Patients
Adult patients (≥18 years of age) with MET -dysregulated advanced
solid tumors refractory to currently available therapies or for which no
effective therapy was available were enrolled in this study.MET -dysregulation was defined as either MET amplification
(determined by fluorescence in situ hybridization or quantitative
polymerase chain reaction with a gene copy number ≥4) or METoverexpression (determined by MET immunohistochemistry intensity
score +3 in ≥50% of tumor cells) or MET mutation (leading to
exon 14 deletion). Other inclusion criteria included availability of at
least one measurable lesion as defined by the Response Evaluation
Criteria in Solid Tumors (RECIST) 1.1, an Eastern Cooperative Oncology
Group performance status (ECOG PS) ≤1, and an adequate organ function.
Prior to receiving capmatinib, patients must have recovered from any
previous anticancer treatment-related toxicities to Grade ≤1 of the
National Cancer Institute Common Terminology Criteria for Adverse Events
(NCI-CTCAE) version 4.03. However, patients with any grade of alopecia
were eligible.
Patients were excluded if they had known hypersensitivity to digoxin or
rosuvastatin or any of the excipients of capmatinib, digoxin or
rosuvastatin or have inadequate organ function. Patient receiving
following treatments were excluded: digoxin or rosuvastatin within 21
days prior to the beginning of the DDI phase (Day 1) and for the
duration of the DDI phase; strong or moderate in vivo inhibitors
and inducers of CYP3A4 that cannot be discontinued at least 1 week prior
to the start of treatment with capmatinib and for the duration of the
study; in vivo inhibitors or inducers of P-gp or BCRP within 30
days prior to starting study treatment, or during the DDI phase;
medicines with a known risk of prolonging the QT interval; unstable or
increasing doses of corticosteroids; proton pump inhibitors within 7
days prior to starting study treatment or during the DDI phase; thoracic
radiotherapy to lung fields ≤4 weeks prior to starting the capmatinib or
patients who did not recover from radiotherapy-related toxicities; major
surgery (except video-assisted thoracic surgery and mediastinoscopy)
within 4 weeks prior (2 weeks for resection of brain metastases) to
starting capmatinib or patients who did not recover from side-effects of
such procedure; homeopathic or naturopathic medicines (except vitamin
supplements) within 5 days prior to the days of blood sample collection
for pharmacokinetic assessment in the DDI phase (i.e., Day 5 to Day 10
and Day 17 to Day 32 of the DDI phase).
This clinical study was designed and implemented in accordance with the
principles of the Declaration of Helsinki and the Good Clinical Practice
guidelines of the International Council for Harmonization, with
applicable local regulations. The study protocol and all amendments were
reviewed by the independent ethics committee or institutional review
board for each center. All patients provided written informed consent
before screening.