Breast Cancer
DB-1303-O-3002: A Phase 3 Study ofDB-1303 vs Investigator's Choice Chemotherapy in HER2-low, Hormone Receptor Positive, Metastatic Breast Cancer
Description
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 ofDB-1303 compared with investigator's choice single agent chemotherapy in the target population.
Approximately 532 subjects with HER2-low (IHC 2+/ISH and IHC 1 +) expression will be randomized 1: 1 across approximately 230 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. The details of study treatment and their schedules are provided below.
Inclusion Notes
For a full description of this trial, please go to the listing on www.clinicaltrials.gov
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:
Is advanced or metastatic
Has HER2low expression (IHC 1+ or IHC 2+/ISH-) as determined- by the central laboratory result from the most recently collected pre-randomization tumor sample (see inclusion criterion 3).
Was never previously reported as HER2-positive (IHC 3+ or ISH+) as per ASCO/CAP guidelines.
Is documented as HR+ (either ER and/or PgR positive [ER or PgR ≥1%]) per ASCO/CAP guidelines (Allison et al 2020). If a subject has had multiple ER/PgR results after metastatic disease, the most recent test result will be used to confirm eligibility.
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; the most recently collected pre-randomization tumor sample that meets the tissue requirements specified in protocol Section 8.6 is required. If no archival specimens are available, a newly acquired biopsy specimen is acceptable. (See Section 8.6 and the laboratory manual for additional details).
ECOG performance status of 0 or 1
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.
Of note with regards to the ≥2 lines of previous ET requirement:
Single agent anti-CDK4/6 therapy for the treatment of metastatic disease is considered a line of therapy
Disease progression on adjuvant ET or progression within 12 months of stopping ET can be treated as one prior line ET; these subjects will only require 1 additional line of ET in the metastatic setting
Any progression >12 months after discontinuing adjuvant ET or completing a course of adjuvant ET will not be considered a line of therapy
Single agent PARP inhibitor therapy is not considered a line of ET
Changes in dosing schedules, or discontinuations/re-starting of the same drugs or the addition of a targeted therapy to an ET without progression (e.g., adding a CDK4/6 to a current aromatase inhibitor regimen) will not be considered separate lines of therapy.
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 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.
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. For all parameters listed below, the most recent results available must be used to meet the inclusion criteria:
| Item | Laboratory Value |
|---|---|
| Hematology (without receiving erythropoietin [EPO], granulocyte colony-stimulating factor [G-CSF], or granulocyte-macrophage colony stimulating factor [GM-CSF] within 14 days and blood, red blood cell (RBC), platelet transfusion within 7 days prior to the sampling) | |
| Platelet count | ≥ 100,000/mm3 |
| Hemoglobin (Hb) | ≥ 9.0 g/dL |
| Absolute neutrophil count (ANC) | ≥ 1500/mm3 |
| Chemistry | |
| Creatinine | Creatinine clearance (CrCl) ≥ 30 mL/min (Cockcroft-Gault equation, see Section 11.6.2) |
| AST and ALT | ≤ 3 × ULN (if liver metastases are present, < 5 × ULN) |
| Total bilirubin | ≤1.5 ×ULN if no liver metastases or <3 × ULN in the presence of Gilbert’s syndrome or liver metastases at baseline |
| Serum albumin | ≥ 2.5 g/dL |
| Coagulation | |
| INR/PT and either partial thromboplastin or activated partial thromboplastin time (aPTT) | ≤ 1.5 × ULN |
Has adequate treatment washout period before randomization, defined as table below.
| Previous treatment | Washout Period |
|---|---|
| Hormonal therapy | ≥ 3 weeks |
| Immunotherapy (non-antibody-based therapy) | ≥ 3 weeks |
| Small molecule targeted agents | ≥ 2 weeks or 5 half-lives, whichever is longer |
| Antibody-based anti-cancer therapy | ≥ 4 weeks with the exception of receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors (e.g., denosumab for the treatment of complications resulting from bone metastases) |
| Chloroquine/Hydroxychloroquine | ≥ 3 months |
| Traditional Chinese Medicine with anti-tumor activity | ≥ 2 weeks |
| Major surgery | ≥ 4 weeks (or 2 weeks for low-invasive cases [e.g., colostomy]), excluding operations or surgeries that can be recovered within 14 days prior to randomization, and have been recovered by the investigator’s assessment, e.g., tumor biopsy, puncture, palliative operation, rectal/gastrostomy, etc. |
| Radiation therapy | ≥ 4 weeks (radiation therapy including palliative radiation therapy to chest). ≥2 weeks (palliative radiation therapy to other areas). |
| CAR-T | ≥2 weeks |
Evidence of post-menopausal status (Section 11.4.1) 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.
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 (Section 11.4.2) 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.
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, as described Section 11.4.2. 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.
Start Date
Tuesday, April 16, 2024
Principal / Contact Name
Mark Taylor, MD