Evaluate BL-B01D1 in Patients With Metastatic or Unresectable Non-Small Cell Lung Cancer (NSCLC) and Other Solid Tumors

Inclusion criteria:

1. Signed the informed consent voluntarily and agreed to follow the programrequirements

2. Either sex

3. Age: ≥18 years

4. Has a life expectancy of ≥3 months

5. Has histologically documented, incurable, locally advanced or metastatic epithelialorigin malignant cancer, priority to include the following tumor types: NSCLC, HER2

• breast cancer, esophageal cancer, SCLC, NPC, and HNSCC. Has documented locally advanced or metastatic HER2 negative (by immunohistochemistry [IHC], score of 0 or 1) Hormone Receptor (HR) positive (HER2-, HR+) OR HER2 negative (IHC score of 0 to 2) HR negative breast cancer (HER2-, HR-) as per ASCO CAPcriteria (ASCO CAP 2023; Wolff et al. 2023), not amenable to curative surgery orradiation with documentation of radiological disease progression while on/afterreceiving most recent treatment regimen for locally advanced or metastatic disease,must have received 1 prior line of chemotherapy for advanced disease and, whenapplicable and if approved in that region, a PD-1/PD-L1 inhibitor, either givenconcurrently or sequentially. When appropriate, must have progression on at least 1prior line of hormonal therapy with or without a targeted therapy (such as CDK4/6,mTOR, or PI3-K inhibitors) administered for treatment of metastatic disease. In Dose Escalation and Dose finding portions of the study, for triple-negativebreast cancer (TNBC, HER2-/HR-) participants must have received PARP inhibitors if aBRCA mutation is present and sacituzumab govitecan as second line treatment.Participants who are HER2 low must have received trastuzumab deruxtecan.

6. Agree to provide archived tumor samples (tissue block or slides) from primary ormetastatic sites within 2 years. In the event that no archival tissue is available afresh tissue biopsy is highly encouraged but not mandatory.

7. Has at least one measurable lesion based on RECIST V1.1 (with the exception ofProstate adenocarcinoma cohort, where subjects with bone metastasis are allowed)

8. Has an Eastern Cooperative Oncology Group performance status (ECOG PS) 0 to 1

9. Toxicity of previous antitumor therapy has returned to level ≤1 as defined byNCI-CTCAE V5.0 (except for asymptomatic laboratory abnormalities such as elevatedALP, hyperuricemia, elevated serum or plasma amylase/lipase, and elevated bloodglucose; except for toxicity that the investigator determined to have no safetyrisk, such as alopecia, grade 2 peripheral neurotoxicity, hypothyroidism stabilizedby hormone replacement therapy, etc.)

10. Has no serious cardiac dysfunction, left ventricular ejection fraction ≥50%

11. Has adequate organ function before registration, defined as: a) Marrow Function:Absolute neutrophil count (ANC) ≥1.2×109 /L, Platelet count ≥100×109 /L, Hemoglobin (Hb) ≥90 g/L b) Hepatic function: Total bilirubin（TBIL≤1.5 ULN, AST and ALT withoutliver metastasis ≤2.5 ULN, AST and ALT with liver metastasis ≤5.0 ULN c) Renalfunction: Creatinine clearance ≥50 mL/min (According to the Cockcroft and Gaultequation)

12. Coagulation function: international normalized ratio (INR) ≤1.5×ULN, and activatedpartial thromboplastin time (APTT) ≤1.5 ULN

13. Urinary protein ≤2+ or ≤1000mg/24 hours

14. Sexually active fertile subjects and their partners must agree to use highlyeffective methods of contraception during the course of the study and for 7 monthsfor females and 4 months for males after the last dose of study treatment. Anadditional contraceptive method, such as a barrier method like a condom is required.

15. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test atscreening and must be nonlactating. Female subjects are considered WOCBP unless oneof the following criteria are met: documented permanent sterilization (hysterectomy,bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausalstatus (defined as 12 months of amenorrhea in a woman >45 years old in the absenceof other biological or physiological causes. In addition, females <55 years old musthave a serum follicle stimulating hormone (fsh) level > 40 mIU/mL to confirmmenopause.

16. For subjects with NSCLC (EGFR mutation): a) Evidence of documented EGFR TKI-sensitizing deletion mutation in EGFR Exon 19 (ex19del) or leucin-arginine substitution point mutation in EGFR Exon 21 (ex21L858R), the serine-isoleucine mutation in EGFR Exon 20 (ex20S768I), theleucine-glutamine substitution mutation in Exon 21 (ex21L861Q), or the glycinesubstitution (with alanine, cysteine, or serine) mutation in Exon 18 (ex18G719X) ator after the time of disease diagnosis and prior to initiation of treatment.

17. For Triple-Negative Breast Cancer (TNBC, HER2-/HR-): a) Histologically or cytologically confirmed and documented locally advanced,recurrent inoperable or metastatic TNBC

18. For Esophageal adenocarcinoma a) Has locally advanced or metastatic adenocarcinoma cell carcinoma of the esophagusor esophagogastric junction cancers, not amenable to curative surgery or radiationwith documentation of radiological disease progression after one line offluoropyrimidine and/or platinum-based chemotherapy treatment regimen for locallyadvanced or metastatic disease. NOTE: Prior therapies such as trastuzumab, zolbetuximab, or IOs are allowed in thestudy.

19. For Prostate adenocarcinoma a) Subject has metastatic castration-resistant prostate cancer (mCRPC) afterprogression on/after an androgen receptor pathway inhibitors (ARPI) treatment, suchas abiraterone, enzalutamide, apalutamide and darolutamide. Note: No prior chemotherapy including docetaxel is allowed Prior treatment withlutetium Lu 177 vipivotide tetraxetan (Pluvicto) is allowed. Enrollment will becapped for lutetium Lu 177 vipivotide tetraxetan-naive participants at approximately 20 or participants with prior lutetium Lu 177 vipivotide tetraxetan treatment atapproximately 20.

20. For NSCLC (EGFR wild type) with squamous histology

21. Has documented locally advanced or metastatic NSCLC, not amenable to curativesurgery or radiation with documentation of radiological disease progressionwhile on/after receiving most recent treatment regimen for locally advanced ormetastatic disease with predominantly squamous cell histology

22. Must have documented negative test results for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). Must have no known genomicalterations in ROS proto-oncogene 1 (ROS1).

23. Progressed or intolerant to one line of platinum-based chemotherapy with α-PD-1/L1 monoclonal antibody given either concurrently or sequentially.

24. For NSCLC (EGFR wild type) with adenocarcinoma histology

25. Has documented locally advanced or metastatic NSCLC, not amenable to curativesurgery or radiation with documentation of radiological disease progressionwhile on/after receiving most recent treatment regimen for locally advanced ormetastatic disease with predominantly adenocarcinoma histology

26. Must have documented negative test results for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). Must have no known genomicalterations in ROS proto-oncogene 1 (ROS1). Progressed or intolerant to one line of platinum-based chemotherapy with α-PD-1/L1monoclonal antibody given either concurrently or sequentially.

27. Ovarian adenocarcinoma a) Has histologic documentation of epithelial ovarian, primary peritoneal, orfallopian tube cancer that has progressed or relapsed on or after a previousplatinum-containing chemotherapy with or without a PARP inhibitor. Note: participants with platinum-sensitive or platinum resistant recurrent ovariancancer (PSR) are eligible. However, enrollment will be capped for platinum-sensitiveor platinum resistant participants at approximately 20 each. Prior bevacizumab treatment is allowed.

28. Endometrial carcinoma a) Has relapsed, advanced and/or metastatic endometrial carcinoma, who haveprogressed on or after prior platinum-based chemotherapy with or withoutimmuno-oncology (IO) treatment

29. For Cervical carcinoma Has relapsed, advanced and/or metastatic cervical carcinoma,who have progressed on or after prior platinum-based chemotherapy with or withoutimmuno-oncology (IO) treatment

Exclusion criteria:

1. Chemotherapy, biological therapy, immunotherapy, radical radiotherapy, targetedtherapy (including small molecule inhibitor of tyrosine kinase), and otheranti-tumor therapy within 2 weeks or 5 half-lives (whichever is shorter) prior tothe first administration; major surgery within 4 weeks prior to the firstadministration; mitomycin and nitrosoureas treatment within 6 weeks prior to thefirst administration

2. Participants with history of severe heart disease, such as symptomatic congestiveheart failure (CHF) ≥ Grade 2 (CTCAE 5.0), New York Heart Association (NYHA) ≥ Grade 2 heart failure, history of transmural myocardial infarction, unstable anginapectoris etc;

3. Subjects with prolonged QT interval (QTc >470 msec), complete left bundle branchblock, Grade 3 atrioventricular block

4. Active autoimmune diseases and inflammatory diseases, such as: systemic lupuserythematosus, psoriasis requiring systemic treatment, rheumatoid arthritis,inflammatory bowel disease and Hashimoto's thyroiditis, etc., except for Type Idiabetes, hypothyroidism that can be controlled only by standard of care treatment,and skin diseases that do not require systemic treatment (such as vitiligo,psoriasis)

5. Other malignant tumors were diagnosed within 5 years prior to the firstadministration with the following exceptions: basal cell carcinoma of the skin,squamous cell carcinoma of the skin and/or carcinoma in situ after radical resection

6. Participants with poorly controlled hypertension by two kinds of antihypertensivedrugs (systolic blood pressure>150 mmHg or diastolic blood pressure>100 mmHg)

7. Participants have Grade 3 lung disease defined according to NCI-CTCAE v5.0, ahistory of interstitial lung disease (ILD)/ pneumonitis

8. Unstable thrombotic events such as deep vein thrombosis, arterial thrombosis, andpulmonary embolism requiring therapeutic intervention within the previous 6 monthsbefore screening; Infusion set-related thrombosis is excluded

9. Participants with primary tumors in the central nervous system (CNS) and active oruntreated CNS metastases and/or carcinomatous meningitis should be excluded.Participants with previously treated brain metastases may participate provided theyare clinically stable for at least 4 weeks and have no evidence of new or enlargingbrain metastases and no requirements for corticosteroids 14 days prior to dosingwith the investigational product (IP). Participants on low dose corticosteroids (<20mg prednisone or equivalent/day) may participate.

10. Participants who have a history of allergies to recombinant humanized antibodies orhuman-mouse chimeric antibodies or any of the components of BL-B01D1

11. Participants have a history of autologous or allogeneic stem cell transplantation (Allo-HSCT)

12. Has received treatment with anthracyclines with a cumulative dose exceeding 360mg/m2

13. Participants with ≥ Grade 2 hypokalemia (low concentration of potassium in theblood) according to CTCAE v5.0 (Grade 1: participant asymptomatic with potassiumlevels <LLN - 3.0 mmol/L or equivalent)

14. Known Human immunodeficiency virus antibody (HIVAb) positive, active tuberculosis,active Hepatitis B virus infection (HBV-DNA copy number> the lower limit ofdetection) or active Hepatitis C virus infection (HCV antibody positive and HCV-RNA > the lower limit of detection)

15. Participants with active infections requiring systemic treatment, such as severepneumonia, bacteremia, sepsis.

16. Received an investigational drug within 4 weeks, or two half-lives (whichever islonger) prior to first dose of study treatment

17. Participants who are pregnant or breastfeeding

18. Other conditions that the investigator believes may make the subject not suitablefor participating in this clinical trial.

19. Participants who have received prior therapy with any ADC targeting EGFR and/or HER3or containing a topoisomerase 1 inhibitor payload (all dose expansion cohorts withexception of TNBC noted below). Note: For TNBC dose expansion cohort, participants with prior ADC therapy targetingHER3 and EGFR or a topoisomerase I inhibitor, such as sacituzumab govitecan may beenrolled with Sponsor consultation prior to enrollment

20. For NSCLC EGFRmut:

21. Participants treated with more than two systemic chemotherapies prior torandomization.NOTE: Progression of disease within 12 months after receiving neoadjuvant andadjuvant chemotherapies is considered 1 prior systemic chemotherapy

22. Previously documented EGFR Exon 20 insertion mutations as primary EGFRmutations

23. For Triple-Negative Breast Cancer (TNBC, HER2-/HR-): a) Participants treated with more than two systemic chemotherapies prior torandomization. NOTE: Progression of disease within 12 months after receiving neoadjuvant andadjuvant chemotherapies is considered 1 prior systemic chemotherapy

24. For Esophageal Carcinoma a) Participants received more than 1 prior line of systemicchemotherapy therapy for locally advanced or metastatic disease. NOTE: this limitonly applies to prior systemic chemotherapy.

25. For Prostate adenocarcinoma: a) Prior treatment with systemic chemotherapy.

26. For NSCLC with EGFR WT squamous or adenocarcinoma histology: a) Participantsreceived more than 1 prior line of systemic chemotherapy for locally advanced ormetastatic disease

27. For Ovarian Carcinoma a) Participants received more than 1 prior line of systemicchemotherapy. Re-treatment with platinum-based chemotherapy is considered one lineof therapy. Prior hormonal therapy is permitted.

28. For Endometrial Carcinoma a) Participants received more than 1 prior line ofsystemic chemotherapy. Re-treatment with platinum-based chemotherapy is consideredone line of therapy. Prior hormonal therapy is permitted.

29. For Cervical Carcinoma a) if received more than 1 prior line of systemicchemotherapy. Re-treatment with platinum-based chemotherapy is considered one lineof therapy.

Notes: Re-treatment with platinum-based chemotherapy is considered one line of therapy.

Note: A participant who does not meet this exclusion criterion may be allowed into the study pending the sponsor's approval, based on current accrual within this dose expansion cohort.

Note: There is no limit on the number of prior lines of non-chemotherapy regimens. ADCs with cytotoxic payloads are considered a line of chemotherapy. For any expansion cohorts, if only limited number of patients can be enrolled with 1 prior line of chemotherapy, the Sponsor has the option to allow participants with more than 1 prior line of chemotherapy to be enrolled, upon Sponsor's approval.