A Study of DB-1317 in Selected Advanced/Metastatic Solid Tumors

Official title

A Phase 1a/1b, Multicenter, Open-Label, First-in-Human Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of DB-1317 in Participants With Selected Advanced/Metastatic Solid Tumors

Overview

This is a multicenter, open-label, multiple-dose, FIH Phase 1a/1b study. Phase 1a adopts an accelerated titration design and a BOIN design to identify the MTD or MAD of DB-1317; Phase 1b includes one randomized dose expansion cohort and two single-arm dose expansion cohorts to further evaluate the safety, tolerability and preliminary efficacy of DB-1317 in selected solid tumors and to identify optimal RP2D.

Detailed description

Phase 1a (Dose Escalation and Backfilling)

Approximately 5 increasing dose levels of DB-1317 dosing every 3 weeks (Q3W) will be evaluated using an accelerated titration design at the first dose level, followed by a BOIN design at subsequent dose levels with the oversight of a Safety Monitoring Committee (SMC). For safety reasons, in any dose level of the dose escalation where a number of participants ≥ 2, a staggered dosing is required. The second participant in each dose level should start dosing no sooner than at least 24 hours after the initial dosing of the first participant. If no safety concerns arise during these 24 hours, the remaining participants can be enrolled into the same dose level with no additional staggering required. Each dose level will be subject to the DLT assessment. After completing the 21-day DLT observation period (Cycle 1), participants will continue to the next treatment cycle and receive DB-1317 on Day 1 of each cycle in the same dose level cohort. Participants who complete the DLT observation period are not allowed to switch to a higher dose level (i.e., intra-participant escalation is not allowed) unless it is deemed necessary and strongly recommended by the investigator with a written approval by the Sponsor.

Upon confirmation of MTD or MAD of DB-1317 based on data from the completed dose-escalation phase, the safety dose range of DB-1317 may be defined based on cumulative data. Following confirmation by the SMC, alternative dosing regimens, such as Q2W may be explored within the established safety dose range.

Phase 1b (Dose Expansion)

Upon completion of the Phase 1a dose escalation, following determination of MTD or MAD, and at the Sponsor's discretion, -one randomized expansion cohort and two single arm expansion cohorts will be opened each enrolling one of the selected solid tumor types, if preliminary anti-tumor activities in these tumor types are observed in Phase 1a part. GC is the tumor type pre-selected for the randomized expansion cohort CRC and PDAC are the two tumor types pre-selected for the single arm expansion cohorts based on ADAM9 expressing data, in vivo anti-tumor activities in non-clinical tumor models, and consideration of unmet medical needs. The final selection of tumor type(s) to be enrolled in the Phase 1b cohorts will be determined by Sponsor based on emerging data from Phase 1a part. Approximately 80 participants will be enrolled in the randomized expansion cohort and randomly assigned in a 1:1 ratio to two dose levels (approximately 40 each) . Approximately 40 participants will be enrolled in each single arm expansion cohort at a selected dose level, and 160 participants will be enrolled in Phase 1b. Dose levels used in Phase 1b part will be determined by Sponsor and SMC based on Phase 1a data. Based on new emerging data from the study, Sponsor may explore other randomized cohorts with other tumor types.

Interventions

• Drug DB-1317
  Administered I.V.

Primary outcome measures

• Phase 1a: Percentage of Participants with Dose-Limiting Toxicities (DLTs) as assessed by CTCAE v5.0. Percentage of participants in Part 1 with DLTs [Time frame: up to 21 days after Cycle 1 Day 1]
• Phase 1a: Percentage of Participants with Treatment Emergent Adverse Events (TEAEs) as assessed by CTCAE v5.0. [Time frame: Up to follow-up period, approximately 1 year post-treatment]
• Phase 1a: Percentage of Participants with Serious Adverse Events (SAEs) as assessed by CTCAE v5.0. [Time frame: Up to follow-up period, approximately 1 year post-treatment]
• Maximum Tolerated Dose (MTD) of DB-1317 [Time frame: Up to the completion of Phase 1a (assessed up to 12 months)]
• Recommended Phase 1b Dose (RP2D) of DB-1317 [Time frame: Up to the completion of Phase 1a (assessed up to 12 months)]
• Phase 1b: Percentage of Participants with Treatment Emergent adverse events (TEAEs) as assessed by CTCAE v5.0. [Time frame: Up to follow-up period, approximately 1 year post-treatment]
• Phase 1b: Percentage of participants with Serious Adverse Events (SAEs) as assessed by CTCAE v5.0. [Time frame: Up to follow-up period, approximately 1 year post-treatment]
• Phase 1b: Objective Response Rate (ORR) as determined by investigator [Time frame: Up to follow-up period, approximately 1 year post-treatment]
• Phase 1b: duration of response (DoR) [Time frame: Up to follow-up period, approximately 1 year post-treatment]
• Phase 1b: disease-control rate (DCR) [Time frame: Up to follow-up period, approximately 1 year post-treatment]

Secondary outcome measures (12)

• Phase 1a: Objective response rate (ORR) [Time frame: Up to follow-up period, approximately 1 year post-treatment]
• Phase 1a: duration of response (DoR) [Time frame: Up to follow-up period, approximately 1 year post-treatment]
• Phase 1a: disease-control rate (DCR) [Time frame: Up to follow-up period, approximately 1 year post-treatment]
• Phase 1a: Time to Response (TTR) [Time frame: Up to follow-up period, approximately 1 year post-treatment]
• Phase 1a & Phase 1b: Progression Free Survival (PFS) [Time frame: Up to follow-up period, approximately 1 year post-treatment]
• Phase 1a & Phase 1b: Overall Survival (OS) [Time frame: From date of first dose until the date of death or lost to follow up, approximately 1 year post-treatment]
• Phase 1a: Prostate-specific antigen (PSA) [Time frame: From date of first dose until the date of first PSA progression, approximately 1 year post-treatment]
• Phase 1a & Phase 1b: Pharmacokinetic-AUC [Time frame: within 3 cycles (each cycle is 21 days)]
• Phase 1a & Phase 1b: Pharmacokinetic-Cmax [Time frame: within 3 cycles (each cycle is 21 days)]
• Phase 1a & Phase 1b: Pharmacokinetic-Tmax [Time frame: within 3 cycles (each cycle is 21 days)]
• Phase 1a & Phase 1b: Pharmacokinetic-Cthrough [Time frame: within 6 cycles (each cycle is 21 days)]
• Phase 1a & Phase 1b: Anti-drug antibody (ADA) prevalence [Time frame: Up to follow-up period, approximately 1 year post-treatment]

Eligibility criteria

Inclusion criteria

• Male or female adults
• Unresectable advanced or metastatic selected solid tumors that have relapsed or progressed on or after standard systemic treatments.
• Only applicable to backfilling participants in Phase 1a and participants in Phase 1b: At least one measurable lesion as assessed by the investigator according to RECIST version 1.1 criteria. Participants with non-measurable disease are allowed for CRPC participants.
• Has a life expectancy of ≥ 3 months.
• Has an ECOG PS of 0-1.
• Has LVEF ≥ 50% within 28 days before enrollment.
• Is willing to provide pre-existing resected tumor samples or undergo fresh tumor biopsy for the measurement of ADAM9 expression level and other biomarkers if no contra-indication.
• Male and female participants of reproductive/childbearing potential must agree to use adequate contraceptive methods

Exclusion criteria

• Prior treatment with ADAM9 targeted therapy.
• Prior treatment with antibody-drug conjugate with topoisomerase I inhibitor.
• Has a medical history of symptomatic congestive heart failure 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 ECG
• Has an average of Fredericia's formula-QT corrected interval (QTcF) prolongation to > 470 ms in males and females
• Has a history of (non-infectious) ILD/pneumonitis
• Has a lung-specific intercurrent clinically significant illness
• Has an uncontrolled infection requiring intravenous injection of antibiotics, antivirals, or antifungals.
• Known human immunodeficiency virus (HIV) infection;Chronic, active, or uncontrolled hepatitis B;
• Known chronic, active, or uncontrolled hepatitis C
• Has clinically significant corneal disease.
• Has clinically active brain metastases
• Has unresolved toxicities from previous anticancer therapy Concurrent malignancy < 3 years.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 6 centers

• USA04-0 — Los Angeles
• USA05-0 — Ann Arbor
• Site USA06-0 — Pittsburgh
• USA02-0 — Houston
• USA03-0 — San Antonio
• USA01-0 — Fairfax

Australia · 4 centers

• AUS03-0 — Liverpool
• AUS01-0 — Randwick
• AUS04-0 — Westmead
• AUS02-0 — Nedlands

China · 4 centers

• Chn01-1/Chn01-2 — Guangzhou
• CHN05-0 — Harbin
• CHN03-0 — Zhengzhou
• CHN04-0 — Jinan

Identifiers

NCT: NCT07141706 · DB-1317-101

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗