Clinical trial NCT06892548: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Advanced Lung Cancer
Keywords: Small cell lung cancer (SCLC)
Non-small cell lung cancer (NSCLC)
Programmed death-ligand 1 (PD-L1)
Vascular endothelial growth factor (VEGF)
Bispecific antibody
BNT324 (DB-1311)
BNT327
Combination with chemotherapy
Combination with other investigational agents
Immunotherapy
Treatment-naïve
Lead sponsor: BioNTech SE
Sponsor class: INDUSTRY
Collaborators: name: DualityBio Inc.
name: Biotheus Inc.
First posted: 2025-03-24
Enrollment: 594
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Primary outcomes:
measure: Part 1 - Occurrence of dose limiting toxicities (DLTs) by dose level
timeFrame: During the DLT evaluation period, i.e., the time of initiation of the first dose of investigational medicinal product (IMP) up to 21 days]
measure: Part 1 - Occurrence of Treatment-emergent adverse events (TEAEs), serious TEAEs, treatment-related TEAEs, and treatment-related serious TEAEs by dose level
timeFrame: 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
measure: Part 1 - Occurrence of dose interruption, reduction, and treatment discontinuations due to TEAEs by dose level
timeFrame: 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
measure: Part 2 cohorts 1 and 2 - Occurrence of TEAEs, serious TEAEs, treatment-related TEAEs, and treatment-related serious TEAEs by cohort and treatment arm
timeFrame: 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
measure: Part 2 cohorts 1 and 2 - Occurrence of dose interruption, reduction, and treatment discontinuation due to TEAEs by cohort and treatment arm
timeFrame: 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
measure: Part 2 cohorts 1 and 2 - Objective response rate (ORR) by cohort and treatment arm
timeFrame: From the time of initiation of the first dose of IMP to end of study, i.e., up to 87 months
measure: Part 2 cohorts 3-7 - ORR by cohort
timeFrame: From the time of initiation of the first dose of IMP to end of study, i.e., up to 87 months
Secondary outcomes:
measure: Part 1 - ORR by dose level
timeFrame: From the time of initiation of the first dose of IMP to end of study, i.e., up to 87 months
measure: Part 1 - Disease control rate (DCR) by dose level
timeFrame: From the time of initiation of the first dose of IMP to end of study, i.e., up to 87 months
measure: Part 2 all cohorts - (PFS) by cohort and treatment arm
timeFrame: From the time of initiation of the first dose of IMP to end of study, i.e., up to 87 months
measure: Part 2 all cohorts - Duration of response (DOR) by cohort and treatment arm
timeFrame: From the time of initiation of the first dose of IMP to end of study, i.e., up to 87 months
measure: Part 2 all cohorts - Overall survival (OS) by cohort and treatment arm
timeFrame: From the time of initiation of the first dose of IMP to end of study, i.e., up to 87 months
measure: Part 2 all cohorts - DCR by cohort and treatment arm
timeFrame: From the time of initiation of the first dose of IMP to end of study, i.e., up to 87 months
measure: Part 2 all cohorts - Time to response (TTR) by cohort and treatment arm
timeFrame: From the time of initiation of the first dose of IMP to end of study, i.e., up to 87 months
measure: Part 2 cohorts 3-7 - Occurrence of TEAEs, serious TEAEs, treatment-related TEAEs, and treatment-related serious TEAEs by cohort and treatment arm
timeFrame: 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
measure: Part 2 cohorts 3-7 - Occurrence of dose interruption, reduction, and treatment discontinuation due to TEAEs by cohort and treatment arm
timeFrame: 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
Other outcomes:
Locations:
city: Fairfax
country: United States
facility: Virginia Cancer Specialists
state: Virginia
Study officials:
affiliation: BioNTech SE
name: BioNTech Responsible Person
role: STUDY_DIRECTOR
References: