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

• ClinicalTrials.gov Identifier: NCT04683939
• Recruitment Status: Terminated
• First Posted: December 24, 2020
• Last Update Posted: October 2, 2023
• Sponsor: BioNTech SE
• Information provided by (Responsible Party): BioNTech SE

Tracking Information

• First Submitted Date: December 21, 2020
• First Posted Date: December 24, 2020
• Last Update Posted Date: October 2, 2023
• Actual Study Start Date: January 18, 2022
• Actual Primary Completion Date: July 24, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 21, 2020)

• Occurrence of treatment-emergent adverse events (TEAEs) within a patient including Grade ≥ 3, serious, fatal TEAE by relationship [ Time Frame: up to 36 months ]
  TEAEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v 5.0.
• Occurrence of dose reductions and discontinuation of BNT141 due to TEAEs throughout the study and up to 60 days after last subject last treatment [ Time Frame: up to 36 months ]
• Occurrence of dose-limiting toxicities (DLTs) within a patient during the DLT evaluation period [ Time Frame: assessed during the first cycle (21 days) in each cohort ]
  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).

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: July 25, 2022)

• BNT141 pharmacokinetic: Area under the concentration time curve (AUC) [ Time Frame: pre-dose until 60 days after last dose ]
• BNT141 pharmacokinetic: Clearance (CL) [ Time Frame: pre-dose until 60 days after last dose ]
• BNT141 pharmacokinetic: Volume of distribution (VD) [ Time Frame: pre-dose until 60 days after last dose ]
• BNT141 pharmacokinetic: Maximum concentration of the drug (Cmax) [ Time Frame: pre-dose until 60 days after last dose ]
• BNT141 pharmacokinetic: Time to maximum concentration (Tmax) [ Time Frame: pre-dose until 60 days after last dose ]
• BNT141 pharmacokinetic: Concentration prior to next dose (Ctrough) [ Time Frame: pre-dose until 60 days after last dose ]
• BNT141 pharmacokinetic: Elimination half-life (t half) [ Time Frame: pre-dose until 60 days after last dose ]
• BNT141 - Objective response rate (ORR) [ Time Frame: up to 36 months ]
  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.
• BNT141 - Disease control rate (DCR) [ Time Frame: up to 36 months ]
  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.
• BNT141 - Duration of response (DOR) [ Time Frame: up to 36 months ]
  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.

Original Secondary Outcome Measures (submitted: December 21, 2020)

• BNT141 pharmacokinetic: Area under the concentration time curve from 0 to infinity (AUC0-inf) [ Time Frame: pre-dose until 60 days after last dose ]
• BNT141 pharmacokinetic: Area under the concentration time curve from 0 to time (AUC0-t) [ Time Frame: pre-dose until 60 days after last dose ]
• BNT141 pharmacokinetic: Clearance (CL) [ Time Frame: pre-dose until 60 days after last dose ]
• BNT141 pharmacokinetic: Volume of distribution (VD) [ Time Frame: pre-dose until 60 days after last dose ]
• BNT141 pharmacokinetic: Maximum concentration of the drug (Cmax) [ Time Frame: pre-dose until 60 days after last dose ]
• BNT141 pharmacokinetic: Time to maximum concentration (Tmax) [ Time Frame: pre-dose until 60 days after last dose ]
• BNT141 pharmacokinetic: Concentration prior to next dose (Ctrough) [ Time Frame: pre-dose until 60 days after last dose ]
• BNT141 pharmacokinetic: Minimum drug concentration observed after administration (Cmin) [ Time Frame: pre-dose until 60 days after last dose ]
• BNT141 pharmacokinetic: Elimination half-life (t half) [ Time Frame: pre-dose until 60 days after last dose ]
• BNT141 - Objective response rate (ORR) [ Time Frame: up to 36 months ]
  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 observed as best overall response.
• BNT141 - Disease control rate (DCR) [ Time Frame: up to 36 months ]
  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.
• BNT141 - Duration of response (DOR) [ Time Frame: up to 36 months ]
  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.
• BNT141 - Anti-drug antibodies [ADAs] response [ Time Frame: pre-dose until 60 days after last dose ]
  The presence and concentration of anti-drug antibodies will be reviewed. Number of positive/negative cases by dose level will be reported.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• Official Title: 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

Brief Summary

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Solid Tumor
• Gastric Cancer
• Gastroesophageal Junction Adenocarcinoma
• Esophageal Adenocarcinoma
• Pancreatic Cancer
• Biliary Tract Cancer
• Cholangiocarcinoma
• Metastatic Cancer

Intervention

• Biological: BNT141
  Intravenous (IV)
• Drug: Nab-paclitaxel
  Intravenous (IV)
• Drug: Gemcitabine
  Intravenous (IV)

Study Arms

• Experimental: Part 1A - BNT141 monotherapy escalation
  Administration once every three weeks (Q3W)
  Intervention: Biological: BNT141
• 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.
  Interventions:

  • Biological: BNT141
  • Drug: Nab-paclitaxel
  • Drug: Gemcitabine

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: September 29, 2023): 13
• Original Estimated Enrollment (submitted: December 21, 2020): 48
• Actual Study Completion Date: July 24, 2023
• Actual Primary Completion Date: July 24, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, United States
• Removed Location Countries: Spain

Administrative Information

• NCT Number: NCT04683939
• Other Study ID Numbers: BNT141-01; 2022-001843-25 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: BioNTech SE
• Original Responsible Party: Same as current
• Current Study Sponsor: BioNTech SE
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: BioNTech Responsible Person; BioNTech SE

• PRS Account: BioNTech SE
• Verification Date: September 2023