A Phase I/IIa, Multicenter, Open-Label, First in Human Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of DB-1419 in Participants With Advanced/Metastatic Solid Tumors
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Study Summary
A Phase 1/2a First-in-Human Study of DB-1419 in Advanced/Metastatic Solid Tumors Dose escalation phase: Evaluate the safety and tolerability of DB-1419 and determine its MTD or RP2D. Dose expansion phase: 1. Evaluate the safety and tolerability of DB-1419 monotherapy in target participants; 2. Evaluate the effectiveness of DB-1419 monotherapy through investigator-assessed ORR. To assess the safety, tolerability, and anti-tumor activities of the study drug DB-1419 in participants with pretreated advanced/metastatic solid tumors unselected for B7H3/PD-L1 expression. To determine the maximum tolerated dose and/or the recommended phase 2 dose (RP2D). Approximately six ascending dose levels of DB-1419 (accelerated titration design for the first dose level and “3+3” design for other dose levels) will be administrated by intravenous infusion. When a dose level is confirmed to be safe by the Safety Monitoring Committee (SMC), backfill participants may be enrolled to further evaluate the safety, tolerability, preliminary efficacy, and PK characteristics. Phase 1b/2a (the dose expansion part) will initiate with selected indications (e.g., small cell lung cancer [SCLC], hepatocellular cancer, and non-small cell lung cancer) randomized to one of two different dose levels for dose optimization. Five other cohorts will enroll participants with melanoma, esophageal squamous cell carcinoma, triple-negative breast cancer, extensive-stage SCLC who have received 4 cycles of first-line induction therapy without disease progression, and other solid tumors to further assess the safety and tolerability, antitumor activity, and other exploratory endpoints of DB-1419.
- Adults aged ≥ 18 years at the time of voluntarily signing informed consent.
- Histologically or cytologically confirmed unresectable advanced/metastatic solid tumor that has relapsed or progressed on or after standard systemic treatments, or refused the standard treatment, or for which no standard treatment is available.
- At least one measurable lesion as assessed by the Investigator according to RECIST v1.1 criteria (Only applicable to backfill participants in phase 1a and participants in phase 1b/2a). CRPC participants with bone-only disease may be eligible on a case-by-case basis after discussion with the Medical Monitor.
- Has a life expectancy of ≥ 3 months.
- Has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1.
- Has LVEF ≥ 50% by either echocardiography (ECHO) or multiple-gated acquisition (MUGA) within 28 days before enrollment.
- Has adequate organ function within 7 days prior to the first dose of study treatment.
- Has adequate treatment washout period prior to the first dose of study treatment.
- Is willing to provide pre-existing resected tumor samples when available or undergo fresh tumor biopsy if feasible 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.
- Is capable of comprehending study procedures and risks outlined in the informed consent and able to provide written consent and agree to comply with the requirements of the study and the schedule of assessments.
- Male and female participants of reproductive/childbearing potential must agree to avoid pregnancy during the study and for at least 4 months and 7 months after the last dose of study treatment, respectively.
- Male participants must not freeze or donate sperm starting at screening and throughout the study period, and at least 4 months after the final study treatment administration. Female participants must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 7 months after the final study treatment administration
- Prior treatment with B7-H3 targeted therapy or prior treatment with ADC containing a topoisomerase I inhibitor payload.
- Has a medical history of symptomatic congestive heart failure (New York Heart Association [NYHA] classes II-IV or serious cardiac arrhythmia requiring treatment.
- Has a medical history of myocardial infarction or unstable angina within 6 months before enrollment.
- 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.
- Has a medical history of interstitial lung diseases (e.g., non-infectious interstitial pneumonia, pneumonitis, pulmonary fibrosis, and severe radiation pneumonitis which needs glucocorticoids and antibiotics) or current interstitial lung diseases or who are suspected to have these diseases by imaging at screening.
- 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.
- Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is allowed.
- Has an uncontrolled infection requiring intravenous injection of antibiotics, antivirals, or antifungals within 2 weeks before first dose of study treatment.
- Know human immunodeficiency virus (HIV) infection.
- Has active viral hepatitis.
- Is a lactating mother, or pregnant as confirmed by pregnancy tests performed within 7 days prior to enrollment.
- Has spinal cord compression or clinically active central nervous system (CNS) metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Participants with asymptomatic CNS metastases who are radiologically and neurologically stable for at least 4 weeks following CNS-directed therapy, and are on stable or decreasing doses of corticosteroids equivalent to ≤10 mg/day prednisone are eligible for study entry.
- Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to NCI-CTCAE v 5.0, Grade ≤ 1 or baseline.
- Has a prior history of immune-related adverse event that required permanent immune checkpoint inhibitor discontinuation per NCCN guidelines.
- NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
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Clinical Study Information for Healthcare Providers
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