Clinical Trial Results:
Phase I/IIa, first-in-human, open-label, dose escalation trial with expansion cohorts to evaluate safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of BNT141 as a monotherapy and in combination with other anti-cancer agents in patients with CLDN18.2-positive solid tumors
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Summary
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EudraCT number |
2022-001843-25 |
Trial protocol |
DK ES NL |
Global end of trial date |
24 Jul 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
03 Aug 2024
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First version publication date |
03 Aug 2024
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
BNT141-01
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04683939 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
BioNTech SE
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Sponsor organisation address |
An der Goldgrube 12, Mainz, Germany, 55131
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Public contact |
BioNTech clinical trials patient information, BioNTech SE, +49 613190840, patients@biontech.de
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Scientific contact |
BioNTech clinical trials patient information, BioNTech SE, +49 613190840, patients@biontech.de
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
13 Oct 2023
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
24 Jul 2023
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
To assess the safety and tolerability of BNT141 at different dose levels and identify the maximum tolerated dose (MTD) or maximally administered dose (MAD) /recommended Phase II dose (RP2D) of BNT141 based on the occurrence of dose-limiting toxicities (DLTs) using the following definitions:
• The MTD defined as the highest tolerated dose, where less than one-third of the patients experience a DLT.
• The MAD defined as the highest dose administered, where all dose levels were tolerated during dose escalation.
• The RP2D defined based on integrated evaluation of safety, tolerability, clinical benefit, pharmacokinetic (PK), and pharmacodynamic data, for all dose levels tested.
However, the sponsor decided to stop the development of BNT141. The study was terminated early and only Part 1A (dose escalation of BNT141 as monotherapy) was conducted. The dose of BNT141 was not fully escalated as planned per protocol (i.e., only four doses were tested).
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.
A Safety Review Committee was established to review safety, clinical, and available PK and pharmacodynamic data on an ongoing basis.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
18 Jan 2022
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Canada: 5
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Country: Number of subjects enrolled |
United States: 8
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Worldwide total number of subjects |
13
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
4
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From 65 to 84 years |
9
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85 years and over |
0
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Recruitment
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Recruitment details |
A total of 15 patients (6 from Canada and 9 from the USA) were screened while 13 patients (5 patients and 8 patients respectively from two countries) were enrolled in this study and 2 patients failed screening (primary reason inclusion/exclusion criteria not met). All patients were enrolled into Part 1A of this study and received BNT141. | ||||||||||||||||||
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Pre-assignment
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Screening details |
Adult patients with Claudin 18.2 (CLDN18.2)-positive tumors. CLDN18.2 positivity was determined by a central laboratory during the pre-screening phase using a validated immunohistochemistry assay and was defined as moderate (50-75%)-to-strong (more than 75%) CLDN18.2 expression. | ||||||||||||||||||
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Period 1
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Period 1 title |
Part 1A (dose escalation of BNT141) (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||
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Arms
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Arm title
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BNT141 monotherapy - Total | ||||||||||||||||||
Arm description |
The total number of patients from Part 1A of this study included in four tested dose cohorts. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
BNT141
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Dispersion for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
BNT141 was administered intravenously (IV) as monotherapy once every three weeks (Q3W) at four dose levels.
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Baseline characteristics reporting groups
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Reporting group title |
BNT141 monotherapy - Total
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Reporting group description |
The total number of patients from Part 1A of this study included in four tested dose cohorts. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
BNT141 monotherapy - Total
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Reporting group description |
The total number of patients from Part 1A of this study included in four tested dose cohorts. | ||
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End point title |
Occurrence of treatment-emergent adverse events (TEAEs) within a patient including Grade ≥ 3, serious, fatal TEAE by relationship [1] | ||||||||||||||||||||||
End point description |
All adverse events (AEs) are included with an onset date on or after the first dose of BNT141 (if the AE was absent before the first dose) or worsened after the first dose of BNT141 (if the AE was present before the first dose). AEs with an onset date >60 days after the last dose of BNT141 are included only if assessed as related to BNT141 by the investigator.
Intensity of AEs was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0, i.e.,:
Grade 1 - Mild
Grade 2 - Moderate
Grade 3 - Severe
Grade 4 - Life-threatening consequences; urgent urgent intervention indicated
Grade 5 - Death related to AE
Safety Set - All patients who received investigational medicinal product (IMP) (i.e., at least one dose of BNT141).
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End point type |
Primary
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End point timeframe |
From start of BNT141 treatment until the second Safety Follow-up Visit (60 ± 7 days after last dose)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: As per protocol, no formal statistical analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Occurrence of dose reductions and discontinuation of BNT141 due to TEAEs [2] | ||||||||||||||||||||||
End point description |
All AEs are included with an onset date on or after the first dose of BNT141 (if the AE was absent before the first dose) or worsened after the first dose of BNT141 (if the AE was present before the first dose). AEs with an onset date >60 days after the last dose of BNT141 are included only if assessed as related to BNT141 by the investigator.
Safety Set - All patients who received IMP (i.e., at least one dose of BNT141).
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End point type |
Primary
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End point timeframe |
From start of BNT141 treatment until the second Safety Follow-up Visit (60 ± 7 days after last dose)
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: As per protocol, no formal statistical analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Occurrence of dose-limiting toxicities (DLTs) within a patient during the DLT evaluation period [3] | ||||||||
End point description |
Serious AEs, non-serious Grade ≥ 3 non-hematological and hematological AEs as defined per DLT criteria and clinically significant abnormal laboratory values Grade ≥ 3 were collected and considered a DLT if assessed by the investigator to be at least possibly related to BNT141. Toxicities clearly not related to BNT141 (e.g., progressive disease, comorbidity, etc.) were not considered a DLT. The NCI-CTCAE v.5.0 was used to grade the intensity of AEs.
Safety Set - All patients who received IMP (i.e., at least one dose of BNT141).
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End point type |
Primary
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End point timeframe |
First treatment cycle (From first dose up to 21 days after first dose)
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: As per protocol, no formal statistical analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
RiboMab PK parameter - Area under the concentration time curve (AUC) | ||||||||||||||
End point description |
Intact RiboMab (full-length and fully assembled antibody) PK serum samples were collected and analyzed.
AUC (0-tau), AUC (0-inf) and AUC (0-504) were estimated from serum concentration data from Cycle 1 using non-compartmental analysis.
AUC (0-inf): Area under the drug concentration-time curve, from time zero to infinity.
AUC (0-504): Area under the drug concentration-time curve, from time zero to 504 hours after the start of the infusion.
AUC (0-tau): Area under the drug concentration-time curve, from time zero over the dosing interval at steady-state (Tau = 504 hours corresponding to 3-weeks administration) after the start of the infusion.
PK Set - All patients with baseline and at least one valid on-treatment/post-treatment PK assessment.
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End point type |
Secondary
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End point timeframe |
First treatment cycle (From first dose up to 21 days after first dose)
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| Notes [4] - The number of patients included in the analysis of AUC (0-inf) & AUC (0-504) is 12 patients only. |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
RiboMab PK parameter - Clearance | ||||||||||
End point description |
Intact RiboMab (full-length and fully assembled antibody) PK serum samples were collected and analyzed.
Clearance was estimated from serum concentration from Cycle 1 data using non-compartmental analysis.
PK Set - All patients with baseline and at least one valid on-treatment/post-treatment PK assessment.
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End point type |
Secondary
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End point timeframe |
First treatment cycle (From first dose up to 21 days after first dose)
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| No statistical analyses for this end point | |||||||||||
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End point title |
RiboMab PK parameter - Volume of distribution at steady state (Vss) | ||||||||||
End point description |
Intact RiboMab (full-length and fully assembled antibody) PK serum samples were collected and analyzed.
Volume of distribution at steady state (Vss) was estimated as mean residence time calculated using last measured concentration (MRT inf) * CL.
PK Set - All patients with baseline and at least one valid on-treatment/post-treatment PK assessment.
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End point type |
Secondary
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End point timeframe |
First treatment cycle (From first dose up to 21 days after first dose)
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| No statistical analyses for this end point | |||||||||||
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End point title |
RiboMab PK parameter - Maximum serum drug concentration (Cmax) | ||||||||||
End point description |
Intact RiboMab (full-length and fully assembled antibody) PK serum samples were collected and analyzed.
Cmax was estimated from serum concentration from Cycle 1 data using non-compartmental analysis.
PK Set - All patients with baseline and at least one valid on-treatment/post-treatment PK assessment.
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End point type |
Secondary
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End point timeframe |
First treatment cycle (From first dose up to 21 days after first dose)
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| No statistical analyses for this end point | |||||||||||
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End point title |
RiboMab PK parameter - Time to reach Cmax (Tmax) | ||||||||||
End point description |
Intact RiboMab (full-length and fully assembled antibody) PK serum samples were collected and analyzed.
Tmax was estimated from serum concentration from Cycle 1 data using non-compartmental analysis.
PK Set - All patients with baseline and at least one valid on-treatment/post-treatment PK assessment.
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End point type |
Secondary
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End point timeframe |
First treatment cycle (From first dose up to 21 days after first dose)
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| No statistical analyses for this end point | |||||||||||
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End point title |
RiboMab PK parameter - Concentration at the end of a dosing interval (taken directly before next administration) (Ctrough) | ||||||||||
End point description |
Intact RiboMab (full-length and fully assembled antibody) PK serum samples were collected and analyzed.
Ctrough was estimated from serum concentration from Cycle 1 data using non-compartmental analysis.
PK Set - All patients with baseline and at least one valid on-treatment/post-treatment PK assessment.
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End point type |
Secondary
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End point timeframe |
Before start of Cycle 3 (plasma sample taken directly before BNT141 Cycle 3 administration)
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| No statistical analyses for this end point | |||||||||||
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End point title |
RiboMab PK parameter - Half-time (t½) | ||||||||||
End point description |
Intact RiboMab (full-length and fully assembled antibody) PK serum samples were collected and analyzed.
T½ was estimated from serum concentration from Cycle 1 data using non-compartmental analysis.
PK Set - All patients with baseline and at least one valid on-treatment/post-treatment PK assessment.
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End point type |
Secondary
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End point timeframe |
First treatment cycle (From first dose up to 21 days after first dose)
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| No statistical analyses for this end point | |||||||||||
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End point title |
Objective response rate (ORR) | ||||||||
End point description |
ORR was defined as the number of patients in whom a complete response (CR) or partial response (PR), per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 is confirmed as best overall response.
Data were not available for this endpoint due to early termination of the study meaning ORR could not be determined.
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End point type |
Secondary
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End point timeframe |
From start of first dose of BNT141 until end of trial or start of a new anti-cancer therapy.
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| Notes [5] - Data were not available for this endpoint due to early termination of the study. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Disease control rate (DCR) | ||||||||
End point description |
DCR was defined as the number of patients in whom a CR or PR or stable disease ([SD], per RECIST 1.1, SD assessed at least 6 weeks after first dose) is observed as best overall response.
Data were not available for this endpoint due to early termination of the study meaning DCR could not be determined.
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End point type |
Secondary
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End point timeframe |
From start of first dose of BNT141 until end of trial or start of a new anti-cancer therapy
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| Notes [6] - Data were not available for this endpoint due to early termination of the study. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Duration of response (DoR) | ||||||||||
End point description |
DoR was defined as the time from first objective response (CR or PR per RECIST 1.1) to first occurrence of objective tumor progression (progressive disease per RECIST 1.1) or death from any cause, whichever occurs first.
Data were not available for this endpoint due to early termination of the study meaning DoR could not be determined.
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End point type |
Secondary
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End point timeframe |
From start of first dose of BNT141 until end of trial or start of a new anti-cancer therapy
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| Notes [7] - Data were not available for this endpoint due to early termination of the study. |
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| No statistical analyses for this end point | |||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From start of IMP treatment until the second Safety Follow-up Visit (60 ± 7 days after last dose)
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Adverse event reporting additional description |
All AEs are presented with an onset date on or after the first dose of BNT141 (if the AE was absent before the first dose) or worsened after the first dose of BNT141 (if the AE was present before the first dose). AEs with an onset date >60 days after the last dose of BNT141 are included only if assessed as related to BNT141 by the investigator.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
26.0
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Reporting groups
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Reporting group title |
BNT141 monotherapy
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Reporting group description |
The total number of patients from Part 1A of this study included in four tested dose cohorts, who received IMP (i.e., at least one dose of BNT141). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
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03 Mar 2021 |
Amendment following feedback from the (United States) Food and Drug Administration (FDA) (23 and 25 February 2021). This update was issued before any trial subjects have been enrolled into the trial. This change had no impact on the planned trial objectives or trial conduct. |
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06 Aug 2021 |
Amendment to specify unique identifiers to the inclusion criteria, to correct an error in the implementation of the change to DLT definitions, and minor administrative changes. This update was issued before any trial subjects have been enrolled into the trial. This change had no impact on the planned trial objectives or trial conduct. |
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13 Jun 2022 |
Amendment to include additional eligible indications; clarification of secondary PK endpoints and revisions of exploratory objectives/endpoints; updates of inclusion and exclusion criteria related to AEs, contraception guidance, receipt of live vaccine prior to start of trial, handling of COVID-19 infection, glomerular filtration rate, previous receipt of BNT141; modifications of schedules of activities; inclusion of 48 hour safety window between second and third patient in each dose cohort to account for any acute safety signals in each new dose level; update of end of trial and patient completion definitions; addition of detailed recommendations for premedication and allowed concomitant medications; update of treatment guidelines for injection/infusion-related reactions (IRRs); update of terms under which treatment will be made available after the end of the trial; Revision of definition of AEs of special interest to include IRRs grade ≥ 3 instead of grade ≥ 2; inclusion of further information on dissemination of trial data; update of serious AE definition regarding inpatient hospitalization or prolongation of existing hospitalization. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
| None reported | |||||||
