A Study of DB-1310 in 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-1310 in subjects with advanced solid tumors.

Detailed Description
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This is a multicenter, non-randomized, open-label, multiple-dose, FIH Phase 1/2a study. Phase 1 adopts the standard 3+3 design to identify the MTD and/or RP2D; Phase 2a is a dose expansion phase to confirm the safety, tolerability and explore efficacy in selected malignant solid tumors treated with DB-1310 as monotherapy or in combination with trastuzumab.

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-1310 in Subjects With Advanced/Metastatic Solid Tumors

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: DB-1310


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). Have relapsed or progressed on or after standard systemic treatments, or intolerable with standard treatment, or for which no standard treatment is available. Documented radiological disease progression during/after most recent treatment regimen for advanced/unresectable, or metastatic disease. At least one measurable lesion as assessed by the investigator according to response evaluation criteria in solid tumors (RECIST) version 1.1 criteria. Subjects with nonmeasurable disease only are allowed in Cohort 2c of Phase 2a. 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 HER3 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. Male and female subjects of reproductive/childbearing potential must agree to use adequate 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 study drug, respectively. Male subjects must not freeze or donate sperm starting at screening and throughout the study period, and at least 4 months after the final study drug administration. Female subjects 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 drug administration. Exclusion Criteria: Prior treatment with HER3 targeted therapy. Prior treatment with antibody drug conjugate with topoisomerase I inhibitor (exclusive of trastuzumab deruxtecan for Cohort 2e of Phase 2a). 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 any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG), e.g., complete left bundle branch block, third-degree heart block, second-degree heart block, or PR interval > 250 milliseconds (ms). 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. Unable or unwilling to discontinue concomitant drugs that are known to prolong the QT interval. 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 intravenous injection of antibiotics, antivirals, or antifungals. Has clinically significant corneal disease. Know human immunodeficiency virus (HIV) infection. Subjects have active viral (any etiology) hepatitis are excluded. However, subjects with positive hepatitis B surface antigen (HBsAg) who have the HBV DNA (viral load) below the lower limit quantification or HBV DNA titer < 1000 cps/mL or 200 IU/mL per local testing and are not currently on viral suppressive therapy may be eligible and should be discussed with the Sponsor's Medical Monitor. However, subjects with a history of hepatitis C virus (HCV) infection who have completed curative antiviral treatment and have the HCV RNA below the lower limit of quantification per local testing are eligible for study entry. Is a lactating mother (women who are willing to temporarily interrupt breastfeeding will also be excluded), or pregnant as confirmed by serum pregnancy tests performed within 7 days prior to Cycle 1 Day 1. Has clinically active brain metastases, defined as untreated and symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms. However, subjects with asymptomatic central nervous system (CNS) metastases who are radiologically and neurologically stable for at least 4 weeks following CNS-directed therapy, and who are on stable or decreasing doses of corticosteroids equivalent to ≤10 mg/day prednisone are eligible for study entry.

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DB-1310 Dose Level 1<br>Enrolled Subjects will receive a single-dose of DB-1310 at Dose Level 1 on Day 1 of each cycle Q3W | Drug: DB-1310<br>* Administered I.V.<br>|
| Experimental: DB-1310 Dose Level 2<br>Enrolled Subjects will receive a single-dose of DB-1310 at Dose Level 2 on Day 1 of each cycle Q3W | Drug: DB-1310<br>* Administered I.V.<br>|
| Experimental: DB-1310 Dose Level 3<br>Enrolled Subjects will receive a single-dose of DB-1310 at Dose Level 3 on Day 1 of each cycle Q3W | Drug: DB-1310<br>* Administered I.V.<br>|
| Experimental: DB-1310 Dose Level 4<br>Enrolled Subjects will receive a single-dose of DB-1310 at Dose Level 4 on Day 1 of each cycle Q3W | Drug: DB-1310<br>* Administered I.V.<br>|
| Experimental: DB-1310 Dose Level 5<br>Enrolled Subjects will receive a single-dose of DB-1310 at Dose Level 5 on Day 1 of each cycle Q3W | Drug: DB-1310<br>* Administered I.V.<br>|
| Experimental: DB-1310 Dose Expansion 1<br>Enrolled Subjects with advanced/unresectable, or metastatic adenocarcinoma NSCLC with EGFR activating mutation who have progressed on or after standard systemic treatments will receive a single-dose of DB-1310 on a selected dose level (RP2D) Day 1 of each cycle Q3W | Drug: DB-1310<br>* Administered I.V.<br>|
| Experimental: DB-1310 Dose Expansion 2<br>Enrolled Subjects with advanced/unresectable, or metastatic NSCLC without EGFR activating mutation who have progressed on or after standard systemic treatments will receive a single-dose of DB-1310 on a selected dose level (RP2D) Day 1 of each cycle Q3W | Drug: DB-1310<br>* Administered I.V.<br>|
| Experimental: DB-1310 Dose Expansion 3<br>Enrolled Subjects with advanced/unresectable, or metastatic CRPC who have progressed on or after standard systemic treatments will receive a single-dose of DB-1310 on a selected dose level (RP2D) Day 1 of each cycle Q3W | Drug: DB-1310<br>* Administered I.V.<br>|
| Experimental: DB-1310 Dose Expansion 4<br>Enrolled Subjects with advanced/unresectable, or metastatic HNSCC who have progressed on or after standard systemic treatments will receive a single-dose of DB-1310 on a selected dose level (RP2D) Day 1 of each cycle Q3W | Drug: DB-1310<br>* Administered I.V.<br>|
| Experimental: DB-1310 Dose Expansion 5<br>Enrolled Subjects with advanced/unresectable, or metastatic BC with HER2-positive (IHC3+, or IHC2+ and ISH+) who have progressed on or after HER2 targeted systemic treatments will receive a single-dose of DB-1310 on a selected dose level (RP2D) Day 1 of each cycle Q3W | Drug: DB-1310<br>* Administered I.V.<br>|
| Experimental: DB-1310 Dose Expansion 6<br>Enrolled Subject with other advanced/unresectable, or metastatic solid tumors who have progressed on or after standard systemic treatment, or for which no standard systemic treatment is available will receive a single-dose of DB-1310 on a selected dose level (RP2D) Day 1 of each cycle Q3W | Drug: DB-1310<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 | 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 v5.0assessed 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-1310 | MTD on the data collected during Part 1 | 12 months | 
| Phase 1: Recommended Phase 2 Dose (RP2D) of DB-1310 | RP2D of DB-1310 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-1310 | within 8 cycles (each cycle is 21 days) | 
| Phase 1 & Phase 2a: Pharmacokinetic-Cmax | Maximum observed plasma concentration (Cmax) of DB-1310 | within 8 cycles (each cycle is 21 days) | 
| Phase 1 & Phase 2a: Pharmacokinetic-Tmax | Time to Cmax of DB-1310 | 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER3, NSCLC, CRPC, HNSCC, BC, non-small cell lung cancer, castration-resistant prostate cancer, head and neck squamous cell carcinoma, breast cancer