Phase I/IIa Study of H002 in NSCLC With Active EGFR Mutation

This is a phase I/IIa, open-label, dose-escalation and expansion study to evaluate the safety, tolerability, PK and preliminary anti-tumor activity of H002 when given orally in patients with active EGFR mutation locally advanced or metastatic non-small cell lung cancer (NSCLC).

The study will contain two parts: Part A is dose escalation phase (i.e., Phase I) and Part B is dose expansion phase (i.e., Phase IIa).

Part A (Dose Escalation Phase) Approximately 36 subjects will be enrolled, based on the "3+3" design for dose escalation and safety evaluation requirements. The total number of subjects will depend upon the number of dose escalations necessary.

Part B (Dose Expansion Phase) Up to 20 subjects will be enrolled in each expansion arm, the total number of subjects will depend upon the number of dose expansions (expansions may be at more than one dose depending upon emerging data).

Eligibility Criteria:
Inclusion Criteria:

1. Males or females aged ≥ 18 years at time of signing informed consent form (ICF).
2. Histological or cytological confirmed diagnosis of unresectable locally advanced or metastatic NSCLC.
3. Subjects must have NSCLC harboring one or more active EGFR mutations known to be associated with EGFR-TKI sensitivity (including, but not limited to Del19 and L858R).

   * Part A: All subjects may provide tumor sample to central laboratory to analyze the EGFR mutation status according to their own willingness;
   * Part B: All subjects must provide tumor sample to central laboratory to analyze the EGFR mutation status. And subjects must have NSCLC harboring EGFR C797S mutation.

   Note: Tumor sample can be either an archival sample or a sample obtained by pretreatment biopsy prior to H002 treatment.
4. Subjects must have radiological documented disease progression while on a previous continuous treatment with osimertinib or another third-generation EGFR-TKI as well as disease progression on the last treatment administered prior to enrolling in the study.
5. Presence of at least one measurable lesion according to RECIST v1.1 per investigator assessment.
6. ECOG performance status of 0-1.
7. Life expectancy ≥ 12 weeks.
8. Adequate hematologic and organ function per protocol.
9. Women of childbearing potential (WOCBP) and fertile males with WOCBP partners must use highly effective contraception per protocol throughout the study. WOCBP must have a negative serum and/or urine pregnancy test result within 7 days prior to the first dose of H002.
10. Signed ICF, and this must be obtained before the performance of any protocol-specific procedures.

Exclusion Criteria:

1. Treatment with any of the following:

   Prior treatment with an EGFR-TKI within 8 days or approximately 5 × t1/2 prior to the first dose of H002, whichever is longer; Prior treatment with immunotherapy or biotherapy within 4 weeks prior to the first dose of H002; Radiotherapy (palliative radiotherapy is completed at least 2 weeks prior to the first dose of H002 can be enrolled) within 4 weeks prior to the first dose of H002; Herbal therapy that has anti-tumor effects within 2 weeks prior to the first dose of H002; Mitomycin and nitrosourea within 6 weeks prior to the first dose of H002; Oral fluorouracil such as tegafur and capecitabine within 2 weeks prior to the first dose of H002; Chemotherapy (except for mitomycin, nitrosourea, and fluorouracil oral drugs), or other anti-tumor drugs for the treatment of NSCLC within 4 weeks or approximately 5 × t1/2 prior to the first dose of H002, whichever is longer.
2. Subjects with EGFR exon 20 insertion mutations only.
3. Prior marketed and/or investigational treatment for EGFR C797S mutation (including, but not limited to BTP-661411, TQB3804 and BLU-945).
4. Is currently participating and receiving investigational therapy or using an investigational device, or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks or 5 × t1/2 of the investigational product, whichever is longer, prior to the first dose of H002.
5. Is expected to require any other form of anti-tumor therapy while on study.
6. Unresolved toxicity greater than CTCAE v5.0 Grade 1 from prior anti-tumor therapy.
7. ≥ CTCAE v5.0 Grade 2 skin toxicity at screening.
8. Treatment with strong inhibitors, strong inducers and sensitive substrates of CYP3A4, substrates and inhibitors for P-glycoprotein (P-gp), as well as substrates for breast cancer resistance protein (BCRP) within 2 weeks prior to the first dose of H002, or anticipation of need for such drugs during study treatment.
9. Uncontrollable pleural effusion, ascites, or pericardial effusion.
10. Subjects who have symptomatic brain metastases, meningeal metastasis or spinal cord compression.
11. Subjects who have a chronic or active infection that required systemic treatment within 2 weeks prior to the first dose of H002.
12. Subjects who have gastrointestinal disorders that will affect oral administration or the investigator judges that the absorption of H002 will be interfered.
13. History of hypersensitivity to active or inactive excipients of H002 or drugs with a similar chemical structure or class to H002.
14. Subjects who received a diagnosis of, and/or tested positive at screening for human immunodeficiency virus (HIV).
15. Subjects with active hepatitis B.
16. Presence or history of malignancy other than NSCLC with the exception of some certain early-stage cancers.
17. Subjects who have clinically significant cardiovascular diseases that occurred within 6 months prior to the first dose of H002, include but not limited to QTc interval ≥ 470 msec.
18. Major surgery or significant traumatic injury occurring within 4 weeks prior to the first dose of H002 or anticipation of need for a major surgery during the study.
19. Medical history of ILD.
20. Medical history of severe eye disease without recovery to CTCAE v5.0 Grade 0 or 1.
21. Severe gastrointestinal disease within 4 weeks prior to the first dose of H002 and did not recover to ≤ CTCAE v5.0 Grade 2.
22. Has any bleeding tendency or coagulopathy within 6 months prior to the first dose of H002.
23. Has known psychiatric disorders that would interfere with cooperation with the requirements of the trial or is still requiring for medication control.
24. Administration of a live, attenuated vaccine within 4 weeks prior to the first dose of H002 or anticipation of need for such a vaccine during the study. Administration of an mRNA Corona Virus Disease 2019 (COVID-19) vaccine within 72 hours prior to the first dose of H002.
25. Female subjects in pregnancy or lactation.
26. Any other circumstances that would, in the investigator's judgment, prevent the subject's participation in the clinical study due to safety concerns or compliance with clinical study procedures.