent 4 weeks, which may interfere with efficacy assessment. 3. History of active interstitial lung disease (ILD) or pneumonia. 4. Concurrent severe systemic diseases, including but not limited to: 4.1 Active autoimmune disease or CNS infection; 4.2 Active infections (e.g., pulmonary tuberculosis, active hepatitis B, HIV infection); 4.3 Moderate to severe hepatic or renal dysfunction (alanine aminotransferase (ALT)/aspartate aminotransferase (AST) \> 3 × ULN, creatinine clearance (CrCl) \< 30 ml/min); 4.4 Uncontrolled heart failure, severe arrhythmia or hypertension; 4.5 Known inherited or acquired bleeding/thrombotic tendency (e.g., hemophilia, coagulopathy, thrombocytopenia); and/or coagulation disorders (international normalized ratio (INR) \> 2.0, prothrombin time (PT) \> 16 s) with bleeding risk, or receiving thrombolysis or anticoagulant treatment. 5. History of allergy or hypersensitivity to the study drug or its components. 6. Major surgery or severe traumatic injury within 28 days prior to enrollment.

Outcomes

Primary Outcomes

3-month Overall Survival Rate

3-month overall survival (OS) rate is defined as the percentage of all enrolled participants who are still alive at 3-months from the date of receiving study treatment.

Time frame: 3-months from the date of receiving study treatment

Secondary Outcomes

Leptomeningeal Metastasis-Progression-Free Survival (LM-PFS)

Time from treatment initiation to the first documentation of leptomeningeal metastasis progression (based on neurological examination, cerebrospinal fluid testing, or neuraxis MRI) or death from any cause, whichever occurs first, in patients with solid tumor-associated leptomeningeal metastasis receiving intrathecal plus intravenous Trastuzumab Rezetecan.

Time frame: From treatment initiation until disease progression, death, or study discontinuation, assessed up to 18 months.

Leptomeningeal Metastasis-Objective Response Rate (LM-ORR)

LM-ORR corresponds to Best Overall Response. It is not a single time-point assessment, but the best leptomeningeal metastasis therapeutic response documented from treatment initiation up to disease progression, study discontinuation, death, or pre-specified maximum follow-up.

Time frame: From treatment initiation until disease progression, death, or study discontinuation, assessed up to 18 months.

Cerebrospinal Fluid Cytology Conversion Rate

For intrathecal treatment: Trastuzumab rezetecan is administered intrathecally once weekly in Cycle 1 and Cycle 2; starting from Cycle 3 and thereafter, intrathecal Trastuzumab rezetecan is given once per 3-week cycle. The cerebrospinal fluid cytology conversion rate is preliminarily evaluated after 6-week intrathecal treatment. Sustained absence of tumor cells in cerebrospinal fluid at this time point is defined as cerebrospinal fluid conversion to negative. The cerebrospinal fluid cytology conversion rate is calculated as: (Number of patients with negative cerebrospinal fluid tumor cells at 6-week post-treatment ÷ Total number of treated patients with leptomeningeal metastasis) × 100%

Time frame: 6 weeks after initiation of intrathecal study treatment

Extracranial Objective Response Rate (EC-ORR)

EC-ORR is defined as the percentage of patients whose best overall response of extracranial lesions is complete response (CR) or partial response (PR). Tumor assessments are performed per RECIST version 1.1from the date of first study treatment until study discontinuation secondary to disease progression.

Time frame: From treatment initiation until disease progression, death, or study discontinuation, assessed up to 18 months.

Leptomeningeal Metastasis-Second Progression-Free Survival (LM-PFS2)

The measurement time of PFS2 is from the date of first disease progression to the date of second disease progression or death. LM-PFS2 is defined as the time from the first leptomeningeal metastasis progression to second leptomeningeal metastasis progression or death from any cause, whichever occurs first. Patients without the above-mentioned events will be censored at the date of last valid follow-up.

Time frame: From the date of first leptomeningeal metastasis progression until second leptomeningeal metastasis progression, death, or study discontinuation, assessed up to 18 months.

Adverse events (AEs)

Number of subjects with treatment-related adverse events, which will be assessed and graded according to NCI-CTCAE version 5.0 criteria.

Time frame: From treatment initiation until 30-day safety follow-up after last study drug administration, assessed up to 18 months.

Changes in the dimensions of the EORTC QLQ-C30 scale

Physical functioning, role functioning, emotional functioning, cognitive functioning, social functioning, and global health status before and after treatment. EORTC QLQ-C30 scores range from 0 to 100. Higher scores represent better quality of life.

Time frame: FFrom treatment initiation up to 21 days after the last treatment cycle

Combined Intrathecal and Systemic Therapy With Trastuzumab Rezetecan for Leptomeningeal Metastases

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts