Clinical trial NCT06827236: A Clinical Study to Find the Optimal Dose of an Investigational Treatment Called BNT323 When Used in Combination With Another Investigational Treatment, BNT327, and to Test if That Combination Treatment is Safe and Beneficial for Patients With Advanced Breast Cancer
Official title: A Phase I/II, Multi-site, Open-label, Two-part Trial to Evaluate the Efficacy, Safety, and Pharmacokinetics of BNT323 in Combination With BNT327 in Participants With Advanced Breast Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Advanced Breast Cancer
Metastatic Breast Cancer
Keywords: Breast Cancer (BC)
Human epidermal growth factor receptor 2 (HER2)
IHC scores 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)
Lead sponsor: BioNTech SE
Sponsor class: INDUSTRY
Collaborators: name: DualityBio Inc.
name: Biotheus Inc.
First posted: 2025-02-14
Enrollment: 320
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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-low (immunohistochemistry \[IHC\] 1+ or IHC 2+/in situ hybridization -), HER2-ultralow (IHC 0, with membrane staining), or HER2-null breast cancer (BC).

Detailed description: The study consists of two parts:

* Part 1 - Dose escalation: In Part 1 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: Part 2 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 three cohorts, i.e., Cohorts 1 (dose optimization cohort), and Cohorts 2 and 3 (exploratory cohorts).

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.

Eligibility criteria: Inclusion Criteria (applicable to all participants and all parts unless otherwise specified):

* Have pathologically documented BC that:

  * Is advanced or metastatic
  * Has a confirmed HER2 status as determined by the local laboratory (Part 1) or the central laboratory (Part 2) 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+, or triple-negative BC) as per current American Society of Clinical Oncology/College of American Pathologists guidelines
* Have measurable disease defined by RECIST 1.1
* Has left ventricular ejection fraction ≥50% by either echocardiography or multi-gated acquisition (scanning) within 28 days before randomization/enrollment.

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 exatecans.
* 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.
  * 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/Exclusion criteria may apply.

Primary outcomes:
measure: Part 1 - Occurrence of dose limiting toxicities (DLTs)
timeFrame: 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
measure: 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
timeFrame: From the time of initiation of the first dose of IMP to 90 days after the last IMP dose
measure: Occurrence of dose interruption, reduction, and discontinuation due to TEAEs
timeFrame: From the time of initiation of the first dose of IMP to 90 days after the last IMP dose
measure: Part 2 - Objective response rate (ORR)
timeFrame: From the time of initiation of the first dose of IMP to end of study, i.e., up to 54 months
Secondary outcomes:
measure: Part 1 - ORR
timeFrame: From the time of initiation of the first dose of IMP to end of study, i.e., up to 54 months
measure: Part 2 - Duration of response (DoR)
timeFrame: From the time of initiation of the first dose of IMP to end of study, i.e., up to 54 months
measure: Part 2 - Disease control rate (DCR)
timeFrame: From the time of initiation of the first dose of IMP to end of study, i.e., up to 54 months
measure: Part 2 - Time to response (TTR)
timeFrame: From the time of initiation of the first dose of IMP to end of study, i.e., up to 54 months
measure: Part 2 Cohort 1 only - Progression free survival (PFS)
timeFrame: From the time of initiation of the first dose of IMP to end of study, i.e., up to 54 months
Other outcomes:
Locations:
city: Port Saint Lucie
country: United States
facility: Hematology - Oncology Associates of the Treasure Coast
state: Florida
city: Chisinau
country: Moldova, Republic of
facility: Institute of Oncology Arensia Exploratory Medicine
Study officials:
affiliation: BioNTech SE
name: BioNTech Responsible Person
role: STUDY_DIRECTOR
References: