A Clinical Study to Test if an Investigational Treatment Called BNT326 is Safe and Potentially Beneficial When Used Alone or in Combination With Other Investigational Treatments Such as BNT327, for People With Advanced Malignant Tumors
- Conditions
- Advanced Solid Tumor
- Interventions
- Registration Number
- NCT07070232
- Lead Sponsor
- BioNTech SE
- Brief Summary
This study will evaluate the safety, efficacy, optimal dose, and pharmacokinetics (PK) of BNT326 as monotherapy (Part 1) and as combination treatment with immunotherapeutic agents (Part 2) in participants with histologically or cytologically confirmed solid tumors that are advanced (i.e., either metastatic or recurrent tumors with no further definitive treatment possible) and/or have relapsed/progressed after prior therapy.
- Detailed Description
Both parts (Part 1 and Part 2) will start enrolling study participants independent of each other.
In Part 1, participants with histologically or cytologically confirmed advanced solid tumors will receive BNT326 monotherapy in the following cohorts:
* Cohort 1A: Cutaneous melanoma (second-line or higher \[2L+\]).
* Cohort 1B: Actionable oncogenic alterations (AGA)-negative non-small cell lung cancer (NSCLC) 2L+.
* Cohort 1C: Epithelial growth factor receptor mutated (EGFRm) NSCLC 2L+.
* Cohort 1D: Rare melanoma (acral/uveal/mucosal melanoma).
* Cohort 1E: Other advanced solid tumors.
* Cohort 1F (drug-drug interaction \[DDI\] Cohort): Advanced solid tumors.
In Part 2, BNT326 will be studied in combination with other immunotherapeutic agents. The first combination treatment will be BNT326 with BNT327. The following cohorts are planned:
* Cohort 2A: Cutaneous melanoma 2L+.
* Cohort 2B: Human epidermal growth factor receptor 2 (HER2)-negative breast cancer.
Participants in Cohorts 1A, 1B, and 1C will be randomized to one of two dose levels of BNT326 in a 1:1 ratio. The sponsor may choose to open a dose randomization cohort in Cohort 2A for further dose optimization after dose escalation. No randomization is planned for Cohorts 1D, 1E, 1F, and 2B.
The study will consist of a screening period, a treatment period, a safety follow-up period, an efficacy follow-up period, and a long-term survival follow-up period. Study treatment will be continued for up to 24 months or until disease progression, withdrawal of consent, termination of the study by the sponsor, or unacceptable toxicity. For each participant, the treatment and follow-up periods are projected to be completed within \~38 months (Part 1) and \~48 months (Part 2), unless participants are continuing to benefit from treatment per investigator's recommendation and upon sponsor approval.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 550
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Part 1 (Cohort 1A) - BNT326 monotherapy BNT326 BNT326 (dose level \[DL1\] or DL2) Part 1 (Cohort 1B) - BNT326 monotherapy BNT326 BNT326 (DL1 or DL2) Part 1 (Cohort 1F, drug-drug interaction [DDI]) - BNT326 + itraconazole BNT326 BNT326 (DL1 or DL2) + itraconazole Part 1 (Cohort 1F, drug-drug interaction [DDI]) - BNT326 + itraconazole Itraconazole BNT326 (DL1 or DL2) + itraconazole Part 1 (Cohort 1F, DDI) - BNT326 + paroxetine BNT326 BNT326 (DL1 or DL2) + paroxetine Part 1 (Cohort 1C) - BNT326 monotherapy BNT326 BNT326 (DL1 or DL2) Part 1 (Cohort 1D) - BNT326 monotherapy BNT326 BNT326 (DL2) Part 1 (Cohort 1E) - BNT326 monotherapy BNT326 BNT326 (DL2) Part 1 (Cohort 1F, DDI) - BNT326 + paroxetine Paroxetine BNT326 (DL1 or DL2) + paroxetine Part 2 (Cohort 2A) - BNT326 + BNT327 BNT326 Combination therapy of BNT326 (DL1 or DL2) and BNT327 (DL1 or DL2) Optionally, combinations with lower doses of BNT326 and/or BNT327 may be explored. Part 2 (Cohort 2A) - BNT326 + BNT327 BNT327 Combination therapy of BNT326 (DL1 or DL2) and BNT327 (DL1 or DL2) Optionally, combinations with lower doses of BNT326 and/or BNT327 may be explored. Part 2 (Cohort 2B) - BNT326 + BNT327 BNT326 Combination therapy of BNT326 (DL1 or DL2) and BNT327 (DL1 or DL2) Optionally, combinations with lower doses of BNT326 and/or BNT327 may be explored. Part 2 (Cohort 2B) - BNT326 + BNT327 BNT327 Combination therapy of BNT326 (DL1 or DL2) and BNT327 (DL1 or DL2) Optionally, combinations with lower doses of BNT326 and/or BNT327 may be explored.
- Primary Outcome Measures
Name Time Method Parts 1 and 2 - All cohorts except Cohort 1F - Occurrence of treatment emergent adverse events (TEAEs), treatment related adverse events (TRAEs), treatment emergent serious adverse events (TESAEs), and treatment related serious adverse events (TRSAEs) from first dose of investigational medicinal product (IMP) up to 42 days (Part 1) and 90 days (Part 2) after the last dose of IMP or until a new systemic anti-cancer therapy is started, whichever occurs first (up to 26 months Part 1 or 27 months Part 2) By cohort and by dose in (Part 1), and by cohort and combination treatment regimen (in Part 2).
Parts 1 and 2 - All cohorts except Cohort 1F - Occurrence of dose interruption, reduction, and treatment discontinuations due to TEAEs from first dose of IMP up to 42 days (Part 1) and 90 days (Part 2) after the last dose of IMP or until a new systemic anti-cancer therapy is started, whichever occurs first (up to 26 months Part 1 or 27 months Part 2) By cohort and by dose in (Part 1), and by cohort and combination treatment regimen (in Part 2)
Parts 1 and 2 - All cohorts except Cohort 1F - Confirmed overall response rate (ORR) from the time of initiation of the first dose of IMP to approximately 38 months (Part 1) and approximately 48 months (Part 2) Defined as the proportion of participants in whom a confirmed complete response (CR) or partial response (PR) based on the investigator's assessment (per Response Evaluation Criteria in Solid Tumors version 1.1 \[RECIST v1.1\]) is observed as best overall response. By cohort and by dose in (Part 1), and by cohort and combination treatment regimen (in Part 2).
Part 2 - Occurrence of dose limiting toxicities (DLTs) from the time of initiation of the first dose of IMP up to 21 days During the DLT observation period.
Part 1 - Cohort 1F (DDI) only - PK assessment: Maximum concentration (Cmax) derived from serum concentrations of BNT326 and unconjugated payload from the time of initiation of the first dose of IMP up to safety follow-up visit, approximately 42 days post last IMP dose Evaluation of Cmax without and in combination with the CYP inhibitors (± itraconazole or ± paroxetine). Treatment comparison using geometric mean ratio of Cycle 3 as compared with Cycle 2 as a reference.
Part 1 - Cohort 1F (DDI) only - PK assessment: Area under the curve (AUC) over the last 17-day dosing interval derived from serum concentrations of BNT326 and unconjugated payload from the time of initiation of the first dose of IMP up to safety follow-up visit, approximately 42 days post last IMP dose Evaluation of AUC over the last 17-day dosing interval without and in combination with the CYP inhibitors (± itraconazole or ± paroxetine). Treatment comparison using geometric mean ratio of Cycle 3 as compared with Cycle 2 as a reference.
- Secondary Outcome Measures
Name Time Method Part 1 - Cohort 1F (DDI) only - Occurrence of TEAEs, TRAEs, TESAEs, and TRSAEs from the time of initiation of the first dose of IMP to 42 days after the last dose of IMP By treatment, with and without itraconazole or paroxetine
Part 1 - Cohort 1F (DDI) only - Occurrence of dose interruption, reduction, and treatment discontinuations due to TEAEs from the time of initiation of the first dose of IMP to 42 days after the last dose of IMP By cohort and dose, with and without itraconazole or paroxetine
Part 1 - Cohort 1F (DDI) only - Occurrence of clinically relevant changes from baseline for vital signs from the time of initiation of the first dose of IMP to 42 days after the last dose of IMP Part 1 - Cohort 1F (DDI) only - Occurrence of clinically relevant changes from baseline for clinical laboratory tests from the time of initiation of the first dose of IMP to 42 days after the last dose of IMP Part 1 - Cohort 1F (DDI) only - Occurrence of clinically relevant changes from baseline for cardiac function from the time of initiation of the first dose of IMP to 42 days after the last dose of IMP Assessments comprise 12-lead electrocardiogram (ECG), echocardiography (ECHO) Multi-gated acquisition (MUGA) (scanning) and left ventricular ejection fraction (LVEF).
Part 1 - Cohort 1F (DDI) only - Occurrence of clinically relevant changes from baseline for Eastern Cooperative Oncology Group performance status (ECOG PS) from the time of initiation of the first dose of IMP to 42 days after the last dose of IMP The ECOG PS grades are: 0 = Fully active, able to carry on all pre-disease performance without restriction, 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work, 2 = Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours, 3 = Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours, 4 = Completely disabled; cannot carry on any selfcare; totally confined to bed or chair, 5 = Dead.
Parts 1 and 2 - All cohorts - Progression-free survival (PFS) based on investigator's assessment from the time of initiation of the first dose of IMP to approximately 38 months (Part 1) and approximately 48 months (Part 2) Defined as the time from first dose of IMP to the first objective tumor progression (progressive disease \[PD\] per RECIST 1.1) or death from any cause, whichever occurs first. By cohort and combination treatment regimen (all cohorts except Cohort 1F, DDI) or by treatment regimen only (for Cohort 1F, DDI).
Parts 1 and 2 - All cohorts - Depth of response (DpR) from the time of initiation of the first dose of IMP to approximately 38 months (Part 1) and approximately 48 months (Part 2) Defined as the maximum percent reduction from baseline in tumor size measured by sum of target lesion diameter. By cohort and combination treatment regimen (all cohorts except Cohort 1F, DDI) or by treatment regimen only (for Cohort 1F, DDI).
Parts 1 and 2 - All cohorts - Disease control rate (DCR) from the time of initiation of the first dose of IMP to approximately 38 months (Part 1) and approximately 48 months (Part 2) Defined as the proportion of participants with a confirmed CR, PR, or stable disease (per RECIST 1.1 based on the investigator's assessment) is observed as best overall response. By cohort and combination treatment regimen (all cohorts except Cohort 1F, DDI) or by treatment regimen only (for Cohort 1F, DDI).
Parts 1 and 2 - All cohorts - Duration of response (DoR) from the time of initiation of the first dose of IMP to approximately 38 months (Part 1) and approximately 48 months (Part 2) Defined as the time from first objective response (CR or PR per RECIST 1.1 based on the investigator's assessment) to first occurrence of objective tumor progression (PD per RECIST 1.1 based on the investigator's assessment) or death from any cause, whichever occurs first. By cohort and combination treatment regimen (all cohorts except Cohort 1F, DDI) or by treatment regimen only (for Cohort 1F, DDI).
Parts 1 and 2 - All cohorts - Time to response (TTR) from the time of initiation of the first dose of IMP to approximately 38 months (Part 1) and approximately 48 months (Part 2) Defined as the time from first dose of IMP to first objective response (CR or PR per RECIST 1.1 based on the investigator's assessment). By cohort and combination treatment regimen (all cohorts except Cohort 1F, DDI) or by treatment regimen only (for Cohort 1F, DDI).
Parts 1 and 2 - All cohorts - Overall survival (OS) from the time of initiation of the first dose of IMP to approximately 38 months (Part 1) and approximately 48 months (Part 2) Defined as the time from first dose of IMP to death from any cause. By cohort and combination treatment regimen (all cohorts except Cohort 1F, DDI) or by treatment regimen only (for Cohort 1F, DDI).
Parts 1 and 2 - All cohorts except Cohort 1F - PK assessment: Cmax derived from serum concentrations of BNT326 ADC, total anti-HER3 antibody component, and unconjugated payload from the time of initiation of the first dose of IMP up to safety follow-up visit, approximately 42 days post last IMP dose (Part 1) and 90 days post last IMP dose (Part 2) For applicable participants, if data permits. By cohort and combination treatment regimen.
Parts 1 and 2 - All cohorts except Cohort 1F - PK assessment: AUC derived from serum concentrations of BNT326 ADC, total anti-HER3 antibody component, and unconjugated payload from the time of initiation of the first dose of IMP up to safety follow-up visit, approximately 42 days post last IMP dose (Part 1) and 90 days post last IMP dose (Part 2) For applicable participants, if data permits. By cohort and combination treatment regimen.
Parts 1 and 2 - All cohorts except Cohort 1F - PK assessment: Time to reach maximum (peak) serum concentration (Tmax) derived from serum concentrations of BNT326 ADC, total anti-HER3 antibody component, and unconjugated payload from the time of initiation of the first dose of IMP up to safety follow-up visit, approximately 42 days post last IMP dose (Part 1) and 90 days post last IMP dose (Part 2) For applicable participants, if data permits. By cohort and combination treatment regimen.
Parts 1 and 2 - All cohorts except Cohort 1F - PK assessment: Elimination half-life (t1/2) derived from serum concentrations of BNT326 ADC, total anti-HER3 antibody component, and unconjugated payload from the time of initiation of the first dose of IMP up to safety follow-up visit, approximately 42 days post last IMP dose (Part 1) and 90 days post last IMP dose (Part 2) For applicable participants, if data permits. By cohort and combination treatment regimen.
Parts 1 and 2 - All cohorts - Anti-drug antibody (ADA) prevalence and ADA incidence up to 1 year from the last dose of IMP For applicable participants. By cohort and combination treatment regimen (against BNT326 and/or BNT327, as applicable).
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Trial Locations
- Locations (9)
Florida Cancer Specialists
🇺🇸Sarasota, Florida, United States
The Christie Hospital
🇬🇧Manchester, United Kingdom
START Midwest, LLC
🇺🇸Grand Rapids, Michigan, United States
South Texas Accelerated Research Therapeutics (START), LLC
🇺🇸San Antonio, Texas, United States
START Mountain Region
🇺🇸West Valley City, Utah, United States
Royal Free Hospital
🇬🇧London, United Kingdom
Royal Marsden Hospital-London
🇬🇧London, United Kingdom
Imperial College London
🇬🇧London, United Kingdom
Royal Marsden Hospital
🇬🇧Sutton, United Kingdom
Florida Cancer Specialists🇺🇸Sarasota, Florida, United States