Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy Trial of BNT141 in Patients With Unresectable or Metastatic CLDN18.2-positive Gastric, Pancreatic, Ovarian and Biliary Tract Tumors
- Conditions
- Gastroesophageal Junction AdenocarcinomaMetastatic CancerCholangiocarcinomaPancreatic CancerSolid TumorGastric CancerEsophageal AdenocarcinomaBiliary Tract Cancer
- Interventions
- Registration Number
- NCT04683939
- Lead Sponsor
- BioNTech SE
- Brief Summary
This study was planned as an open-label, multi-site, Phase I/IIa dose escalation, safety, and pharmacokinetic (PK) trial of BNT141 followed by expansion cohorts in patients with Claudin 18.2 (CLDN18.2)-positive tumors.
The sponsor decided to stop the development of BNT141 on 24 July 2023 and the study was terminated early.
- Detailed Description
The study design consisted of three parts:
* Part 1A was a dose escalation of BNT141 as monotherapy in patients with advanced unresectable or metastatic CLDN18.2-positive solid tumors for which there was no available standard therapy considered to confer clinical benefit, or the patient was not a candidate for such available therapy. The dose of BNT141 was planned to be escalated until the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of BNT141 as monotherapy was defined. However, due to the early study termination, the dose of BNT141 was not fully escalated as planned per protocol (i.e., only four doses were tested, i.e., 0.15 mg/kg, 0.30 mg/kg, 0.45 mg/kg, and 0.60 mg/kg). Once the MTD was reached, up to 10 additional patients with CLDN18.2 expressing pancreatic and biliary tract cancers were planned to be enrolled at the MTD level to obtain additional data on safety, PK and pharmacodynamics (PD). Eligible tumor types were gastric cancer, gastroesophageal junction (GEJ) and esophageal adenocarcinoma, pancreatic, biliary tract (cholangiocarcinoma and gallbladder cancer), and mucinous ovarian cancers. Additionally, patients with specific tumors (including colorectal cancer, non-small-cell lung cancer, gastric subtype of endocervical adenocarcinoma) where there is scientific evidence that the CLDN18.2 could be elevated could be tested for CLDN18.2 expression.
* Part 1B was planned to be a dose escalation of BNT141 in combination with nab-paclitaxel and gemcitabine in patients with locally advanced unresectable or metastatic CLDN18.2-positive pancreatic adenocarcinoma or cholangiocarcinoma who were eligible for treatment with nab-paclitaxel and gemcitabine. Part 1B intended to define the MTD and/or RP2D of the combination. Once the MTD was reached, up to 10 additional patients with CLDN18.2-expressing pancreatic adenocarcinoma or cholangiocarcinoma were planned to be enrolled at the MTD level to obtain additional data on safety, PK and PD. The MTD of BNT141 in combination with nab-paclitaxel and gemcitabine in Part 1B was planned to not exceed the monotherapy BNT141 MTD determined in Part 1A.
* Part 2 (Expansion) was planned to consist of two predefined expansion cohorts in patients with CLDN18.2-positive solid tumors eligible for treatment with nab-paclitaxel and gemcitabine.
Part 1B and Part 2 did not proceed and no participant was enrolled in Part 1B and Part 2.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 13
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Part 1A - BNT141 monotherapy escalation BNT141 Administration once every three weeks (Q3W) Part 1B - BNT141 in combination with nab-paclitaxel and gemcitabine BNT141 BNT141 was planned to be administered Q3W. Nab-paclitaxel and gemcitabine was planned to be administered on three days of each 28-day cycle. Part 1B - BNT141 in combination with nab-paclitaxel and gemcitabine Nab-paclitaxel BNT141 was planned to be administered Q3W. Nab-paclitaxel and gemcitabine was planned to be administered on three days of each 28-day cycle. Part 1B - BNT141 in combination with nab-paclitaxel and gemcitabine Gemcitabine BNT141 was planned to be administered Q3W. Nab-paclitaxel and gemcitabine was planned to be administered on three days of each 28-day cycle. Part 2 - predefined expansion cohorts BNT141 BNT141 in combination with nab-paclitaxel and gemcitabine Part 2 - predefined expansion cohorts Nab-paclitaxel BNT141 in combination with nab-paclitaxel and gemcitabine Part 2 - predefined expansion cohorts Gemcitabine BNT141 in combination with nab-paclitaxel and gemcitabine
- Primary Outcome Measures
Name Time Method Occurrence of Treatment-emergent Adverse Events (TEAEs) Within a Patient Including Grade ≥ 3, Serious, Fatal TEAE by Relationship From start of BNT141 treatment until the second Safety Follow-up Visit (60 ± 7 days after last dose), up to 30 weeks. All TEAEs are included, i.e., AEs 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 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 AEOccurrence of Dose Reductions and Discontinuation of BNT141 Due to TEAEs From start of BNT141 treatment until the second Safety Follow-up Visit (60 ± 7 days after last dose), up to 30 weeks. All TEAEs are included, i.e., AEs 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
Occurrence of Dose-limiting Toxicities (DLTs) Within a Patient During the DLT Evaluation Period First treatment cycle (From first dose up to 21 days after first dose) 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.
- Secondary Outcome Measures
Name Time Method RiboMab PK Parameter - Area Under the Concentration Time Curve (AUC) First treatment cycle (From first dose up to 21 days after first dose) 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.RiboMab PK Parameter - Clearance First treatment cycle (From first dose up to 21 days after first dose) 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.RiboMab PK Parameter - Volume of Distribution at Steady State (Vss) First treatment cycle (From first dose up to 21 days after first dose) 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.RiboMab PK Parameter - Maximum Serum Drug Concentration (Cmax) First treatment cycle (From first dose up to 21 days after first dose) 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.RiboMab PK Parameter - Time to Reach Cmax (Tmax) First treatment cycle (From first dose up to 21 days after first dose) 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.RiboMab PK Parameter - Concentration at the End of a Dosing Interval (Taken Directly Before Next Administration) (Ctrough) Before start of Cycle 3 (plasma sample taken directly before BNT141 Cycle 3 administration) 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.
Ctrough values are available for participants treated with dose level 1 and dose level 2 only.RiboMab PK Parameter - Half-time (t½) First treatment cycle (From first dose up to 21 days after first dose) 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.Objective Response Rate (ORR) From start of first dose of BNT141 until end of trial or start of a new anti-cancer therapy, up to 30 weeks ORR was defined as the number of patients in whom a complete response (CR) or partial response (PR), per RECIST 1.1 is confirmed as best overall response.
Disease Control Rate (DCR) From start of first dose of BNT141 until end of trial or start of a new anti-cancer therapy, up to 30 weeks 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.
Duration of Response (DoR) From start of first dose of BNT141 until end of trial or start of a new anti-cancer therapy, up to 30 weeks 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.
Trial Locations
- Locations (7)
City of Hope
🇺🇸Duarte, California, United States
START
🇺🇸San Antonio, Texas, United States
University of Montreal - Centre Hospitalier de l´Université de Montréal
🇨🇦Montréal, Canada
St. Michaels Hospital
🇨🇦Toronto, Canada
NEXT Oncology
🇺🇸San Antonio, Texas, United States
Princess Margaret Cancer Centre - University Health Network
🇨🇦Toronto, Canada
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States