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

Study Overview
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Brief Summary
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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.

Official Title
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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

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

Intervention / Treatment
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* Biological: BNT141
* Drug: Nab-paclitaxel
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1A - BNT141 monotherapy escalation<br>Administration once every three weeks (Q3W) | Biological: BNT141<br>* Intravenous (IV)<br>|
| Experimental: Part 1B - BNT141 in combination with nab-paclitaxel and gemcitabine<br>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<br>* Intravenous (IV)<br>Drug: Nab-paclitaxel<br>* Intravenous (IV)<br>Drug: Gemcitabine<br>* Intravenous (IV)<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CLDN18.2-positive solid tumors, Gastric cancer, Gastric adenocarcinoma, Gastroesophageal junction adenocarcinoma, Esophageal adenocarcinoma, Esophageal cancer, Pancreatic cancer, Pancreatic ductal adenocarcinoma, Biliary tract cancers, Cholangiocarcinoma, Mucinous ovarian cancers, Metastatic, Treatment, Therapy, Targeted immunotherapy, Metastatic cancer, Ribomab, CLDN18.2-positive tumors, Biomarker, Precision medicine, Precision oncology, Solid tumors, mRNA