Clinical trial NCT04455620: BNT151 as a Monotherapy and in Combination With Other Anti-cancer Agents in Patients With Solid 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 BNT151 as a Monotherapy and in Combination With Other Anti-cancer Agents in Patients With Solid Tumors
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Solid Tumor
Keywords: Solid Tumors
Lead sponsor: BioNTech SE
Sponsor class: INDUSTRY
First posted: 2020-07-02
Enrollment: 62
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is an open-label, multicenter Phase I/IIa dose escalation, safety, pharmacokinetic (PK) and pharmacodynamic (PD) trial of BNT151 with expansion cohorts in various solid tumor indications. The trial consists of Part 1, Part 2A and Part 2B with adaptive design elements:

The monotherapy dose escalation, (Part 1) of this clinical trial will enroll patients with various solid tumors that are metastatic or of advanced unresectable stage for whom there is no available standard therapy likely to confer clinical benefit, or patients who are not candidates for such available therapy. The Part 1 of the trial also plans to implement a dedicated biomarker cohort in BNT151 monotherapy: The Biomarker Cohort will recruit patients at selected sites in the US only. The objective of the cohort is to observe PD activity and drug-induced changes in the blood and tumor.

During combination dose escalation (Part 2A), patients of different specific solid tumors (one cohort per indication) will be enrolled and treated with a combination of BNT151 and the respective standard of care (SoC) treatment.

Part 2B is the expansion phase where a predefined number of patients in each indication cohort will be treated with the confirmed recommended phase II dose (RP2D) of BNT151 in combination with respective SoC.


Eligibility criteria: Inclusion Criteria:

* Histological documentation of the original primary tumor via a pathology report.
* Measurable disease per RECIST1.1.

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 patient who is not a candidate for such available therapy. If there is no contraindication, patients should have exhausted all SoC therapies before entering the trial, 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 trial and are willing to participate in the trial prior to any trial-related assessments or procedures.
* Eastern Cooperative Oncology Group (ECOG) 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 trial visits as required by the protocol.
* Women of childbearing potential (WOCBP) must have a negative serum (beta-human chorionic gonadotropin \[beta-hCG\]) test/value at screening. Patients 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 trial, 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 trial and for 6 months after receiving the last dose of BNT151.
* WOCBP must agree to use highly effective contraception during the trial 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 patients 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 or device within 28 days before administration of first dose of trial 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 trial treatment; immunotherapy/monoclonal antibodies within 3 weeks of the start of trial treatment; any live vaccine within 4 weeks of the start of trial treatment; nitrosoureas, antibody-drug conjugates, or radioactive isotopes within 6 weeks of the start of trial treatment.
* Ongoing participation in the active treatment phase of interventional clinical trial.
* 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) v5.0 Grade ≤1.

Medical conditions:

* Current evidence of new or growing brain or leptomeningeal metastases during screening. Patients 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 (CT) or magnetic resonance imaging (MRI) 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 (SLE), 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 patients with isolated vitiligo, resolved childhood asthma or atopic dermatitis, controlled hypoadrenalism or hypopituitarism, and patients with a history of Grave's disease with stable thyroid function. Patients with controlled hyperthyroidism must be negative for thyroglobulin, thyroid peroxidase antibodies, and thyroid stimulating immunoglobulin prior to administration of trial 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). Patients with positive serology must have HBV viral load below the limit of quantification.
* Active HCV infection; patients who have completed curative antiviral treatment with HCV viral load below the limit of quantification are allowed.
* Known hypersensitivity to a component of any trial treatment.
* Any contraindication to the combination therapies as per United States Prescribing Information (USPI) or Summary of Product Characteristics (SmPC) for patients 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 ECGs 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 trial 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 \[NYHA\] 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 patient to receive therapy according to the protocol or adversely affect the ability of the patient to comply with the informed consent process, protocol, or protocol-required visits and procedures.
* Is pregnant or breastfeeding.

Primary outcomes:
measure: Occurrence of dose limiting toxicities (DLTs) within a patient during the DLT evaluation period in Part 1.
timeFrame: up to 21 days
measure: Occurrence of treatment emergent adverse event (TEAE) within a patient including Grade ≥3, serious, fatal TEAE by relationship.
timeFrame: through study completion, an average of 6 months
measure: Occurrence of dose reduction and discontinuation of investigational medicinal product (IMP) within a patient due to TEAE.
timeFrame: through treatment completion, an average of 4 months
Secondary outcomes:
measure: Objective response rate (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 1.1]) is observed as best overall response.
timeFrame: through study completion, an average of 6 months
measure: Disease control rate (DCR) is defined as the proportion of patients in whom a CR or PR or stable disease (SD) (per RECIST 1.1, SD assessed at least 6 weeks after first dose) is observed as best overall response.
timeFrame: through study completion, an average of 6 months
measure: Duration of response (DOR) is defined as the time from first objective response (CR or PR per RECIST 1.1) to first occurrence of objective tumor progression (Progressive disease (PD) per RECIST 1.1) or death from any cause, whichever occurs first.
timeFrame: through study completion, an average of 6 months
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
city: Nashville
country: United States
facility: Sarah Cannon Research Institute at Tennessee Oncology
state: Tennessee
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: NEXT Oncology
state: Texas
city: Barcelona
country: Spain
facility: Vall d´Hebron Institute of Oncology (VHIO)
city: Madrid
country: Spain
facility: START Madrid - HM CIOCC
Study officials:
affiliation: BioNTech SE
name: BioNTech Responsible Person
role: STUDY_DIRECTOR
References: