Metastatic Breast Cancer
Conditions
Keywords
HER2-low, IHC 2+, BC, Breast Cancer
Brief summary
The goal of this clinical trial is to assess the efficacy of DB-1303/BNT323 compared with investigator's choice chemotherapy in terms of progression-free survival (PFS) by blinded independent central review (BICR) in the HR+, HER2-low (immunohistochemistry \[IHC\]2+/in situ hybridization \[ISH\]- and IHC 1+) population.
Detailed description
The study is a Phase III, Randomized, Multi-center, Open-label study in HER2-low, HR+ metastatic breast cancer subjects whose disease has progressed on at least 2 lines of prior ET or within 6 months of first line ET + Cyclin-dependent kinase (CDK) 4/6 inhibitor in the metastatic setting. The primary purpose of the study is to determine the efficacy and safety of DB-1303/BNT323 compared with investigator's choice single agent chemotherapy in the target population. Approximately 532 subjects with HER2 IHC 2+/ISH- and IHC 1+ (HER2-low\] expression will be randomized 1:1 across approximately 255 centers globally to receive either DB-1303 or investigator's choice single agent chemotherapy (capecitabine, paclitaxel or nab-paclitaxel) until Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 defined disease progression (PD), unless there is unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation is met.
Interventions
Sponsors
DualityBio Inc.
BioNTech SE
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1\. 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). 2\. 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 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines. 4. Is documented as HR+ (either estrogen receptor \[ER\] and/or progesterone receptor \[PgR\] 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, 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; 4\. Eastern Cooperative Oncology Group performance status of 0 or 1. 5\. 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, mammalian target of rapamycin \[mTOR\] or phosphoinositide 3-kinase \[PI3-K\] 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 (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). 9\. Has LVEF ≥ 50% by either echocardiography (ECHO) or multiple-gated acquisition (MUGA) within 28 days before randomization. 10\. Adequate organ and bone marrow function within 14 days before randomization. 11\. Has adequate treatment washout period before randomization. 12\. 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. For women of childbearing potential, a negative result for serum pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be available at the screening visit and urine beta-human chorionic gonadotropin (β-HCG) pregnancy test prior to each administration of study treatment. Women of childbearing potential are defined as those who are not surgically sterile (i.e., underwent bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal. 13\. 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. Not all methods of contraception are highly effective. Abstinence is acceptable only as true abstinence when this is in line with the preferred and usual lifestyle of the subject for the duration of the study treatment and the drug washout period (7 months). Periodic abstinence (e.g., calendar ovulation, symptothermal, post ovulation methods), the rhythm method, and the withdrawal method are not acceptable methods of contraception. Female subjects must not donate ova, or retrieve for their own use, from the time of screening and throughout the study treatment period, and for at least 7 months after the last dose of study treatment. They should refrain from breastfeeding throughout this time. Preservation of ova may be considered prior to randomization in this study. 14\. 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). Abstinence is acceptable only as true abstinence when this is in line with the preferred and usual lifestyle of the subject for the duration of the study treatment and the drug washout period. Periodic abstinence (e.g., calendar ovulation, symptothermal, post ovulation methods), the rhythm method, and the withdrawal method are not acceptable methods of contraception. It is strongly recommended for the female partners of a male subject also use at least one highly effective method of contraception throughout this period. In addition, male subjects should refrain from fathering a child or donating sperm throughout the duration of the study 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). Preservation of sperm should be considered prior to randomization in this study. 15\. Must be able and willing to comply with the protocol requirements and must sign and date the informed consent form prior to any screening evaluations.
Exclusion criteria
1. Ineligible for all options in the investigator's choice chemotherapy arm. 2. 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 adverse events or compromise the ability of the subject to give written informed consent. 3. 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. 4. Uncontrolled or significant cardiovascular disease 5. 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 to have these diseases by imaging at screening. 6. 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. 7. Previous treatment with anti-HER2 therapy. 8. Prior treatment with antibody-drug conjugate that comprised an exatecan derivative that is a topoisomerase I inhibitor. 9. Prior randomization or treatment in a previous DB-1303/BNT323 study regardless of treatment assignment. 10. 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. 11. 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). 12. 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. NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival (PFS) in the HR+, HER2-low population | Up to approximately 51 months | PFS by BICR according to RECIST 1.1 in the HR+, HER2-low population |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival (OS) in the HR+, HER2-low population | Up to approximately 51 months | OS in the HR+, HER2-low population |
| Objective response rate (ORR) in the HR+, HER2-low population | Up to approximately 51 months | ORR by BICR and Investigator assessment according to RECIST 1.1 in the HR+, HER2-low population |
| PFS by Investigator assessment | Up to approximately 51 months | PFS by Investigator assessment according to RECIST 1.1 in the HR+, HER2-low population |
| Duration of response (DoR) in the HR+, HER2-low population | Up to approximately 51 months | DoR by BICR and Investigator assessment according to RECIST 1.1 in the HR+, HER2-low population |
| Treatment-emergent adverse events (TEAEs) | from the time of the subject signing the informed consent form (ICF) until the follow-up period is completed (35 days after the last dose of study treatment | TEAEs per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 |
| Serious adverse events (SAEs) | from the time of the subject signing the ICF until the follow-up period is completed (35 days after the last dose of study treatment | SAEs per NCI CTCAE v5.0 |
| Patient reported outcomes (PROs): European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) - C30 | Up to approximately 51 months | Change from baseline in the functioning/symptom/global quality of life (QoL) subscales of EORTC QLQ-C30. Scale scores range from 0-100. For functioning and global QoL scales, higher scores indicate better functioning or global health status. For symptom scales, higher scores indicate greater symptom burden. |
| Patient reported outcomes (PROs): EORTC QLQ-BR45 | Up to approximately 51 months | Change from baseline in the functioning/symptom subscales of EORTC QLQ-BR45. Scale scores range from 0-100. For functioning scales, higher scores indicate better functioning. For symptom scales, higher scores indicate greater symptom burden. |
| Patient reported outcomes (PROs): European Quality of Life Five Dimension Five Level Scale (EQ-5D-5L) | Up to approximately 51 months | Change from baseline in EQ-5D-5L health state utility index score and Visual Analogue Scale (VAS) score. VAS score range from 0-100, higher scores indicate better health status. |
| European Quality of Life Five Dimension Five Level Scale (EQ-5D-5L) | Up to approximately 51 months | EQ-5D-5L health state utility index score and Visual Analogue Scale (VAS) score. The change from baseline value will be reported. |
Countries
Argentina, Australia, Belgium, Canada, China, France, Germany, Hong Kong, Hungary, Israel, Italy, Poland, South Korea, Spain, Turkey (Türkiye), United Kingdom, United States
Contacts
PRINCIPAL_INVESTIGATORJoyce O'Shaughnessy, PHD
Texas Oncology - Baylor Charles A. Sammons Cancer center
Outcome results
None listed