A Study of DB-1303 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-1303 in subjects with advanced solid tumors that express HER2.

Detailed Description
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This is a multicenter, non-randomized, 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.

Official Title
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A Phase 1/2a, Multicenter, Open-Label, First in Human Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of DB-1303 in Patients With Advanced/Metastatic Solid Tumors

Conditions
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HER2-positive Advanced Solid Tumor

Intervention / Treatment
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* Biological: DB-1303
* Drug: Pertuzumab Injection
* Drug: Ritonavir
* Drug: Itraconazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 0-1. 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. Exclusion Criteria: 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 1. 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. 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.

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DB-1303 Dose Level 1<br>Enrolled Subjects will receive a single-dose of DB-1303 at Dose Level 1 on Day 1 of each cycle Q3W | Biological: DB-1303<br>* Administered IV<br>|
| Experimental: DB-1303 Dose Level 2<br>Enrolled Subjects will receive a single-dose of DB-1303 at Dose Level 2 on Day 1 of each cycle Q3W | Biological: DB-1303<br>* Administered IV<br>|
| Experimental: DB-1303 Dose Level 3<br>Enrolled Subjects will receive a single-dose of DB-1303 at Dose Level 3 on Day 1 of each cycle Q3W | Biological: DB-1303<br>* Administered IV<br>|
| Experimental: DB-1303 Dose Level 4<br>Enrolled Subjects will receive a single-dose of DB-1303 at Dose Level 4 on Day 1 of each cycle Q3W | Biological: DB-1303<br>* Administered IV<br>|
| Experimental: DB-1303 Dose Level 5<br>Enrolled Subjects will receive a single-dose of DB-1303 at Dose Level 5 on Day 1 of each cycle Q3W | Biological: DB-1303<br>* Administered IV<br>|
| Experimental: DB-1303 Dose Expansion 1<br>Enrolled Subjects will be randomized to receive a single-dose of DB-1303 on a selected dose level 1 or dose level 2 Day 1 of each cycle Q3W | Biological: DB-1303<br>* Administered IV<br>|
| Experimental: DB-1303 Dose Expansion 2<br>Enrolled Subjects will receive a single-dose of DB-1303 on a selected dose level (RP2D) Day 1 of each cycle Q3W | Biological: DB-1303<br>* Administered IV<br>|
| Experimental: DB-1303 Dose Expansion 3<br>Enrolled Subjects will receive a single-dose of DB-1303 on a selected dose level (RP2D) Day 1 of each cycle Q3W | Biological: DB-1303<br>* Administered IV<br>|
| Experimental: DB-1303 Dose Expansion 4<br>Enrolled Subjects will receive a single-dose of DB-1303 on a selected dose level (RP2D) Day 1 of each cycle Q3W | Biological: DB-1303<br>* Administered IV<br>|
| Experimental: DB-1303 Dose Expansion 5<br>Enrolled Subjects will receive a single-dose of DB-1303 on a selected dose level (RP2D) Day 1 of each cycle Q3W | Biological: DB-1303<br>* Administered IV<br>|
| Experimental: DB-1303 Dose Level 6<br>Enrolled Subjects will receive a single-dose of DB-1303 at Dose Level 6 on Day 1 of each cycle Q3W | Biological: DB-1303<br>* Administered IV<br>|
| Experimental: DB-1303 Dose Level 7<br>Enrolled Subjects will receive a single-dose of DB-1303 at Dose Level 7 on Day 1 of each cycle Q3W | Biological: DB-1303<br>* Administered IV<br>|
| Experimental: DB-1303 Dose Expansion 6<br>Enrolled Subjects will receive a single-dose of DB-1303 on a selected dose level (RP2D) Day 1 of each cycle Q3W | Biological: DB-1303<br>* Administered IV<br>|
| Experimental: DB-1303 Dose Expansion 7<br>Enrolled Subjects will receive a single-dose of DB-1303 on a selected dose level (RP2D) Day 1 of each cycle Q3W | Biological: DB-1303<br>* Administered IV<br>|
| Experimental: DB-1303 Dose Expansion 8<br>Enrolled Subjects will receive a single-dose of DB-1303 on a selected dose level (RP2D) Day 1 of each cycle Q3W | Biological: DB-1303<br>* Administered IV<br>|
| Experimental: DB-1303 Dose Expansion 9<br>Enrolled Subjects will be randomized to receive a single-dose of DB-1303 on a selected dose level 1 or dose level 2 on Day 1 of each cycle Q3W | Biological: DB-1303<br>* Administered IV<br>|
| Experimental: DB-1303 Dose Expansion 10<br>Enrolled Subjects will receive a single-dose of DB-1303 on a selected dose level (RP2D) Day 1 of each cycle Q3W along with ritonavir and itraconazole to assess the DDI potential | Biological: DB-1303<br>* Administered IV<br>Drug: Ritonavir<br>* Administered oral<br>Drug: Itraconazole<br>* Administered oral<br>|
| Experimental: DB-1303 Dose Expansion 11<br>Enrolled Subjects will receive a single-dose of DB-1303 on a selected dose level (RP2D) Day 1 of each cycle Q3W | Biological: DB-1303<br>* Administered IV<br>|
| Experimental: DB-1303 Dose Expansion 12<br>Enrolled Subjects will receive a single-dose of DB-1303 on a selected dose level 1 or dose level 2 in combination with Pertuzumab on Day 1 of each cycle Q3W | Biological: DB-1303<br>* Administered IV<br>Drug: Pertuzumab Injection<br>* Administered IV<br>|
| Experimental: DB-1303 Dose Expansion 13<br>Enrolled Subjects will receive a single-dose of DB-1303 on a selected dose level (RP2D) Day 1 of each cycle Q3W | Biological: DB-1303<br>* Administered IV<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 C1D1 | 
| Phase 1: Percentage of Participants with Treatment Emergent Adverse Events (TEAEs) ot Treatment Emergent Adverse Event of Special Interest include those >/= G3 or leading to dose reduction, interruption or discontinuation 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 | 
| Phase 1: Maximum Tolerated Dose (MTD) of DB-1303 | MTD on the data collected during Part 1 | 12 months | 
| Phase 1: Recommended Phase 2 Dose (RP2D) of DB-1303 | RP2D of DB-1303 based on the data collected during Part 1 | 12 months | 
| Phase 2: Percentage of Participants with Treatment Emergent Adverse Events (TEAEs) ot Treatment Emergent Adverse Event of Special Interest include those >/= G3 or leading to dose reduction, interruption or discontinuation 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 2: 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 2: 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 2: Pharmacokinetic-AUC | Area under the concentration-time curve from time 0 to infinity of DB-1303 | Pre-Dose, 30 minutes post end of infusion, 4 hours, 8 hours, 24 hours, 72 hours, 7 days, 14 days post start of infusion at Cycle 1 and Cycle 3. Pre-dose and within 30 minutes post end of infusion up to Cycle 8, End of Treatment and Safety Follow-up Visit | 
| Phase 1 & Phase 2: Pharmacokinetic-Cmax | Maximum observed plasma concentration (Cmax) of DB-1303 | Pre-Dose, 30 minutes post end of infusion, 4 hours, 8 hours, 24 hours, 72 hours, 7 days, 14 days post start of infusion at Cycle 1 and Cycle 3. Pre-dose and within 30 minutes post end of infusion up to Cycle 8, End of Treatment and Safety Follow-up Visit | 
| Phase 1 & Phase 2: Pharmacokinetic-Tmax | Time to Cmax of DB-1303 | Pre-Dose, 30 minutes post end of infusion, 4 hours, 8 hours, 24 hours, 72 hours, 7 days, 14 days post start of infusion at Cycle 1 and Cycle 3. Pre-dose and within 30 minutes post end of infusion up to Cycle 8, End of Treatment and Safety Follow-up Visit | 
| Phase 1 & Phase 2: Pharmacokinetic-T1/2 | Terminal elimination half-life | Pre-Dose, 30 minutes post end of infusion, 4 hours, 8 hours, 24 hours, 72 hours, 7 days, 14 days post start of infusion at Cycle 1 and Cycle 3. Pre-dose and within 30 minutes post end of infusion up to Cycle 8, End of Treatment and Safety Follow-up Visit | 
| Phase 1 & Phase 2: Pharmacokinetic-Ctrough | Trough concentration of DB-1303 | Pre-Dose, 30 minutes post end of infusion, 4 hours, 8 hours, 24 hours, 72 hours, 7 days, 14 days post start of infusion at Cycle 1 and Cycle 3. Pre-dose and within 30 minutes post end of infusion up to Cycle 8, End of Treatment and Safety Follow-up Visit | 
| Phase 1 & Phase 2: Pharmacodynamics-ADA | Data gathered from blood to determine Levels of anti-drug antibody (ADA) against DB 1303 in serum compared to baseline. | Before infusion on C1D1, C1D15, Before infusion on day 1 of C2, C4, C6, C8, C10 and every 4 cycles until end of treatment, EOT visit, Safety FU Visit, and 60 and 90 days after last dose (if possible) | 
| Phase 1 & 2: Disease Control Rate (DCR) as assessed by RECIST 1.1 | Proportion of participants who had a best response rating of CR or PR, or SD using RECIST V1.1. | Up to follow-up period, approximately 1 year post-treatment | 
| Phase 1 & 2: Duration of Response (DoR) as assessed by RECIST 1.1 | The duration of time from date of first CR or PR to date of progressive disease or death due to any cause, whichever comes first using RECIST V1.1 | Up to follow-up period, approximately 1 year post-treatment | 
| Phase 1 & 2: Time to Response (TTR) as assessed by RECIST 1.1 | The duration of time when receiving the first dose of study drug to the first date that is evaluated as either CR or PR using RECIST V1.1 | Up to follow-up period, approximately 1 year post-treatment | 
| Phase 2: Time on Therapy | The duration of time from participant receiving first dose of study drug to the last dose + 21 days | Up to 21 days after the participant's last dose | 
| Phase 2: Percent change in target lesions as assessed by RECIST 1.1 | The percent change in the participant's target lesions from baseline to last study scan using RECIST V1.1 | Up to follow-up period, approximately 1 year post-treatment | 
| Phase 2 Cohort b only: Progression-Free Survival | Time from subject receiving the first dose to disease progression or death by any cause | Up to follow-up period, approximately 1 year post-treatment | 
| Phase 2 Cohort b only: Overall Survival | Time from subject receiving the first dose to death by any cause | Up to follow-up period, approximately 1 year post-treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2 high, metastatic cancer, HER2-positive GEJ, Uterine serous papillary carcinoma, USPC, recurrent cancer, carcinoma, neoplasms, breast neoplasms, gastrointestinal neoplasms, endometrial neoplasms, biliary tract neoplasms, Antineoplastic Agents, Biological, stomach cancer, bile duct cancer, Cholangiocarcinoma, liver cancer, liver neoplasms, NSCLC, Non-Small Cell Lung Cancer, NSCLC HER2 mutation, HER2 Low Breast Cancer, HER2, HER2-positive, HER2-positive Breast Cancer, HER2-positive Gastric Cancer, HER2-positive Endometrial Cancer, HER2-positive Biliary Tract Cancer, HER2-positive Advanced Solid Tumor, HER2 low