Prospective registration

A Phase I Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetic Characteristics, and Preliminary Anti-tumor Efficacy of HJ-004-02 Tablets in Patients with Advanced Non-squamous Non-small Cell Lung Cancer with Epidermal Growth Factor Receptor (EGFR) Mutations

A Phase I Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetic Characteristics, and Preliminary Anti-tumor Efficacy of HJ-004-02 Tablets in Patients with Advanced Non-squamous Non-small Cell Lung Cancer with Epidermal Growth Factor Receptor (EGFR) Mutations

Bo Ning 

Caicun Zhou 

6th Floor, Renzi Building, Shanghaitech University, No. 1 Zhongke Road, Pudong New Area, Shanghai

No. 1800, Yuntai Road, Pudong New Area, Shanghai

Jing Medicine Technology (Shanghai) Co., Ltd.

Shanghai East Hospital

Yes

Shanghai East Hospital Drug/Medical Device Clinical Trial Ethics Committee

Siwei Bao

No. 1800, Yuntai Road, Pudong New Area, Shanghai

Shanghai East Hospital

No. 1800, Yuntai Road, Pudong New Area, Shanghai

Jing Medicine Technology (Shanghai) Co., Ltd.

EGFR mutation-positive locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC)

Interventional study

1

Single arm 

Primary Objective:To evaluate the safety and tolerability of HJ-004-02 tablets and to determine the maximum tolerated dose (MTD) or the recommended Phase II dose (RP2D).

Male or female, aged >=18 years and <75 years at the time of signing the informed consent form (ICF). A signed ICF must be obtained before any protocol-specified procedures are performed. 2. Histologically or cytologically confirmed unresectable locally advanced or metastatic non-squamous NSCLC. 3. Subjects must have experienced disease progression after standard therapy, or be intolerant to or unsuitable for standard therapy, or have no available standard therapy. 4. Subjects must provide 3-5 archived tumor tissue slides and/or paracentesis tumor tissue and/or pathological tissue specimens from within 2 years. If older than 2 years, the Sponsor will determine eligibility. If disease progression has occurred after the last EGFR-TKI treatment, 3-5 archived tumor tissue slides and/or paracentesis tumor tissue and/or pathological tissue specimens from after the end of treatment and within 1 year must be provided. If older than 1 year, the Sponsor will determine eligibility for IHC testing. Subjects must be willing to consider collection of peripheral blood for ctDNA testing during the study, if the investigator deems it safe and feasible. 5. Subjects must have non-squamous NSCLC with one or more positive EGFR mutations, including but not limited to EGFR L858R, Del19, T790M, C797S, Exon20 ins (V769/D770) mutations, and rare mutations (S768I, L861Q, G719A, E709V, L747P, etc.). Note: Subjects with EGFR L858R/ T790M or Del19/ T790M double mutations are excluded from Phase Ib. 6. At least one measurable lesion according to RECIST v1.1 (In Phase Ia, lesions that are assessable but not measurable are acceptable). Note: For lesions previously treated with radiotherapy, they can only be considered measurable lesions if disease progression at that site has been clearly documented after radiotherapy. 7. ECOG performance status score of 0-1 (see Appendix 1: ECOG Performance Status Scale). 8. Life expectancy >=12 weeks. 9. Adequate hematologic and organ function, and no hematopoietic growth factors, blood transfusions, or platelet (PLT) therapy within 2 weeks before sampling for laboratory tests. (1) Hematologic Function:Absolute neutrophil count (ANC) >= 1.5×10^9/L;Platelet count (PLT) >= 100×10^9/L;Hemoglobin (HGB) >=9.0 g/dL; (2)Hepatic Function:Total bilirubin (TBIL) <=1.5 × upper limit of normal (ULN) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) For those without liver metastases, <=2.5 × ULN, orFor those with liver metastases, <=5 × ULN; (3)Renal Function:Creatinine <=1.5 × ULN; if >1.5 × ULN, creatinine clearance ≥50 mL/min [Creatinine clearance calculated using the Cockcroft-Gault formula (see Appendix 2: Cockcroft-Gault Formula)] (4)Coagulation Panel Note: For subjects receiving anticoagulant therapy, the investigator will determine whether the international normalized ratio (INR) and activated partial thromboplastin time (APTT) are within a safe therapeutic range. INR <= 1.5×ULN;APTT <= 1.5×ULN. 10. Women of childbearing potential (WOCBP) and male subjects of reproductive potential with a WOCBP partner must use highly effective contraception throughout the study (from signing the ICF until 6 months after the last dose of HJ-004-02 tablets, see Appendix 3: Contraceptive Measures, Definitions, and Requirements for Women of Childbearing Potential) and are prohibited from donating sperm or eggs. WOCBP must have a negative serum pregnancy test result within 7 days before the first dose of HJ-004-02 tablets.

1.Have received any of the following treatments: (1) Have received EGFR-TKI therapy within 8 days before the first dose of HJ-004-02 tablets, including but not limited to osimertinib, afatinib, gefitinib, or erlotinib; (2) Have received immunotherapy or biological therapy within 4 weeks before the first dose of HJ-004-02 tablets; (3) Have received radiotherapy within 4 weeks before the first dose of HJ-004-02 tablets (Note: Subjects who have completed palliative radiation at least 2 weeks before the first dose of HJ-004-02 tablets may be enrolled); (4) Have received herbal or traditional Chinese medicine treatment with anti-tumor indications within 2 weeks before the first dose of HJ-004-02 tablets; (5) Have received chemotherapy or other anti-tumor drug therapy within 4 weeks before the first dose of HJ-004-02 tablets; (6) Prior treatment with other PROTAC drugs targeting EGFR mutations. 2. Participation in an investigational drug study with treatment or use of an investigational device within 4 weeks before the first dose of HJ-004-02 tablets. 3. Anticipated need for any other form of anti-tumor therapy during the study. 4. Toxicity from prior therapy has not resolved to <=Grade 1 according to NCI-CTCAE v5.0 criteria, with the exception of alopecia and long-term stable chronic disease. 5. Presence of histological transformation, and ALK, HER2, KRAS, ROS1, FGFR, NTRK, RET, BRAF gene abnormalities in EGFR-TKI non-dependent drug resistance; 6. History of severe eye disorder prior to the first dose of HJ-004-02 tablets, or subjects with an eye disorder > Grade 1 (CTCAE v5.0) prior to the first dose of HJ-004-02 tablets. 7. History of severe dermatosis prior to the first dose of HJ-004-02 tablets, or subjects with dermatosis > Grade 1 (CTCAE v5.0) prior to the first dose of HJ-004-02 tablets, or adverse reactions from prior anti-tumor therapy have not resolved to <=Grade 1 (CTCAE v5.0) (except for toxicities deemed by the investigator to pose no safety risk, such as alopecia, ≤Grade 2 peripheral neurotoxicity, stable hypothyroidism after hormone replacement therapy, etc.). 8. Subjects with gastrointestinal diseases that, in the investigator's judgment, may affect oral administration or interfere with the absorption of HJ-004-02 tablets; or subjects with severe gastrointestinal diseases (e.g., refractory diarrhoea, refractory vomiting, colitis, etc.) within 4 weeks before the first dose of HJ-004-02 tablets that have not resolved to <=Grade 2 (CTCAE v5.0). 9. Subjects who have received treatment with P-gp inhibitors, potent CYP3A4 inhibitors or inducers within 2 weeks before the first dose of HJ-004-02 tablets, or who are expected to require such drugs during the study treatment. 10. Subjects with uncontrolled pleural effusion, ascites, or pericardial effusion requiring repeated drainage procedures, as judged by the investigator. 11. Subjects with symptomatic brain metastasis, metastases to meninges, or spinal cord compression. Subjects who have received prior treatment for brain metastasis but are asymptomatic and stable at enrollment, and do not require corticosteroid therapy or are receiving <=4 mg/day of dexamethasone (or equivalent dose) within 4 weeks before the first dose of HJ-004-02 tablets, may be enrolled. 12. Subjects with an active infection of >=Grade 2 requiring systemic intravenous antibiotic therapy within 2 weeks before the first dose of HJ-004-02 tablets. 13. Subjects with a history of allergy to the active ingredient or inactive excipients of HJ-004-02 tablets, or to drugs with a similar chemical structure or class to HJ-004-02 tablets. 14. Subjects with a confirmed immunodeficiency disease, and/or a positive HIV test result at screening. 15. Subjects with active hepatitis B [defined as positive hepatitis B surface antigen (HBsAg) and HBV-DNA >= the lower limit of detection specified by the study site] or active hepatitis C [defined as positive anti-HCV antibody and HCV-RNA >= the lower limit of detection specified by the study site]. 16. Subjects with positive syphilis antibodies and a positive titer test (when the treponemal antibody test is positive, a non-treponemal antibody test is required). 17. Active tuberculosis. 18. Presence of a malignancy other than the indication of this study within <=5 years before the first dose of HJ-004-02 tablets (except for those with no known active disease within 3 years before the first dose and a very low potential risk of recurrence), but not including early-stage cancers (carcinoma in situ or Stage I), basal cell carcinoma of the skin, squamous cell carcinoma of skin, cervical carcinoma in situ, low-risk prostate cancer (Gleason grading score <7 and prostate-specific antigen <10 ng/mL), or breast cancer in situ, provided these cancers have been curatively treated and require no further therapy. 19. Subjects who have had a clinically significant cerebrovascular disorder within 6 months before the first dose of HJ-004-02 tablets, including but not limited to: (1)Two-dimensional echocardiogram showing a left ventricular ejection fraction (LVEF) <50%; (2)Acute myocardial infarction; (3)Severe/angina unstable; (4)History of arterial thromboembolism, including but not limited to cerebrovascular accident, etc.; (5)Cardiac failure congestive [New York Heart Association (NYHA) >Class II, see Appendix 4: New York Heart Association (NYHA) Functional Classification]; (6)Any clinically significant resting ECG rhythm, conduction, or morphological abnormalities, complete left bundle branch block, third-degree heart block, second-degree heart block, PR interval >250 ms; (7)Mean resting QTc interval >=470 ms obtained from 3 ECGs (corrected using the Fridericia formula, see Appendix 5: Formulas for Calculating QTcF and RR); (8)Any factors that increase the risk of QTc interval prolongation or arrhythmic events, such as hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death in a first-degree relative under 40 years of age, or any concomitant medication known to prolong the QT interval; (9)Hypertension that cannot be controlled by antihypertensive drugs (systolic blood pressure >160 mmHg and/or diastolic blood pressure >100 mmHg). (10)Other cerebrovascular disorders that the investigator considers unsuitable for enrollment. 20. Subjects who have undergone major surgery or severe traumatic injury within 4 weeks before the first dose of HJ-004-02 tablets, or who are expected to require major surgery during the study. 21. History of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis requiring steroid therapy, or any evidence of clinically active ILD. 22. Subjects with any haemorrhagic diathesis or coagulopathy within 6 months before the first dose of HJ-004-02 tablets. 23. Subjects with a known psychiatric illness that may interfere with study compliance or still requires drug therapy for control. 24. Those who have received a live attenuated vaccine within 28 days before the first dose of the investigational product or plan to receive one during the study and within 60 days after the end of investigational product treatment. 25. Female subjects who are pregnant or breastfeeding. 26. Any other condition that, in the investigator's judgment, would hinder the subject's participation in the clinical study (for safety reasons) or interfere with compliance with clinical study procedures (e.g., difficulty with intravenous blood collection). Any severe, acute, or chronic medical or psychiatric illness or laboratory abnormality that may increase the risk associated with trial participation or investigational product use, or may interfere with the interpretation of study results, and in the investigator's judgment would make the subject unsuitable for participation in this study.

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CRF;EDC