A Clinical Study to Investigate the Efficacy and Safety of an Investigational Combination Therapy With BNT324 and BNT327 in Patients With Advanced Lung Cancer

A Phase Ib/II, Multi-site, Open-label, Two-part Trial to Evaluate the Efficacy, Safety, Pharmacokinetics, and Recommended Combination Dose of BNT324 With BNT327 in Participants With Advanced Lung Cancer

This study aims to investigate the combination of BNT324, a B7-H3 antibody-drug conjugate (ADC) with BNT327, a programmed death-ligand 1 (PD-L1) and vascular endothelial growth factor (VEGF) bispecific antibody, in participants with advanced/metastatic or relapsed/progressive small cell lung cancer (SCLC) and non small cell lung cancer (NSCLC).

Study Overview

• Status: Recruiting
• Conditions: Advanced Lung Cancer
• Intervention / Treatment: Biological: BNT324; Biological: BNT327

Detailed Description

This is a two-part study designed to evaluate and establish two safe combination dose levels (recommended Phase 2 dose [RP2D] and a lower/another combination dose level [RP2D-1]) of BNT324 with BNT327 (Part 1), to determine the optimal combination dose (dose optimization [DO]) in NSCLC and SCLC lead indication cohorts at the RP2D and RP2D-1, to evaluate the preliminary efficacy in selected lung cancer cohorts at the highest combination dose level (in a signal seeking Part 2), and to confirm the clinical efficacy of BNT324 in combination with BNT327 at the optimal dose level in participants with advanced lung cancer in expansion cohorts (proof-of-concept [POC] cohorts).

The study consists of a screening period, a treatment period, a safety follow-up period, and a long-term survival follow-up period.

In Part 1 participants with histologically or cytologically confirmed relapsed or progressive lung cancer (both SCLC and NSCLC are eligible) will receive BNT324 in combination with BNT327 using a dose escalation design.

In Part 2 of the study, BNT324 will be studied in combination with BNT327 at the RP2D compared to RP2D-1 in participants with advanced metastatic treatment-naïve NSCLC (DO Cohort 1) and relapsed/progressive SCLC after failure of cytotoxic chemotherapy with or without immuno-oncology (IO) (DO Cohort 2). The totality of the available data (e.g., safety, efficacy, pharmacokinetics etc.) will be reviewed to select the optimal dose. After the optimal dose is selected, additional participants in each cohort may be enrolled in the selected optimal dose.

In the signal seeking cohorts (Cohort 3-7), participants will receive BNT324 in combination with BNT327 at the RP2D from Part 1.

A predefined number of participants in Part 2 Cohort 1 and Cohort 2 will be randomized to one of the two dose levels (RP2D and RP2D-1) selected from Part 1 in a 1:1 ratio. Additional participants in Part 2 Cohort 1 and Cohort 2 may be enrolled in the selected optimal dose to further assess the efficacy and safety profile.

No randomization is planned for any other cohort in Part 2 or Part 1.

• Study Type: Interventional
• Enrollment (Estimated): 594
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: BioNTech clinical trials patient information; Phone Number: +49 6131 9084; Email: patients@biontech.de

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Recruiting
      • Chris O'Brien Lifehouse
  • South Australia
    • Bedford Park, South Australia, Australia, 5042
      • Recruiting
      • Flinders Medical Centre
  • Victoria
    • Bendigo, Victoria, Australia, 3550
      • Recruiting
      • Bendigo Hospital
    • Geelong, Victoria, Australia, 3220
      • Recruiting
      • Barwon Health
    • Saint Albans, Victoria, Australia, 3021
      • Recruiting
      • Sunshine Hospital
  • Western Australia
    • Subiaco, Western Australia, Australia, 6008
      • Recruiting
      • St John of God Subiaco Hospital
• China
  • Anhui
    • Hefei, Anhui, China, 230088
      • Recruiting
      • Anhui Provincial Cancer Hospital
  • Beijing Municipality
    • Beijing, Beijing Municipality, China, 100142
      • Recruiting
      • Beijing Cancer Hospital
    • Beijing, Beijing Municipality, China, 102200
      • Recruiting
      • Beijing GoBroad Hospital
  • Fujian
    • Fuzhou, Fujian, China, 350001
      • Recruiting
      • Fujian Medical University Union Hospital
    • Fuzhou, Fujian, China, 350014
      • Recruiting
      • Fujian Cancer Hospital
  • Guangxi Zhuang
    • Nanning, Guangxi Zhuang, China, 530021
      • Recruiting
      • Guangxi Medical University Cancer Hospital
  • Henan
    • Weihui, Henan, China, 453100
      • Recruiting
      • The First Affiliated Hospital of Xinxiang Medical University
    • Zhengzhou, Henan, China, 450003
      • Recruiting
      • Henan Provincial Cancer Hospital
  • Hubei
    • Jingzhou, Hubei, China, 434000
      • Recruiting
      • Jingzhou First People's Hospital
    • Xiangyang, Hubei, China, 441021
      • Recruiting
      • Xiangyang Central Hospital
    • Yichang, Hubei, China, 443000
      • Recruiting
      • Yichang Central People's Hospital
  • Hunan
    • Changsha, Hunan, China, 410005
      • Recruiting
      • Hunan Province People's Hospital
  • Jiangsu
    • Nanjing, Jiangsu, China, 210029
      • Recruiting
      • Nanjing Chest Hospital
  • Jiangxi
    • Nanchang, Jiangxi, China, 330006
      • Recruiting
      • The Second Affiliated Hospital of Nanchang University
    • Nanchang, Jiangxi, China, 330209
      • Recruiting
      • The First Affiliated Hospital of NanChang University
    • Nanchang, Jiangxi, China, 330209
      • Recruiting
      • Jiangxi Cancer Hospital
  • Jilin
    • Changchun, Jilin, China, 130000
      • Recruiting
      • Jilin Cancer Hospital
  • Linyi
    • Shandong, Linyi, China, 276001
      • Recruiting
      • Linyi Cancer Hospital
  • Shaanxi
    • Xi'an, Shaanxi, China, 710061
      • Recruiting
      • The First Affiliated Hospital of Xian Jiaotong University
  • Shandong
    • Jinan, Shandong, China, 250117
      • Recruiting
      • Shandong Cancer Hospital
    • Jinan, Shandong, China, 250013
      • Recruiting
      • Jinan Central Hospital
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China, 200125
      • Recruiting
      • Shanghai GoBroad Cancer Hospital
  • Sichuan
    • Chengdu, Sichuan, China, 611100
      • Recruiting
      • West China Hospital, Sichuan University
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310022
      • Recruiting
      • Zhejiang Cancer Hospital
    • Hangzhou, Zhejiang, China, 310016
      • Recruiting
      • Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine
    • Hangzhou, Zhejiang, China, 310003
      • Recruiting
      • First Affiliated Hospital, Zhejiang University School of Medicine
• France
  • Marseille, France, 13005
    • Recruiting
    • Assistance Publique-Hôpitaux de Marseille
  • Suresnes, France, 92151
    • Recruiting
    • Hopital Foch
• Italy
  • Candiolo, Italy, 10060
    • Recruiting
    • IRCCS Istituto di Candiolo
• Poland
  • Gdansk, Poland, 80-214
    • Recruiting
    • Uniwersyteckie Centrum Kliniczne
  • Katowice, Poland, 40-519
    • Recruiting
    • Pratia Onkologia Katowice
  • Poznan, Poland, 60-192
    • Recruiting
    • Centrum Medyczne Pratia Poznan
• Spain
  • Barcelona, Spain, 08028
    • Recruiting
    • Hospital Universitari Dexeus
  • Barcelona, Spain, 08036
    • Recruiting
    • Clinica Universidad de Navarra
  • Seville, Spain, 41014
    • Recruiting
    • Hospital Universitario Nuestra Señora de Valme
  • Torrejón de Ardoz, Spain, 28850
    • Recruiting
    • Hospital Universitario de Torrejón
• Taiwan
  • Kaohsiung City, Taiwan, 807
    • Recruiting
    • Kaohsiung Medical University Chung-Ho Memorial Hospital
  • Taichung, Taiwan, 40705
    • Recruiting
    • Taichung Veterans General Hospital
  • Tainan, Taiwan, 704
    • Recruiting
    • National Cheng Kung University Hospital
  • Taipei, Taiwan, 11217
    • Recruiting
    • Taipei Veterans General Hospital
  • Taipei, Taiwan, 106
    • Recruiting
    • National Taiwan University Cancer Center
• Turkey (Türkiye)
  • Adana, Turkey (Türkiye), 01230
    • Recruiting
    • Adana City Hospital
  • Ankara, Turkey (Türkiye), 06100
    • Recruiting
    • Hacettepe University Medical Faculty
  • Ankara, Turkey (Türkiye), 06800
    • Recruiting
    • Ankara City Hospital
  • Ankara, Turkey (Türkiye), 06105
    • Recruiting
    • Dr. Abdurrahman Yurtaslan Oncology Teaching and Research Hospital
  • Istanbul, Turkey (Türkiye), 34010
    • Recruiting
    • Koc University Hospital
  • Istanbul, Turkey (Türkiye), 31755
    • Recruiting
    • Yeditepe University Medical School Hospital
  • Sakarya, Turkey (Türkiye), 54187
    • Recruiting
    • Sakarya Training and Research Hospital
• United Kingdom
  • Bristol, United Kingdom, BS2 8ED
    • Recruiting
    • Bristol Haematology and Oncology Centre
  • Leeds, United Kingdom, LS97TF
    • Recruiting
    • St. James's University Hospital
  • Liverpool, United Kingdom, L7 8YA
    • Recruiting
    • The Clatterbridge Cancer Center
  • London, United Kingdom, W1T 7HA
    • Recruiting
    • University College London Hospital
  • London, United Kingdom, SW170QT
    • Recruiting
    • St George's Hospitals NHS Foundation Trust
  • Manchester, United Kingdom, M204BX
    • Recruiting
    • The Christie NHS Foundation Trust
• United States
  • Arizona
    • Phoenix, Arizona, United States, 13400
      • Recruiting
      • Mayo Clinic Arizona
  • California
    • Beverly Hills, California, United States, 90212
      • Recruiting
      • Precision NextGen Oncology and Research Center
    • Los Angeles, California, United States, 90048
      • Recruiting
      • Cedars Sinai Medical Center
    • Santa Monica, California, United States, 90404
      • Recruiting
      • UCLA - David Geffen School of Medicine
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • University of Colorado Cancer Center
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Recruiting
      • Mayo Clinic in Florida
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Recruiting
      • University of Iowa Hospitals & Clinics PARENT
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Recruiting
      • Mayo Clinic-Rochester
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Recruiting
      • John Theurer Cancer Center At Hackensack UMC
  • New York
    • New York, New York, United States, 10021
      • Recruiting
      • Memorial Sloan Kettering Cancer Center (MSKCC)
    • New York, New York, United States, 10029
      • Recruiting
      • Icahn School of Medicine at Mount Sinai PRIME
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Recruiting
      • Cleveland Clinic Taussig Cancer Institute Case Comprehensive Cancer Center
  • Texas
    • Dallas, Texas, United States, 75246
      • Recruiting
      • Texas Oncology - DFW
    • Houston, Texas, United States, 77030
      • Recruiting
      • MD Anderson Cancer Center
    • Tyler, Texas, United States, 75702
      • Recruiting
      • Texas Oncology - Northeast
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Recruiting
      • Virginia Cancer Specialists

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Aged ≥18 years at the time of giving informed consent.

• Histological or cytological confirmed unresectable advanced/metastatic lung cancer. Histological classification may be based on tumor samples prior to metastatic disease. Participants with mixed histology must be classified based on the main component. Participants with NSCLC are eligible with any or no PD-L1 expression. Participants with AGA-positive disease must have received targeted therapy prior to enrollment in this study.

  • Part 1: Participants with NSCLC and SCLC
  • Part 2 Cohort 1: Participants with NSCLC (subpopulation 1) AGA negative, 1L
  • Part 2 Cohort 2: Participants with SCLC, 2L+
  • Part 2 Cohort 3: Participants with NSCLC (subpopulation 1) AGA negative, 2L+
  • Part 2 Cohort 4: Participants with NSCLC (subpopulation 2) AGA negative, 1L
  • Part 2 Cohort 5: Participants with NSCLC (subpopulation 2) AGA negative, 2L+
  • Part 2 Cohort 6: Participants with NSCLC AGA positive
  • Part 2 Cohort 7: Participants with SCLC, 1L
• Have measurable disease defined by RECIST version 1.1.
• Have an Eastern Cooperative Oncology Group performance status of 0 or 1.
• Have a life expectancy of ≥12 weeks.

Exclusion Criteria:

• Prior treatment with B7-H3 targeted therapy.
• Prior treatment with ADC with topoisomerase inhibitor (e.g., datopotamab deruxtecan, trastuzumab deruxtecan). Note: This exclusion applies to participants in the first-line/treatment-naïve cohorts in the advanced/metastatic setting. Prior treatment with ADC with topoisomerase inhibitor payload is only allowed for participants in the second-line plus cohorts in the advanced/metastatic setting.
• Is a candidate to locoregional treatment (including surgical resection, stereotactic radiotherapy or tumor ablation) with potential to induce complete or near complete response and prolonged tumor control (sometimes described as "radical" intent), per investigator's assessment.
• Has a history of significant hematologic toxicity to prior lines of therapy, as assessed by investigator, e.g., Grade 4 febrile neutropenia or recurrent/persistent Grade 3 to 4 neutropenia.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply to all or some participants depending on the cohort.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1 - BNT324 + BNT327 combination therapy; Escalating combination dose levels of BNT324 and BNT327 to define RP2D and RP2D-1 for NSCLC and SCLC.	Biological: BNT324; Intravenous infusion; Other Names: DB-1311; Biological: BNT327; Intravenous infusion
Experimental: Part 2 - Cohort 1: RP2D of BNT324 + BNT327 and RP2D-1 of BNT324 + BNT327; In subpopulation 1 of NSCLC actionable oncogenic alteration (AGA) negative, first-line (1L)	Biological: BNT324; Intravenous infusion; Other Names: DB-1311; Biological: BNT327; Intravenous infusion
Experimental: Part 2 - Cohort 2: RP2D of BNT324 + BNT327 and RP2D-1 of BNT324 + BNT327; In SCLC, second-line plus (2L+)	Biological: BNT324; Intravenous infusion; Other Names: DB-1311; Biological: BNT327; Intravenous infusion
Experimental: Part 2 - Cohort 3: RP2D of BNT324 + BNT327; In subpopulation 1 of NSCLC AGA negative, 2L+	Biological: BNT324; Intravenous infusion; Other Names: DB-1311; Biological: BNT327; Intravenous infusion
Experimental: Part 2 - Cohort 4: RP2D of BNT324 + BNT327; In subpopulation 2 of NSCLC AGA negative, 1L	Biological: BNT324; Intravenous infusion; Other Names: DB-1311; Biological: BNT327; Intravenous infusion
Experimental: Part 2 - Cohort 5: RP2D of BNT324 + BNT327; In subpopulation 2 of NSCLC AGA negative, 2L+	Biological: BNT324; Intravenous infusion; Other Names: DB-1311; Biological: BNT327; Intravenous infusion
Experimental: Part 2 - Cohort 6: RP2D of BNT324 + BNT327; In NSCLC AGA positive	Biological: BNT324; Intravenous infusion; Other Names: DB-1311; Biological: BNT327; Intravenous infusion
Experimental: Part 2 - Cohort 7: RP2D of BNT324 + BNT327; In SCLC, 1L	Biological: BNT324; Intravenous infusion; Other Names: DB-1311; Biological: BNT327; Intravenous infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1 - Occurrence of dose limiting toxicities (DLTs) by dose level		During the DLT evaluation period, i.e., the time of initiation of the first dose of investigational medicinal product (IMP) up to 21 days]
Part 1 - Occurrence of Treatment-emergent adverse events (TEAEs), serious TEAEs, treatment-related TEAEs, and treatment-related serious TEAEs by dose level		From the time of the first dose of IMP to 90 days after the last IMP dose or until new anticancer therapy is started, whichever occurs first
Part 1 - Occurrence of dose interruption, reduction, and treatment discontinuations due to TEAEs by dose level		From the time of the first dose of IMP to 90 days after the last dose of IMP or until new anticancer therapy is started, whichever occurs first
Part 2 cohorts 1 and 2 - Occurrence of TEAEs, serious TEAEs, treatment-related TEAEs, and treatment-related serious TEAEs by cohort and treatment arm		From the time of the first dose of IMP to 90 days after the last IMP dose or until new anticancer therapy is started, whichever occurs first
Part 2 cohorts 1 and 2 - Occurrence of dose interruption, reduction, and treatment discontinuation due to TEAEs by cohort and treatment arm		From the time of the first dose of IMP to 90 days after the last IMP dose or until new anticancer therapy is started, whichever occurs first
Part 2 cohorts 1 and 2 - Objective response rate (ORR) by cohort and treatment arm	ORR defined as the proportion of participants in whom a confirmed complete response (CR) or partial response (PR) is observed as best overall response (per response evaluation criteria in solid tumors [RECIST] version 1.1 based on the investigator's assessment).	From the time of initiation of the first dose of IMP to end of study, i.e., up to 87 months
Part 2 cohorts 3-7 - ORR by cohort	ORR, defined as the proportion of participants in whom a confirmed CR or PR is observed as best overall response (per RECIST version 1.1 based on the investigator's assessment).	From the time of initiation of the first dose of IMP to end of study, i.e., up to 87 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1 - ORR by dose level	ORR, defined as the proportion of participants in whom a confirmed CR or PR is observed as best overall response (per RECIST version 1.1 based on the investigator's assessment).	From the time of initiation of the first dose of IMP to end of study, i.e., up to 87 months
Part 1 - Disease control rate (DCR) by dose level	DCR, defined as the proportion of participants with confirmed CR, PR, or stable disease (SD) as best overall response (per RECIST version 1.1 based on the investigator's assessment).	From the time of initiation of the first dose of IMP to end of study, i.e., up to 87 months
Part 2 all cohorts - (PFS) by cohort and treatment arm	PFS defined as the time from first dose of IMP to the first objective tumor progression (PD) or death from any cause, whichever occurs first, per RECIST version 1.1 based on the investigator's assessment.	From the time of initiation of the first dose of IMP to end of study, i.e., up to 87 months
Part 2 all cohorts - Duration of response (DOR) by cohort and treatment arm	DOR, defined as the time from first objective response (CR or PR) to first occurrence of objective tumor progression (PD) or death from any cause, whichever occurs first (per RECIST version 1.1 based on the investigator's assessment).	From the time of initiation of the first dose of IMP to end of study, i.e., up to 87 months
Part 2 all cohorts - Overall survival (OS) by cohort and treatment arm	OS, defined as the time from first dose of IMP to death from any cause.	From the time of initiation of the first dose of IMP to end of study, i.e., up to 87 months
Part 2 all cohorts - DCR by cohort and treatment arm	DCR, defined as the proportion of participants with confirmed CR, PR, or SD as best overall response (per RECIST version 1.1 based on the investigator's assessment).	From the time of initiation of the first dose of IMP to end of study, i.e., up to 87 months
Part 2 all cohorts - Time to response (TTR) by cohort and treatment arm	TTR, defined as the time from first dose of IMP to first objective response (CR or PR per RECIST version 1.1 based on the investigator's assessment).	From the time of initiation of the first dose of IMP to end of study, i.e., up to 87 months
Part 2 cohorts 3-7 - Occurrence of TEAEs, serious TEAEs, treatment-related TEAEs, and treatment-related serious TEAEs by cohort and treatment arm		From the time of the first dose of IMPs to 90 days after the last IMP dose or until new anticancer therapy is started, whichever occurs first
Part 2 cohorts 3-7 - Occurrence of dose interruption, reduction, and treatment discontinuation due to TEAEs by cohort and treatment arm		From the time of the first dose of IMP to 90 days after the last IMP dose or until new anticancer therapy is started, whichever occurs first

Collaborators and Investigators

• Sponsor: BioNTech SE
• Collaborators: DualityBio Inc.; Biotheus Inc.
• Investigators: Study Director: BioNTech Responsible Person, BioNTech SE

Study record dates

Study Major Dates

• Study Start (Actual): May 2, 2025
• Primary Completion (Estimated): August 1, 2027
• Study Completion (Estimated): June 1, 2031

Study Registration Dates

• First Submitted: March 19, 2025
• First Submitted That Met QC Criteria: March 19, 2025
• First Posted (Actual): March 24, 2025

Study Record Updates

• Last Update Posted (Actual): May 19, 2026
• Last Update Submitted That Met QC Criteria: May 18, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Immunotherapy; Non-small cell lung cancer (NSCLC); Small cell lung cancer (SCLC); Bispecific antibody; Treatment-naïve; Programmed death-ligand 1 (PD-L1); Vascular endothelial growth factor (VEGF); Combination with chemotherapy; Combination with other investigational agents; BNT324 (DB-1311); BNT327
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Carcinoma, Non-Small-Cell Lung; Small Cell Lung Carcinoma
• Other Study ID Numbers: BNT324-01; 2024-520238-31-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No