Phase I/IIa Dose-Escalation Study of BNT142 in CLDN6-Positive Advanced Solid Tumors: Safety, Tolerability, and Preliminary Efficacy Evaluation

Trial ID: 2024-512639-58-00
Protocol: BNT142-01
Sponsor: BioNTech SE

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Diseases & Conditions

Endometrial cancer Neoplasm malignant Malignant neoplasm of unknown primary site Ovarian cancer

Objectives

The primary objective of this study is to assess the **safety** and tolerability of BNT142 at all dose levels tested in patients with CLDN6-positive advanced solid tumors. This is crucial for determining the maximum tolerated dose (MTD), maximum administered dose (MAD), and recommended Phase 2 dose (RP2D) based on the occurrence of dose-limiting toxicities (DLTs). The MTD is defined as the highest dose where less than one-third of patients experience a DLT, while the MAD is the highest dose administered where all dose levels were tolerated during dose escalation. The RP2D will be determined through an integrated evaluation of safety, tolerability, clinical benefit, pharmacokinetics, and pharmacodynamics data from all dose levels tested.

Secondary objectives include:

Characterizing the **pharmacokinetics** profile of the BNT142-encoded protein RiboMab02.1 in Part 1 of the study.
Evaluating the anti-tumor activity of BNT142 according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. For ovarian cancer patients, this evaluation will incorporate RECIST 1.1 and cancer antigen-125 (CA) definitions as agreed by the Gynecological Cancer Intergroup (GCIG).

These secondary objectives aim to provide a comprehensive understanding of the drug's behavior in the body and its potential efficacy in reducing tumor size or progression, which is essential for advancing therapeutic strategies for patients with advanced solid tumors.

Participants

The clinical trial involves a total of **211 participants** diagnosed with **solid tumors**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific criteria, including histological or cytological documentation of a metastatic or unresectable solid tumor, and a **CLDN6-positive tumor sample** confirmed by a central laboratory. The trial includes individuals with advanced or metastatic ovarian cancer, non-squamous non-small cell lung cancer, endometrial, or testicular cancer, among others, who have exhausted standard therapies. The study population also includes a vulnerable population, indicating that additional ethical considerations are in place. Lifestyle factors such as diet and physical activity are not specified in the available data.

Plans and Procedures

The clinical trial is a **Phase I/IIa** study designed to evaluate the safety and preliminary efficacy of **BNT142** in patients with **CLDN6-positive advanced solid tumors**. This trial is structured as a first-in-human, open-label, multicenter, dose-escalation study with expansion cohorts. The primary objective is to assess the safety and tolerability of BNT142 across all dose levels, while secondary objectives include evaluating the anti-tumor activity according to the **Response Evaluation Criteria in Solid Tumors (RECIST) 1.1**. The trial is expected to commence recruitment on August 16, 2024, and conclude by November 14, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histological or cytological documentation of a metastatic or unresectable solid tumor and a **CLDN6-positive** tumor sample. Following the screening, participants will enter the dose-escalation phase (Part 1) to identify the maximum tolerated dose (MTD) and the maximum administered dose (MAD) of BNT142. The expansion phase (Part 2) will further evaluate the anti-tumor activity. Study visits will include regular assessments for treatment-emergent adverse events (TEAEs), dose-limiting toxicities (DLTs), and pharmacokinetic parameters.

The expected duration of participant involvement will vary depending on individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include the occurrence of serious or fatal TEAEs, dose reductions, or discontinuation of BNT142 due to adverse events. The trial will adhere to rigorous safety monitoring protocols to ensure participant well-being throughout the study duration.

Treatment

The clinical trial involves the experimental medication **BNT142**, which is a **dispersion for injection**. This investigational product is developed by BioNTech SE and is characterized by its active substance, also named BNT142, which originates from **nucleic acid**. The pharmaceutical form of BNT142 is a dispersion intended for injection, and it is administered as a **solution for infusion**. The trial is designed to evaluate the safety and preliminary efficacy of BNT142 in patients with CLDN6-positive advanced solid tumors. The dosing regimen involves a dose-escalation approach to determine the maximum tolerated dose (MTD), maximum administered dose (MAD), and recommended Phase 2 dose (RP2D) based on the occurrence of dose-limiting toxicities (DLTs). The frequency of administration and specific dosing schedules are determined as part of the trial's protocol, with careful monitoring of participant compliance and response to the treatment.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus remains solely on the administration and evaluation of BNT142. The trial aims to assess the anti-tumor activity of BNT142 according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, with additional criteria for ovarian cancer patients as defined by the Gynecological Cancer Intergroup (GCIG). The trial does not include a pediatric formulation, and BNT142 is not classified as an orphan drug. Participant compliance and response to the treatment are closely monitored throughout the study to ensure accurate assessment of the investigational product's safety and efficacy.

Efficacy

The efficacy of BNT142 in the clinical trial will be assessed using several parameters. For Part 2 of the trial, the primary endpoint is the **Objective Response Rate (ORR)**, which is defined as the proportion of patients achieving a confirmed complete response (CR) or partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. For patients with ovarian cancer, the ORR will also incorporate the Gynecological Cancer Intergroup (GCIG) criteria, which includes cancer antigen-125 (CA 125) levels. Secondary endpoints include the Disease Control Rate (DCR), which measures the proportion of patients achieving CR, PR, or stable disease (SD) as the best overall response, with SD assessed at least 6 weeks after the first dose. The Duration of Response (DOR) is also evaluated, defined as the time from the first objective response to the first occurrence of tumor progression or death.

Pharmacokinetic (PK) parameters will be analyzed, including the area under the concentration-time curve (AUC), clearance (CL), volume of distribution (Vd), maximum observed concentration (Cmax), time to maximum concentration (tmax), concentration prior to the next dose (Ctrough), minimum observed concentration (Cmin), and half-life (t½). These parameters will be measured at specified intervals to understand the drug's behavior in the body. The trial will utilize validated scales and laboratory tests to ensure accurate and reliable data collection. The efficacy assessments will be conducted at various timepoints throughout the trial to monitor the treatment's impact on the disease.

Inclusion and Exclusion Criteria

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Inclusion Criteria

For both parts: Histological or cytological documentation of a solid tumor that is metastatic or unrespectable provided as a pathology report.
CLDN6-positive tumor sample as assessed by central laboratory testing using a Validated immunohistochemistry (IHC) assay (CLAUDENTIFY®6 IHC-Assay) in formalin-fixed paraffin-embedded (FFPE) neoplastic tissues or alternatively from fresh tissue if archival tissue is unavailable
Measurable disease per RECIST 1.1 (measurable per RECIST 1.1 or evaluable per GCIG criteria for ovarian tumors).
For Part 1 (Dose escalation): Patients with advanced/metastatic ovarian cancer (including fallopian tube and peritoneal), non-squamous non-small cell lung cancer (NSCLC), endometrial, or testicular cancer, for whom there is no available standard therapy likely to confer clinical benefit, or the patient is not a candidate for such available therapy, or patients with not otherwise specified (NOS) tumors, rare tumors and cancer of unknown primary (CUP), not included in the predefined eligible tumor types. Patients must have received all available standard therapies, including targeted therapies based on mutation status, and failed at least first line standard of care (SOC) therapy prior to enrollment

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Exclusion Criteria

Prior and concomitant therapy: 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 study treatment; nitrosoureas, antibody-drug conjugates, or radioactive isotopes within 6 weeks of the start of study treatment.
Radiotherapy in the last 6 weeks prior to the first dose of BNT142 (excluding brain radiotherapy for which 3 weeks prior to the first dose of BNT142 is allowed).
Concurrent systemic (oral or intravenous [IV]) steroid therapy >10 mg prednisone daily or its equivalent for an underlying condition apart from physiologic corticosteroid replacement therapy.
Major surgery within 4 weeks before the first dose of BNT142
Ongoing or active infection requiring intravenous (IV) treatment with anti-infective therapy that has been administered less than 2 weeks prior to the first dose of BNT142.
Prior treatment with a CLDN6 targeting therapy.
Side effects of any prior therapy or procedures for any medical condition not recovered to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v.5) Grade ≤1, except for anorexia, fatigue, hyperthyroidism, hypothyroidism, and peripheral neuropathy, which must have recovered to Grade ≤2. Alopecia of any grade is allowed.
Medical conditions Current evidence of new or growing brain or leptomeningeal metastases during screening. Patients with known brain metastases may be ligible if they: i. Had radiotherapy, surgery or stereotactic surgery for the brain metastases; ii. Have no neurological symptoms (excluding Grade ≤2 neuropathy); iii. Have stable brain metastasis on the Computerized Tomography (CT) or Magnetic Resonance Imaging (MRI) scan within 4 weeks before signing the Informed Consent Form (ICF) iv. Are not undergoing acute corticosteroid therapy or steroid taper.
Pregnant or breastfeeding or planning to get pregnant within 6 months of the last dose of BNT142.