Inclusion Criteria:
Patients will be included in the study only if they meet all the following criteria:
1. Patient must be capable to understand the purpose of the study and have signed written
informed consent form (ICF) prior to beginning specific protocol procedures.
2. Female or male patients ≥ 18 years of age at the time of signing ICF.
3. Patients must be capable to swallow capsules intact (without chewing, crushing, or
opening).
4. Histologically documented NSCLC.
5. Patients may have symptoms attributed to brain metastases.
6. No indication for immediate local therapy (neurosurgery, brain radiotherapy) of brain
metastases per local investigator.
Note: in case of immediate local therapy is needed, the study's medical monitor should
be consulted.
7. Type II leptomeningeal disease per European Association of Neuro-Oncology (EANO)
- -
European Society for Medical Oncology (ESMO) Clinical Practice Guidelines are allowed.
8. Patients with confirmed ROS1 rearrangement. Prior to study enrollment, patients must
have had confirmation of ROS1 rearrangement, which should have been determined locally
by a certified laboratory using methods such as fluorescent in situ hybridization
(FISH), next generation sequencing (NGS), quantitative PCR (qPCR), or
immunohistochemistry (IHC).
9. Measurable disease according to RANO-BM criteria, with at least one measurable brain
lesion of ≥10 mm on T1-weighted, gadolinium-enhanced magnetic resonance imaging (MRI).
10. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
11. Minimum life expectancy of ≥ 6 weeks at screening.
12. No limit in number of prior chemotherapies, immunotherapy or other non-ROS1 TKI
regimens.
13. Patients must not have previously received any ROS1 TKI-based treatment.
14. Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram (ECHO) or multigated
acquisition (MUGA) scan.
15. If feasible, archival tumor biopsy sample at baseline (from primary tissue or any
metastatic site) should be provided.
16. Patient has adequate bone marrow, liver, and renal function:
- I. Hematological (without platelet, red blood cell transfusion, and/or granulocyte
colony-stimulating factor support within 7 days before first study treatment dose):
White blood cell (WBC) count > 3.0 x 109/L, absolute neutrophil count (ANC) ≥ 1.5 x
109/L, platelet count ≥ 100.0 x109/L, and hemoglobin ≥ 8.0 g/dL (≥ 4.96 mmol/L).
- II. Hepatic: Total bilirubin ≤ 1.5 times upper limit of normal (ULN) (≤ 3 in patients
with liver metastases or know history of Gilbert's disease); alkaline phosphatase
(ALP) ≤ 2.5 times ULN; aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3
times ULN (≤ 5 in patients with liver metastases); international normalized ratio
(INR) < 1.5.
- III. Renal: serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 40 mL/min/1.73 m2
based on Cockcroft-Gault glomerular filtration rate estimation for patients with
creatinine levels above institutional normal.
17. Resolution of all acute toxic effects of prior anti-cancer therapy to grade ≤ 1 as
determined by the US National Cancer Institute (NCI)-Common Terminology Criteria for
Adverse Events (CTCAE) version 5.0 (v.5.0) (except for alopecia or other toxicities
not considered a safety risk for the patient at investigator's discretion).
18. Women of childbearing potential (WOCBP) who are sexually active with a non-sterilized
male partner must have a negative serum pregnancy test within 14 days before study
treatment initiation. In addition, they must agree to use one highly effective method
of birth control from the time of screening until 2 months after the last dose of
study treatments. Female patients must refrain from egg cell donation and
breastfeeding during this same period.
Note: Due to a potential loss of effectiveness of hormonal contraceptives caused by
interaction with study intervention, if WOCBP use hormonal contraceptives (including
oral hormonal contraceptives), they must use either another form of non-hormonal
highly effective contraception or a reliable barrier method.
19. Male participants who are sexually active with a WOCBP partner must be surgically
sterile or using an acceptable method of contraception from the time of screening
until 4 months after the last administration of the study drug. Male participants must
not donate or bank sperm during this same period.
20. Patient must be accessible for treatment and follow-up.
Exclusion Criteria:
Any patient meeting ANY of the following criteria will be excluded from the study:
1. Major surgery within four weeks of the start of treatment.
2. Type I leptomeningeal disease per ESMO-EANO guidelines.
3. Any of the following cardiac criteria:
- I. Mean resting corrected QT interval (ECG interval measured from the onset of the QRS
complex to the end of the T wave) for heart rate (QTc) > 470 msec obtained from 3
ECGs, using the screening clinic ECG machine-derived QTc value.
- II. Any clinically important abnormalities in rhythm, conduction or morphology of
resting ECG (e.g., complete left bundle branch block, third degree heart block, second
degree heart block, PR interval > 250 msec).
- III. Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events such as heart failure, hypokalemia, congenital long QT syndrome, family history
of long QT syndrome, or any concomitant medication known to prolong the QT interval.
4. Clinically significant cardiovascular disease (either active or within 6 months prior
to enrollment): myocardial infarction, unstable angina, coronary/peripheral artery
bypass graft, symptomatic congestive heart failure (New York Heart Association
Classification Class ≥ II), cerebrovascular accident or transient ischemic attack,
symptomatic bradycardia, requirement for anti-arrhythmic medication. Ongoing cardiac
dysrhythmias of NCI CTCAE grade ≥ 2.
5. Known clinically significant active infections not controlled with systemic treatment
(bacterial, fungal, viral including HIV positivity).
6. Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut
syndrome) or other malabsorption syndromes that would impact on drug absorption.
7. Peripheral neuropathy grade ≥ 2.
8. History of extensive, disseminated, bilateral, or presence of NCI CTCAE grade 3 or 4
interstitial fibrosis or interstitial lung disease (ILD) including a history of
pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, ILD, obliterative
bronchiolitis, and pulmonary fibrosis. Patients with a history of prior radiation
pneumonitis are not excluded.
9. Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or study
drug administration, or that may interfere with the interpretation of study results
and, in the judgment of the Investigator, would make the patient inappropriate for
entry into this study or could compromise the protocol objectives in the opinion of
the Investigator.
10. Presence or history of any other primary malignancy other than NSCLC within 5 years
prior to enrollment into the study.
Note: Patients with a history of adequately treated basal or squamous cell carcinoma
of the skin or any adequately treated in situ carcinoma may be included in the study.
11. Current use or anticipated need for drugs that are known to be strong Cytochrome P450,
family 3, subfamily A (CYP3A) inhibitors or inducers.
Note: midazolam requires diligent monitoring in situations where there is an
unprecedented necessity for co-administration. These cases should be discussed with
the study's medical monitor.
12. Patients requiring concomitant use of chronic systemic (intravenously [IV] or oral)
corticosteroids at doses higher than 8 mg dexamethasone per day or other
immunosuppressive medications except for managing adverse events (AEs); (inhaled
steroids or intra articular steroid injections are permitted in this study).
Note: The use of stable corticosteroid therapy in patients with brain metastases should be
discussed with the Sponsor's Medical Monitor.
