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).
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
380
Beverly Hills Cancer Center
Beverly Hills, California, United States
RECRUITINGHematology - Oncology Associates of the Treasure Coast
Port Saint Lucie, Florida, United States
RECRUITINGWinship Cancer Institute of Emory University
Atlanta, Georgia, United States
RECRUITINGSTART Midwest, LLC
Grand Rapids, Michigan, United States
Part 1 - Occurrence of dose limiting toxicities (DLTs)
By dose level.
Time frame: 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
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
In Part 1 by dose level. In Part 2 by cohort and arm.
Time frame: From the time of initiation of the first dose of IMP to 90 days after the last IMP dose
Occurrence of dose interruption, reduction, and discontinuation due to TEAEs
In Part 1 by dose level. In Part 2 by cohort and arm.
Time frame: From the time of initiation of the first dose of IMP to 90 days after the last IMP dose
Part 2 - Objective response rate (ORR)
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.
Time frame: From the time of initiation of the first dose of IMP to last tumor assessment scan, i.e., up to 36 months.
Part 1 - ORR
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.
Time frame: From the time of initiation of the first dose of IMP to last tumor assessment scan, i.e., up to 36 months.
Part 2 - Duration of response (DoR)
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.
Time frame: From the time of initiation of the first dose of IMP to last tumor assessment scan, i.e., up to 36 months.
Part 2 - Disease control rate (DCR)
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.
Time frame: From the time of initiation of the first dose of IMP to last tumor assessment scan, i.e., up to 36 months.
Part 2 - Time to response (TTR)
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.
Time frame: From the time of initiation of the first dose of IMP to last tumor assessment scan, i.e., up to 36 months.
Part 2 Cohort 1 only - Progression free survival (PFS)
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.
Time frame: From the time of initiation of the first dose of IMP to last tumor assessment scan, i.e., up to 36 months.
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Saint Luke's Hospital of Kansas City
Kansas City, Missouri, United States
RECRUITINGWashington University School of Medicine
St Louis, Missouri, United States
RECRUITINGSummit Medical Group
Florham Park, New Jersey, United States
RECRUITINGMemorial Sloan Kettering Hospital
New York, New York, United States
RECRUITINGSouth Texas Accelerated Research Therapeutics (START), LLC
San Antonio, Texas, United States
RECRUITINGSunnybrook Health Sciences Centre
Toronto, Canada
RECRUITING...and 29 more locations