An Open Label, Multicenter, Phase II Study of Dacomitinib for EGFR Mutated Non-Small Cell Lung Cancer (NSCLC) With Brain Metastases

Provision of a voluntarily given, personally signed and dated, written informed consent document;

Age≥18 years, male or female;

The presence of an EGFR activating mutation (exon 19 deletion or the L858R mutation in exon 21) in tumor specimen determined by the local laboratory. It is acceptable for subjects with the presence of the exon 20 T790M mutation together with either EGFR activating mutation (exon 19 deletion or the L858R mutation in exon 21) to be included in this study;

Evidence of newly diagnosed stage IIIB/IV (based on Union for International Cancer Control (UICC) staging system version 7) or recurrent (minimum of 12 months disease free interval between completion of systemic therapy and recurrence of NSCLC required) NSCLC of adenocarcinoma histo- and/or cytopathology or its pathologically accepted variants using tumor specimen (assessed according to accepted standards by a local laboratory). For this purpose the World Health Organization/International Association of Study of Lung Cancer Histologic Classification of Lung Cancer Criteria will be used and the diagnosis of NSCLC NOS (not otherwise specified), squamous or mixed adeno-squamous lung carcinomas will not be allowed;

Have an ECOG PS of 0 or 1;

No prior treatment with systemic therapy for locally advanced or metastatic NSCLC. Completed neoadjuvant/adjuvant chemotherapy/immunotherapy and/or combined modality chemotherapy/radiation therapy permitted only in cases in which there is a minimum of 12 months disease free interval between completion of systemic therapy and recurrence of NSCLC. Prior treatment with an EGFR-TKI or other TKIs is not allowed;

Brain metastases lesions should be more than or equal to 3 metastatic lesions in the brain . At least one target lesion's diameter among these lesions should be more than 1 centimeter（ Patients with CNS metastases. whose condition was neurologically stable were eligible. Any previous definitive treatment or glucocorticoid therapy had to be completed at least 2 weeks before initiation of the trial treatment.）.

Radiologically measurable disease by RECIST v1.1 criteria:

1. At least one target lesion that has not previously been radiated, and is measurable according to RECIST v1.1;

2. Acceptable radiologic procedures for disease assessment include contrast enhanced conventional or spiral computed tomography (CT), or contrast enhanced magnetic resonance imaging (MRI); Non contrast CT scan is acceptable only for subjects who are both allergic to intravenous contrast and unable to cooperate with MRI, or MRI is not available. The following are not allowed as sole documentation of target lesions: CT component of positron emission tomography (PET)/CT, ultrasound alone, nuclear scans (including bone or PET scans), chest X-ray or bone radiographs, and tumor markers;

Adequate organ function, including:

1. Estimated creatinine clearance \>30 mL/min (as determined by Cockcroft-Gault formula or the study site's standard formula);

2. Urinary protein \<3+ by urine dipstick. If urine protein by dipstick is ≥3+, then a urine protein/creatinine ratio (UPC) should be obtained. The subject may enter only if UPC is \<2.0;

3. Absolute neutrophil count (ANC) ≥1500 cells/mm3;

4. Platelets ≥100,000 cells/mm3;

5. Hemoglobin ≥10.0 g/dL；

6. Bilirubin≤1.5 x ULN;

7. AST (also known as SGOT) and ALT (also known as SGPT) \<2.5 x ULN (\<5.0 x ULN if hepatic metastases).

Female subjects must be postmenopausal (defined as 12 months of amenorrhea following last menses), or they or their partners must be surgically sterile, or must agree to use effective contraception while receiving study treatment and for at least 3 months thereafter. The definition of effective contraception will be based on the judgment of the investigator using following criteria:

Acceptable contraception for women include implants, injectables, combined oral contraceptives, intrauterine devices (IUDs), sexual abstinence, or a partner who has been surgically sterile (e.g. by vasectomy) for at least 6 months. Acceptable contraception for a male includes surgical sterility (e.g. by vasectomy) for at least 6 months, sexual abstinence, or condoms plus spermicide.

All female subjects with reproductive potential must have a negative pregnancy test (serum or urine) prior to starting study treatment;

Male subjects or their female partners must be surgically sterile or must agree to use effective contraception while receiving study treatment and for at least 3 months thereafter. The definition of effective contraception will be based on the judgment of the investigator. Or female partners must be postmenopausal (defined as 12 months of amenorrhea following last menses);

Willing and able to comply with study scheduled visits, treatment plans, laboratory tests, and other study procedures.

Other severe acute or chronic medical condition that may increase the risk associated with study participation or investigational drug administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study;

Use of narrow therapeutic index drugs that are CYP2D6 substrates (procainamide, pimozide, and thioridazine etc.) from screening to randomization.

What this study is about