REPotrectinib in ROS1-positive Non-small Cell Lung Cancer Patients With Active Brain mEtastasis

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 signedwritten 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, oropening).

4. Histologically documented NSCLC.

5. Patients may have symptoms attributed to brain metastases.

6. No indication for immediate local therapy (neurosurgery, brain radiotherapy) ofbrain metastases per local investigator. Note: in case of immediate local therapy is needed, the study's medical monitorshould be consulted.

7. Type II leptomeningeal disease per European Association of Neuro-Oncology (EANO) -European Society for Medical Oncology (ESMO) Clinical Practice Guidelines areallowed.

8. Patients with confirmed ROS1 rearrangement. Prior to study enrollment, patients musthave had confirmation of ROS1 rearrangement, which should have been determinedlocally by a certified laboratory using methods such as fluorescent in situhybridization (FISH), next generation sequencing (NGS), quantitative PCR (qPCR), orimmunohistochemistry (IHC).

9. Measurable disease according to RANO-BM criteria, with at least one measurable brainlesion 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 TKIregimens.

13. Patients must not have previously received any ROS1 TKI-based treatment.

14. Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram (ECHO) ormultigated acquisition (MUGA) scan.

15. If feasible, archival tumor biopsy sample at baseline (from primary tissue or anymetastatic site) should be provided.

16. Patient has adequate bone marrow, liver, and renal function: I. Hematological (without platelet, red blood cell transfusion, and/or granulocytecolony-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 inpatients with liver metastases or know history of Gilbert's disease); alkalinephosphatase (ALP) ≤ 2.5 times ULN; aspartate transaminase (AST) and alaninetransaminase (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 m2based on Cockcroft-Gault glomerular filtration rate estimation for patients withcreatinine levels above institutional normal.

17. Resolution of all acute toxic effects of prior anti-cancer therapy to grade ≤ 1 asdetermined by the US National Cancer Institute (NCI)-Common Terminology Criteria forAdverse Events (CTCAE) version 5.0 (v.5.0) (except for alopecia or other toxicitiesnot considered a safety risk for the patient at investigator's discretion).

18. Women of childbearing potential (WOCBP) who are sexually active with anon-sterilized male partner must have a negative serum pregnancy test within 14 daysbefore study treatment initiation. In addition, they must agree to use one highlyeffective method of birth control from the time of screening until 2 months afterthe last dose of study treatments. Female patients must refrain from egg celldonation and breastfeeding during this same period. Note: Due to a potential loss of effectiveness of hormonal contraceptives caused byinteraction with study intervention, if WOCBP use hormonal contraceptives (includingoral hormonal contraceptives), they must use either another form of non-hormonalhighly effective contraception or a reliable barrier method.

19. Male participants who are sexually active with a WOCBP partner must be surgicallysterile or using an acceptable method of contraception from the time of screeninguntil 4 months after the last administration of the study drug. Male participantsmust 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 theQRS 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 ofresting 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 arrhythmicevents such as heart failure, hypokalemia, congenital long QT syndrome, familyhistory of long QT syndrome, or any concomitant medication known to prolong the QTinterval.

4. Clinically significant cardiovascular disease (either active or within 6 monthsprior to enrollment): myocardial infarction, unstable angina, coronary/peripheralartery bypass graft, symptomatic congestive heart failure (New York HeartAssociation Classification Class ≥ II), cerebrovascular accident or transientischemic attack, symptomatic bradycardia, requirement for anti-arrhythmicmedication. Ongoing cardiac dysrhythmias of NCI CTCAE grade ≥ 2.

5. Known clinically significant active infections not controlled with systemictreatment (bacterial, fungal, viral including HIV positivity).

6. Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gutsyndrome) 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 4interstitial fibrosis or interstitial lung disease (ILD) including a history ofpneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, ILD, obliterativebronchiolitis, and pulmonary fibrosis. Patients with a history of prior radiationpneumonitis are not excluded.

9. Other severe acute or chronic medical or psychiatric condition or laboratoryabnormality that may increase the risk associated with study participation or studydrug administration, or that may interfere with the interpretation of study resultsand, in the judgment of the Investigator, would make the patient inappropriate forentry into this study or could compromise the protocol objectives in the opinion ofthe Investigator.

10. Presence or history of any other primary malignancy other than NSCLC within 5 yearsprior to enrollment into the study. Note: Patients with a history of adequately treated basal or squamous cell carcinomaof the skin or any adequately treated in situ carcinoma may be included in thestudy.

11. Current use or anticipated need for drugs that are known to be strong CytochromeP450, family 3, subfamily A (CYP3A) inhibitors or inducers. Note: midazolam requires diligent monitoring in situations where there is anunprecedented necessity for co-administration. These cases should be discussed withthe 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 otherimmunosuppressive medications except for managing adverse events (AEs); (inhaledsteroids 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.