A Phase 1/2a, Multicenter, Open-Label, First in Human Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of DB-1303/BNT323 in Patients With Advanced/Metastatic Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 796
- 试验地点
- 191
- 主要终点
- Phase 1: Percentage of Participants with Dose-Limiting Toxicities (DLTs) as assessed by CTCAE v5.0.
研究概览
简要总结
This is a dose-escalation and dose-expansion Phase 1/2a trial to evaluate the safety and tolerability of DB-1303/BNT323 in subjects with advanced solid tumors that express HER2.
详细描述
This is a multicenter, non-randomized (Except for Dose Expansion 1 and Dose Expansion 9 cohorts), open-label, multiple-dose, 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 MTD/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 HER2-expressing malignant solid tumors.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Has a pathologically documented HER2-positive or HER2-expressing (except for cohort 2h where the requirement is HER2-null), advanced/unresectable, recurrent, or metastatic malignant solid tumor that is refractory to or intolerable with standard treatment, or for which no standard treatment is available.
- •At least 1 measurable lesion (per RECIST 1.1)
- •Provide signed informed consent
- •ECOG performance status (PS) of 0-
- •LVEF ≥ 50% by ECHO or MUGA
- •Adequate organ functions
- •Provide pre-existing diagnosis of HER2 status or resected tumor samples or undergo fresh tumor biopsy for HER2 testing.
- •Life expectancy of ≥ 3 months.
- •Additional Inclusion Criteria for Part 2 Expansion Group 9:
- •1. Has pathologically documented advanced/unresectable, recurrent, or metastatic EC (including UCS and USPC) and has progressed on or after at least 1 line of systemic treatment including platinum-based therapy and exposure to ICI but no more than prior 3 lines of therapy for advanced/unresectable, or metastatic disease. Note: endocrine therapy will not qualify as a systemic therapy line.
排除标准
- •History of symptomatic CHF (New York Heart Association [NYHA] classes II-IV) or serious cardiac arrhythmia requiring treatment.
- •History of myocardial infarction or unstable angina within 6 months before Day
- •Average QTcF > 450 ms in males and > 470 ms in females
- •History of clinically significant lung diseases
- •Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
- •HIV infection with AIDS defining illness or active viral hepatitis.
- •Clinically active brain metastases
- •Unresolved toxicities from previous anticancer therapy, defined as toxicities not yet resolved to NCI-CTCAE version 5.0, Grade ≤ 1 or baseline.
- •A known hypersensitivity to either the drug substances or inactive ingredients in the drug product.
- •Part 2 (expansion) Only:Multiple primary malignancies within 3 years, except adequately resected non- melanoma skin cancer, curatively treated in-situ disease, other solid tumors curatively treated, or contralateral breast cancer.
研究组 & 干预措施
DB-1303/BNT323 Dose Expansion 3
Enrolled Subjects will receive a single-dose of DB-1303/BNT323 on a selected dose level (RP2D) Day 1 of each cycle Q3W
干预措施: DB-1303/BNT323 (Biological)
DB-1303/BNT323 Dose Expansion 4
Enrolled Subjects will receive a single-dose of DB-1303/BNT323 on a selected dose level (RP2D) Day 1 of each cycle Q3W
干预措施: DB-1303/BNT323 (Biological)
DB-1303/BNT323 Dose Expansion 5
Enrolled Subjects will receive a single-dose of DB-1303/BNT323 on a selected dose level (RP2D) Day 1 of each cycle Q3W
干预措施: DB-1303/BNT323 (Biological)
DB-1303/BNT323 Dose Level 6
Enrolled Subjects will receive a single-dose of DB-1303/BNT323 at Dose Level 6 on Day 1 of each cycle Q3W
干预措施: DB-1303/BNT323 (Biological)
DB-1303/BNT323 Dose Level 7
Enrolled Subjects will receive a single-dose of DB-1303/BNT323 at Dose Level 7 on Day 1 of each cycle Q3W
干预措施: DB-1303/BNT323 (Biological)
DB-1303/BNT323 Dose Expansion 6
Enrolled Subjects will receive a single-dose of DB-1303/BNT323 on a selected dose level (RP2D) Day 1 of each cycle Q3W
干预措施: DB-1303/BNT323 (Biological)
DB-1303/BNT323 Dose Expansion 7
Enrolled Subjects will receive a single-dose of DB-1303/BNT323 on a selected dose level (RP2D) Day 1 of each cycle Q3W
干预措施: DB-1303/BNT323 (Biological)
DB-1303/BNT323 Dose Expansion 8
Enrolled Subjects will receive a single-dose of DB-1303/BNT323 on a selected dose level (RP2D) Day 1 of each cycle Q3W
干预措施: DB-1303/BNT323 (Biological)
DB-1303/BNT323 Dose Expansion 9
Enrolled Subjects will be randomized to receive a single-dose of DB-1303/BNT323 on a selected dose level 1 or dose level 2 on Day 1 of each cycle Q3W
干预措施: DB-1303/BNT323 (Biological)
DB-1303/BNT323 Dose Expansion 10
Enrolled Subjects will receive a single-dose of DB-1303/BNT323 on a selected dose level (RP2D) Day 1 of each cycle Q3W along with ritonavir or itraconazole to assess the DDI potential
干预措施: DB-1303/BNT323 (Biological)
DB-1303/BNT323 Dose Expansion 10
Enrolled Subjects will receive a single-dose of DB-1303/BNT323 on a selected dose level (RP2D) Day 1 of each cycle Q3W along with ritonavir or itraconazole to assess the DDI potential
干预措施: Ritonavir (Drug)
DB-1303/BNT323 Dose Expansion 17
Enrolled Subjects will receive a single-dose of DB-1303/BNT323 on a selected dose level (RP2D) Day 1 of each cycle Q3W
干预措施: DB-1303/BNT323 (Biological)
DB-1303/BNT323 Dose Expansion 10
Enrolled Subjects will receive a single-dose of DB-1303/BNT323 on a selected dose level (RP2D) Day 1 of each cycle Q3W along with ritonavir or itraconazole to assess the DDI potential
干预措施: Itraconazole (Drug)
DB-1303/BNT323 Dose Expansion 11
Enrolled Subjects will receive a single-dose of DB-1303/BNT323 on a selected dose level (RP2D) Day 1 of each cycle Q3W
干预措施: DB-1303/BNT323 (Biological)
DB-1303/BNT323 Dose Expansion 12
Enrolled Subjects will receive a single-dose of DB-1303/BNT323 on a selected dose level 1 or dose level 2 in combination with Pertuzumab on Day 1 of each cycle Q3W
干预措施: DB-1303/BNT323 (Biological)
DB-1303/BNT323 Dose Expansion 12
Enrolled Subjects will receive a single-dose of DB-1303/BNT323 on a selected dose level 1 or dose level 2 in combination with Pertuzumab on Day 1 of each cycle Q3W
干预措施: Pertuzumab Injection (Drug)
DB-1303/BNT323 Dose Expansion 13
Enrolled Subjects will receive a single-dose of DB-1303/BNT323 on a selected dose level (RP2D) Day 1 of each cycle Q3W
干预措施: DB-1303/BNT323 (Biological)
DB-1303/BNT323 Dose Level 5
Enrolled Subjects will receive a single-dose of DB-1303/BNT323 at Dose Level 5 on Day 1 of each cycle Q3W
干预措施: DB-1303/BNT323 (Biological)
DB-1303/BNT323 Dose Expansion 1
Enrolled Subjects will be randomized to receive a single-dose of DB-1303/BNT323 on a selected dose level 1 or dose level 2 Day 1 of each cycle Q3W
干预措施: DB-1303/BNT323 (Biological)
DB-1303/BNT323 Dose Expansion 2
Enrolled Subjects will receive a single-dose of DB-1303/BNT323 on a selected dose level (RP2D) Day 1 of each cycle Q3W
干预措施: DB-1303/BNT323 (Biological)
DB-1303/BNT323 Dose Level 1
Enrolled Subjects will receive a single-dose of DB-1303/BNT323 at Dose Level 1 on Day 1 of each cycle Q3W
干预措施: DB-1303/BNT323 (Biological)
DB-1303/BNT323 Dose Level 2
Enrolled Subjects will receive a single-dose of DB-1303/BNT323 at Dose Level 2 on Day 1 of each cycle Q3W
干预措施: DB-1303/BNT323 (Biological)
DB-1303/BNT323 Dose Level 3
Enrolled Subjects will receive a single-dose of DB-1303/BNT323 at Dose Level 3 on Day 1 of each cycle Q3W
干预措施: DB-1303/BNT323 (Biological)
DB-1303/BNT323 Dose Level 4
Enrolled Subjects will receive a single-dose of DB-1303/BNT323 at Dose Level 4 on Day 1 of each cycle Q3W
干预措施: DB-1303/BNT323 (Biological)
DB-1303/BNT323 Dose Expansion 14
China Only:Subjects who were previously treated with trastuzumab and taxane will receive a single-dose of DB-1303/BNT323 on a selected dose level (RP2D) Day 1 of each cycle Q3W
干预措施: DB-1303/BNT323 (Biological)
DB-1303/BNT323 Dose Expansion 15
China Only: Enrolled Subjects will receive a single-dose of DB-1303/BNT323 on a selected dose level (RP2D) Day 1 of each cycle Q3W
干预措施: DB-1303/BNT323 (Biological)
DB-1303/BNT323 Dose Expansion 16
Enrolled Subjects will receive a single-dose of DB-1303/BNT323 on a selected dose level (RP2D) Day 1 of each cycle Q3W
干预措施: DB-1303/BNT323 (Biological)
结局指标
主要结局
Phase 1: Percentage of Participants with Dose-Limiting Toxicities (DLTs) as assessed by CTCAE v5.0.
时间窗: up to 21 days after C1D1
Percentage of participants in Part 1 with DLTs
Phase 1: Maximum Tolerated Dose (MTD) of DB-1303
时间窗: Up to Safety Follow-Up visit, approximately 35 days post-treatment
MTD on the data collected during Part 1
Phase 1: Recommended Phase 2 Dose (RP2D) of DB-1303
时间窗: Up to Safety Follow-Up visit, approximately 35 days post-treatment
RP2D of DB-1303 based on the data collected during Part 1
Phase 1: Percentage of participants with AEs in Part 1 graded according to NCI CTCAE v5.0
时间窗: Up to Safety Follow-Up visit, approximately 35 days post-treatment
Percentage of Participants with Treatment Emergent Adverse Events (TEAEs) or Treatment Emergent Adverse Event of Special Interest include those \>/= G3 leading to dose reduction, interruption or discontinuation as assessed by CTCAE v5.0, abnormal vital signs, abnormal 12-lead ECGs, abnormal safety laboratory tests, abnormal ECOG PS, abnormal ECHO/MUGA (LVEF).
Phase 1: Percentage of Participants with Serious Adverse Events (SAEs) as assessed by CTCAE v5.0.
时间窗: Up to follow-up period, approximately 1 year post-treatment
Percentage of Participants with SAEs in Part 1 graded according to NCI CTCAE v5.0
Phase 2: Percentage participants with Serious Adverse Events (SAEs) as assessed by CTCAE v5.0.
时间窗: Up to follow-up period, approximately 1 year post-treatment
Percentage of participants with SAEs in Part 2 graded according to NCI CTCAE v5.0
Phase 2 (Dose Expansion 10 only): To evaluate the effect of ritonavir on DB-1303 and P1003 PK in subjects with HER2-expressing, HER2-amplified, or HER2-mutated advanced solid malignant tumors
时间窗: up to safety follow-up visit, approx. 35 days post-treatment
Maximum observed plasms concentration (Cmax) and Area under the concentration-time curve from 0 to infinity of DB-1303 and P1003 (+/- Ritonavir)
Phase 2 (Dose Expansion 10 only): To evaluate the effect of itraconazole on DB-1303 and P1003 PK in subjects with HER2-expressing, HER2-amplified, or HER2-mutated advanced solid malignant tumors.
时间窗: up to safety follow-up visit, approx. 35 days post-treatment
Maximum observed plasms concentration (Cmax) and Area under the concentration-time curve from 0 to infinity of DB-1303 and P1003 (+/- Itraconazole)
Phase 2: Percentage of Objective Response Rate (ORR) as assessed by RECIST 1.1.
时间窗: Up to follow-up period, approximately 1 year post-treatment
The percentage of subjects who had a best response of CR or PR, for Part 2 only which was maintained ≥4 weeks.
Percentage of participants with AEs in Part 2 graded according to NCI CTCAE v5.0
时间窗: Up to follow-up period, approximately 1 year post-treatment
Phase 2: Percentage of Participants with Treatment Emergent Adverse Events (TEAEs) or Treatment Emergent Adverse Event of Special Interest include those \>/= G3 leading to dose reduction, interruption or discontinuation as assessed by CTCAE v5.0, abnormal vital signs, abnormal 12-lead ECGs, abnormal safety laboratory tests, abnormal ECOG PS, abnormal ECHO/MUGA (LVEF).
次要结局
- Phase 1 & Phase 2: Pharmacokinetic-Tmax(Up to safety follow up visit, approx. 35 days post-treatment)
- Phase 1 & Phase 2: Pharmacokinetic-Ctrough(Up to safety follow up visit, approx. 35 days post-treatment)
- Phase 1 & Phase 2: Pharmacokinetic-AUC(Up to safety follow up visit, approx. 35 days post-treatment)
- Phase 1 & Phase 2: Pharmacokinetic-Cmax(Up to safety follow up visit, approx. 35 days post-treatment)
- Phase 1 & Phase 2: Pharmacodynamics-ADA(Up to safety follow up visit, approx. 35 days post-treatment)
- Phase 2: Percent change in target lesions as assessed by RECIST 1.1(Up to follow-up period, approximately 1 year post-treatment)
- Phase 2 Cohort b Only: Percentage of ORR as assessed by IRC and as assessed by investigator based on RECIST 1.1 for HER2-expressing subjects and in subjects with prior ICI treatment(Up to follow-up period, approximately 1 year post-treatment)
- To evaluate the safety of DB-1303 with/without ritonavir or itraconazole(Up to follow-up period, approximately 1 year post-treatment)
- Phase 1 & Phase 2: Pharmacokinetic-T1/2(Up to safety follow up visit, approx. 35 days post-treatment)
- Phase 1 & 2: Duration of Response (DoR) as assessed by RECIST 1.1(Up to follow-up period, approximately 1 year post-treatment)
- Phase 1 and 2 Cohort b only: Progression-Free Survival(Up to follow-up period, approximately 1 year post-treatment)
- Phase 1 & 2: Disease Control Rate (DCR) as assessed by RECIST 1.1(Up to follow-up period, approximately 1 year post-treatment)
- Phase 1 and 2 Cohort b only: Overall Survival(Up to follow-up period, approximately 1 year post-treatment)
- Phase I: Percentage of Objective Response Rate (ORR) as assessed by investigator based on RECIST 1.1(Up to follow-up period, approximately 1 year post-treatment)
- Phase 1 & 2: Time to Response (TTR) as assessed by RECIST 1.1(Up to follow-up period, approximately 1 year post-treatment)
- Phase 2: Time on Therapy(Up to 21 days after the participant's last dose)