Phase I Study of Repotrectinib and Osimertinib in NSCLC Patients

Inclusion Criteria:

1. Patients of age ≥18.
2. Histological or cytological confirmation of locally advanced or metastatic,non-squamous cell lung carcinoma (NSCLC) in patients who are not candidates for localcurative treatment through radical surgery and/or radiotherapy.
3. Stage IV, according to Tumor-nodes-metastasis (TNM) Version 8, including M1a (malignant effusion) or M1b (distant metastasis), or locally advanced disease forwhich there is no curative treatment (including patients who progress afterchemoradiotherapy in Stage III disease).
4. Patients must have been locally diagnosed with EGFR activating mutation (includingexon 18, exon 19, exon 21 and mutation T790M) based on FDA approved test (or a localequivalent laboratory developed) test (LDT)). Confirmatory central review will beperformed for all patients, in case of discrepancy on EGFR status, central review willprevail.
5. Eastern cooperative oncology group (ECOG) performance status 0-1.
6. Existence of measurable or evaluable disease (according to RECIST 1.1 criteria).
7. Patients with asymptomatic central nervous system (CNS) metastases (treated oruntreated) and/or asymptomatic leptomeningeal carcinomatosis are eligible to enroll ifthey satisfy the following criteria:

• Patients requiring steroids at a stable or decreasing dose (≤ 12 mg/daydexamethasone or equivalent) for at least 14 days are eligible. Patients onstable doses of levetiracetam (same dose for 14 days) are eligible to beenrolled.
• A minimum of 14 days must have elapsed from the completion of whole brainradiation treatment (WBRT) before the start of treatment with repotrectinib, andall side effects (with the exception of alopecia) from WBRT are resolved to CTCAEgrade ≤ 1.

8. Having available tumor tissue samples, via a biopsy or surgical resection of theprimary tumor or metastatic tumor tissue, within 60 days prior to the start oftreatment.
9. Life expectancy ≥12 weeks, as determined by a physician.
10. Adequate hematological function, defined as: absolute neutrophil count (ANC) >1.5 x 109/L, platelet count >100.0 x 109/L, and hemoglobin >9.0 g/dL (transfusion allowed atbaseline).
11. Adequate liver function, defined as: total bilirubin <1.5 x upper limit of normal (ULN), alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) <2.5 xULN.
12. Adequate renal function, defined as: calculated (Cockcroft-Gault formula) or measuredcreatinine clearance >50 mL/min and proteinuria <2+ (dipstick).
13. Ability to take part in all study procedures, per investigators.
14. Prior cytotoxic chemotherapy and prior immunotherapy (e.g., anti-PD-1, anti-programmeddeath ligand 1 (PDL1), anti-T cell immunoglobulin and mucin domain- containing protein 3 (TIM3), anti-OX40) for advanced or metastatic disease is allowed if:

• At the time of starting treatment with repotrectinib, at least 14 days or 5half-lives (whichever is shorter) must have elapsed after discontinuation ofprior therapy (or at least 42 days for prior nitrosoureas, mitomycin C, andliposomal doxorubicin).
• All side effects from prior treatments must have resolved to grade ≤ 1 (NCI CTCAEVersion 5.0) with the exception of alopecia or other side effects that theinvestigator does not consider to be a risk to patient safety.
• Patients with advanced solid tumors harboring ALK, ROS1, neurotrophic tyrosinekinase (NTRK) 1, 2, or 3 rearrangements are eligible if at the time of startingtreatment at least 14 days or 5 half-lives (whichever is shorter) have elapsedafter discontinuation of prior therapy.
• There is no limit to the number of prior chemotherapies, immunotherapy, or TKIregimens.

15. All women of childbearing potential (WOCBP), must agree to use highly effectivecontraception methods during the study treatment period and for at least 2 monthsafter the last dose of EGFR TKI. Male partners of female (WOCBP) patients agree to usecondoms during the study and for 2 months after the last dose. Male patients withfemale partners of WOCBP should use condom protection for 6 months in addition totheir female partner (WOCBP) using highly effective contraceptive methods for 4 monthsafter the last dose. Sexually active men, and women of childbearing potential, who areunwilling to use a contraception method are not eligible for the study.
16. Provision of written informed consent, signed and dated by the patient and theinvestigator, before any study interventions are performed.
17. Part B expansion cohorts only (after the RP2D has been identified):

• Disease progression following osimertinib with no evidence of tertiary EGFRmutation (i.e., C797S) or MET amplification.
• Disease progression following first or second generation EGFR TKI (for example,erlotinib,gefitinib, afatinib, dacomitinib) regardless of T790M status.

Exclusion Criteria:

1. Prior exposure to repotrectinib.
2. Diagnosis with any other lung cancer subtype apart from adenocarcinoma includingpatients with mixed NSCLC with predominantly squamous cell cancer, or with anysmall-cell lung cancer component, or a tertiary mutation.
3. Presence or history of any other primary malignancy other than NSCLC within 5 yearsprior to enrollment into the study.
4. Patients with a history of adequately treated basal or squamous cell carcinoma of theskin or any adequately treated in situ carcinoma may be included in the study.
5. Presence of only one measurable or evaluable tumor lesion that has already beenresected or irradiated prior to enrollment in the study.
6. Known presence of EGFR exon 20 insertion mutation based on most recent applicablemolecular testing.
7. Clinically significant cardiovascular disease (either active or within 6 months priorto enrollment): myocardial infarction, unstable angina, coronary/peripheral arterybypass graft, symptomatic congestive heart failure (New York Heart AssociationClassification Class ≥ II), cerebrovascular accident or transient ischemic attack,symptomatic bradycardia, requirement for anti-arrhythmic medication. Ongoing cardiacdysrhythmias of NCI CTCAE grade ≥2.
8. Any of the following cardiac criteria:

• 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 obtainedfrom 3 ECGs, using the screening clinic ECG machine-derived QTc value
• 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)
• 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 theQT interval

9. Known active infections requiring ongoing treatment (bacterial, fungal, viralincluding HIV positivity).
10. Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gutsyndrome) or other malabsorption syndromes that would impact on drug absorption.
11. Peripheral neuropathy ≥ grade 2.
12. History of extensive, disseminated, bilateral, or presence of CTCAE grade 3 or 4interstitial fibrosis or interstitial lung disease including a history of pneumonitis,hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease,obliterative bronchiolitis, and pulmonary fibrosis. Patients with a history of priorradiation pneumonitis are not excluded.
13. 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.
14. For Part B expansion cohorts only (after the RP2D has been identified), presence of atertiary EGFR mutation (i.e., GFR C797S) mutations and hepatocyte growth factorreceptor (MET) amplification.
15. Current use or anticipated need for drugs that are known to be strong Cytochrome P450,family 3, subfamily A (CYP3A) inhibitors or inducers.