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

Official title

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

Overview

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).

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.

Interventions

• Biological BNT324
  Intravenous infusion
• Biological BNT327
  Intravenous infusion

Primary outcome measures

• Part 1 - Occurrence of dose limiting toxicities (DLTs) by dose level [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: From the time of initiation of the first dose of IMP to end of study, i.e., up to 87 months]

Secondary outcome measures (9)

• Part 1 - ORR by dose level [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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]

Eligibility criteria

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.

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

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 29 centers

• Anhui Provincial Cancer Hospital — Hefei
• Beijing Cancer Hospital — Beijing
• Beijing GoBroad Hospital — Beijing
• Fujian Medical University Union Hospital — Fuzhou
• Fujian Cancer Hospital — Fuzhou
• Guangxi Medical University Cancer Hospital — Nanning
• The First Affiliated Hospital of Xinxiang Medical University — Weihui
• Henan Provincial Cancer Hospital — Zhengzhou
• … and 21 more centers

United States · 16 centers

• Mayo Clinic Arizona — Phoenix
• Precision NextGen Oncology and Research Center — Beverly Hills
• Cedars Sinai Medical Center — Los Angeles
• UCLA - David Geffen School of Medicine — Santa Monica
• University of Colorado Cancer Center — Aurora
• Mayo Clinic in Florida — Jacksonville
• University of Iowa Hospitals & Clinics PARENT — Iowa City
• Mayo Clinic-Rochester — Rochester
• … and 8 more centers

Spain · 8 centers

• Hospital Universitari Dexeus — Barcelona
• Clinica Universidad de Navarra — Barcelona
• Hospital Universitari Vall d'Hebron — Barcelona
• Hospital Universitario Reina Sofia — Córdoba
• Hospital Quironsalud Malaga — Málaga
• Hospital Universitario Nuestra Señora de Valme — Seville
• Hospital Universitario de Torrejón — Torrejón de Ardoz
• Hospital Universitari i Politecnic La Fe — Valencia

Turkey (Türkiye) · 7 centers

• Adana City Hospital — Adana
• Hacettepe University Medical Faculty — Ankara
• Dr. Abdurrahman Yurtaslan Oncology Teaching and Research Hospital — Ankara
• Ankara City Hospital — Ankara
• Yeditepe University Medical School Hospital — Istanbul
• … and 2 more centers

Australia · 6 centers

• Chris O'Brien Lifehouse — Camperdown
• Flinders Medical Centre — Bedford Park
• Bendigo Hospital — Bendigo
• Barwon Health — Geelong
• Sunshine Hospital — Saint Albans
• St John of God Subiaco Hospital — Subiaco

United Kingdom · 6 centers

Center list to be confirmed — check the primary protocol.

Taiwan · 5 centers

• Kaohsiung Medical University Chung-Ho Memorial Hospital — Kaohsiung City
• Taichung Veterans General Hospital — Taichung
• National Cheng Kung University Hospital — Tainan
• National Taiwan University Cancer Center — Taipei
• Taipei Veterans General Hospital — Taipei

France · 4 centers

• Centre Hospitalier Intercommunal de Créteil — Créteil
• Assistance Publique-Hôpitaux de Marseille — Marseille
• Hôpital Foch — Suresnes
• Hopital Larrey — Toulouse

Italy · 4 centers

• IRCCS Istituto di Candiolo — Candiolo
• IRCCS Ospedale San Raffaele — Milan
• Istituto Nazionale Tumori Regina Elena IRCCS — Roma
• Azienda Ospedaliera Universitaria Integrata Verona (Ospedale Borgo Roma) — Verona

Poland · 3 centers

• Uniwersyteckie Centrum Kliniczne — Gdansk
• Pratia Onkologia Katowice — Katowice
• Centrum Medyczne Pratia Poznań — Poznan

Identifiers

NCT: NCT06892548 · BNT324-01 · 2024-520238-31-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗