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

Overview

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 (also known as trastuzumab pamirtecan and DB-1303) in combination with BNT327 (also known as pumitamig and PM8002) 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 (Arms 1-4). No randomization is planned for any other cohort in Part 2.

Interventions

• Drug BNT323
  Intravenous infusion
• Drug BNT327
  Intravenous infusion

Primary outcome measures

• Part 1 - Occurrence of dose limiting toxicities (DLTs) [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 [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 [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) [Time frame: From the time of initiation of the first dose of IMP to last tumor assessment scan, i.e., up to 36 months.]

Secondary outcome measures (5)

• Part 1 - ORR [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) [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) [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) [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) [Time frame: From the time of initiation of the first dose of IMP to last tumor assessment scan, i.e., up to 36 months.]

Eligibility 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 as standard of care testing prior to study screening (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.

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 antibody-drug conjugates 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 received prior treatment with BNT323.
• Participants who received prior treatment with a programmed death-ligand 1 (PD-L1) / vascular endothelial growth factor (VEGF) bispecific antibody. Note: Prior treatment with programmed death 1 (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/Exclusion criteria apply.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 25 centers

• Beverly Hills Cancer Center — Beverly Hills
• Hoag Memorial Hospital Presbyterian — Newport Beach
• Hematology - Oncology Associates of the Treasure Coast — Port Saint Lucie
• University Cancer & Blood Center, LLC — Athens
• Winship Cancer Institute of Emory University — Atlanta
• University of Illinois Hospital & Health Sciences System — Chicago
• Brigitte Harris Cancer Pavilion BHCP — Detroit
• START Midwest, LLC — Grand Rapids
• … and 17 more centers

Turkey (Türkiye) · 10 centers

• Medical Park Seyhan Hospital — Adana
• Adana City Hospital — Adana
• Hacettepe University Medical Faculty — Ankara
• Dr Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital — Ankara
• Ankara City Hospital — Ankara
• Yeditepe Universitesi Kosuyolu Hastanesi — Istanbul
• Koc University Hospital — Istanbul
• IAU Medical Park Florya Hospital — Istanbul
• … and 2 more centers

China · 9 centers

• The First Affiliated Hospital of Bengbu Medical College — Bengbu
• Jilin Cancer Hospital — Changchun
• Sichuan Cancer Hospital — Chengdu
• Sichuan Provincial People's Hospital — Chengdu
• The First Affiliated Hospital of Chongqing Medical University — Chongqing
• Huizhou First Hospital — Huizhou
• Guangxi Medical University Affiliated Tumor Hospital — Nanning
• Fudan University Shanghai Cancer — Shanghai
• … and 1 more center

United Kingdom · 7 centers

• Addenbrooke s Hospital — Cambridge
• Velindre Cancer Centre — Cardiff
• St James's University Hospital — Leeds
• Royal Free Hospital — London
• Royal Marsden Hospital — London
• The Christie Hospital — Manchester
• Royal Marsden Hospital-Sutton — Sutton

Spain · 6 centers

• Hospital HM Nou Delfos — Barcelona
• NEXT Barcelona — Barcelona
• Hospital Clinic de Barcelona — Barcelona
• MD Anderson Cancer Centre — Madrid
• Centro Integral Oncologico Clara Campal — Madrid
• NEXT Madrid — Pozuelo de Alarcón

Italy · 4 centers

• Azienda Ospedaliera Universitaria Policlinico Sant Orsola Malpighi IRCCS — Bologna
• IEO Istituto Europeo di Oncologia — Milan
• Istituto Nazionale Tumori Fondazione G. Pascale — Naples
• Fondazione Policlinico Universitario Agostino Gemelli IRCCS — Roma

France · 3 centers

• Clinique Victor Hugo - Centre Jean Bernard — Le Mans
• ICO - Site René Gauducheau — Saint-Herblain
• Institut Claudius Regaud — Toulouse

Australia · 1 center

• Cancer Research SA — Adelaide

Canada · 1 center

• Sunnybrook Health Sciences Centre — Toronto

Georgia · 1 center

• LLC Arensia Exploratory Medicine — Tbilisi

Moldova · 1 center

• Institute of Oncology Arensia Exploratory Medicine — Chisinau

Identifiers

NCT: NCT06827236 · BNT323-03 · 2024-517979-20-00 · 1011776

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗