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

Inclusion Criteria

• Males or females aged ≥ 18 years at time of signing informed consent form (ICF).
• Histological or cytological confirmed diagnosis of unresectable locally advanced or metastatic NSCLC.
• 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.
• 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.
• Presence of at least one measurable lesion according to RECIST v1.1 per investigator assessment.
• ECOG performance status of 0-1.
• Life expectancy ≥ 12 weeks.
• Adequate hematologic and organ function per protocol.
• 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.
• Signed ICF, and this must be obtained before the performance of any protocol-specific procedures.

Exclusion Criteria

• 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.
• Subjects with EGFR exon 20 insertion mutations only.
• Prior marketed and/or investigational treatment for EGFR C797S mutation (including, but not limited to BTP-661411, TQB3804 and BLU-945).
• 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.
• Is expected to require any other form of anti-tumor therapy while on study.
• Unresolved toxicity greater than CTCAE v5.0 Grade 1 from prior anti-tumor therapy.
• ≥ CTCAE v5.0 Grade 2 skin toxicity at screening.
• 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.
• Uncontrollable pleural effusion, ascites, or pericardial effusion.
• Subjects who have symptomatic brain metastases, meningeal metastasis or spinal cord compression.
• Subjects who have a chronic or active infection that required systemic treatment within 2 weeks prior to the first dose of H002.
• Subjects who have gastrointestinal disorders that will affect oral administration or the investigator judges that the absorption of H002 will be interfered.
• History of hypersensitivity to active or inactive excipients of H002 or drugs with a similar chemical structure or class to H002.
• Subjects who received a diagnosis of, and/or tested positive at screening for human immunodeficiency virus (HIV).
• Subjects with active hepatitis B.
• Presence or history of malignancy other than NSCLC with the exception of some certain early-stage cancers.
• 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.
• 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.
• Medical history of ILD.
• Medical history of severe eye disease without recovery to CTCAE v5.0 Grade 0 or 1.
• Severe gastrointestinal disease within 4 weeks prior to the first dose of H002 and did not recover to ≤ CTCAE v5.0 Grade 2.
• Has any bleeding tendency or coagulopathy within 6 months prior to the first dose of H002.
• Has known psychiatric disorders that would interfere with cooperation with the requirements of the trial or is still requiring for medication control.
• 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.
• Female subjects in pregnancy or lactation.
• 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.