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.
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 treatment \[2L+\]). * 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) 2L+. * Cohort 1E: Other advanced solid tumors 2L+. * Cohort 1F (drug-drug interaction \[DDI\] Cohort): Advanced solid tumors. * Cohort 1G: Cervical cancer 2L+. In Part 2, BNT326 will be studied as monotherapy or in combination with other immunotherapeutic agents. The first combination treatment will be BNT326 with BNT327 (also known as pumitamig, BMS-986545, or PM8002). The following cohorts are planned: * Cohort 2A: BNT326 + pumitamig for cutaneous melanoma 2L+. * Cohort 2B: BNT326 + pumitamig for human epidermal growth factor receptor 2 (HER2)-negative breast cancer 2L+/first line treatment (1L). * Cohort 2C (Optional): BNT326 + pumitamig for cutaneous melanoma first-line or higher treatment (1L+). This cohort may be added if BNT326 + pumitamig for cutaneous melanoma 2L+ is tolerated, and shows signs of efficacy. * Cohort 2D: BNT326 + pumitamig for gastric cancer (GC)/gastroesophageal junction cancer (GEJC) 2L+. * Cohort 2E: BNT326 + pumitamig for colorectal cancer 2L+. * Cohort 2F: BNT326 + pumitamig for cervical cancer 2L+. Participants in Cohorts 1A, 1B, and 1C (dose optimization cohorts) will be randomized to one of two dose levels (DLs) of BNT326 in a 1:1 ratio. In the dose expansion of Cohorts 2A and 2B, participants will be randomized 1:1 to one of two DLs of BNT326 and pumitamig combination treatment. During the randomized dose optimization and contribution of components of Cohorts 2D and 2E, participants will be randomized in a 1:1:1 ratio to one of three treatment arms (BNT326 DL2 or one of two DLs of BNT326 and pumitamig combination treatment). No randomization is planned for Cohorts 1D, 1E, 1F, 1G, 2C and 2F. 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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
980
Intravenous (IV) infusion
IV infusion
Oral administration
Oral administration
Hartford Healthcare
Hartford, Connecticut, United States
NOT_YET_RECRUITINGYale University
New Haven, Connecticut, United States
RECRUITINGFlorida Cancer Specialists
Sarasota, Florida, United States
RECRUITINGMoffitt Cancer Center
Tampa, Florida, United States
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)
By cohort and by dose in (Part 1), and by cohort and combination treatment regimen (in Part 2).
Time frame: 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)
Parts 1 and 2 - All cohorts except Cohort 1F - Occurrence of dose interruption, reduction, and treatment discontinuations due to TEAEs
By cohort and by dose in (Part 1), and by cohort and combination treatment regimen (in Part 2)
Time frame: 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)
Parts 1 and 2 - All cohorts except Cohort 1F - Confirmed overall response rate (ORR)
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).
Time frame: from the time of initiation of the first dose of IMP up to approximately 38 months (Part 1) and approximately 48 months (Part 2)
Part 2 - Occurrence of dose limiting toxicities (DLTs)
During the DLT observation period.
Time frame: from the time of initiation of the first dose of IMP up to 21 days
Part 1 - Cohort 1F (DDI) only - PK assessment: Maximum concentration (Cmax) derived from serum concentrations of BNT326 ADC and unconjugated payload
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.
Time frame: 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 - Cohort 1F (DDI) only - PK assessment: Area under the curve (AUC) over the last 17-day dosing interval derived from serum concentrations of BNT326 ADC and unconjugated payload
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.
Time frame: 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 - Cohort 1F (DDI) only - Occurrence of TEAEs, TRAEs, TESAEs, and TRSAEs
By treatment, with and without itraconazole or paroxetine
Time frame: 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 dose interruption, reduction, and treatment discontinuations due to TEAEs
By cohort and dose, with and without itraconazole or paroxetine
Time frame: 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 vital signs
Time frame: 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
Time frame: 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
Assessments comprise 12-lead electrocardiogram (ECG), echocardiography (ECHO) Multi-gated acquisition (MUGA) (scanning) and left ventricular ejection fraction (LVEF).
Time frame: 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 Eastern Cooperative Oncology Group performance status (ECOG PS)
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.
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Massachusetts General Hospital
Boston, Massachusetts, United States
RECRUITINGSTART Midwest, LLC
Grand Rapids, Michigan, United States
RECRUITINGMemorial Sloan Kettering Hospital
New York, New York, United States
RECRUITINGDuke Cancer Institute
Durham, North Carolina, United States
NOT_YET_RECRUITINGThe University of Texas MD Anderson Cancer Center
Houston, Texas, United States
RECRUITINGSouth Texas Accelerated Research Therapeutics (START), LLC
San Antonio, Texas, United States
RECRUITING...and 29 more locations
Time frame: from the time of initiation of the first dose of IMP to 42 days after the last dose of IMP
Parts 1 and 2 - All cohorts - Progression-free survival based on investigator's assessment
Defined as the time from first dose of IMP to the first objective tumor progression (progressive disease \[PD\] per RECIST v1.1) 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).
Time frame: from the time of initiation of the first dose of IMP up to approximately 38 months (Part 1) and approximately 48 months (Part 2)
Parts 1 and 2 - All cohorts - Depth of response
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).
Time frame: from the time of initiation of the first dose of IMP up to approximately 38 months (Part 1) and approximately 48 months (Part 2)
Parts 1 and 2 - All cohorts - Disease control rate
Defined as the proportion of participants with a confirmed CR, PR, or stable disease (per RECIST v1.1 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).
Time frame: from the time of initiation of the first dose of IMP up to approximately 38 months (Part 1) and approximately 48 months (Part 2)
Parts 1 and 2 - All cohorts - Duration of response
Defined as the time from first objective response (CR or PR per RECIST v1.1 based on the investigator's assessment) to first occurrence of objective tumor progression (PD per RECIST v1.1 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).
Time frame: from the time of initiation of the first dose of IMP up to approximately 38 months (Part 1) and approximately 48 months (Part 2)
Parts 1 and 2 - All cohorts - Time to response
Defined as the time from first dose of IMP to first objective response (CR or PR per RECIST v1.1 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).
Time frame: from the time of initiation of the first dose of IMP up to approximately 38 months (Part 1) and approximately 48 months (Part 2)
Parts 1 and 2 - All cohorts - Overall survival
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).
Time frame: from the time of initiation of the first dose of IMP up to approximately 38 months (Part 1) and approximately 48 months (Part 2)
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
For applicable participants, if data permits. By cohort and combination treatment regimen.
Time frame: 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)
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
For applicable participants, if data permits. By cohort and combination treatment regimen.
Time frame: 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)
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
For applicable participants, if data permits. By cohort and combination treatment regimen.
Time frame: 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)
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
For applicable participants, if data permits. By cohort and combination treatment regimen.
Time frame: 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)
Parts 1 and 2 - All cohorts - Anti-drug antibody (ADA) prevalence and ADA incidence
For applicable participants. By cohort and combination treatment regimen (against BNT326 and/or BNT327, as applicable).
Time frame: up to 1 year from the last dose of IMP