A Study of DB-1303 vs Investigator's Choice Chemotherapy in Metastatic Breast Cancer

Study Overview
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Brief Summary
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The goal of this clinical trial is to assess the efficacy of DB-1303 compared with investigator's choice chemotherapy in terms of progression-free survival (PFS) by blinded independent central review (BICR) in the HR+, HER2-low (IHC 2+/ISH- and IHC 1+）population.

Detailed Description
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The study is an open-label, multi-center, randomized study in HR+, HER2-low breast cancer subjects whose disease has progressed on at least 2 lines of prior ET or within 6 months of first line ET + CDK4/6 inhibitor in the metastatic setting. The primary purpose of the study is to determine the efficacy and safety of DB-1303 compared with investigator's choice single agent chemotherapy in the target population. Approximately 466 subjects with HER2 IHC 2+/ISH- and IHC 1+ (HER2-low] expression will be randomized 1:1 across approximately 180 centers globally to receive either DB-1303 or investigator's choice single agent chemotherapy (capecitabine, paclitaxel or nab-paclitaxel) until RECIST 1.1 defined disease progression (PD), unless there is unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation is met.

Official Title
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A Phase 3, Randomized, Multi-center, Open-Label Study of DB-1303 Versus Investigator's Choice Chemotherapy in Human Epidermal Growth Factor Receptor 2 (HER2)-Low, Hormone Receptor Positive (HR+) Metastatic Breast Cancer Patients Whose Disease Has Progressed on Endocrine Therapy (ET) (DYNASTY-Breast02)

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: DB-1303
* Drug: Capecitabine
* Drug: Paclitaxel
* Drug: Nab-paclitaxel


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). Pathologically documented breast cancer that: 1) Is advanced or metastatic 2) Has HER2-low expression (IHC 1+ or IHC 2+/ISH-) as determined by the central laboratory result. 3) Was never previously reported as HER2-positive (IHC 3+ or ISH+) as per ASCO/CAP guidelines. 4) Is documented as HR+ (either ER and/or PgR positive [ER or PgR ≥1%]) per ASCO/CAP guidelines (Allison et al 2020). 3. Must have an adequate tumor tissue sample available for assessment of HER2 by central laboratory, preferably in formalin fixation and paraffin embedding (FFPE) blocks based on a mandatory FFPE tumor sample obtained at the time of metastatic disease or later; 4. ECOG performance status of 0 or 1. 5. Must have had either: Disease progression on endocrine therapy + CDK4/6 inhibitor within 6 months of starting first line treatment for metastatic disease and considered appropriate for chemotherapy as the next treatment by the investigator, OR Disease progression on at least 2 previous lines of ET with or without a targeted therapy (such as CDK4/6, mTOR or PI3-K inhibitors) administered for the treatment of metastatic disease. 6. No prior chemotherapy for advanced or metastatic breast cancer. Subjects who have received chemotherapy in the neo-adjuvant or adjuvant setting are eligible, as long as they have had a disease-free interval (defined as completion of systemic chemotherapy to diagnosis of advanced or metastatic disease) of >12 months. 7. Life expectancy ≥12 weeks at screening. 8. Subjects must have at least one measurable lesion as defined per RECIST v1.1 or have non-measurable, bone-only disease that can be assessed by CT or MRI or X-Ray. Lytic or mixed lytic bone lesions that can be assessed by CT or MRI or X-Ray in the absence of measurable disease as defined above is acceptable; subjects with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible. 9. Female subjects of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception from the time of screening and must agree to continue using such precautions for 7 months after the last dose of study treatment. 10. Non-sterilized male subjects who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening and throughout the duration of the study treatment and the washout period Exclusion Criteria: Ineligible for all options in the investigator's choice chemotherapy arm. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, uncontrolled or significant cardiovascular disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the subject to give written informed consent. Clinically uncontrolled pleural effusion, ascites or pericardial effusion requiring drainage, peritoneal shunt or cell-free concentrated ascites reinfusion therapy within 2 weeks prior to the randomization. Uncontrolled or significant cardiovascular disease Has as a history of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening. Subjects with prior use of immunosuppressive medication within 14 days prior to first study dose, except for intranasal and inhaled corticosteroids or systemic corticosteroids at doses less than 10 mg/day of prednisone or equivalent. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline. Previous treatment with anti-HER2 therapy. Prior treatment with antibody-drug conjugate that comprised an exatecan derivative that is a topoisomerase I inhibitor. Prior randomization or treatment in a previous DB-1303 study regardless of treatment assignment.20. Has substance abuse or any other medical conditions such as psychological conditions, that may, in the opinion of the Investigator, interfere with the subject's participation in the clinical study or evaluation of the clinical study results.

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<br>Enrolled Subjects will be randomized to receive a 8 mg/kg IV dose of DB-1303 on Day 1 of each cycle Q3W | Drug: DB-1303<br>* IV<br>|
| Active Comparator: investigator's choice single agent chemotherapy<br>Enrolled Subjects will be randomized to receive investigator's choice single agent chemotherapy (capecitabine:1000 or 1250 mg/m2, Oral, Twice daily orally for 2 weeks followed by a 1-week rest period in 3-week cycles; paclitaxel：80 mg/m2， IV, Every week (QW) in 3-week cycles; or nab-paclitaxel: 100 mg/m2, IV, Every week (QW) for 3 weeks followed by a one-week rest period in 4-week cycles) until RECIST 1.1 defined disease progression (PD), unless there is unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation is met. | Drug: Capecitabine<br>* Oral<br>Drug: Paclitaxel<br>* IV<br>Drug: Nab-paclitaxel<br>* IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) in the HR+, HER2-low population | PFS by BICR according to response evaluation criteria in solid tumors (RECIST) 1.1 in the HR+, HER2-low population | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to approximately 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) in the HR+, HER2-low population | OS in the HR+, HER2-low population | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to approximately 56 months | 
| Objective response rate (ORR) in the HR+, HER2-low population | ORR by BICR and Investigator assessment according to RECIST 1.1 in the HR+, HER2-low population | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to approximately 56 months | 
| Duration of response (DoR) in the HR+, HER2-low population | DoR by BICR and Investigator assessment according to RECIST 1.1 in the HR+, HER2-low population | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to approximately 56 months | 
| TEAEs | TEAEs per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0, physical examinations, changes from baseline in laboratory findings, electrocardiograms (ECGs), ECHO/MUGA and vital signs | from the time of the subject signing the ICF until the follow-up period is completed (35 [+7] days after the last dose of study treatment | 
| SAEs | SAEs per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0, physical examinations, changes from baseline in laboratory findings, electrocardiograms (ECGs), ECHO/MUGA and vital signs | from the time of the subject signing the ICF until the follow-up period is completed (35 [+7] days after the last dose of study treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2-low, IHC 2+, BC, Breast Cancer