Phase 3 Randomized Study of DB-1303 Versus Investigator's Choice Chemotherapy in HER2-low, HR+ Metastatic Breast Cancer Post-Endocrine Therapy
- Trial ID
- 2023-507333-17-00
- Protocol
- DB-1303-O-3002
- Sponsor
- Dualitybio Inc.
Trial statistics
Objectives
The primary objective of this study is to evaluate the **efficacy** of DB-1303 compared with investigator's choice chemotherapy in terms of a hazard ratio (HR) for progression-free survival (PFS) as assessed by blinded independent central review (BICR) in patients with hormone receptor-positive (HR+), HER2-low metastatic breast cancer. This objective is clinically relevant as it aims to determine the potential of DB-1303 to delay disease progression in a specific patient population where current treatment options may be limited.
Secondary objectives include:
- Assessing the efficacy of DB-1303 followed by any subsequent anti-cancer therapy compared with investigator's choice chemotherapy followed by any subsequent anti-cancer therapy in terms of HR for overall survival (OS) in the HR+, HER2-low population.
- Further evaluating the efficacy of DB-1303 compared with investigator's choice chemotherapy in terms of PFS by investigator assessment, objective response rate (ORR), and duration of response (DoR) by BICR and investigator assessment in the HR+, HER2-low population.
- Assessing the safety and tolerability profile of DB-1303 compared with investigator's choice chemotherapy.
- Evaluating symptoms, functioning, and health-related quality of life (HRQoL) in subjects treated with DB-1303 compared with investigator's choice single-agent chemotherapy.
- Assessing the impact of treatment and disease state on health utility using the EQ-5D-5L.
Participants
The clinical trial involves a total of **442 participants** diagnosed with **HER2-low, Hormone Receptor Positive, Metastatic Breast Cancer**. The study population includes both male and female adults aged 18 years and older, with an emphasis on those who have adequate organ and bone marrow function. Participants were selected based on specific criteria, including the requirement for a pathologically documented advanced or metastatic breast cancer with HER2-low expression and hormone receptor positivity. The trial excludes individuals with prior chemotherapy for advanced or metastatic breast cancer, although those who have undergone chemotherapy in the neo-adjuvant or adjuvant setting with a disease-free interval of more than 12 months are eligible. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and a life expectancy of at least 12 weeks. Lifestyle considerations such as the use of effective contraception for participants of childbearing potential are mandated. The trial does not include a vulnerable population, ensuring a focus on individuals who meet the health and disease-specific criteria outlined in the study protocol.
Plans and Procedures
The clinical trial is a **Phase 3**, randomized, multi-center, open-label study designed to evaluate the efficacy and safety of **DB-1303** compared to investigator's choice chemotherapy in patients with **HER2-low, hormone receptor-positive, metastatic breast cancer**. The primary objective is to assess progression-free survival (PFS) as determined by blinded independent central review (BICR) in the target population. The trial will involve a comparison between DB-1303 and standard chemotherapy options, including **paclitaxel**, **capecitabine**, and **paclitaxel albumin-bound**. The study is expected to conclude by May 27, 2025, with recruitment starting on March 23, 2024.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as age, organ function, and previous treatment history. The trial will include follow-up visits to monitor treatment response and safety, with assessments conducted according to **RECIST 1.1** criteria. The end-of-study visit will evaluate the overall outcomes and any adverse events experienced during the trial. The expected duration of participant involvement is up to 20 weeks, depending on the treatment arm and individual response to therapy.
Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they choose to withdraw consent. The trial will also monitor secondary endpoints, including overall survival (OS), objective response rate (ORR), and duration of response (DoR), alongside patient-reported outcomes and quality of life measures. Safety assessments will include monitoring of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
Treatment
The clinical trial involves the administration of several treatments, including both experimental and comparator medications. The experimental medication, **DB-1303**, is an antibody-drug conjugate administered via **intravenous infusion**. The pharmaceutical form is specified as an intravenous infusion, and the dosing is based on **mg/kg**. The maximum treatment period for DB-1303 is 12 weeks. Participant compliance will be monitored through regular assessments and adherence checks.
**Paclitaxel** is used as a comparator treatment in this study. It is provided as a concentrate for solution for infusion and administered through **intravenous infusion**. The dosage is calculated in **mg/m²**, with a maximum daily dose of 80 mg/m². The treatment period extends up to 20 weeks. Monitoring of administration and participant adherence will be conducted throughout the trial.
Another comparator, **Capecitabine**, is administered orally in the form of film-coated tablets. The dosage is also based on **mg/m²**, with a maximum daily dose of 1250 mg/m². The treatment duration is set for 20 weeks. Compliance with the oral administration schedule will be tracked through participant diaries and pill counts.
**Paclitaxel albumin-bound** is included as a biologic comparator, provided as a dispersion for infusion. It is administered via **intravenous infusion** with a dosage of 100 mg/m² per day, and the treatment period is 20 weeks. Adherence to the infusion schedule will be monitored by healthcare professionals at the study sites.
All treatments are administered under the supervision of qualified healthcare professionals, and participant compliance is ensured through structured monitoring protocols. The trial aims to evaluate the efficacy of DB-1303 compared to the investigator's choice of chemotherapy in patients with HER2-low, hormone receptor-positive metastatic breast cancer. The study design includes regular assessments to ensure adherence to dosing schedules and to monitor any adverse effects or deviations from the protocol.
Efficacy
The efficacy of the investigational product **DB-1303** will be assessed in a Phase 3, randomized, multi-center, open-label clinical trial involving patients with **metastatic breast cancer** characterized by low expression of the human epidermal growth factor receptor 2 (HER2-low) and hormone receptor positivity (HR+). The primary endpoint for evaluating efficacy is progression-free survival (PFS), which will be assessed by blinded independent central review (BICR) according to the response evaluation criteria in solid tumors (RECIST) version 1.1. This assessment will focus on the HR+, HER2-low population.
Secondary endpoints include overall survival (OS), objective response rate (ORR), and duration of response (DoR) as evaluated by both BICR and investigator assessment, also according to RECIST 1.1. Additional secondary endpoints involve the evaluation of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Patient-reported outcomes (PROs) will be measured using changes from baseline in EORTC QLQ-C30 and EORTC QLQ-BR45 scale scores, as well as the EQ-5D-5L health state utility index. The schedule for these assessments will be aligned with the trial protocol, ensuring systematic data collection and analysis throughout the study duration.
Inclusion and Exclusion Criteria
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 HER2low expression (IHC 1+ or IHC 2+/ISH-) 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).
- Must have an adequate tumor tissue sample available for assessment of HER2 by central laboratory, in formalin fixation and paraffin embedding (FFPE) blocks based on a mandatory FFPE tumor sample preferably obtained at the time of metastatic disease or later.
- ECOG performance status of 0 or 1
- Must have had either: 1) 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 2) 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.
- 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.
- Life expectancy ≥12 weeks at screening.
- Subjects must have at least one measurable lesion as defined per RECIST v1.1, (For bone-only disease, subjects with lytic or mixed lytic bone lesions that can be measured by CT or MRI are eligible; subjects with sclerotic/osteoblastic bone lesions are not eligible).
- Has LVEF ≥ 50% by either echocardiography (ECHO) or multiple-gated acquisition (MUGA) within 28 days before randomization.
- Adequate organ and bone marrow function within 14 days before randomization.
- Has adequate treatment washout period before randomization, as defined in the protocol.
- Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential who are sexually active with a non-sterilized male partner.
- 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.
- 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 (4 months after the last dose of DB-1303, 6 months after the last dose of paclitaxel or nab-paclitaxel, and 3 months after the last dose of capecitabine).
Exclusion Criteria
- Ineligible for all options in the investigator’s choice chemotherapy arm. Subjects with contraindications to capecitabine, paclitaxel, and nab-paclitaxel treatment, per local prescribing information, cannot be enrolled to the study.
- Active primary immunodeficiency, known human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection. Subjects should be tested for HIV prior to randomization if required by local regulations or by the institutional review board (IRB)/independent ethics committee (IEC)
- Receipt of live, attenuated vaccine (mRNA and replication-deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of study treatment. Note: Subjects, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of study treatment.
- Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline or Grade ≤ 2 anemia.
- Pregnant or breastfeeding female subjects, or subjects who are planning to become pregnant.
- Subjects with a known hypersensitivity to either the drug substances, inactive ingredients in the drug product or other monoclonal antibodies.
- History of another primary malignancy within 3 years, except adequately resected non melanoma skin cancer, curatively treated in situ disease, other solid tumors curatively treated, or contralateral breast cancer.
- 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
- Participation in another clinical study with a study treatment administered recently (i.e. the washout period is less than five half-lives prior to the first dose of study treatment or 30 days prior to the first dose of study treatment if the half-life is unknown) or concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow up period of an interventional study. Of note, tissue screening for this study while a subject is on follow-up in another clinical study is acceptable.
- Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, uncontrolled or significant cardiovascular disease, serious chronic gastrointestinal conditions associated with diarrhoea, 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.
- 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.
- Clinically uncontrolled pleural effusion, ascites or pericardial effusion requiring repeated drainage, peritoneal shunt or cell-free concentrated ascites reinfusion therapy within 2 weeks prior to the randomization.
- Uncontrolled or significant cardiovascular disease
- Has a medical history of interstitial lung diseases (e.g., non-infectious interstitial pneumonia, pneumonitis /, pulmonary fibrosis, and radiation pneumonitis, which needs glucocorticoids and antibiotics) or current interstitial lung diseases or who are suspected have these diseases 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.
- Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (i.e., pulmonary emboli within three months prior to study randomization, severe asthma, severe chronic obstructive pulmonary disorder [COPD], restrictive lung disease, significant pleural effusion etc.), and any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (i.e., rheumatoid arthritis, Sjogren’s syndrome, sarcoidosis etc.), and/or prior pneumonectomy (complete).
- Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals within 14 days prior to the first dose of study treatment.
- Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Subjects with clinically inactive brain metastases may be included in the study. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants within 7 days prior to first study dose may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study randomization.
- Individuals who are dependent on the Sponsor, clinical site, or Investigator (e.g., is an employee of the Sponsor or the clinical trial site, a dependent of the Investigator, or any site staff member otherwise supervised by the Investigator).
- Individuals who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities, in accordance with local regulations.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 23 Mar 2024 | 10 |
 France | Not Recruiting | 23 Mar 2024 | 25 |
 Germany | Not Recruiting | 23 Mar 2024 | 7 |
 Hungary | Not Recruiting | 23 Mar 2024 | 7 |
 Italy | Not Recruiting | 23 Mar 2024 | 14 |
 Poland | Not Recruiting | 23 Mar 2024 | 7 |
 Spain | Not Recruiting | 23 Mar 2024 | 7 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CAPECITABINE | Comparator | — | ORAL | 1250 | 20 | SUB12474MIG |
PACLITAXEL ALBUMIN-BOUND | Comparator | — | INTRAVENIOUS INFUSION | 100 | 20 | SUB127678 |
PACLITAXEL ALBUMIN-BOUND | Comparator | — | INTRAVENIOUS INFUSION | 100 | 20 | SUB127678 |
PACLITAXEL | Comparator | — | INTRAVENIOUS INFUSION | 80 | 20 | SUB09583MIG |
DB-1303 | Test | INTRAVENOUS INFUSION | INTRAVENIOUS INFUSION | 0 | 12 | PRD10812581 |
CAPECITABINE | Comparator | — | ORAL | 1250 | 20 | SUB12474MIG |
CAPECITABINE | Comparator | — | ORAL | 1250 | 20 | SUB12474MIG |
PACLITAXEL | Comparator | — | INTRAVENIOUS INFUSION | 80 | 20 | SUB09583MIG |
CAPECITABINE | Comparator | — | ORAL | 1250 | 20 | SUB12474MIG |