DB-1311-O-1001 : A Phase 1/2a, Multicenter, Open-Label, First in Human Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of DB-1311 in Subjects with Advanced/Metastatic Solid Tumors

The purpose of this research is to assess the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of DB-1311 in Subjects with Advanced/Metastatic Solid Tumors.

The purpose of this research study is to test the safety and possible harms of DB-1311 study drug
when it is given to people at different dose levels. The researchers want to find out what effects
(good and bad) DB-1311 study drug has on you or people with Advanced/Metastatic Solid Tumors.

Inova Schar Cancer
8081 Innovation Park Drive
Fairfax, VA 22031

1. Male or female adults (defined as ≥ 18 years of age or acceptable age according to local regulations at the time of voluntarily signing of informed consent).
2. Histologically or cytologically confirmed unresectable advanced/metastatic solid tumor that has relapsed or progressed on or after standard systemic treatments, or is intolerable with standard treatment; or for which no standard treatment is available.
3. At least one measurable lesion as assessed by the investigator according to response evaluation criteria in solid tumors (RECIST) version 1.1 criteria. Castrate-resistant prostate cancer (CRPC) participants with bone only disease may be eligible on a case-by- case basis after discussion with the Medical Monitor.
4. Has LVEF ≥ 50% by either echocardiography (ECHO) or multiple-gated acquisition (MUGA) within 28 days before enrollment.

5. Is willing to provide pre-existing resected tumor samples or undergo fresh tumor biopsy for the measurement of B7-H3 level and other biomarkers if no contraindication.

   Note: there is no minimum B7-H3 expression level mandatory for entry into the study.

6. SCLC participants (Phase 2a Cohort 1 ONLY):
   • Pathologically documented locally advanced, or metastatic SCLC not amenable to curative surgery or radiation.
   • Relapsed/progressed on or after 2 cycles of platinum-based chemotherapy in combination with/without anti-PD-1/anti-PD-L1 monoclonal antibody or intolerant to completion of 2 cycles of platinum-based chemotherapy due to the toxicity for locally advanced or metastatic disease.
7. NSCLC participants (Phase 2a Cohort 2 ONLY):
   • Pathologically documented locally advanced, or metastatic NSCLC and is not amenable to curative surgery or radiation.
   • Has received prior treatment with platinum-based chemotherapy regimen and/or anti-PD-1/PD-L1 antibody-based regimen in the advanced/unresectable, or metastatic setting unless unable or unwilling. Participants with NSCLC known to harbor a genomic alteration(s) other than EGFR mutation(s) (e.g., ALK rearrangement, ROS1 rearrangement, KRAS G12C mutation, BRAF V600E mutation, NTRK1/2/3 Gene fusion, MET Exon 14 skipping, RET rearrangement etc.) for which treatment is available must have also received prior treatment with at least 1 genotype-directed therapy.
8. ESCC participants (Phase 2a Cohort 3 ONLY):
   • Pathologically documented locally advanced, or metastatic ESCC and is not amenable to curative surgery or radiation.
   • Having received at least one prior therapy for unresectable disease. Patients with recurrence within 6 months of completion of neoadjuvant or adjuvant therapy will be considered as having received one prior therapy for unresectable disease.
9. CRPC participants (Phase 2a Cohort 4 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.
   • Having received prior docetaxel (before or after an AR-targeted therapy). Docetaxel rechallenge was allowed.
   • Having received prior novel hormone therapy.

10. Melanoma participants (Phase 2a Cohort 5 ONLY)

    • Histologically or cytologically confirmed diagnosis of unresectable Stage III or metastatic melanoma not amenable to local therapy, must have had either:

    • Previously treated with a PD-1 or PD-L1 inhibitor.
    • If participants with BRAF gene mutant melanoma, must have had a prior treatment regimen that included vemurafenib, dabrafenib, or another BRAF gene and/or mitogen-activated protein kinase (MEK) protein inhibitor.
11. Participants with other solid tumors (Phase 2a Cohort 6 ONLY)
    • Histologically or cytologically confirmed solid tumors.
    • Progressed or relapsed after at least one prior standard therapeutic regimen (Patients who have not received all approved or standard treatments for their cancer must be informed that these alternatives to receiving DB-1311 are available prior to consenting to participate in this trial).

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 Heart Association [NYHA] classes II-IV) or serious cardiac arrhythmia requiring treatment.
4. Has a medical history of myocardial infarction or unstable angina within 6 months before 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. Has a medical history of interstitial lung diseases (e.g., non-infectious interstitial pneumonia, pneumonitis, pulmonary fibrosis, and severe radiation pneumonitis) or current interstitial lung diseases or who are suspected to have these diseases by imaging at screening.
7. 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 pulmonary compromise or requirement for supplemental oxygen.
8. Any autoimmune, connective tissue or inflammatory disorders (e.g., rheumatoid arthritis, Sjögren's, sarcoidosis) where there is documented, or a suspicion of pulmonary involvement at the time of screening.
9. Know human immunodeficiency virus (HIV) infection.
10. Subjects have active viral (any etiology) hepatitis are excluded. However, subjects with a history of hepatitis C virus (HCV) infection who have completed curative antiviral treatment and have a viral load below the limit of quantification are eligible for study entry.
11. Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Subjects with clinically inactive brain metastases may be included in the study. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study randomization.
12. Has multiple primary malignancies within 3 years before enrollment, except adequately resected non-melanoma skin cancer (e.g., resected basal or squamous cell skin cancer), curatively treated in-situ disease (e.g., carcinoma in situ of the cervix or breast), other solid tumors curatively treated (e.g., superficial bladder cancer), or contralateral breast cancer.