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Protocol NumberAZD3759-003
NCT Number(ClinicalTrials.gov Identfier)NCT03653546

2019-05-01 - 2022-12-31

Phase II/III

Recruiting4

ICD-10C34.90

Malignant neoplasm of unspecified part of unspecified bronchus or lung

ICD-10C34.91

Malignant neoplasm of unspecified part of right bronchus or lung

ICD-10C34.92

Malignant neoplasm of unspecified part of left bronchus or lung

ICD-10C7A.090

Malignant carcinoid tumor of the bronchus and lung

ICD-10Z51.12

Encounter for antineoplastic immunotherapy

ICD-9162.9

Malignant neoplasm of bronchus and lung, unspecified

A Randomized, Open-label, Controlled, Multi-Center Phase II/III Study to Assess the Efficacy and Safety of AZD3759 vs. a Standard of Care Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (Erlotinib or Gefitinib), as First Line Treatment in Patients with Epidermal Growth Factor Receptor Mutation Positive Advanced Non-Small Cell Lung Cancer with Central Nervous System Metastasis

  • Trial Applicant

    TAIWAN TIGERMED CONSULTING CO

  • Sponsor

    Alpha Biopharma (Jiangsu) Co. Limited

  • Trial scale

    Multi-Regional Multi-Center

  • Update

    2025/08/20

Investigators and Locations

Principal Investigator Shang-Yin Wu Division of General Internal Medicine
National Taiwan University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator Cheng-Ta Yang Division of Hematology & Oncology
Linkou Chang Gung Medical Foundation

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator TSUNG -YING YANG Division of Thoracic Medicine
Taichung Veterans General Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator James Chih-Hsin Yang Division of Hematology & Oncology
National Taiwan University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Condition/Disease

Advanced Non-Small Cell Lung Cancer with Central Nervous System Metastasis

Objectives

This is a Phase II/III randomized, open-label, multicenter study to compare the efficacy and safety of first line single-agent AZD3759 vs. Erlotinib or Gefitinib treatment in patients with advanced NSCLC with CNS metastases. Eligible patients with documented EGFR mutation+ (L858R and/or Exon 19Del) TKI-naïve advanced NSCLC and documented intracranial disease will be enrolled. Primary Objective: The primary objective of this study is to determine if administration of single agent AZD3759 compared to Standard of Care (SoC) EGFR-TKI as first-line therapy results in a significant increase in Progression Free Survival (PFS) in the study patient population by Blinded Independent Central Radiological(BICR) review. Secondary Objectives: Key secondary objective for this study is to determine if AZD3759 vs. SoC EGFR TKI administration demonstrates additional benefit in terms of safety, Objective Response Rate (ORR), Disease Control Rate (DCR), Duration of Response (DoR), and overall PFS using modified RECIST 1.1 criteria by investigator assessment. Additional secondary objectives include assessment of Health Related Quality of Life (HRQoL), neurological function, and Overall Survival (OS).

Test Drug

AZD3759

Active Ingredient

C22H23 ClFN5O3 .HCl

Dosage Form

Oral

Dosage

50mg, 100mg

Endpoints

Primary Outcome Measures :
PFS assessed by Blinded Independent Central Radiological [ Time Frame: 36 months ]
To assess if first line treatment with AZD3759 results in significant PFS efficacy compared to Gefitinib or Erlotinib as determined by Blinded Independent Central Radiological (BICR) review using RECIST 1.1.


Secondary Outcome Measures :
PFS assess by investigator [ Time Frame: 36 months ]
Investigator assessment of PFS using RECIST 1.1

Intracranial PFS (iPFS) assessed by investigator [ Time Frame: 36 months ]
Intracranial PFS (iPFS) assessed by investigator using RECIST 1.1

Intracranial PFS (iPFS) assessed by BICR [ Time Frame: 36 months ]
Intracranial PFS (iPFS) assessed by Blinded Independent Central Radiological (BICR) using RECIST 1.1

Extracranial PFS (ePFS) assessed by investigator [ Time Frame: 36 months ]
Extracranial PFS (ePFS) assessed by investigator using RECIST 1.1

Extracranial PFS (ePFS) assessed by BICR [ Time Frame: 36 months ]
Extracranial PFS (ePFS) assessed by Blinded Independent Central Radiological (BICR) using RECIST 1.1

Objective Response Rate (ORR） assessed by investigator using RECIST 1.1 [ Time Frame: 36 months ]
Objective Response Rate (ORR) for Intracranial lesions and Extracranial lesions assessed separately by investigator using RECIST 1.1

Disease Control Rate (DCR) assessed by investigator using RECIST 1.1 [ Time Frame: 36 months ]
Disease Control Rate (DCR) for Intracranial lesions and Extracranial lesions assessed separately by investigator using RECIST 1.1

Duration of Response (DoR) assessed by investigator using RECIST 1.1 [ Time Frame: 36 months ]
Duration of Response (DoR) for Intracranial lesions and Extracranial lesions assessed separately by investigator using RECIST 1.1

Overall ORR assessed by investigator using RECIST 1.1 [ Time Frame: 36 months ]
Overall ORR assessed by investigator using RECIST 1.1

Overall DCR assessed by investigator using RECIST 1.1 [ Time Frame: 36 months ]
Overall DCR assessed by investigator using RECIST 1.1

Overall DoR assessed by investigator using RECIST 1.1 [ Time Frame: 36 months ]
Overall DoR assessed by investigator using RECIST 1.1

ORR for Intracranial lesions assessed by investigator using RANO-BM [ Time Frame: 36 months ]
ORR for Intracranial lesions assessed by investigator using RANO-BM

DCR for Intracranial lesions assessed by investigator using RANO-BM [ Time Frame: 36 months ]
DCR for Intracranial lesions assessed by investigator using RANO-BM

DoR for Intracranial lesions assessed by investigator using RANO-BM [ Time Frame: 36 months ]
DoR for Intracranial lesions assessed by investigator using RANO-BM

Overall Survival [ Time Frame: 36 months ]
Overall Survival

Change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30). [ Time Frame: 36 months ]
The 30-items questionnaire measures cancer patients' functioning and symptoms. The scale range of EORTC QLQ-C30 is 30-126. Lower values represent a better outcome.

Change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire BN20 (EORTC QLQ-BN20). [ Time Frame: 36 months ]
The 20-items questionnaire was used among brain cancer patients. The scale range of EORTC BN20 is 20-80. Lower values represent a better outcome.

Neurological function improvement rate assessed by Mini-Mental Status Examination (MMSE) [ Time Frame: 36 months ]
Neurological function improvement rate assessed by Mini-Mental Status Examination (MMSE)

Neurological function improvement rate assessed by RANO-BM criteria [ Time Frame: 36 months ]
Neurological function improvement rate assessed by RANO-BM criteria

Number of participants with treatment-related Adverse Events as assessed by CTCAE v5.0 [ Time Frame: 36 months ]
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0

Number of participants with treatment-related Serious Adverse Events as assessed by CTCAE v5.0 [ Time Frame: 36 months ]
Number of participants with treatment-related Serious Adverse Events as assessed by CTCAE v5.0

Incidence of laboratory abnormalities collected by hematology tests during the study as assessed by CTCAE v5.0 [ Time Frame: 36 months ]
Incidence of laboratory abnormalities collected by hematology tests during the study as assessed by CTCAE v5.0

Incidence of laboratory abnormalities collected by biochemistry tests during the study as assessed by CTCAE v5.0 [ Time Frame: 36 months ]
Incidence of laboratory abnormalities collected by biochemistry tests during the study as assessed by CTCAE v5.0

Incidence of laboratory abnormalities collected byurinalysis tests during the study as assessed by CTCAE v5.0 [ Time Frame: 36 months ]
Incidence of laboratory abnormalities collected byurinalysis tests during the study as assessed by CTCAE v5.0

Rhythm, PR, R-R, QRS and QT intervals and an overall evaluation of ECG assessed during the study period. [ Time Frame: 36 months ]
Rhythm, PR, R-R, QRS and QT intervals and an overall evaluation of ECG assessed during the study period.

Systolic and Diastolic Blood Pressure assessed during the study period. [ Time Frame: 36 months ]
Systolic and Diastolic Blood Pressure assessed during the study period.

Pulse rate assessed during the study period. [ Time Frame: 36 months ]
Pulse rate to assessed during the study period.

Body temperature assessed during the study period. [ Time Frame: 36 months ]
Body temperature assessed during the study period.

PFS assess by BICR [ Time Frame: 36 months ]
Blinded Independent Central Radiological (BICR) assessment of PFS using modified RECIST 1.1.

Inclution Criteria

1. Properly completed patient informed consent
2. Male or female aged at least 18 years
3. Histologically or cytologically confirmed diagnosis of NSCLC with activating EGFR
mutations including L858R and/or Exon19Del. EGFR mutation status will be
determined by local or central laboratory testing on tumour tissue or plasma utilizing a
validated methodology which has been approved by the regulatory authority.
4. No prior treatment with chemotherapy, EGFR-TKIs, or biological therapies that are
considered first line treatment for advanced NSCLC.
5. All patients must have a documented diagnosis of advanced (Stage IV) NSCLC with
Magnetic Resonance Imaging (MRI) documented CNS metastases that include brain
metastases (BM). BM + patients with co-existent leptomeningeal involvement are
eligible for the study.
6. Eligible patients are not candidates for definitive surgical resection or radiation of all
lesions in the opinion of the treating physician.
7. All patients must be stable without any systemic (oral or parenteral) corticosteroid or
anticonvulsant therapy for at least 2 weeks prior to study treatment. Inhaled nonabsorbable and topical corticosteroid use are permitted as indicated.
8. Patients may have prior placement of a properly functioning CNS shunt or Ommaya
reservoir.
9. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 with no
deterioration over the previous 2 weeks.
10. Women of child-bearing potential and male subjects shall agree to take medically
acceptable contraception measures while on study treatment and for 3 months following
completion of study treatment. All women of child-bearing potential must have a
negative blood pregnancy test at screening.
11. 1) For Patients with measurable CNS lesions must have AT LEAST ONE site of CNS
lesion, which was not previously irradiated, that can be accurately measured at baseline
as ≥ 10 mm in the longest diameter by MRI and which is suitable for accurate repeated
measurements. Measurable extracranial disease is not required.
2) For Patients with non-measurable CNS lesions must have AT LEAST ONE
extracranial lesion, which has not been previously irradiated, within the screening period
that can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except
lymph nodes which must have short axis ≥ 15 mm) by CT/MRI and are suitable for
accurate repeated measurement.

Exclusion Criteria

1. Prior treatment with an EGFR-TKI.
2. Positive for T790M mutation documented by central or local laboratory using an
approved or validated methodology of testing.
3. Patients receiving any investigational drug, biological, immunological therapy within
the previous 21 days for their malignancy.
4. Any major surgical procedure (excluding the need for placement of vascular access or a
CNS shunt), or significant traumatic injury within 4 weeks of the first dose of study
treatment, or have an anticipated need for major surgery during the study.
5. Documented presence of leptomeningeal (LM) disease only by absence of documented
BM by MRI and/or positive CSF cytology for malignant cells.
6. Prior radiation therapy for CNS metastases that involves measurable or non-measurable
sites of disease to assess efficacy
7. Patients receiving radiation to more than 30% of the bone marrow must be completed 2
weeks before the first dose of study treatment.
8. Patients currently receiving (or unable to stop use at least 1 week prior to receiving the
first dose of study drugs) medications or herbal supplements that are known to be potent
inhibitors or inducers of CYP3A4/5 (Appendix G).
9. Prior gastric resection or surgical procedure that would interfere with absorption of
study medications.
10. History of concurrent and/or other active malignancy requiring treatment within 5 years
of study treatment, excluding prior treated squamous cell or basal carcinomas or
carcinoma in situ.
11. History of any type of documented interstitial lung disease or radiation pneumonitis.
12. Presence of any severe or uncontrolled systemic disease or condition, including: (i)
uncontrolled hypertension or diabetes; (ii) serious cardiac, pulmonary or renal
conditions; (iii) active bleeding diatheses; (iv) any active type of bacterial, viral, fungal
or other infection that would pose a significant risk to the patient in the opinion of the
investigator; or (v) active Hepatitis B or positive HCV antibodies or positive HIV test
result.
13. Women who are pregnant or lactating. Women of child-bearing potential (WOCBP),
and fertile men with a WOCBP-partner not using adequate birth control.
14. Patients with unstable and/or symptomatic metastases: any CNS or distant metastases
that are unstable are symptomatic and not controlled by prior surgery, radiotherapy or
corticosteroids to control symptoms for a period of within 3 weeks of initiation study
treatment.
15. Any unresolved toxicities from prior therapy, greater than Common Terminology
Criteria for Adverse Events (CTCAE) grade 1 at the time of starting study treatment,
with exception of alopecia. Patients are having undergone any major surgical procedure
within 4 weeks prior to first study drug administration.
16. Patients with a significant cardiovascular disease or condition, including any of the
following:
a. Congestive heart failure (CHF) currently requiring therapy and patients with New
York Heart Associate Class III/IV CHF (see Appendix M)
b. Need for antiarrhythmic medical therapy for a ventricular arrhythmia or patients
with uncontrolled or unstable cardiac arrhythmias
c. Severe conduction disturbance (e.g., second- or third-degree AV block)
d. Angina pectoris requiring therapy
e. QTc interval > 450 msec (males) or > 470 msec (females)
f. History of congenital long QT syndrome, congenital short QT syndrome, Torsades
de Pointes, or Wolff Parkinson White syndrome
g. LVEF < 50% as determined by echocardiography or MUGA scan
h. Myocardial infarction diagnosed within the last 6 months.
17. Inadequate bone marrow reserve or organ function as demonstrated by any of the
following laboratory values:
a. Absolute neutrophil count < 1.5 x 109
/L
b. Platelet count < 100 x 109
/L (Transfusion-dependent patients are excluded)
c. Haemoglobin < 90 g/L
d. Alanine aminotransferase > 2.5 times the upper limit of normal (ULN) if no
demonstrable liver metastases or > 5 times ULN in the presence of liver metastases
e. Aspartate aminotransferase > 2.5 times ULN if no demonstrable liver metastases
or > 5 times ULN in the presence of liver metastases
f. Total bilirubin > 1.5 times ULN. Total bilirubin >3 times the ULN in patients with
documented Gilbert’s Syndrome (unconjugated hyperbilirubinemia) or in the
presence of liver metastases
g. Creatinine >1.5 times ULN concurrent with creatinine clearance < 50 mL/min
(measured or calculated by Cockcroft and Gault equation). Confirmation of
creatinine clearance is only required when creatinine is >1.5 times ULN;
h. If bone metastases are present and liver function is otherwise considered adequate
by the investigator, then isolated elevated alkaline phosphatase (ALP) will not
exclude the patient;
18. History of hypersensitivity to active or inactive excipients of study drugs or drugs with
a similar chemical structure or class to study drugs.
19. Judgment by the investigator that the patient should not participate in the study if the
patient is unlikely to comply with all study procedures and treatment.
20. History of recent stroke (< 6 months), or prior CNS injury that has persistent
neurologic deficits that would confound neurologic assessments.
21. Significant medical or psychiatric illness that would interfere with compliance and
ability to tolerate treatment as outlined in the protocol.
In addition, the following are considered criteria for exclusion from the exploratory
genetic research:
22. Previous allogeneic bone marrow transplant.
23. Non-leukocyte depleted whole blood transfusion within 120 days of the date of the
genetic sample collection.

The Estimated Number of Participants

  • Taiwan

    28 participants

  • Global

    432 participants

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