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 trial is an open-label, multi-site, Phase I/IIa dose escalation, safety, and pharmacokinetic (PK) trial of BNT141 followed by expansion cohorts in patients with CLDN18.2-positive tumors.

The trial design consists of three parts:

Part 1A is a dose escalation of BNT141 as monotherapy in patients with advanced unresectable or metastatic Claudin 18.2 (CLDN18.2)-positive 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. The dose of BNT141 will be escalated until the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of BNT141 as monotherapy are defined. Eligible tumor types are 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 can be tested for CLDN18.2 expression.

Part 1B is a dose escalation of BNT141 in combination with nab-paclitaxel and gemcitabine in patients with advanced unresectable or metastatic CLDN18.2-positive pancreatic adenocarcinoma or cholangiocarcinoma who are eligible for treatment with nab-paclitaxel and gemcitabine. Part 1B intends to define the MTD and/or RP2D of the combination.

Part 2 with adaptive design elements will be added at a later stage.

Study Overview

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

• 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, M5B 1W8
    • St. Michaels Hospital
  • Toronto, Canada, M5G1X5
    • Princess Margaret Cancer Centre - University Health Network
• 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 (SOC) therapy prior to enrolment. Measurable or evaluable disease per RECIST 1.1. Eligible tumor types are 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 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 intravenous [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 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 (CT) or magnet resonance imaging (MRI) scan within 4 weeks before signing the informed consent form (ICF).
• Not undergoing acute corticosteroid therapy or steroid taper.

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1A - BNT141 monotherapy escalation; Administration once every three weeks (Q3W)	Biological: BNT141; Intravenous (IV)
Experimental: Part 1B - BNT141 in combination with nab-paclitaxel and gemcitabine; BNT141 will be administered once every three weeks (Q3W). Nab-paclitaxel and gemcitabine will be administered on three days of each 28-day cycle.	Biological: BNT141; Intravenous (IV); Drug: Nab-paclitaxel; Intravenous (IV); Drug: Gemcitabine; 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	TEAEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v 5.0.	up to 36 months
Occurrence of dose reductions and discontinuation of BNT141 due to TEAEs throughout the study and up to 60 days after last subject last treatment		up to 36 months
Occurrence of dose-limiting toxicities (DLTs) within a patient during the DLT evaluation period	DLTs are assessed during the first cycle (21 days) in each cohort to determine maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D).	assessed during the first cycle (21 days) in each cohort

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
BNT141 pharmacokinetic: Area under the concentration time curve (AUC)		pre-dose until 60 days after last dose
BNT141 pharmacokinetic: Clearance (CL)		pre-dose until 60 days after last dose
BNT141 pharmacokinetic: Volume of distribution (VD)		pre-dose until 60 days after last dose
BNT141 pharmacokinetic: Maximum concentration of the drug (Cmax)		pre-dose until 60 days after last dose
BNT141 pharmacokinetic: Time to maximum concentration (Tmax)		pre-dose until 60 days after last dose
BNT141 pharmacokinetic: Concentration prior to next dose (Ctrough)		pre-dose until 60 days after last dose
BNT141 pharmacokinetic: Elimination half-life (t half)		pre-dose until 60 days after last dose
BNT141 - Objective response rate (ORR)	ORR is defined as the proportion of patients in whom a complete response (CR) or partial response (PR), per Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 is confirmed as best overall response.	up to 36 months
BNT141 - Disease control rate (DCR)	DCR is defined as the proportion of patients in whom a CR or PR or stable disease (SD) (per RECIST v 1.1, SD assessed at least 6 weeks after first dose) is observed as best overall response.	up to 36 months
BNT141 - Duration of response (DOR)	DOR is defined as the time from first objective response (CR or PR per RECIST v 1.1) to first occurrence of objective tumor progression (progressive disease per RECIST v 1.1) or death from any cause, whichever occurs first.	up to 36 months

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, 2023
• Last Update Submitted That Met QC Criteria: September 29, 2023
• Last Verified: September 1, 2023

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