An Exploratory Study Of Crizotinib Efficacy In Non-Small Cell Lung Cancer Patients With Anaplastic Lymphoma Kinase Translocation Determined By Different Molecular Diagnostic Methods
This is an exploratory non-randomized study in patients with locally advanced or metastatic
NSCLC. Patients who are eligible to apply for Extended Access Program of crizotinib must
have ALK translocation detected by RT-PCR, IHC or FISH analyses methods. Patients who
failed and progressed through at least one line of platinum containing chemotherapy and who
are older than 70 years old with failure of chemotherapy will be eligible for this study. We
will screen EML4-ALK fusion gene by RT-PCR (HotSart Taq Master Mix Kits, Qiaqen) from
patients' malignant pleural effusions and the detail was described in previous study. We
will also use IHC analyses (5A4 monoclonal antibody, Novocastra) to screen ALK protein
expression in patients' FFPE tumor sections. We will further do FISH analysis by using
commercial Vysis LSI ALK Dual Color, Break Apart Rearrangement Probe (2p23) (Abott Molecular
Inc., Des Plaines, IL) to detect ALK rearrangement in positive screening tumors. Samples are
deemed to be FISH-positive if more than 15% of 50 scored tumor cells had split ALK 5' and 3'
probe signals or had isolated 3' signals. Patients who have ALK rearrangement determined
in any of 3 molecular analyses methods and apply for crizotinib will receive 250mg of
crizotinib twice daily until disease progression, unacceptable toxicities or the withdrawal
of consent is noted.
Patients will be monitored carefully for the development of adverse experiences. Adverse
experiences will be evaluated according to criteria outlined in the National Cancer
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Patients
will also be monitored for clinical and/or radiographic evidence of disease progression
according to RECIST 1.1.
The primary endpoint of the study is overall response rate in patients with positive ALK
determined from different molecular analysis methods. The secondary endpoint included
overall response in specific subsets of patients, progression-free survival (PFS), and
overall survival (OS) at 1 year. PFS is defined as the time from day 1 of crizotinib to
disease progression or patient's death. OS was defined as the time from day 1 of crizotinib
treatment to patient's death.
During the treatment, patients will have safety measurements performed at specified time
points. Disease response will be assessed during the study by radiographic (e.g., CT or
MRI), and clinical (e.g., physical examination) evaluations, if applicable. Overall tumor
response will be assessed at the designated time points (every 12 weeks, using Response
Evaluation Criteria in Solid Tumors (RECIST, Version 1.1). The crizotinib treatment could be
continued after RECIST-defined disease progression if clinical benefit is still noted by
Time Perspective: Prospective
Overall response rate in patients with positive ALK determined from different molecular analysis methods.
It is defined as the time from day 1 of crizotinib to disease progression or patient's death.
James Chih-Hsin Yang, MD, PhD
National Taiwan University Hospital
Taiwan: Department of Health