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

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

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.

Study Overview

• Status: Terminated
• Conditions: Gastric Cancer; Pancreatic Cancer; Solid Tumor; Metastatic Cancer; Cholangiocarcinoma; Esophageal Adenocarcinoma; Biliary Tract Cancer; Gastroesophageal Junction Adenocarcinoma
• Intervention / Treatment: Drug: Gemcitabine; Drug: Nab-paclitaxel; Drug: BNT141

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.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Montréal, Canada, H2X3E4
    • University of Montreal - Centre Hospitalier de l´Université de Montréal
  • Toronto, Canada, M5G1X5
    • Princess Margaret Cancer Centre - University Health Network
  • Toronto, Canada, M5B1W8
    • St. Michaels Hospital
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
    • San Antonio, Texas, United States, 78229
      • NEXT Oncology
    • San Antonio, Texas, United States, 78229
      • START

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key inclusion criteria:

For all Parts:

• Metastatic or unresectable solid tumor.
• Histological or cytological documentation of a solid tumor via a pathology report.
• CLDN18.2-positive tumor sample defined as moderate-to-strong CLDN18.2 protein expression defined as intermediate (2+) to strong (3+) staining intensity in ≥ 50% of tumor cells as assessed by central testing using a CLIA-validated immunohistochemistry assay in formalin-fixed, paraffin-embedded (FFPE) neoplastic tissues. New biopsies and archival bio-samples are allowed. Bone biopsies are not allowed. Cytology specimens (including fine needle aspirates) will not be accepted for CLDN18.2 examination. If archival tissue samples from several points of time are available, the most recent one is preferred. Patients with a lower expression level or with CLDN18.2-negative cancers are not eligible.

Trial part-specific inclusion criteria:

For Part 1A: Patients with solid tumors, for which there is no available standard therapy likely to confer clinical benefit, or the patient is not a candidate for such available therapy. Patients must have received all available standard therapies and failed at least first-line standard of care therapy prior to enrolment. Measurable or evaluable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Eligible tumor types are gastric cancer, 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 can be tested for CLDN18.2 expression.

For Part 1B: Patients with advanced pancreatic adenocarcinoma or cholangiocarcinoma who are eligible for treatment with nab-paclitaxel and gemcitabine. Measurable or evaluable disease per RECIST 1.1.

Key exclusion criteria:

• Receiving: radiotherapy, chemotherapy, or molecularly-targeted agents within 3 weeks or 5 half-lives (whichever is longer) of the start of trial treatment; immunotherapy/monoclonal antibodies within 3 weeks of the start of trial treatment (excluding BNT141); nitrosoureas, antibody-drug conjugates, or radioactive isotopes within 6 weeks of the start of trial treatment. Palliative radiotherapy will be allowed.
• Receives concurrent systemic (oral or IV) steroid therapy >10 mg prednisone daily or its equivalent for an underlying condition. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is permitted.
• Major surgery within 4 weeks before the first dose of BNT141.
• Prior treatment with a CLDN18.2 targeting monoclonal antibodies (mAb) other than BNT141.
• Ongoing or active infection requiring IV treatment with anti-infective therapy that has been administered less than 2 weeks prior to the first dose of BNT141.
• Side effects of any prior therapy or procedures for any medical condition not recovered to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.5.0 Grade ≤ 1, with the exception of anorexia, fatigue, hyperthyroidism, hypothyroidism, and peripheral neuropathy, which must have recovered to ≤ Grade 2. Alopecia of any grade is allowed.

• Current evidence of new or growing brain or leptomeningeal metastases during screening. Patients with known brain or leptomeningeal metastases may be eligible if they have:

  • Radiotherapy, surgery or stereotactic surgery for the brain or leptomeningeal metastases.
  • No neurological symptoms (excluding Grade ≤ 2 neuropathy).
  • Stable brain or leptomeningeal disease on the computer tomography or magnet resonance imaging scan within 4 weeks before signing the informed consent form.
  • Not undergoing acute corticosteroid therapy or steroid taper.

Additional inclusion and exclusion criteria did apply (please refer to the clinical study protocol for detailed information).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1A - BNT141 monotherapy escalation; Administration once every three weeks (Q3W)	Drug: BNT141; Intravenous (IV)
Experimental: Part 1B - BNT141 in combination with nab-paclitaxel and 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.	Drug: Gemcitabine; IV; Drug: Nab-paclitaxel; IV; Drug: BNT141; Intravenous (IV)
Experimental: Part 2 - predefined expansion cohorts; BNT141 in combination with nab-paclitaxel and gemcitabine	Drug: Gemcitabine; IV; Drug: Nab-paclitaxel; IV; Drug: BNT141; Intravenous (IV)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of Treatment-emergent Adverse Events (TEAEs) Within a Patient Including Grade ≥ 3, Serious, Fatal TEAE by Relationship	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 AE	From start of BNT141 treatment until the second Safety Follow-up Visit (60 ± 7 days after last dose), up to 30 weeks.
Occurrence of Dose Reductions and Discontinuation of BNT141 Due to TEAEs	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	From start of BNT141 treatment until the second Safety Follow-up Visit (60 ± 7 days after last dose), up to 30 weeks.
Occurrence of Dose-limiting Toxicities (DLTs) Within a Patient During the DLT Evaluation Period	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.	First treatment cycle (From first dose up to 21 days after first dose)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
RiboMab PK Parameter - Area Under the Concentration Time Curve (AUC)	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.	First treatment cycle (From first dose up to 21 days after first dose)
RiboMab PK Parameter - Clearance	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.	First treatment cycle (From first dose up to 21 days after first dose)
RiboMab PK Parameter - Volume of Distribution at Steady State (Vss)	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.	First treatment cycle (From first dose up to 21 days after first dose)
RiboMab PK Parameter - Maximum Serum Drug Concentration (Cmax)	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.	First treatment cycle (From first dose up to 21 days after first dose)
RiboMab PK Parameter - Time to Reach Cmax (Tmax)	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.	First treatment cycle (From first dose up to 21 days after first dose)
RiboMab PK Parameter - Concentration at the End of a Dosing Interval (Taken Directly Before Next Administration) (Ctrough)	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.	Before start of Cycle 3 (plasma sample taken directly before BNT141 Cycle 3 administration)
RiboMab PK Parameter - Half-time (t½)	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.	First treatment cycle (From first dose up to 21 days after first dose)
Objective Response Rate (ORR)	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.	From start of first dose of BNT141 until end of trial or start of a new anti-cancer therapy, up to 30 weeks
Disease Control Rate (DCR)	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.	From start of first dose of BNT141 until end of trial or start of a new anti-cancer therapy, up to 30 weeks
Duration of Response (DoR)	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.	From start of first dose of BNT141 until end of trial or start of a new anti-cancer therapy, up to 30 weeks

Collaborators and Investigators

• Sponsor: BioNTech SE
• Investigators: Study Director: BioNTech Responsible Person, BioNTech SE

Study record dates

Study Major Dates

• Study Start (Actual): January 18, 2022
• Primary Completion (Actual): July 24, 2023
• Study Completion (Actual): July 24, 2023

Study Registration Dates

• First Submitted: December 21, 2020
• First Submitted That Met QC Criteria: December 21, 2020
• First Posted (Actual): December 24, 2020

Study Record Updates

• Last Update Posted (Actual): October 2, 2024
• Last Update Submitted That Met QC Criteria: September 6, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: Biomarker; Treatment; Solid tumors; Gastric cancer; Metastatic; Esophageal adenocarcinoma; Therapy; Precision medicine; Pancreatic cancer; mRNA; Cholangiocarcinoma; Esophageal cancer; CLDN18.2-positive solid tumors; Gastric adenocarcinoma; Gastroesophageal junction adenocarcinoma; Pancreatic ductal adenocarcinoma; Biliary tract cancers; Mucinous ovarian cancers; Targeted immunotherapy; Metastatic cancer; Ribomab; CLDN18.2-positive tumors; Precision oncology
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Stomach Diseases; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Neoplastic Processes; Esophageal Diseases; Biliary Tract Diseases; Pancreatic Diseases; Stomach Neoplasms; Neoplasm Metastasis; Adenocarcinoma; Pancreatic Neoplasms; Cholangiocarcinoma; Esophageal Neoplasms; Biliary Tract Neoplasms; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Paclitaxel; Gemcitabine
• Other Study ID Numbers: BNT141-01; 2022-001843-25 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No