A Phase 1/2a Study of DB-1311/BNT324 in Advanced/Metastatic Solid Tumors

Inclusion Criteria:

1. Male or female adults (defined as ≥ 18 years of age or acceptable age according tolocal regulations at the time of voluntarily signing of informed consent).

2. Histologically or cytologically confirmed unresectable advanced/metastatic solidtumor that has relapsed or progressed on or after standard systemic treatments, oris intolerable with standard treatment; or for which no standard treatment isavailable.

3. At least one measurable lesion as assessed by the investigator according to responseevaluation criteria in solid tumors (RECIST) version 1.1 criteria (measurabledisease as defined by RANO 2.0 criteria for GBM subjects). Castrate-resistantprostate cancer (CRPC) subjects with bone only disease may be eligible on a case-by-case basis after discussion with the Medical Monitor.

4. Has a life expectancy of ≥ 3 months.

5. Has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1.

6. Has LVEF ≥ 50% by either echocardiography (ECHO) or multiple-gated acquisition (MUGA) within 28 days before enrollment.

7. Has adequate organ function within 7 days prior to Day 1 of Cycle 1

8. Has adequate treatment washout period prior to Day 1 of Cycle 1

9. Is willing to provide pre-existing resected tumor samples or undergo fresh tumorbiopsy for the measurement of B7-H3 level and other biomarkers if nocontraindication. Note: there is no minimum B7-H3 expression level mandatory for entry into the study.

10. Is capable of comprehending study procedures and risks outlined in the informedconsent and able to provide written consent and agree to comply with therequirements of the study and the schedule of assessments.

11. Male and female subjects of reproductive/childbearing potential must agree to useadequate contraceptive methods (e.g., double barrier or intrauterine contraceptive)during the study and for at least 4 months and 7 months after the last dose of studydrug, respectively.

12. Male subjects must not freeze or donate sperm starting at screening and throughoutthe study period, and at least 4 months after the final study drug administration.

13. Female subjects must not donate, or retrieve for their own use, ova from the time ofscreening and throughout the study treatment period, and for at least 7 months afterthe final study drug administration.

14. SCLC subjects (Phase 2a Cohort 1 ONLY):

• Pathologically documented locally advanced, or metastatic SCLC not amenable tocurative surgery or radiation.

• Prior therapy with at least one platinum-based line as systemic therapy forextensive stage disease with at least two cycles of therapy (except in the caseof early objective PD).

• Prior treatment regimens with irinotecan, topotecan or any other TOP Iinhibitor including investigational TOP I inhibitors are not allowed.

15. NSCLC subjects (Phase 2a Cohort 2 ONLY):

• Pathologically documented locally advanced, or metastatic NSCLC and is notamenable to curative surgery or radiation.

• Has received prior treatment with platinum-based chemotherapy regimen and/oranti-PD-1/PD-L1 antibody-based regimen in the advanced/unresectable, ormetastatic setting unless unable or unwilling. Subjects with NSCLC known toharbor a genomic alteration(s) other than EGFR mutation(s) (e.g., ALKrearrangement, ROS1 rearrangement, KRAS G12C mutation, BRAF V600E mutation,NTRK1/2/3 Gene fusion, MET Exon 14 skipping, RET rearrangement etc.) for whichtreatment is available must have also received prior treatment with at least 1genotype-directed therapy.

16. ESCC subjects (Phase 2a Cohort 3 ONLY):

• Pathologically documented locally advanced, or metastatic ESCC and is notamenable to curative surgery or radiation.

• Having received at least one prior therapy for unresectable disease. Patientswith recurrence within 6 months of completion of neoadjuvant or adjuvanttherapy will be considered as having received one prior therapy forunresectable disease.

17. CRPC subjects (Phase 2a Cohort 4 ONLY):

• Pathologically documented metastatic adenocarcinoma of the prostate cancer.

• Progressive metastatic CRPC as defined: 1) castrate levels of serumtestosterone < 50 ng/dL AND 2) progressive disease as defined by PCWG3criteria.

• Having received prior docetaxel (before or after an AR-targeted therapy).Docetaxel rechallenge was allowed.

• Having received prior novel hormone therapy.

18. Melanoma subjects (Phase 2a Cohort 5 ONLY) • Histologically or cytologicallyconfirmed diagnosis of unresectable Stage III or metastatic melanoma not amenable tolocal therapy, must have had either:

> Previously treated with a PD-1 or PD-L1 inhibitor.

> If subjects with BRAF gene mutant melanoma, must have had a prior treatmentregimen that included vemurafenib, dabrafenib, or another BRAF gene and/ormitogen-activated protein kinase (MEK) protein inhibitor.

19. HCC subjects (Phase 2a Cohort 6 ONLY)

• Histological/cytological confirmed diagnosis of HCC or clinically confirmeddiagnosis of HCC as per American Association for the Study of Liver Diseases (AASLD) criteria (fibrolamellar HCC, sarcomatoid HCC, or mixedcholangiocarcinoma and HCC are not eligible), and:

• Has received 1 or 2 prior systemic therapy regimens for recurrent or metastaticdisease;

• Has experienced disease progression during or after treatment with ananti-PD-1/L1 agent administered either as monotherapy or in combination. Note: Subjects basically should receive prior standard therapy.

• However, if the investigator judges the therapy is not appropriate for thesubject, the prior standard therapy is not necessarily mandated for the eligibility.

• Has a Child-Pugh class A liver score within 7 days of first dose of study drug.

20. Cervical cancer subjects (Phase 2a Cohort 7 ONLY) • Has recurrent or metastaticcervical cancer with squamous cell, adenocarcinoma, or adenosquamous histology, and:

• Has experienced disease progression during or after treatment with a standard ofcare systemic chemotherapy doublet, or platinum-based therapy (if eligible), definedas either: d. paclitaxel + cisplatin + bevacizumab + anti-PD-(L)1 agent, or e.paclitaxel + carboplatin + bevacizumab + anti-PD-(L)1 agent, or f. paclitaxel +topotecan + bevacizumab + anti-PD-(L)1 agent Note: In cases where bevacizumab and/oranti-PD-(L)1 agent is not a standard of care therapy or the subject was ineligiblefor such treatment according to local standards, prior treatment with bevacizumaband/or anti-PD-(L)1 agent is not required.

• Has received 1 or 2 prior systemic therapy regimens for recurrent or metastaticcervical cancer. Chemotherapy administered in the adjuvant or neoadjuvant setting,or in combination with radiation therapy, should not be counted as a systemictherapy regimen. Single agent therapy with an anti-PD(L)1 agent for recurrent ormetastatic cervical cancer should be counted.

21. Subjects with other solid tumors (Phase 2a Cohort 8 ONLY) • Histologically orcytologically confirmed solid tumors. • Progressed or relapsed after at least oneprior standard therapeutic regimen (Patients who have not received all approved orstandard treatments for their cancer must be informed that these alternatives toreceiving DB-1311/BNT324 are available prior to consenting to participate in thistrial).

22. HNSCC subjects (Phase 2a Cohort 9 and Cohort 13)

• Histologically or cytologically confirmed refractory/metastatic (R/M) HNSCC (notincluding NPC) that is considered incurable by local therapies.

• Progressed on or after prior standard therapeutic regimen.

23. Subjects with rare tumors (Phase 2a Cohort 10 ONLY) Histologically or cytologicallyconfirmed rare tumor types. Progressed or relapsed after at least one prior standardtherapeutic regimen (Patients who have not received all approved or standardtreatments for their cancer must be informed that these alternatives to receivingDB-1311/BNT324 are available prior to consenting to participate in this trial).

24. Post lutetium-177 CRPC subjects (Phase 2a Cohort 11 ONLY): Pathologically documented metastatic adenocarcinoma of the prostate cancer.Progressive metastatic CRPC as defined: 1) castrate levels of serum testosterone < 50 ng/dL AND 2) progressive disease as defined by PCWG3 criteria.

25. Taxane-naive CRPC subjects (Phase 2a Cohort 12, 16, 17 ONLY)

• Pathologically documented metastatic adenocarcinoma of the prostate cancer.Progressive metastatic CRPC as defined: 1) castrate levels of serumtestosterone < 50 ng/dL AND 2) progressive disease as defined by PCWG3criteria. 26, PROC subjects (Phase 2a Cohort 14 ONLY)

• Subjects must have a confirmed diagnosis of OC, primary peritoneal cancer, orfallopian tube cancer, all of which with high-grade serous or endometrioidhistology..

• Subjects must have platinum-resistant disease:

• Received at least 1 but ≤ 3 lines of prior systemic anticancer therapy and haveradiographic progressed on or after their most recent line of therapy.

27. CSPC with suboptimal PSA response (Phase 2a Cohort 18 ONLY)

• Pathologically documented adenocarcinoma of the prostate cancer.

• Having advanced/unresectable, or metastatic disease and confirmed by imaging (e.g.,CT and/or bone scan).

• Having received ADT and enzalutamide or abiraterone for ≥4 months, with suboptimalPSA response.

28. Additional inclusion criteria for DDI cohort: has a study treatment expectancyof >= 2.5 months. Able to withhold CYP3A/P-gp/OATP1B inhibitors or substrates orCYP3A inducers as concomitant treatments for certain period.

Exclusion Criteria:

Unless otherwise specified, the exclusion criteria are common to both Phase 1 and Phase 2a. Subjects who meet any of the following criteria will be excluded from the study:

1. Prior treatment with B7-H3 targeted therapy.

2. Prior treatment with antibody drug conjugate with topoisomerase inhibitor (e.g.,trastuzumab deruxtecan).

3. Has a medical history of symptomatic congestive heart failure (CHF) (New York HeartAssociation [NYHA] classes II-IV) or serious cardiac arrhythmia requiring treatment.

4. Has a medical history of myocardial infarction or unstable angina within 6 monthsbefore enrollment.

5. Has an average of Fredericia's formula-QT corrected interval (QTcF) prolongation to > 470 millisecond (ms) in males and females based on a 12-lead electrocardiogram (ECG) in triplicate.

6. Use of concomitant medications known to prolong the QT interval. If the use isdeemed necessary, they should be administered with caution and closely monitoringthe QT interval, after discussed with the Sponsor.

7. Has a medical history of interstitial lung diseases (e.g., non-infectiousinterstitial pneumonia, pneumonitis, pulmonary fibrosis, and severe radiationpneumonitis) or current interstitial lung diseases or who are suspected to havethese diseases by imaging at screening.

8. Has a history of underlying pulmonary disorder including, but not limited to,pulmonary emboli within 3 months of the start of study treatment, severe asthma,severe COPD, restrictive lung disease, and other clinically significant pulmonarycompromise or requirement for supplemental oxygen.

9. Clinically significant gastrointestinal disorder including, but not limited to,history of gastrointestinal fistulation that need long-term intravenous nutrition;gastrointestinal dysfunction that need long-term enteral nutrition through the tubefeeding; gastrointestinal obstruction/perforation that not recovered within 6 monthsprior to the enrollment.

10. Untreated or incompletely treated esophageal and/or gastric varices with bleeding orhigh risk of bleeding; A prior bleeding event due to esophageal and/or gastricvarices within 6 months prior to initiation of study treatment (Only applicable toHCC patients).

11. Metastatic disease that involves major airways or blood vessels (e.g., patients withvascular invasion of the major portal vein and inferior vena cava).

12. Clinically uncontrolled pleural effusion, ascites or pericardial effusion requiringdrainage, peritoneal shunt or cell-free concentrated ascites reinfusion therapywithin 2 weeks prior to the enrollment.

13. Any autoimmune, connective tissue or inflammatory disorders (e.g., rheumatoidarthritis, Sjögren's, sarcoidosis) where there is documented, or a suspicion ofpulmonary involvement at the time of screening.

14. Has an uncontrolled infection requiring intravenous injection of antibiotics,antivirals, or antifungals.

15. Know human immunodeficiency virus (HIV) infection.

16. Subjects have active viral (any etiology) hepatitis are excluded. However, subjectswith serologic evidence of chronic hepatitis B virus (HBV) infection (defined by apositive hepatitis B surface antigen [HBsAg] test or a positive hepatitis B coreantibody test) who have a viral load below the limit quantification (e.g., HBV DNAtiter < 1000 cps/mL or 200 IU/mL) and are willing to and maintain antiviraltreatment if required, are eligible. However, subjects with a history of hepatitis Cvirus (HCV) infection who have completed curative antiviral treatment and have aviral load below the limit of quantification are eligible for study entry.

17. Is a lactating mother (women who are willing to temporarily interrupt breastfeedingwill also be excluded), or pregnant as confirmed by pregnancy tests performed within 7 days prior to enrollment.

18. Has spinal cord compression or clinically active central nervous system metastases,defined as untreated and symptomatic, or requiring therapy with corticosteroids oranticonvulsants to control associated symptoms. Subjects with clinically inactivebrain metastases may be included in the study. Subjects with treated brainmetastases that are no longer symptomatic and who require no treatment withcorticosteroids or anticonvulsants may be included in the study if they haverecovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks musthave elapsed between the end of whole brain radiotherapy and study randomization.

19. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to NCI-CTCAE version 5.0, grade ≤ 1 orbaseline. Subjects with chronic Grade 2 toxicities (e.g., Grade 2 neuropathy) may beeligible based on the discussion and agreement between Investigator and Sponsor.

20. Has multiple primary malignancies within 3 years before enrollment, exceptadequately resected non-melanoma skin cancer (e.g., resected basal or squamous cellskin cancer), curatively treated in-situ disease (e.g., carcinoma in situ of thecervix or breast), other solid tumors curatively treated (e.g., superficial bladdercancer), or contralateral breast cancer.

21. Has substance abuse or any other medical conditions that would increase the safetyrisk to the subject or interfere with participation or evaluation of the clinicalstudy in the opinion of the investigator.

22. Has known hypersensitivity to either the drug substances or inactive ingredients inthe drug product.

23. Patients with other reasons that, in the opinion of the Investigator, make themunsuitable to participate in this study.

24. Additional exclusion criteria for DDI cohort: Has a contraindication for receivinglopinavir, ritonavir or itraconazole according to the prescribing information is notable to take lopinavir, ritonavir or itraconazole by oral intake.