Patients With Advanced Non-small Cell Lung Cancer With Meningeal Progression After Osimertinib TreatmentPhase 1NCT07361705
Zorifertinib With Osimertinib for NSCLC With Meningeal Progression
A Phase 1 study testing Zorifertinib and Osimertinib Combination Therapy in people with Patients With Advanced Non-small Cell Lung Cancer With Meningeal Progression After Osimertinib Treatment, run by Alpha Biopharma (Jiangsu) Co., Ltd. at 5 sites in China.
Trial summary
This is a clinical trial that aims to test Zorifertinib when used together with a known drug, Osimertinib. The goal is to learn if this combination is safe and works for people with advanced Non-Small Cell Lung Cancer (NSCLC) whose cancer has spread to the membranes surrounding the brain and spinal cord (a condition… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Patients With Advanced Non-small Cell Lung Cancer With Meningeal Progression After Osimertinib Treatment
- What is being tested?
- Zorifertinib and Osimertinib Combination Therapy
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 42 participants
- Where
- 5 sitesChina
- Study dates
- 31 Jan 2026to 15 Sep 2028
- Phase
- Phase 1
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- For inclusion in the study, patients must meet all of the following criteria.
- The patient or the guardian is required to understand and sign the informed consent form of this study.
- During the screening period, subjects must have a previous histological or cytological diagnosis of NSCLC with a sensitising EGFR mutation (including L858R and/or Exon19Del).
- Only patients who have developed meningeal progression after osimertinib treatment (at a standard dose of 80 mg QD; if the dose is 160 mg QD, it must be reduced to 80 mg QD for at least 1 week before receiving study treatment) (new-onset meningeal progression, or patients with existing meningeal progression that is poorly controlled using osimertinib combined with available conventional treatment [CNS symptoms not relieved or CSF cytology not turning negative], but the available conventional treatment must be washed out for at least 4 weeks) and have no extracranial progression are allowed to be enrolled.
- Subjects with leptomeningeal metastases should have the positive results of cerebrospinal fluid (CSF) cytology. Subjects with negative CSF cytology but highly suspected of leptomeningeal metastases in combination with CSF biochemical test and brain or spinal cord MRI imaging examination are allowed to be enrolled into the study.
- Subjects with meningeal progression and brain parenchyma progression are allowed to be enrolled.
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- Subjects must have at least one repeatedly evaluable, measurable target lesion (intracranial and/or extracranial) according to mRECIST 1.1 criteria or a repeatedly evaluable lesion according to RANO-LM criteria.
- Subjects must be ≥ 18 years old before signing the informed consent form (ICF).
- If there are neurological symptoms, the following conditions must be met: Able to take and swallow oral medication; No need to increase the hormone dose to enhance control of central nervous system symptoms for at least 1 week before study treatment. If a patient is taking hormone for the purpose of treating endocrine dysfunction or tumor-related symptoms (not central nervous system-related), the dose must be stable or reduced within 5 days before the study medication. Note: The hormone dose should be stable 5 days before the baseline brain MRI.
- All toxicities related to anti-tumor therapy (including radiotherapy) must have resolved to ≤ Grade 1 (CTCAE 5.0, it is sufficient for neurotoxicity related to platinum treatment to resolve to ≤ Grade 2 [CTCAE]) before starting the study treatment. Patients with alopecia of any grade are allowed to be enrolled.
- The screening period examination of patients must meet the followings:
- Neutrophil count ≥ 1.5 x 109/L
- Platelet ≥ 100 x 109/L
- Hemoglobin ≥ 9 g/dL
- Blood creatinine ≤ 1.5 x ULN, or creatinine clearance (Cockcroft-Gault formula) ≥ 50 mL/min
- Total bilirubin ≤ 1.5 x ULN (for patients with Gilbert's syndrome or metastases to liver, ≤3 x ULN is acceptable)
- Glutamic-oxaloacetic transferase ≤ 2 x ULN (for patients with metastases to liver, ≤ 3 x ULN is acceptable)
- Glutamic-pyruvic transaminase ≤ 2 x ULN (for patients with metastases to liver, ≤ 3 x ULN is acceptable)
- The estimated survival time of subjects is ≥ 6 weeks.
- Karnofsky Performance Status (KPS) scale score ≥ 60.
Who cannot join
- Patients must not enter the study if any of the following exclusion criteria is met:
- Subjects who plan to receive brain radiotherapy or intrathecal injection during the period from signing ICF to study medication.
- Radiotherapy history within 28 days before study drug administration is not allowed for enrollment, and palliative radiation to the skeleton occurring within 14 days before study drug administration is also not allowed for enrollment.
- Subjects who have undergone major surgery (e.g. intrathoracic, intraperitoneal or pelvic surgery) within 4 weeks prior to the first dose of study treatment or who have not yet recovered from the side effects associated with such surgery are not allowed to be enrolled.
- In addition to NSCLC, there are other malignant tumors, or a history of other malignant tumors within 5 years, except for the following cases: Complete resection of skin basal cell and squamous cell carcinoma and radical resection of any type of carcinoma in situ.
- Suffering from clinically significant and uncontrollable cardiac disorder and/or heart-related events within 6 months, such as:
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- Unstable angina within 6 months before the screening period; (2) Myocardial infarction within 6 months before the screening period; (3) Documented history of heart failure (NYHA Class III-IV) or left ventricular ejection fraction (LVEF) < 50%; (4) Uncontrollable hypertension: systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg, with or without antihypertensive drug treatment; the drugs are allowed to be adjusted before the screening period; (5) Ventricular arrhythmia; (6) Supraventricular or sinus arrhythmias but difficult to control with drugs; (7) Arrhythmias that cannot be controlled by other drugs; (8) QTcF >470 ms (mean value of three readings corrected using the Fridericia formula) during the screening period.
- The patient has any factors that increase the risk of QTc prolongation or arrhythmic events, such as electrolyte disturbances, including: Grade 2 or higher hypokalemia according to CTCAE (electrolyte disturbances should be corrected to ≤Grade 1 according to CTCAE and documented before the first dose); heart failure, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death in a first-degree relative under the age of 40, or any concomitant medication known to prolong the QT interval and lead to torsades de pointes.
- 6. Suffering from gastrointestinal disorders or serious impairment of gastrointestinal function, which may significantly affect drug absorption (e.g. ulcerative diseases, uncontrollable nausea, or vomiting, diarrhea, or malabsorption syndrome).
- 7. Unable to discontinue the following medications before the start of the study drug and during the study according to the withdrawal period provided in Appendix 13.6 (see Appendix 13.6 for specific withdrawal periods):
- Strong CYP3A4 inducers or inhibitors;
- Drugs mainly metabolised by CYP3A4;
- Drugs that may cause QT interval prolongation or torsade de pointe. 8. Patients with a previous or concurrent HIV infection are not allowed to enroll. Patients who are HCV antibody positive can be enrolled if HCV-RNA is undetectable (the lower limit of normal for HCV-RNA detection is based on the test values of each site) and there is no concurrent hepatitis B virus (HBV) infection. HBV-infected individuals are allowed to be enrolled if they meet the following criteria: 1) Patients with active hepatitis B must meet the following conditions: Antiviral treatment is given for at least 6 weeks before starting study treatment, HBV DNA must be <100 IU/mL, and ALT and AST levels must be <ULN; 2) Patients with resolved hepatitis B or chronic hepatitis B must meet the following criteria: Patients have received prophylactic antiviral treatment for at least 2-4 weeks before the start of study treatment, transaminases have been below ULN for >6 months, and HBV DNA is below 100 IU/mL (if in an inactive carrier state) 9. Women who are pregnant or lactating. Women of childbearing potential are required to use highly effective contraceptive methods during the dosing period and for 3 months after discontinuation of the drug. Fertile males must also use highly effective contraceptive methods during the dosing period and for 6 months after discontinuation of the drug.
- A woman of child-bearing potential is defined as a non-postmenopausal woman who has experienced menarche and has not undergone sterilization (hysterectomy or bilateral salpingo-oophorectomy) or has no other causes of permanent infertility (such as Mullerian agenesis) determined by the investigator. Postmenopause is defined as amenorrhea ≥ 12 months without other biological or physiological reasons.
- 10. Due to existence of other serious, acute or chronic medical diseases (e.g. uncontrollable diabetes or psychic disorder or abnormal laboratory tests), the investigators judged that participating in the study treatment may bring more risks to the subjects or make it difficult to explain the study results.
- 11. Previously suffering from interstitial lung disease, including clinically significant radiation pneumonia (e.g. affecting daily life or requiring treatment intervention).
- 12. Subjects who have previously received treatment with zorifertinib drug product or drug substance.
- 13. A clear known history of allergy to the active ingredient or excipients of zorifertinib or to drugs with a chemical structure or class similar to zorifertinib.
- 14. Due to other combined diseases or other factors, investigators judged that participating in the clinical trial may bring greater risks to subjects.
Trial locations and contacts
5 sites in 1 country. Contact the study team or a site near you to ask about taking part.
5 sites in 1 country
China5 sites, 5 recruiting
- Recruiting
Cancer Hospital Chinese Academy of Medical Sciences
Beijing, Beijing Municipality, 100021
Jie Wang, M.D., +86 13910704699, zlhuxi@163.com
- Recruiting
Chinese Academy of Medical Sciences Cancer Hospital Shenzhen Hospital
Guangzhou, Province, 518117
Jianhua Chang Chief Physician, Doctor, 13916619284, changjianhua@163.com
- Recruiting
Henan Cancer Hospital
Henan, Province, 450008
Yanqiu Zhao Chief Physician, Master Degree, 13938252350, 13938252350@163.com
- Recruiting
Shanxi Cancer Hospital
Shanxi, Province, 030013
Qingxiang Guo Chief Physician, Master, 13503503193, 1911932798@qq.com
- Recruiting
The First Affiliated Hospital of China Medical University
Shengyang, City, 110001
Mingfang Zhao Chief Physician, Doctor, 13644055129, zhaomf618@126.com
About this study
Official title: An Open-Label, Multicentre, Phase 1 Clinical Study to Evaluate the Safety and Efficacy of Zorifertinib Combined With Osimertinib in Patients With Advanced Non-Small Cell Lung Cancer With Meningeal Progression After Osimertinib Treatment
This is a clinical trial that aims to test Zorifertinib when used together with a known drug, Osimertinib. The goal is to learn if this combination is safe and works for people with advanced Non-Small Cell Lung Cancer (NSCLC) whose cancer has spread to the membranes surrounding the brain and spinal cord (a condition called leptomeningeal metastases) after being treated with Osimertinib.
- Being tested
- Zorifertinib and Osimertinib Combination Therapy
- Keywords
- NSCLC, Leptomeningeal Metastases, Leptomeningeal Carcinomatosis, Meningeal Metastases, EGFR, Osimertinib, Zorifertinib
- Medical subject headings
- Meningeal Carcinomatosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Zorifertinib and Osimertinib Combination TherapyDrug
Also called AZD3759, AZD9291
Zorifertinib is an oral tablet (50 mg or 100 mg). Osimertinib is an oral tablet (80 mg). In this Phase 1 study, all participants will receive the combination. Osimertinib is given at a fixed dose of 80 mg once daily. Zorifertinib is given twice daily, with dose levels under evaluation (starting at 100 mg BID, potentially escalating to 150 mg BID, 200 mg BID, or higher). Dose escalation follows a "3+3" design based on dose-limiting toxicity (DLT) assessment in the first 21-day cycle. Treatment continues until disease progression, unacceptable toxicity, or meeting other discontinuation criteria.
| Study group | Role | What they receive |
|---|---|---|
| Zorifertinib + Osimertinib (Dose Escalation) | Experimental | All enrolled participants will receive the investigational combination therapy of Zorifertinib and Osimertinib. This is a Phase 1 study consisting of a dose escalation part (Part A) and a dose expansion part (Part B). In Part A, Zorifertinib dose will be escalated (starting at 100 mg twice daily) alongside a fixed dose of Osimertinib (80 mg once daily) using a "3+3" design to determine the recommended dose. In Part B, additional participants will receive the combination at the recommended dose to further evaluate safety, efficacy, and pharmacokinetics. Treatment continues until disease progression, unacceptable toxicity, or meeting other discontinuation criteria. Receives: Drug: Zorifertinib and Osimertinib Combination Therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Determination of Recommended Dose Based on Incidence of Dose-Limiting Toxicities (DLTs)
A composite endpoint to determine the recommended dose of Zorifertinib in combination with Osimertinib. This is based on the occurrence of protocol-defined Dose-Limiting Toxicities (DLTs) within treatment. The Recommended Dose (RD) is the highest dose level at which the DLT rate is deemed acceptable by the Safety Review Committee (SRC) for further evaluation in the expansion cohort.
Measured: During the first 21 days of continuous administration for each participant in the dose-escalation phase.
Secondary outcomes (14)
Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs)
Frequency, severity, and relationship to study treatment of all AEs and SAEs.
Measured: From first dose until last dose (up to 12 months).
Objective Response Rate (ORR) for Leptomeningeal Metastases (per RANO-LM)
Proportion of participants with leptomeningeal disease achieving a Complete Response (CR) or Partial Response (PR) as assessed by the investigator according to RANO-LM neuroimaging criteria.
Measured: From first dose until disease progression or death from any cause, assessed up to 12 months.
Leptomeningeal Progression-Free Survival (LM-PFS) (per RANO-LM)
Time from first dose to the first documented progression in the leptomeninges according to RANO-LM criteria, or death from any cause, whichever occurs first
Measured: From first dose until leptomeningeal progression or death from any cause, assessed up to 12 months.
Leptomeningeal Progression-Free Survival (LM-PFS) Rate at 3, 6, and 9 Months
Proportion of participants without leptomeningeal progression (as per RANO-LM criteria) at 3, 6, and 9 months after first dose.
Measured: Assessed at 3, 6, and 9 months from first dose.
Overall Survival (OS) Rate at 3, 6, and 9 Months
Proportion of participants alive at 3, 6, and 9 months after first dose.
Measured: Assessed at 3, 6, and 9 months from first dose.
Cerebrospinal Fluid (CSF) Cytological Response Rate
Proportion of participants achieving clearance of tumor cells (conversion from positive to negative cytology) in cerebrospinal fluid (CSF).
Measured: CSF samples are collected at screening, at Week 6 (Day 22, corresponding to Cycle 2 Day 1 of a 21-day cycle), and every 6 weeks thereafter until disease progression, assessed up to 12 months.
Complete Response (CR) Rate Based on Neurological Examination
Proportion of participants achieving a Complete Response (CR) based on protocol-specified neurological examination.
Measured: Assessed at screening and at the end of every 21-day treatment cycle until disease progression, assessed up to 12 months.
Objective Response Rate (ORR) for Overall Tumors (per mRECIST 1.1)
Proportion of participants achieving Complete Response (CR) or Partial Response (PR) in overall systemic tumor burden, as assessed by the investigator using mRECIST 1.1 criteria.
Measured: From first dose until disease progression or death from any cause, assessed up to 12 months.
Duration of Response (DoR) for Overall Tumors (per mRECIST 1.1)
Time from the first documented overall tumor response (CR or PR) to the first documented overall disease progression or death due to any cause, whichever occurs first, assessed using mRECIST 1.1 criteria.
Measured: From first documented response until progression or death, assessed up to 12 months.
Progression-Free Survival (PFS) for Overall Tumors (per mRECIST 1.1)
Time from first dose to the first documented overall disease progression as per mRECIST 1.1 criteria, or death from any cause, whichever occurs first.
Measured: From first dose until overall progression or death, assessed up to 12 months.
Objective Response Rate (ORR) for Intracranial Tumors (per mRECIST 1.1)
Proportion of participants achieving Complete Response (CR) or Partial Response (PR) in intracranial tumor burden, as assessed by the investigator using mRECIST 1.1 criteria.
Measured: From first dose until intracranial disease progression or death from any cause, assessed up to 12 months.
Duration of Response (DoR) for Intracranial Tumors (per mRECIST 1.1)
Time from the first documented intracranial tumor response (CR or PR) to the first documented intracranial disease progression or death due to any cause, whichever occurs first, assessed using mRECIST 1.1 criteria.
Measured: From first documented response until intracranial progression or death, assessed up to 12 months.
Change in Neurological Assessment in Neuro-Oncology (NANO) Score
Change from baseline in the Neurological Assessment in Neuro-Oncology (NANO) score, as specified for leptomeningeal metastasis (NANO-LM). The NANO scale evaluates 9 neurological domains, with an overall response score where higher scores indicate worsening neurological function.
Measured: Assessed at screening, on Days 1, 8, 15 (Cycle 1), and at the end of each subsequent 21-day treatment cycle until the End of Treatment visit, assessed up to 12 months.
Progression-Free Survival (PFS) for Intracranial Tumors (per mRECIST 1.1)
Time from first dose to the first documented intracranial disease progression as per mRECIST 1.1 criteria, or death from any cause, whichever occurs first.
Measured: From first dose until intracranial progression or death, assessed up to 12 months.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Jan 2026
- Study start31 Jan 2026
- Primary completion23 Apr 2028 (estimated)
- Study completion15 Sep 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (21)Papers the sponsor has linked to this study.
- Other trials for Patients With Advanced Non-small Cell Lung Cancer With Meningeal Progression After Osimertinib TreatmentStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 42 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Alpha Biopharma (Jiangsu) Co., Ltd.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07361705
- Sponsor's protocol ID
- AZD3759-005
- Status last verified
- Jun 2026
- First submitted
- 4 Dec 2025
- Last updated
- 22 Jun 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Zhou Q, Song Y, Zhang X, Chen GY, Zhong DS, Yu Z, Yu P, Zhang YP, Chen JH, Hu Y, Feng GS, Song X, Shi Q, Yang LL, Zhang PH, Wu YL. A multicenter survey of first-line treatment patterns and gene aberration test status of patients with unresectable Stage IIIB/IV nonsquamous non-small cell lung cancer in China (CTONG 1506). BMC Cancer. 2017 Jul 3;17(1):462. doi: 10.1186/s12885-017-3451-x.
PubMed 28673332Yin 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.
PubMed 31027690Yang JCH, Kim DW, Kim SW. Osimertinib activity in patients (pts) with leptomeningeal (LM) disease from non-small cell lung cancer (NSCLC): Updated results from BLOOM, a phase I study. [J]. Journal of Clinical Oncology, 2016, 34(15_suppl):9002-9002.
Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y, Cho EK, Voon PJ, Planchard D, Su WC, Gray JE, Lee SM, Hodge R, Marotti M, Rukazenkov Y, Ramalingam SS; FLAURA Investigators. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018 Jan 11;378(2):113-125. doi: 10.1056/NEJMoa1713137. Epub 2017 Nov 18.
PubMed 29151359Schag CC, Heinrich RL, Ganz PA. Karnofsky performance status revisited: reliability, validity, and guidelines. J Clin Oncol. 1984 Mar;2(3):187-93. doi: 10.1200/JCO.1984.2.3.187.
PubMed 6699671Omuro AM, Kris MG, Miller VA, Franceschi E, Shah N, Milton DT, Abrey LE. High incidence of disease recurrence in the brain and leptomeninges in patients with nonsmall cell lung carcinoma after response to gefitinib. Cancer. 2005 Jun 1;103(11):2344-8. doi: 10.1002/cncr.21033.
PubMed 15844174Mok TS, Wu Y-L, Ahn M-J, Garassino MC, Kim HR, Ramalingam SS, Shepherd FA, He Y, Akamatsu H, Theelen WS, Lee CK, Sebastian M, Templeton A, Mann H, Marotti M, Ghiorghiu S, Papadimitrakopoulou VA; AURA3 Investigators. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med. 2017 Feb 16;376(7):629-640. doi: 10.1056/NEJMoa1612674. Epub 2016 Dec 6.
PubMed 27959700Le Rhun E, Weller M, Brandsma D, Van den Bent M, de Azambuja E, Henriksson R, Boulanger T, Peters S, Watts C, Wick W, Wesseling P, Ruda R, Preusser M; EANO Executive Board and ESMO Guidelines Committee. EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with leptomeningeal metastasis from solid tumours. Ann Oncol. 2017 Jul 1;28(suppl_4):iv84-iv99. doi: 10.1093/annonc/mdx221. No abstract available.
PubMed 28881917Janne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, Ahn MJ, Kim SW, Su WC, Horn L, Haggstrom D, Felip E, Kim JH, Frewer P, Cantarini M, Brown KH, Dickinson PA, Ghiorghiu S, Ranson M. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015 Apr 30;372(18):1689-99. doi: 10.1056/NEJMoa1411817.
PubMed 25923549Jackman DM, Holmes AJ, Lindeman N, Wen PY, Kesari S, Borras AM, Bailey C, de Jong F, Janne PA, Johnson BE. Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinib. J Clin Oncol. 2006 Sep 20;24(27):4517-20. doi: 10.1200/JCO.2006.06.6126. No abstract available.
PubMed 16983123Iuchi T, Shingyoji M, Itakura M, Yokoi S, Moriya Y, Tamura H, Yoshida Y, Ashinuma H, Kawasaki K, Hasegawa Y, Sakaida T, Iizasa T. Frequency of brain metastases in non-small-cell lung cancer, and their association with epidermal growth factor receptor mutations. Int J Clin Oncol. 2015 Aug;20(4):674-9. doi: 10.1007/s10147-014-0760-9. Epub 2014 Oct 22.
PubMed 25336382Gow CH, Chien CR, Chang YL, Chiu YH, Kuo SH, Shih JY, Chang YC, Yu CJ, Yang CH, Yang PC. Radiotherapy in lung adenocarcinoma with brain metastases: effects of activating epidermal growth factor receptor mutations on clinical response. Clin Cancer Res. 2008 Jan 1;14(1):162-8. doi: 10.1158/1078-0432.CCR-07-1468.
PubMed 18172267Goss G, Tsai CM, Shepherd FA, Bazhenova L, Lee JS, Chang GC, Crino L, Satouchi M, Chu Q, Hida T, Han JY, Juan O, Dunphy F, Nishio M, Kang JH, Majem M, Mann H, Cantarini M, Ghiorghiu S, Mitsudomi T. Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2016 Dec;17(12):1643-1652. doi: 10.1016/S1470-2045(16)30508-3. Epub 2016 Oct 14.
PubMed 27751847Eichler AF, Kahle KT, Wang DL, Joshi VA, Willers H, Engelman JA, Lynch TJ, Sequist LV. EGFR mutation status and survival after diagnosis of brain metastasis in nonsmall cell lung cancer. Neuro Oncol. 2010 Nov;12(11):1193-9. doi: 10.1093/neuonc/noq076. Epub 2010 Jul 13.
PubMed 20627894Liao BC, Lee JH, Lin CC, Chen YF, Chang CH, Ho CC, Shih JY, Yu CJ, Yang JC. Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Non-Small-Cell Lung Cancer Patients with Leptomeningeal Carcinomatosis. J Thorac Oncol. 2015 Dec;10(12):1754-61. doi: 10.1097/JTO.0000000000000669.
PubMed 26334749
Study at a glance
From the registry record, last updated by the sponsor on 22 Jun 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Open-Label, Multicentre, Phase 1 Clinical Study to Evaluate the Safety and Efficacy of Zorifertinib Combined With Osimertinib in Patients With Advanced Non-Small Cell Lung Cancer With Meningeal Progression After Osimertinib Treatment
- ClinicalTrials.gov ID
- NCT07361705
- Acronym / sponsor ID
- AZD3759-005
- Keywords
- NSCLC, Leptomeningeal Metastases, Leptomeningeal Carcinomatosis, Meningeal Metastases, EGFR, Osimertinib, Zorifertinib
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 42 participants (estimated)
- Lead sponsor
- Alpha Biopharma (Jiangsu) Co., Ltd.Industry (pharma, biotech, devices)
- Study start
- 31 Jan 2026 (actual)
- Primary completion
- 23 Apr 2028 (estimated)
- Study completion
- 15 Sep 2028 (estimated)
- First posted
- 23 Jan 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is a clinical trial that aims to test Zorifertinib when used together with a known drug, Osimertinib. The goal is to learn if this combination is safe and works for people with advanced Non-Small Cell Lung Cancer (NSCLC) whose cancer has spread to the membranes surrounding the brain and spinal cord (a condition called leptomeningeal metastases) after being treated with Osimertinib.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Zorifertinib + Osimertinib (Dose Escalation) | Experimental | Drug: Zorifertinib and Osimertinib Combination TherapyAll enrolled participants will receive the investigational combination therapy of Zorifertinib and Osimertinib. This is a Phase 1 study consisting of a dose escalation part (Part A) and a dose expansion part (Part B). In Part A, Zorifertinib dose will be escalated (starting at 100 mg twice daily) alongside a fixed dose of Osimertinib (80 mg once daily) using a "3+3" design to determine the recommended dose. In Part B, additional participants will receive the combination at the recommended dose to further evaluate safety, efficacy, and pharmacokinetics. Treatment continues until disease progression, unacceptable toxicity, or meeting other discontinuation criteria. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (20 listed)
- For inclusion in the study, patients must meet all of the following criteria.
- The patient or the guardian is required to understand and sign the informed consent form of this study.
- During the screening period, subjects must have a previous histological or cytological diagnosis of NSCLC with a sensitising EGFR mutation (including L858R and/or Exon19Del).
- Only patients who have developed meningeal progression after osimertinib treatment (at a standard dose of 80 mg QD; if the dose is 160 mg QD, it must be reduced to 80 mg QD for at least 1 week before receiving study treatment) (new-onset meningeal progression, or patients with existing meningeal progression that is poorly controlled using osimertinib combined with available conventional treatment [CNS symptoms not relieved or CSF cytology not turning negative], but the available conventional treatment must be washed out for at least 4 weeks) and have no extracranial progression are allowed to be enrolled.
- Subjects with leptomeningeal metastases should have the positive results of cerebrospinal fluid (CSF) cytology. Subjects with negative CSF cytology but highly suspected of leptomeningeal metastases in combination with CSF biochemical test and brain or spinal cord MRI imaging examination are allowed to be enrolled into the study.
Key exclusion criteria (19 listed)
- Subjects who plan to receive brain radiotherapy or intrathecal injection during the period from signing ICF to study medication.
- Radiotherapy history within 28 days before study drug administration is not allowed for enrollment, and palliative radiation to the skeleton occurring within 14 days before study drug administration is also not allowed for enrollment.
- Subjects who have undergone major surgery (e.g. intrathoracic, intraperitoneal or pelvic surgery) within 4 weeks prior to the first dose of study treatment or who have not yet recovered from the side effects associated with such surgery are not allowed to be enrolled.
- In addition to NSCLC, there are other malignant tumors, or a history of other malignant tumors within 5 years, except for the following cases: Complete resection of skin basal cell and squamous cell carcinoma and radical resection of any type of carcinoma in situ.
- Suffering from clinically significant and uncontrollable cardiac disorder and/or heart-related events within 6 months, such as:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Zorifertinib and Osimertinib Combination TherapyAlso: AZD3759, AZD9291Zorifertinib is an oral tablet (50 mg or 100 mg). Osimertinib is an oral tablet (80 mg). In this Phase 1 study, all participants will receive the combination. Osimertinib is given at a fixed dose of 80 mg once daily. Zorifertinib is given twice daily, with dose levels under evaluation (starting at 100 mg BID, potentially escalating to 150 mg BID, 200 mg BID, or higher). Dose escalation follows a "3+3" design based on dose-limiting toxicity (DLT) assessment in the first 21-day cycle. Treatment continues until disease progression, unacceptable toxicity, or meeting other discontinuation criteria. | Drug | Zorifertinib + Osimertinib (Dose Escalation) |
Primary outcome
Determination of Recommended Dose Based on Incidence of Dose-Limiting Toxicities (DLTs)
Time frame: During the first 21 days of continuous administration for each participant in the dose-escalation phase.
A composite endpoint to determine the recommended dose of Zorifertinib in combination with Osimertinib. This is based on the occurrence of protocol-defined Dose-Limiting Toxicities (DLTs) within treatment. The Recommended Dose (RD) is the highest dose level at which the DLT rate is deemed acceptable by the Safety Review Committee (SRC) for further evaluation in the expansion cohort.
14 secondary outcomes
Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: From first dose until last dose (up to 12 months).
Objective Response Rate (ORR) for Leptomeningeal Metastases (per RANO-LM)
Time frame: From first dose until disease progression or death from any cause, assessed up to 12 months.
Leptomeningeal Progression-Free Survival (LM-PFS) (per RANO-LM)
Time frame: From first dose until leptomeningeal progression or death from any cause, assessed up to 12 months.
Leptomeningeal Progression-Free Survival (LM-PFS) Rate at 3, 6, and 9 Months
Time frame: Assessed at 3, 6, and 9 months from first dose.
Overall Survival (OS) Rate at 3, 6, and 9 Months
Time frame: Assessed at 3, 6, and 9 months from first dose.
Cerebrospinal Fluid (CSF) Cytological Response Rate
Time frame: CSF samples are collected at screening, at Week 6 (Day 22, corresponding to Cycle 2 Day 1 of a 21-day cycle), and every 6 weeks thereafter until disease progression, assessed up to 12 months.
Complete Response (CR) Rate Based on Neurological Examination
Time frame: Assessed at screening and at the end of every 21-day treatment cycle until disease progression, assessed up to 12 months.
Objective Response Rate (ORR) for Overall Tumors (per mRECIST 1.1)
Time frame: From first dose until disease progression or death from any cause, assessed up to 12 months.
Duration of Response (DoR) for Overall Tumors (per mRECIST 1.1)
Time frame: From first documented response until progression or death, assessed up to 12 months.
Progression-Free Survival (PFS) for Overall Tumors (per mRECIST 1.1)
Time frame: From first dose until overall progression or death, assessed up to 12 months.
Objective Response Rate (ORR) for Intracranial Tumors (per mRECIST 1.1)
Time frame: From first dose until intracranial disease progression or death from any cause, assessed up to 12 months.
Duration of Response (DoR) for Intracranial Tumors (per mRECIST 1.1)
Time frame: From first documented response until intracranial progression or death, assessed up to 12 months.
Change in Neurological Assessment in Neuro-Oncology (NANO) Score
Time frame: Assessed at screening, on Days 1, 8, 15 (Cycle 1), and at the end of each subsequent 21-day treatment cycle until the End of Treatment visit, assessed up to 12 months.
Progression-Free Survival (PFS) for Intracranial Tumors (per mRECIST 1.1)
Time frame: From first dose until intracranial progression or death, assessed up to 12 months.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Jun 2026.
- Results publication: PubMed 28673332Zhou Q, Song Y, Zhang X, Chen GY, Zhong DS, Yu Z, Yu P, Zhang YP, Chen JH, Hu Y, Feng GS, Song X, Shi Q, Yang LL, Zhang PH, Wu YL. A multicenter survey of first-line treatment patterns and gene aberration test status of patients with unresectable Stage IIIB/IV nonsquamous non-small cell lung cancer in China (CTONG 1506). BMC Cancer. 2017 Jul 3;17(1):462. doi: 10.1186/s12885-017-3451-x.
- Results publication: PubMed 31027690Yin 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.
- Results publicationYang JCH, Kim DW, Kim SW. Osimertinib activity in patients (pts) with leptomeningeal (LM) disease from non-small cell lung cancer (NSCLC): Updated results from BLOOM, a phase I study. [J]. Journal of Clinical Oncology, 2016, 34(15_suppl):9002-9002.
- Results publication: PubMed 29151359Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y, Cho EK, Voon PJ, Planchard D, Su WC, Gray JE, Lee SM, Hodge R, Marotti M, Rukazenkov Y, Ramalingam SS; FLAURA Investigators. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018 Jan 11;378(2):113-125. doi: 10.1056/NEJMoa1713137. Epub 2017 Nov 18.
- Results publication: PubMed 6699671Schag CC, Heinrich RL, Ganz PA. Karnofsky performance status revisited: reliability, validity, and guidelines. J Clin Oncol. 1984 Mar;2(3):187-93. doi: 10.1200/JCO.1984.2.3.187.
- Results publication: PubMed 15844174Omuro AM, Kris MG, Miller VA, Franceschi E, Shah N, Milton DT, Abrey LE. High incidence of disease recurrence in the brain and leptomeninges in patients with nonsmall cell lung carcinoma after response to gefitinib. Cancer. 2005 Jun 1;103(11):2344-8. doi: 10.1002/cncr.21033.
- Results publication: PubMed 27959700Mok TS, Wu Y-L, Ahn M-J, Garassino MC, Kim HR, Ramalingam SS, Shepherd FA, He Y, Akamatsu H, Theelen WS, Lee CK, Sebastian M, Templeton A, Mann H, Marotti M, Ghiorghiu S, Papadimitrakopoulou VA; AURA3 Investigators. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med. 2017 Feb 16;376(7):629-640. doi: 10.1056/NEJMoa1612674. Epub 2016 Dec 6.
- Results publication: PubMed 28881917Le Rhun E, Weller M, Brandsma D, Van den Bent M, de Azambuja E, Henriksson R, Boulanger T, Peters S, Watts C, Wick W, Wesseling P, Ruda R, Preusser M; EANO Executive Board and ESMO Guidelines Committee. EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with leptomeningeal metastasis from solid tumours. Ann Oncol. 2017 Jul 1;28(suppl_4):iv84-iv99. doi: 10.1093/annonc/mdx221. No abstract available.
- Results publication: PubMed 25923549Janne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, Ahn MJ, Kim SW, Su WC, Horn L, Haggstrom D, Felip E, Kim JH, Frewer P, Cantarini M, Brown KH, Dickinson PA, Ghiorghiu S, Ranson M. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015 Apr 30;372(18):1689-99. doi: 10.1056/NEJMoa1411817.
- Results publication: PubMed 16983123Jackman DM, Holmes AJ, Lindeman N, Wen PY, Kesari S, Borras AM, Bailey C, de Jong F, Janne PA, Johnson BE. Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinib. J Clin Oncol. 2006 Sep 20;24(27):4517-20. doi: 10.1200/JCO.2006.06.6126. No abstract available.
- Results publication: PubMed 25336382Iuchi T, Shingyoji M, Itakura M, Yokoi S, Moriya Y, Tamura H, Yoshida Y, Ashinuma H, Kawasaki K, Hasegawa Y, Sakaida T, Iizasa T. Frequency of brain metastases in non-small-cell lung cancer, and their association with epidermal growth factor receptor mutations. Int J Clin Oncol. 2015 Aug;20(4):674-9. doi: 10.1007/s10147-014-0760-9. Epub 2014 Oct 22.
- Results publication: PubMed 18172267Gow CH, Chien CR, Chang YL, Chiu YH, Kuo SH, Shih JY, Chang YC, Yu CJ, Yang CH, Yang PC. Radiotherapy in lung adenocarcinoma with brain metastases: effects of activating epidermal growth factor receptor mutations on clinical response. Clin Cancer Res. 2008 Jan 1;14(1):162-8. doi: 10.1158/1078-0432.CCR-07-1468.
- Individual participant dataSharing planned: No
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
5 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Zorifertinib and Osimertinib Combination Therapy in people with Patients With Advanced Non-small Cell Lung Cancer With Meningeal Progression After Osimertinib Treatment, run by Alpha Biopharma (Jiangsu) Co., Ltd. at 5 sites in China.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 20 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 22 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in China. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact John Ge, M.D (+86 (0)21-63862197, john.ge@alphabiopharma.com.cn), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Determination of Recommended Dose Based on Incidence of Dose-Limiting Toxicities (DLTs) (time frame: During the first 21 days of continuous administration for each participant in the dose-escalation phase.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07361705, which also lists 21 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Jun 2026.