Zorifertinib Plus Intra-Ommaya CSF Chemotherapy for Leptomeningeal Progression in NSCLC After Third-Generation EGFR-TKI

April 22, 2026 updated by: Jinghai Wan, Cancer Institute and Hospital, Chinese Academy of Medical Sciences

A Prospective Study of Zorifertinib Plus Intra-Ommaya CSF Chemotherapy for Leptomeningeal Progression in NSCLC After Third-Generation EGFR-TKI Therapy

A Prospective Study of Zorifertinib Combined with Intra-Ommaya Reservoir Cerebrospinal Fluid Chemotherapy for Leptomeningeal Progression in NSCLC Patients After Third-Generation EGFR-TKI Therapy

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

This study is a prospective clinical trial evaluating the preliminary efficacy and safety of zorifertinib combined with intra-Ommaya reservoir cerebrospinal fluid (CSF) chemotherapy in patients with non-small cell lung cancer (NSCLC) who develop leptomeningeal progression after prior third-generation EGFR-TKI therapy.

The study will enroll patients with advanced NSCLC harboring EGFR-sensitive mutations (L858R and/or Exon 19Del) who experience leptomeningeal progression without concurrent extracranial disease progression following third-generation EGFR-TKI treatment. A total of 38 participants are planned for enrollment. Upon enrollment, participants will receive oral zorifertinib plus pemetrexed administered via the Ommaya reservoir for CSF chemotherapy, alongside standard clinical care. Treatment will continue until disease progression, occurrence of intolerable toxicity, initiation of new anti-tumor therapy, withdrawal of informed consent, loss to follow-up, death, or any other circumstance deemed by the investigator as requiring treatment discontinuation-whichever occurs first.

Study Type

Interventional

Enrollment (Estimated)

38

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • China
      • Beijing, China
        • National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
        • Contact:
          • National Cancer Center/Cancer Hospital
          • Phone Number: 8610-87788495
          • Email: cancergcp@163.com

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • 1. Have fully understood the study and voluntarily signed the Informed Consent Form (ICF).

    2. Subjects must be 18-75 years old before signing the Informed Consent Form (ICF).

    3. During the screening phase, subjects must be diagnosed with non-small cell lung cancer (NSCLC) and test positive for EGFR-sensitive mutations (L858R and/or Exon 19Del).

    4. Subjects who developed leptomeningeal progression after treatment with third-generation EGFR-TKIs and have no extracranial progression. The original third-generation EGFR-TKIs may be continued at the original dose or reduced dose.

    5. Subjects diagnosed with leptomeningeal metastasis must have positive cerebrospinal fluid (CSF) cytology results. Subjects with negative CSF cytology but clinically diagnosed leptomeningeal metastasis based on symptoms, brain or spinal MRI imaging are also eligible for enrollment.

    6. Subjects with both leptomeningeal progression and brain parenchymal progression are allowed to enroll.

    7. Have undergone Ommaya reservoir implantation, with confirmation of no surgery-related complications and normal function of the Ommaya reservoir.

    8. If accompanied by neurological symptoms, the following conditions must be met: able to take oral medication and swallow drugs; no need to increase hormone dosage to control central nervous system symptoms for at least 1 week prior to study treatment (i.e., symptom stability).

    9. All anti-tumor therapy-related toxicities must have recovered to ≤ Grade 1 per CTCAE 5.0 criteria prior to starting study treatment (neurotoxicity related to platinum-based therapy may recover to ≤ Grade 2 per CTCAE 5.0 criteria); alopecia of any grade is allowed for enrollment.

    10. Screening period test results must meet the following criteria:

  • Neutrophil count ≥ 1.5 × 10⁹/L
  • Platelet count ≥ 100 × 10⁹/L
  • Hemoglobin ≥ 90 g/L
  • Serum creatinine ≤ 1.5 × ULN, or creatinine clearance (calculated via Cockcroft-Gault formula) ≥ 50 mL/min
  • Total serum bilirubin ≤ 1.5 × ULN (≤ 3 × ULN allowed for patients with Gilbert syndrome or liver metastasis)
  • Aspartate aminotransferase (AST) ≤ 2.5 × ULN (≤ 5 × ULN allowed for patients with liver metastasis)
  • Alanine aminotransferase (ALT) ≤ 2.5 × ULN (≤ 5 × ULN allowed for patients with liver metastasis) 11. Estimated survival duration ≥ 3 months. 12. Karnofsky Performance Status (KPS) score ≥ 60.

Exclusion Criteria:

  • 1. Subjects with a history of cranial or spinal radiotherapy within 6 months prior to study drug administration are ineligible for enrollment. Radiotherapy for bone metastases within 3 months prior to study drug administration is also not permitted.

    2. Subjects who have undergone major surgical procedures (e.g., intrathoracic, intra-abdominal, or pelvic surgery) within 4 weeks prior to the first dose of study treatment, or who have not yet recovered from side effects related to such surgeries, are ineligible for enrollment.

    3. Subjects with any other currently active malignant tumor besides NSCLC are excluded.

    4. Subjects with clinically significant, uncontrolled cardiac disease and/or cardiac events occurring within the past 6 months, such as:

    1. Myocardial infarction within 6 months prior to screening;
    2. Documented history of heart failure (NYHA Class III-IV);
    3. Uncontrolled hypertension: systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg, regardless of antihypertensive medication use (adjustment of antihypertensive drugs prior to screening is permitted);
    4. Drug-refractory arrhythmias;
    5. Screening QTcF >470 ms;
    6. Left ventricular ejection fraction (LVEF) <50%. 5. Subjects with gastrointestinal diseases or severe impairment of gastrointestinal function that may significantly affect drug absorption (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).

    6. Subjects unable to discontinue the following medications within 1 week prior to study drug administration and during the study period:

    1. Strong inducers or strong inhibitors of CYP3A4;
    2. Drugs that may prolong the QT interval or induce torsades de pointes. 7. Subjects with prior or current HIV infection are excluded. HCV antibody-positive subjects may be enrolled if HCV RNA is undetectable (with the lower limit of detection defined per each center's standards) and there is no concurrent hepatitis B virus (HBV) infection. HBV-infected subjects may be enrolled if they meet the following conditions:
    1. For active hepatitis B patients: at least 6 weeks of antiviral therapy prior to starting study treatment, with HBV DNA <100 IU/mL and ALT/AST levels <ULN;
    2. For resolved or chronic hepatitis B patients: at least 2 weeks of prophylactic antiviral therapy prior to starting study treatment, with HBV DNA below 100 IU/mL (e.g., inactive carriers) and ALT/AST levels <ULN.

    8. Pregnant or breastfeeding women; women of childbearing potential must agree to use highly effective contraception during the treatment period and for 3 months after the last dose; fertile men must also use highly effective contraception during the treatment period and for 6 months after the last dose.

    9. Subjects with a prior history of interstitial lung disease, including clinically significant radiation pneumonitis (e.g., affecting daily life or requiring therapeutic intervention).

    10. Subjects who have previously received zorifertinib or its active pharmaceutical ingredient.

    11. Known hypersensitivity to zorifertinib's active ingredients, excipients, or drugs with similar chemical structures or classes.

    12. Subjects with other comorbid diseases or factors that, in the investigator's judgment, would pose excessive risk to the subject upon participation in the clinical trial.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Zorifertinib Plus Intra-Ommaya CSF Chemotherapy
Zorifertinib Plus Intra-Ommaya CSF Chemotherapy for Leptomeningeal Progression in NSCLC After Third-Generation EGFR-TKI Therapy
Drug: Zorifertinib Plus Intra-Ommaya CSF Chemotherapy
Zorifertinib Plus Intra-Ommaya CSF Chemotherapy for Leptomeningeal Progression in NSCLC After Third-Generation EGFR-TKI Therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Response Assessment in Neuro - Oncology Leptomeningeal Metastases (RANO - LM) criteria
Time Frame: Until the end of the study (up to 3 years)

RANO-LM uses a categorical classification (no single numeric score range) to define disease status:

Complete Response (CR): All LM-related lesions disappear, no increase in ventricular size.

Partial Response (PR): All measurable LM nodules shrink by ≥50% (sum of perpendicular diameters), no increase in ventricular size.

Stable Disease (SD): Neither PR nor Progressive Disease (PD) criteria are met.

Progressive Disease (PD): Any of the following:

  1. New measurable LM nodule(s);
  2. ≥50% increase in the product of perpendicular diameters of any measurable nodule (≥25% if the largest diameter is <10mm);
  3. ≥25% increase in Evan's index (marker of hydrocephalus progression);
  4. New linear meningeal enhancement (excluding post-lumbar puncture changes).
Until the end of the study (up to 3 years)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Survival (OS)
Time Frame: Until the end of the study (up to 3 years)
Overall Survival (OS)
Until the end of the study (up to 3 years)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Cancer Institute and Hospital, Chinese Academy of Medical Sciences

Collaborators

Alpha Biopharma (Jiangsu) Co., Ltd.

Investigators

  • Study Chair: Wan Jinghai, Chinese Academy of Medical Sciences

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

May 30, 2026

Primary Completion (Estimated)

May 30, 2027

Study Completion (Estimated)

May 30, 2028

Study Registration Dates

First Submitted

April 17, 2026

First Submitted That Met QC Criteria

April 22, 2026

First Posted (Actual)

April 24, 2026

Study Record Updates

Last Update Posted (Actual)

April 24, 2026

Last Update Submitted That Met QC Criteria

April 22, 2026

Last Verified

April 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NCC6051

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

all IPD collected throughout the trial

IPD Sharing Time Frame

Beginning 1 year after publication with no end date

IPD Sharing Access Criteria

Access Criteria Individual participant data (IPD) and supporting documents for this trial will be shared with qualified researchers upon reasonable request, pending independent review committee approval and a signed Data Sharing Agreement.

  • Who: Qualified researchers conducting legitimate scientific research (e.g., academic/healthcare institutions) with proper ethical approvals for their proposals.
  • What: De-identified IPD (demographics, baseline traits, efficacy endpoints like LM-PFS/OS/LM-ORR, safety data) and core documents (protocol, SAP, ICF template). Extra materials (e.g., imaging guidelines) may be provided upon request.
  • How: Submit requests to the sponsor's data sharing contact (cancergcp@163.com). Access requires formal proposal review to align with trial's ethical/legal/privacy rules and completion of the Data Sharing Agreement.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • ANALYTIC_CODE
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Subscribe