IRB Study Number 23-1244
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
Dose escalation only: To determine the MTD/MAD and/or RP2D of BNT314 administered as monotherapy.
Establish the safety profile of BNT314.
Secondary Objectives
To characterize the PK of BNT314 administered as monotherapy.
To characterize the immunogenicity of BNT314 administered as monotherapy.
To evaluate the preliminary antitumor activity of BNT314 administered as monotherapy based on RECIST 1.1.
Inclusion Criteria
5.3.1 Inclusion criteria for all trial parts
Have the ability to voluntarily give informed consent by signing and dating the informed consent form (ICF) before initiation of any trial-specific procedures.
Are willing and able to comply with scheduled visits, treatment schedule, laboratory tests, lifestyle restrictions, and other requirements of the trial. This includes that they are able to understand and follow trial-related instructions.
Are ≥18 years of age at the time of giving informed consent.
Have measurable disease according to RECIST v1.1 (Eisenhauer et al. 2009). NOTE: Patients that present with no other measurable lesions apart from the ones that received external beam radiation therapy or locoregional therapy, must show radiographic evidence of subsequent growth of these lesions.
Have a life expectancy of >3 months.
Have ECOG PS score of 0 or 1 at screening.
7 Have adequate coagulation function at screening as determined by:
• International normalized ratio (INR) or prothrombin time ≤1.5 × upper limit normal (ULN; unless on therapeutic anticoagulants with values within therapeutic window).
• Activated partial thromboplastin time (aPTT) ≤1.5 × ULN (unless on therapeutic anticoagulants with values within therapeutic window).
8 Have adequate bone marrow/hematologic function at screening as determined by:
• Absolute neutrophil count (ANC) ≥1.5 × 109/L (≥1500/μL) (patients may not use granulocyte colony stimulating factor or granulocyte-macrophage colony stimulating factor to achieve these ANC levels in the past 7 d).
• Platelet count ≥100 × 109/L (≥100,000/μL).
• Hemoglobin ≥9 g/dL.
• Any blood transfusions ≤28 d before first dose of trial treatment should be documented.
9 Have adequate hepatic function at screening as determined by:
• Total bilirubin ≤1.5 × ULN OR direct bilirubin ≤ULN for patients with total bilirubin levels >1.5 × ULN. Exception for patients in monotherapy: Patients with Gilbert’s syndrome must have a total bilirubin <3 mg/dL and direct bilirubin ≤ULN.
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 ULN for patients with or without liver metastases.
• Albumin ≥30 g/L.
10 Have adequate renal function at screening as determined by:
• Glomerular filtration rate (GFR) ≥45 mL/min/1.73 m² according to the abbreviated Modification of Diet in Renal Disease equation:
GFR = 175 × (Screatinin -1.154) × (age-0.203) where the serum creatinine level is expressed in mg/dL; multiply it by 0.742 if the patient is female; multiply it by 1.212, if the individual is African-American (Levey et al. 2007).
Have adequate pancreas function at screening as determined by serum amylase and lipase with no signs and symptoms of pancreatitis. If required, contact the trial Medical Monitor for guidance.
Patients of childbearing potential (POCBP; Section 10.5) must have a negative urine and serum beta human chorionic gonadotropin (beta-hCG) test at screening. Patients that are postmenopausal or permanently sterilized (verified by medical records) will not be considered POCBP, and therefore are not required to undergo pregnancy testing.
POCBP must agree to practice a highly effective form of contraception (Section 10.5.1) and to require their male partners to use condoms with a spermicidal agent, starting at Visit D1 and thereafter until 60 d after receiving the last trial treatment.
POCBP must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during trial, starting at Visit D1 and thereafter until 60 d after receiving the last trial treatment.
Men who are sexually active and have not had a bilateral vasectomy or orchidectomy must agree to use condoms with a spermicidal agent and to require their female partners to practice a highly effective form of contraception (Section 10.5.1) during the trial, starting at Visit D1 and thereafter until 90 d after receiving the last trial treatment.
Men must be willing to refrain from sperm donation, starting at Visit D1 and thereafter until 90 d (one sperm cycle) after receiving the last trial treatment.
5.3.2 Inclusion criteria for monotherapy dose escalation only
- Patients must have a histologically confirmed advanced malignant solid tumor (CRC, NSCLC, TNBC, ovarian, endometrial, cervical, prostate, gastric/GEJ, pancreatic, or cholangiocarcinoma), having experienced disease progression on or after standard therapy, or were intolerant of or not eligible for standard therapy.
5.3.3 Inclusion criteria for monotherapy MSS/pMMR metastatic CRC backfill cohorts only
- • Patients with previously documented MSS/pMMR metastatic CRC (which was assessed as part of the patient’s prior treatment per FDA/CE approved test) who have received at least one prior 5-FUbased therapy (e.g., 5 fluorouracil/leucovorin with either oxaliplatin or irinotecan), or S1 containing systemic treatment regimen for locally advanced/unresectable and/or metastatic disease. Prior targeted therapy (i.e., BRAF, KRAS or EGFR mutation) is permitted, but previous CPI treatment is not allowed. Maintenance treatment is considered being part of one treatment line.
• Intolerant/refractory to or had documented PD on or after standard systemic therapy.
5.3.4 Inclusion criteria for combination therapy SRI and dose expansion only
Individuals are eligible for enrollment in this trial only if all the following criteria apply (indications for the SRI are the same as for the combination expansion cohorts):
- For patients in Expansion Cohort 1:
• Patients with histologically confirmed locally advanced/unresectable and/or metastatic cancer with MSI-H/dMMR status (CRC, endometrial, ovarian, gastric/GEJ).
• Testing for MSI-H/dMMR should have been performed (using an FDA/CE approved test) as part of the patient’s prior treatment and must be available prior to enrollment.
• With documented PD on or after standard therapy, i.e., as 2L+ treatment, CPI experienced (i.e., received at least one dose of anti-PD-1/PD-L1).
- For patients in Expansion Cohort 2:
• Patients with locally advanced/unresectable and/or metastatic NSCLC (NSQ and SQ cell carcinoma).
• Tumor must express PD-L1 (Tumor Proportion Score [TPS]) ≥1% as part of the patient’s prior treatment, with no EGFR, ROS1 (c-ros oncogene)1 or anaplastic lymphoma kinase (ALK) genomic tumor aberrations per local assessment and clinical practice.
• With documented PD on or after standard therapy, i.e., as 2L+ treatment, CPI experienced.
- For patients in Expansion Cohort 3:
• Patients with locally advanced/unresectable and/or metastatic TNBC; i.e., HER2-negative status and ER and PROGR-negative status as per ASCO/CAP.
• Tumor must express PD-L1 (CPS ≥1) as part of the patient’s prior treatment (per local testing).
• As 2L treatment, CPI-naïve or CPI experienced. Neoadjuvant/adjuvant therapy will not qualify as required prior treatment line.
- For patients in Expansion Cohort 4:
• Patients with locally advanced/unresectable and/or metastatic MSS/pMMR endometrial cancer.
• Testing for MSS/pMMR status should have been performed (using an FDA/CE approved test) as part of the patient’s prior treatment and must be available prior to enrollment.
• As 2L treatment, CPI-naïve or CPI experienced.
• Prior CPI and best overall response (BOR) to prior CPI should be documented if patient had available and relevant prior CPI-containing SOC or CPI-containing experimental treatment.
- For patients in Expansion Cohort 5:
• Patients with locally advanced/unresectable and/or metastatic gastric/GEJ cancer.
• Tumor must express PD-L1 (CPS ≥1) assessed as part of the patient’s prior treatment (per local test).
• HER2 status should be documented per local assessment.
• With documented PD on or after standard therapy, i.e., as 2L+ treatment, CPI-naïve or CPI experienced.
Exclusion Criteria
- Patients that have uncontrolled intercurrent illness, including but not limited to:
• Ongoing or active infection requiring treatment with anti-infective therapy administered less than two weeks prior to first dose.
• Symptomatic congestive heart failure (Grade III or IV as classified by the New York Heart Association), unstable angina pectoris, or symptomatic untreated cardiac arrhythmia. Treated and/or asymptomatic cardiac arrythmia/atrial fibrillation (AF) will be allowed.
• History of arterial thrombosis or pulmonary embolism within six months before the first dose of trial treatment.
• History of myocardial infarction within six months before the first dose of trial treatment.
• Uncontrolled hypertension defined as systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥100 mm Hg, despite optimal medical management.
• Prolonged QTc interval at baseline of ≥470 milliseconds using Fridericia’s QT correction formula.
• Ongoing or recent (within one year of screening) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments, which may suggest risk for immunerelated AEs (irAEs).
• History of Grade 3 or higher irAEs that led to treatment discontinuation of a CPI. A patient with irAEs below Grade 3 that led to discontinuation should be discussed with the sponsor. Grade 3 irAEs that have fully recovered may also be discussed.
• History of chronic liver disease (e.g., alcoholic hepatitis or nonalcoholic steatohepatitis, drug-related or autoimmune hepatitis) or evidence of hepatic cirrhosis.
• History of non-treated intracerebral arteriovenous malformation (shunts), non-treated cerebral aneurysm, spinal cord compression (from disease), carcinomatous meningitis, or stroke will be excluded.
• History of acute or chronic pancreatitis of any etiology within 6 weeks prior to the start of trial treatment.
• Evidence of interstitial lung disease.
• Ongoing pneumonitis or history of noninfectious pneumonitis that has required steroids.
• Transient ischemic attack less than one month prior to screening will be excluded.
• History of brain/central nervous system (CNS) metastases. Patients with newly identified or known unstable or symptomatic CNS metastases will be excluded. Patients with previously treated brain metastases are allowed provided lesions are radiologically stable (i.e., without evidence of progression) for at least 28 days by repeat imaging, latest imaging performed maximum six weeks prior to C1D1.
• Serious, non-healing wound, skin ulcer (of any grade), or bone fracture will be excluded.
• Other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s judgment, contraindicate patient participation in this clinical trial (e.g., acute or chronic pancreatitis, active hepatitis). Known primary immunodeficiencies, either cellular (e.g., DiGeorge syndrome, T-cell negative severe combined immunodeficiency [SCID]) or combined T- and B-cell immunodeficiencies (e.g., T- and B-cell negative SCID, Wiskott Aldrich syndrome, ataxia telangiectasia, common variable immunodeficiency).
• Major surgery within three weeks before signature of the ICF unless fully recovered from the surgery in the opinion of the investigator.
- Prior therapy:
• Radiotherapy within 14 d prior to first BNT314 administration. Palliative radiotherapy will be allowed, but not to target lesions.
• Any EpCAM- or 4-1BB-targeting treatment.
• Treatment with an anticancer agent within four weeks or for systemic therapies after at least five half-lives of the drug, whichever is shorter, prior to trial treatment administration.
• Patient has received any investigational agent (including investigational vaccines) or used an invasive investigational medical device within 28 d before the planned first dose of BNT314 or is currently enrolled in an interventional trial. Patients who are in the follow-up phase of an interventional trial may participate if they have not received an investigational agent within 28 d (or five half-lives, whichever is longer) of the first dose of BNT314.
• Patient has a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 d of the first dose of BNT314. Inhaled or topical steroids, and adrenal or pituitary replacement steroid >10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
• Patient has received granulocyte or granulocyte/macrophage colony stimulating factor (G-CSF/GM-CSF) support within two weeks prior to first BNT314 administration or is chronically transfusion dependent; G-CSF and other hematopoietic factors may be used in the management of acute toxicity (such as febrile neutropenia) or prophylactically, when clinically indicated at the investigator’s discretion.
• Any positive test for hepatitis B (defined as positive for hepatitis B surface antigen [HBsAg] or hepatitis B virus DNA), indicating acute or chronic infection.
• Any positive test for hepatitis C (defined as positive for hepatitis C virus antibody or hepatitis C virus RNA), indicating acute or chronic infection.
• Received any live vaccine within 30 d prior to the start of trial treatment.
Known alcohol dependency within six months enrollment in this trial.
Planned enrollment in another trial of an IMP, starting after Visit D1 and continuously until the last planned visit in this trial.
Have a medical, psychological, or social condition which, in the opinion of the investigator, could compromise their wellbeing if they participate in the trial, or that could prevent, limit, or confound the protocol specified assessments or procedures, or that could impact adherence to protocoldescribed requirements.
Are subject to exclusion periods from another investigational trial.
Are vulnerable individuals as per International Council for Harmonisation (ICH) E6 definition, i.e., are individuals whose willingness to participate in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate.
