Sponsor decision

This was an open-label, multicenter Phase I/IIa dose escalation, safety, pharmacokinetic and pharmacodynamic (PD) study of BNT151 with expansion cohorts in various solid tumor indications.

The study was planned to be performed in Part 1, Part 2A, and Part 2B with adaptive design elements. Part 2 was not conducted because of the clinical study being terminated early.

The monotherapy dose escalation, (Part 1) of this clinical study enrolled participants with various solid tumors that are metastatic or of advanced unresectable stage for whom there was no available standard therapy likely to confer clinical benefit, or participants who are not candidates for such available therapy. Dose escalation followed an accelerated titration design, i.e., started with single participant cohorts followed by larger participant cohorts informed by the 3+3 design.

Part 1 of the study also planed to implement a dedicated biomarker cohort in BNT151 monotherapy. The biomarker cohort was planned to recruit participants at selected sites in the United States (US) only. The objective of the cohort was to observe PD activity and drug-induced changes in the blood and tumor and only to generate data for exploratory endpoints or additional research. However, the biomarker cohort was not opened, and therefore no data were generated.

During combination dose escalation (Part 2A), participants with squamous cell carcinoma of head and neck, and hepatocellular carcinoma were planned to be enrolled and treated with a combination of BNT151 and pembrolizumab. Once Part 2A was completed, participants with renal cell carcinoma, non-small cell lung cancer, and triple negative breast cancer were planned to be enrolled (Part 2B) and treated with a combination of BNT151 with the respective standard of care (SoC).

The study was terminated early due to sponsor's decision after careful considerations including recruitment projections and available data, and not due to any safety concerns. At the time of the termination, fewer dose levels were tested than anticipated.

INCLUSION CRITERIA:

• Histological documentation of the original primary tumor via a pathology report.
• Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

For Part 1:

• Histologically confirmed solid tumor that is metastatic or of advanced unresectable stage and for whom there is no available standard therapy likely to confer clinical benefit, or participant who is not a candidate for such available therapy. If there is no contraindication, participants should have exhausted all SoC therapies before entering the study, if possible.

For all Parts:

• ≥18 years of age.
• Must sign an informed consent form (ICF) indicating that he or she understands the purpose and procedures required for the study and are willing to participate in the study prior to any study-related assessments or procedures.
• Eastern Cooperative Oncology Group performance status of 0 to 1.
• Adequate coagulation function at screening as required by the protocol.
• Adequate hematologic function at screening as required by the protocol.
• Adequate hepatic function at screening as required by the protocol.
• Adequate renal function at screening as required by the protocol.
• Able and willing to attend study visits as required by the protocol.
• Women of childbearing potential (WOCBP) must have a negative serum (beta-human chorionic gonadotropin) test/value at screening. Participants who are postmenopausal or permanently sterilized can be considered as not having reproductive potential.
• WOCBP must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the entire study, until 6 months after last BNT151 treatment.
• A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control, e.g. either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, and all men must also not donate sperm during the study and for 6 months after receiving the last dose of BNT151.
• WOCBP must agree to use highly effective contraception during the study and for 6 months after receiving the last dose of BNT151. Birth control methods are considered highly effective if they have a failure rate of less than 1% per year, when used consistently and correctly.
• Biomarker cohort: At selected US sites only: at enrollment participants must agree to have one pre-dose biopsy and lesion that is deemed accessible by the investigator. If possible, at least one on-treatment biopsy should be accessible from same tumor lesion.

EXCLUSION CRITERIA:

• Use of any investigational medical product (IMP) or device within 28 days before administration of first dose of study treatment.
• Has been receiving: radiotherapy, chemotherapy, or molecularly-targeted agents or tyrosine kinase inhibitors within 2 weeks or 5 half-lives (whichever is longer) of the start of study treatment; immunotherapy/monoclonal antibodies within 3 weeks of the start of study treatment; any live vaccine within 4 weeks of the start of study treatment; nitrosoureas, antibody-drug conjugates, or radioactive isotopes within 6 weeks of the start of study treatment.
• Ongoing participation in the active treatment phase of interventional clinical study.
• Receives concurrent systemic (oral or IV) steroid therapy >10 mg prednisone daily or its equivalent for an underlying condition.
• Has had major surgery within the 4 weeks before the first dose of BNT151.
• 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 BNT151.
• Has ongoing side effects to any prior therapy or procedures for any medical condition not recovered to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 Grade ≤1.

Medical conditions:

• Current evidence of new or growing brain or leptomeningeal metastases during screening. Participants with known brain metastases may be eligible if they:
• had radiotherapy, surgery or stereotactic surgery for the brain metastases;
• have no neurological symptoms (excluding Grade ≤2 neuropathy);
• have stable brain metastasis on the computed tomography or magnetic resonance imaging scan within 4 weeks before signing the informed consent;
• are not undergoing acute corticosteroid therapy or steroid taper.
• Has a history of a cerebrovascular accident or transient ischemic attack less than 6 months ago.
• Effusions (pleural, pericardial, or ascites) requiring drainage.
• History of autoimmune disease active or past including but not limited to inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis, scleroderma, or multiple sclerosis. Has any active immunologic disorder requiring immunosuppression with steroids or other immunosuppressive agents (e.g., azathioprine, cyclosporine A) with the exception of participants with isolated vitiligo, resolved childhood asthma or atopic dermatitis, controlled hypoadrenalism or hypopituitarism, and participants with a history of Grave's disease with stable thyroid function. Participants with controlled hyperthyroidism must be negative for thyroglobulin, thyroid peroxidase antibodies, and thyroid stimulating immunoglobulin prior to administration of study treatment.
• Known history of seropositivity for human immunodeficiency virus (HIV) with CD4+ T-cell (CD4+) counts <350 cells/µL and with a history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections.
• Known history/positive serology for hepatitis B requiring active antiviral therapy (unless immune due to vaccination or resolved natural infection or unless passive immunization due to immunoglobulin therapy). Participants with positive serology must have hepatitis B viral load below the limit of quantification.
• Active hepatitis C virus (HCV) infection; participants who have completed curative antiviral treatment with HCV viral load below the limit of quantification are allowed.
• Any contraindication to the combination therapies as per United States Prescribing Information or Summary of Product Characteristics for participants receiving BNT151 in combination with other systemic anticancer agent(s).
• Another primary malignancy that has not been in remission for at least 2 years, with the exception of those with a negligible risk of metastasis or death (including but not limited to adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer, or ductal carcinoma in situ).

Other comorbidities:

• Abnormal electrocardiograms that are clinically significant, such as Fridericia-corrected QT prolongation >480 ms.
• In the opinion of the treating investigator, has any concurrent conditions that could pose an undue medical hazard or interfere with the interpretation of the study results; these conditions include, but are not limited to:
• Ongoing or active infection requiring antibiotic/antiviral/antifungal therapy
• Concurrent congestive heart failure (New York Heart Association Functional Classification Class III or IV)
• Concurrent unstable angina
• Concurrent cardiac arrhythmia requiring treatment (excluding asymptomatic atrial fibrillation)
• Acute coronary syndrome within the previous 6 months
• Pulmonary embolism within the previous 3 months
• Significant pulmonary disease (shortness of breath at rest or on mild exertion) for example due concurrent severe obstructive pulmonary disease.
• Cognitive, psychological or psychosocial impediment that would impair the ability of the participant to receive therapy according to the protocol or adversely affect the ability of the participant to comply with the informed consent process, protocol, or protocol-required visits and procedures.
• Is pregnant or breastfeeding.

Treated set, i.e., defined as all participants who received IMP (i.e., at least one dose of BNT151).

Deaths and serious AEs: All events from the signing of the study-specific ICF until early study termination, i.e., up to 31 months. Other AEs: All TEAEs, i.e., AEs reported from the start of study drug treatment until until early study termination, i.e., up to 30 months.

Other AEs: All TEAEs, i.e., any AE with an onset date on or after the first dose of BNT151 (if the AE was absent before the first dose) or worsened after the first dose of BNT151 (if the AE was present before the first dose). AEs with an onset date >60 days after the last dose of BNT151 were included only if assessed as related to BNT151 by the investigator.

If a participant experienced more than one event in a category, the participant is counted only once in that category.