The Efficacy and Safety of LMV-12 Combined With Osimertinib in NSCLC

Study Overview
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Brief Summary
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This is an open-label, single-arm, dose-escalation, multicenter phase I clinical trial. The primary endpoint of this study is to evaluated the safety, tolerability, pharmacokinetic profile and preliminary efficacy of HE003 in combination with osimertinib in patients with advanced solid tumors who have failed previous standard therapy.

Official Title
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A Prospective Clinical Research of Efficacy and Safety of LMV-12(HE003) Combined With Osimertini in the Treatment of Advanced Non-small Cell Lung Cancer That Has Previously Failed EGFR Inhibitor Therapy

Conditions
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Non Small Cell Lung Cancer

Intervention / Treatment
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* Drug: LMV-12(HE003) and Osimertinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eligible subjects selected for this study must meet all of the following criteria: Sign written informed consent before implementing any trial-related procedures; Age ≥18 years old; No limit on the gender; Histological or cytological confirmed advanced or metastatic non-small cell lung cancer, ineligible for radical surgery, relapse after failure of previous treatment with first-line (including first, second, and third generation)EGFR inhibitors. Cohort A：EGFR T790M negative, MET amplification,(IHC: ++ or +++) Cohort B：EGFR T790M negative, RET fusion. Laboratory tests for organ function levels must meet the following requirements: Absolute neutrophil count ≥ 1.5 × 109/L; Platelet count ≥ 100 × 109/L; Hemoglobin ≥ 9 g/dL; Bilirubin ≤1.5 times ULN; e) AST and ALT ≤2.5 times ULN (total bilirubin ≤3 times the upper limit of normal and AST and ALT ≤5 times the upper limit of normal are permitted if hepatic metastases are present); f) Serum creatinine ≤ 1.5 times ULN or creatinine clearance ≥ 60 mL/min (according to the Cockcroft-Gault formula); For premenopausal women of childbearing potential a pregnancy test must be performed within 7 days prior to initiation of treatment, a serum pregnancy test must be negative, and they must be non-lactating; all enrolled patients (whether male or female) should use adequate barrier contraception throughout the treatment period and for 3 months after completion of treatment. Exclusion Criteria: Subjects treated with CYP isozyme inducers or inhibitors (see Appendix 4 for details) within 3 weeks prior to enrollment; Pregnant or lactating women; History of immunodeficiency or other acquired, congenital immunodeficiency diseases; Patients with prior bone marrow transplantation or prior solid organ transplantation; Patients with a combination of gastrointestinal perforation, gastrointestinal fistula, or non-gastrointestinal fistula; Prior history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid therapy, or any evidence of clinically active interstitial lung disease. Hepatitis B, hepatitis C, or human immunodeficiency virus (HIV-positive). Hepatitis B is eligible for this study at <500 IU/mL (or 2500 cps/mL) by quantitative HBV-DNA testing, and hepatitis C (HCV) antibody-positive patients are eligible for this study only if the polymerase chain reaction shows HCV RNA negativity; Fulfillment of any of the following cardiac criteria: (i) Bazetts' mean corrected QT interval (QTc) derived from electrocardiogram (ECG) examination at rest >470 msec (women) or >450 msec (men) (in the case of the 1st abnormality, retested once within 48 h and calculated by averaging the results of the 2 times); and (ii) a wide variety of clinically significant rhythmic, conduction, and resting ECG morphologic Abnormalities, such as complete left bundle branch block, grade III conduction block, grade II conduction block, PR interval >250 msec; (iii) Myocardial ischemia or myocardial infarction of grade I or higher, or congestive heart failure of grade ≥2 (New York Heart Association (NYHA) classification); (iv) Factors that may increase the risk of prolongation of QTc or the risk of arrhythmic events, such as coronary artery disease, heart failure hypokalemia, congenital long QT syndrome, family history of a first-degree relative with long QT syndrome or sudden unexplained death before the age of 40, and ongoing use of any medication known to prolong the QT interval;

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| cohort A<br>Patients with MET amplication（IHC: MET++ or +++ ）and without EGFR T790 mutaion. | Drug: LMV-12(HE003) and Osimertinib<br>* 1 cycle was 28 days. LMV-12(HE003), 60mg, continuously for 21 days, and the drug was discontinued for 7 days. Osimertinib, 80mg, continuously for 28 days.<br>|
| cohort B<br>Patients with RET fusion and without EGFR T790 mutaion. | Drug: LMV-12(HE003) and Osimertinib<br>* 1 cycle was 28 days. LMV-12(HE003), 60mg, continuously for 21 days, and the drug was discontinued for 7 days. Osimertinib, 80mg, continuously for 28 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR | Defined as the proportion of subjects in complete remission (CR) and partial remission (PR) to the total subjects | 1 year | 
| PFS | Defined as the time from the beginning of treatment to the first imaging disease progression or death (whichever occurs first) | 1 year | 
| DOR | Defined as the time interval from the first record of disease remission to disease progression or death (whichever occurs first) | 1 year | 
| DCR | Defined as the proportion of subjects with complete remission (CR), partial remission (PR) and stable disease (SD) to the total subjects | 1 year | 
| OS | Defined as the time from the start of treatment to the death of the subject due to any cause. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Event | Number of participants experiencing clinical and laboratory adverse events (AEs) | 1 year |