First-in-human Study of DB-1305 for Advanced/Metastatic Solid Tumors

Study Overview
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Brief Summary
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This is a dose-escalation and dose-expansion Phase 1/2a trial to evaluate the safety and tolerability of DB-1305 in subjects with advanced solid tumors.

Detailed Description
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This is a multicenter, non-randomized, open-label, multiple-dose, first in human (FIH) study. The study consists of two parts: Part 1 adopts an accelerated titration at first dose level followed with classic 3+3 design to identify the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D); Part 2 is a dose expansion phase to confirm the safety, tolerability and explore efficacy in selected malignant solid tumors at the MTD/the RP2D. This study will enroll subjects with advanced/unresectable, recurrent, or metastatic malignant solid tumors.

Official Title
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A Phase 1/2a, Multicenter, Open-Label, Non-Randomized First in Human Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of DB-1305 in Subjects With Advanced/Metastatic Solid Tumors

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: DB-1305
* Combination Product: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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). Histologically or cytologically confirmed unresectable advanced/ metastatic solid tumors who have relapsed or progressed on or after standard systemic treatments or for which no standard treatment is available. At least one measurable lesion as assessed by the investigator according to response evaluation criteria in solid tumors (RECIST) version 1.1 criteria. 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 functions within 7 days prior to Day 1 of Cycle 1. Has adequate treatment washout period prior to Day 1 of Cycle 1. Is willing to provide pre-existing resected tumor samples or undergo fresh tumor biopsy for the measurement of Trop-2 level and other biomarkers if no contraindication. 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. Exclusion Criteria: Has a medical history of symptomatic congestive heart failure (CHF) (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) or current interstitial lung diseases or who are suspected to have these diseases by imaging at screening. Has an uncontrolled infection requiring IV injection of antibiotics, antivirals, or antifungals. Subjects have human immunodeficiency virus (HIV) infection with acquired immune deficiency syndrome (AIDS) defining illness are not eligible for enrollment; However, subjects have had HIV infection with a cluster of differentiation 4 (CD4)+ T cell count > 350 cells/µL and no history of an AIDS-defining illness are eligible for entry. NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DB-1305 Dose Level 1<br>Enrolled subjects will receive a single-dose of DB-1305 at Dose Level 1 on Day 1 of each cycle Q3W | Drug: DB-1305<br>* Administered I.V.<br>* Other names: DB-1305 for Injection;|
| Experimental: DB-1305 Dose Level 2<br>Enrolled subjects will receive a single-dose of DB-1305 at Dose Level 2 on Day 1 of each cycle Q3W | Drug: DB-1305<br>* Administered I.V.<br>* Other names: DB-1305 for Injection;|
| Experimental: DB-1305 Dose Level 3<br>Enrolled subjects will receive a single-dose of DB-1305 at Dose Level 3 on Day 1 of each cycle Q3W | Drug: DB-1305<br>* Administered I.V.<br>* Other names: DB-1305 for Injection;|
| Experimental: DB-1305 Dose Level 4<br>Enrolled subjects will receive a single-dose of DB-1305 at Dose Level 4 on Day 1 of each cycle Q3W | Drug: DB-1305<br>* Administered I.V.<br>* Other names: DB-1305 for Injection;|
| Experimental: DB-1305 Dose Level 5<br>Enrolled subjects will receive a single-dose of DB-1305 at Dose Level 5 on Day 1 of each cycle Q3W | Drug: DB-1305<br>* Administered I.V.<br>* Other names: DB-1305 for Injection;|
| Experimental: DB-1305 Dose Expansion 1<br>Enrolled subjects with NSCLC with AGAs who will receive a single-dose of DB-1305 on a selected dose level once every 3 weeks | Drug: DB-1305<br>* Administered I.V.<br>* Other names: DB-1305 for Injection;|
| Experimental: DB-1305 Dose Expansion 2<br>Enrolled subjects with NSCLC without AGAs who will receive a single-dose of DB-1305 on a selected dose level once every 3 weeks | Drug: DB-1305<br>* Administered I.V.<br>* Other names: DB-1305 for Injection;|
| Experimental: DB-1305 Dose Expansion 3<br>Enrolled subjects with OC who will receive a single-dose of DB-1305 on a selected dose level once every 3 weeks | Drug: DB-1305<br>* Administered I.V.<br>* Other names: DB-1305 for Injection;|
| Experimental: DB-1305 Dose Expansion 4<br>Enrolled subjects with BC who will receive a single-dose of DB-1305 on a selected dose level (RP2D) once every 3 weeks | Drug: DB-1305<br>* Administered I.V.<br>* Other names: DB-1305 for Injection;|
| Experimental: DB-1305 Dose Expansion 5<br>Enrolled subjects with TNBC who have progressed on or after standard systemic treatments and without prior treatment of sacituzumab govitecan who will receive a single-dose of DB-1305 on a selected dose level (RP2D) once every 3 weeks | Drug: DB-1305<br>* Administered I.V.<br>* Other names: DB-1305 for Injection;|
| Experimental: DB-1305 Dose Expansion 6<br>Enrolled subjects with TNBC with treatment failure on sacituzumab govitecan who will receive a single-dose of DB-1305 on a selected dose level (RP2D) once every 3 weeks | Drug: DB-1305<br>* Administered I.V.<br>* Other names: DB-1305 for Injection;|
| Experimental: DB-1305 Dose Expansion 7<br>Enrolled subjects with EC with disease progression on or after treatment with at least one platinum-containing regimen for advanced or metastatic disease with or without immune checkpoint inhibitor (ICI) who will receive a single-dose of DB-1305 on a selected dose level (RP2D) once every 3 weeks | Drug: DB-1305<br>* Administered I.V.<br>* Other names: DB-1305 for Injection;|
| Experimental: DB-1305 Dose Expansion 8<br>Enrolled subjects with malignant mesothelioma who have progressed on or after standard systemic treatments who will receive a single-dose of DB-1305 on a selected dose level (RP2D) once every 3 weeks | Drug: DB-1305<br>* Administered I.V.<br>* Other names: DB-1305 for Injection;|
| Experimental: DB-1305 Dose Expansion 9<br>Enrolled subjects with CC who have progressed on or after standard systemic treatments who will receive a single-dose of DB-1305 on a selected dose level (RP2D) once every 3 weeks | Drug: DB-1305<br>* Administered I.V.<br>* Other names: DB-1305 for Injection;|
| Experimental: DB-1305 Dose Expansion 10<br>Enrolled subjects with other advanced or metastatic solid tumors who have progressed on or after standard systemic treatments who will receive a single-dose of DB-1305 on a selected dose level (RP2D) once every 3 weeks | Drug: DB-1305<br>* Administered I.V.<br>* Other names: DB-1305 for Injection;|
| Experimental: DB-1305 Dose Expansion 11<br>Enrolled subjects with NSCLC without AGAs who has not received PD-1/PD-L1, PD-L2, CTLA-4 directed immunotherapy and previously received ≤1 line of platinum-based chemotherapy for advanced or metastatic NSCLC who will receive a single-dose of DB-1305 on a selected dose level in combination with pembrolizumab 200mg once every 3 weeks | Drug: DB-1305<br>* Administered I.V.<br>* Other names: DB-1305 for Injection;Combination Product: Pembrolizumab<br>* Administered I.V.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Percentage of Participants with Dose-Limiting Toxicities (DLTs) as assessed by CTCAE v5.0. | Percentage of participants in Part 1 with DLTs | up to 21 days after Cycle 1 Day 1 | 
| Phase 1: Percentage of Participants with Treatment Emergent Adverse Events (TEAEs) as assessed by CTCAE v5.0. | Percentage of participants with AEs in Part 1 graded according to NCI CTCAE v5.0 | Up to follow-up period, approximately 1 year post-treatment | 
| Phase 1: Percentage of Participants with Serious Adverse Events (SAEs) as assessed by CTCAE v5.0. | Percentage of Participants with SAEs in Part 1 graded according to NCI CTCAE v5.0 | Up to follow-up period, approximately 1 year post-treatment | 
| Maximum Tolerated Dose (MTD) of DB-1305 | MTD on the data collected during Part 1 | 12 months | 
| Phase 1: Recommended Phase 2 Dose (RP2D) of DB-1305 | RP2D of DB-1305 based on the data collected during Part 1 | 12 months | 
| Phase 2a: Percentage of Participants with Treatment Emergent adverse events (TEAEs) as assessed by CTCAE v5.0. | Percentage of participants with AEs in Part 2 graded according to NCI CTCAE v5.0 | Up to follow-up period, approximately 1 year post-treatment | 
| Phase 2a: Percentage participants with Serious Adverse Events (SAEs) as assessed by CTCAE v5.0. | Percentage of participants with SAEs in Part 2 graded according to NCI CTCAE v5.0 | Up to follow-up period, approximately 1 year post-treatment | 
| Phase 2a: Percentage of Objective Response Rate (ORR) as assessed by RECIST 1.1. | The percentage of subjects who had a best response rating of CR and PR, for Part 2 only which was maintained ≥4 weeks | Up to follow-up period, approximately 1 year post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 & Phase 2a: Pharmacokinetic-AUC | Area under the concentration-time curve from time 0 to infinity of DB-1305 | within 8 cycles (each cycle is 21 days) | 
| Phase 1 & Phase 2a: Pharmacokinetic-Cmax | Maximum observed plasma concentration (Cmax) of DB-1305 | within 8 cycles (each cycle is 21 days) | 
| Phase 1 & Phase 2a: Pharmacokinetic-Tmax | Time to Cmax of DB-1305 | within 8 cycles (each cycle is 21 days) | 
| Phase 1 & Phase 2a: Pharmacokinetic-T1/2 | Terminal elimination half-life | within 8 cycles (each cycle is 21 days) |