Locally Advanced Breast Cancer, Unresectable Breast Carcinoma, Metastatic Breast Cancer
Conditions
Keywords
Breast Cancer (BC), Human epidermal growth factor receptor 2 (HER2), IHC scores 0, 1+, 2+, and 3+, Antibody drug conjugate (ADC), Programmed Death-1 (PD-1), Programmed Death Ligand-1 (PD-L1), Programmed Death-1 monoclonal antibodies, Anti vascular endothelial growth factor-A (anti-VEGF-A)
Brief summary
This is a Phase I/II, multi-site, open-label, two-part study designed to evaluate the efficacy, safety, optimized dose and contribution of components of BNT323 in combination with BNT327 in participants with hormone receptor-positive (HR+) or hormone receptor-negative (HR-), Human epidermal growth factor receptor (HER)2-positive, HER2-low (immunohistochemistry \[IHC\] 1+ or IHC 2+/in situ hybridization -), HER2-ultralow (IHC 0, with membrane staining) or HER2-null breast cancer (BC), or triple-negative breast cancer (TNBC).
Detailed description
The study consists of two parts: * Part 1 - Dose escalation: In this part of the study, participants with histologically confirmed, chemotherapy-pretreated advanced HR+, HER2-low or HER2-ultralow BC will receive BNT323 in combination with BNT327 (BNT323 + BNT327) in a dose escalation design. This will define the recommended Phase 2 dose (RP2D) for the BNT323 + BNT327 combination therapy. * Part 2 - Dose optimization and exploratory cohorts: This part of the study will be an expansion phase, aiming to evaluate the efficacy and safety of the optimal dose combination and providing a more robust comparison against the other treatments. It will start once the enrollment in Part 1 is completed and the sponsor in conjunction with the Safety Review Committee has assessed available Part 1 efficacy and safety data. Part 2 of the study will have four cohorts, i.e., Cohorts 1 (dose optimization cohort), and Cohorts 2, 3, and 4 (exploratory cohorts). Recruitment to Cohorts 2, 3, and 4 will begin with RP2D from Part 1 and in parallel to randomization in Cohort 1. Randomization is planned for Cohort 1 in Part 2, i.e., participants will be randomized in 2:2:1:1 ratio into one of the four arms (RP2D of BNT323 + BNT327, lower dose of RP2D of BNT323 + BNT327, BNT323 monotherapy, and BNT327 monotherapy). No randomization is planned for any other cohort in Part 2.
Sponsors
BioNTech SE
DualityBio Inc.
Biotheus Inc.
BioNTech (Shanghai) Pharmaceuticals Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria (applicable to all participants and all parts unless otherwise specified): * Have pathologically documented BC that: * Is locally advanced, unresectable or metastatic. * Has a confirmed HER2 status as determined by the local laboratory (Part 1, Part 2 Cohorts 2 and 4) or the central laboratory (Part 2, Cohorts 1 and 3) from the most recently collected pre-randomization tumor sample. * Has a documented history of HER2 expression consistent with the subgroup definitions (i.e., HER2-low, HER2-ultralow, HER2-null, HER2-positive, or TNBC) as per current American Society of Clinical Oncology/College of American Pathologists guidelines. * Have measurable disease defined by RECIST v1.1. * Has left ventricular ejection fraction ≥55% by either echocardiography or multi-gated acquisition (scanning) within 28 days before randomization/enrollment. Key
Exclusion criteria
* Have history of small bowel obstruction requiring hospitalization within the past 3 months prior to the first dose of IMP. * Have an uncontrolled intercurrent illness that would limit compliance with study requirement or substantially increase risk of incurring adverse events. * Have clinically uncontrolled pleural effusion, ascites or pericardial effusion requiring drainage, peritoneal shunt, or cell-free concentrated ascites reinfusion therapy within 2 weeks prior to randomization/enrollment. * Have a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, have current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening. * Had prior treatment with topoisomerase I inhibitors, including ADCs with topoisomerase I inhibitor payloads such as trastuzumab deruxtecan. * Have received any of the following therapies or drugs prior to the initiation of the study: * Participants who have previously been randomized to or received treatment in a previous study with BNT323, regardless of treatment assignment. * Participants who received prior treatment with a PD-L1/VEGF bispecific antibody. Note: Prior treatment with PD-1/VEGF bispecific antibodies, PD-1/PD-L1 inhibitors or anti-VEGF therapies are permitted. * Have received other systemic immunostimulatory agents or immunosuppressive therapies (such as interferon-α, interleukin-2, or methotrexate) within 4 weeks prior to the initiation of study treatment or are within five half-lives of the treatment drug (whichever is longer). Exception: excluding local, intranasal, intraocular, intra-articular or inhaled corticosteroids, short term use (≤7 days) of corticosteroids for prophylaxis (e.g., prevention of contrast agent allergy) or treatment of non-autoimmune conditions (e.g., delayed hypersensitivity reactions caused by exposure to allergens). * Have received systemic corticosteroids (at a dosage greater than 10 mg/day of prednisone or an equivalent dose of other corticosteroids) within 3 weeks prior to the initiation of study treatment. NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1 - Occurrence of dose limiting toxicities (DLTs) | During the DLT evaluation period (Cycle 1), i.e., the time of initiation of the first dose of investigational medicinal product (IMP) up to 21 days | By dose level. |
| Occurrence of Treatment-emergent adverse events (TEAEs), Grade ≥3 TEAEs, serious adverse events (SAEs), treatment-related TEAEs, treatment-related Grade ≥3 TEAEs, and treatment-related SAEs | From the time of initiation of the first dose of IMP to 90 days after the last IMP dose | In Part 1 by dose level. In Part 2 by cohort and arm. |
| Occurrence of dose interruption, reduction, and discontinuation due to TEAEs | From the time of initiation of the first dose of IMP to 90 days after the last IMP dose | In Part 1 by dose level. In Part 2 by cohort and arm. |
| Part 2 - Objective response rate (ORR) | From the time of initiation of the first dose of IMP to last tumor assessment scan, i.e., up to 36 months. | ORR defined as the proportion of participants in whom a confirmed complete response (CR) or partial response (PR) (per Response Evaluation Criteria in Solid Tumors version 1.1 \[RECIST v1.1\] based on the investigator's assessment) is observed as best overall response. By cohort and arm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1 - ORR | From the time of initiation of the first dose of IMP to last tumor assessment scan, i.e., up to 36 months. | ORR defined as the proportion of participants in whom a confirmed CR or PR (per RECIST v1.1 based on the investigator's assessment) is observed as best overall response. By dose level. |
| Part 2 - Duration of response (DoR) | From the time of initiation of the first dose of IMP to last tumor assessment scan, i.e., up to 36 months. | DoR defined as the time from first objective response (CR or PR per RECIST v1.1 based on the investigator's assessment) to first occurrence of objective tumor progression (progressive disease \[PD\], per RECIST v1.1 based on the investigator's assessment) or death from any cause, whichever occurs first. By cohort and arm. |
| Part 2 - Disease control rate (DCR) | From the time of initiation of the first dose of IMP to last tumor assessment scan, i.e., up to 36 months. | DCR defined as the proportion of participants with confirmed CR, PR, or stable disease (per RECIST v1.1 based on the investigator's assessment) as best overall response. By cohort and arm. |
| Part 2 - Time to response (TTR) | From the time of initiation of the first dose of IMP to last tumor assessment scan, i.e., up to 36 months. | TTR defined as the time from first dose of IMP to first objective response (CR or PR per RECIST v1.1 based on the investigator's assessment). By cohort and arm. |
| Part 2 Cohort 1 only - Progression free survival (PFS) | From the time of initiation of the first dose of IMP to last tumor assessment scan, i.e., up to 36 months. | PFS based on the investigator's assessment defined as the time from first dose of IMP to the first objective tumor progression (PD per RECIST v1.1) or death from any cause, whichever occurs first. By arm. |
Countries
Canada, China, France, Georgia, Moldova, Turkey (Türkiye), United Kingdom, United States
Contacts
CONTACTBioNTech clinical trials patient information
STUDY_DIRECTORBioNTech Responsible Person
BioNTech SE
Outcome results
None listed