Evaluation of mFOLFIRINOX With or Without BNT321 as Adjuvant Therapy in Resected Pancreatic Ductal Adenocarcinoma
- Trial ID
- 2023-506014-47-00
- Protocol
- BNT321-02
- Sponsor
- BioNTech SE
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **safety** and identify the recommended dose for Phase II (RP2D) of BNT321 in combination with mFOLFIRINOX as adjuvant therapy in patients with R0 or R1 resected pancreatic ductal adenocarcinoma (PDAC) during Phase I. In Phase II, the primary objective shifts to evaluating the efficacy of mFOLFIRINOX combined with BNT321 versus mFOLFIRINOX alone as adjuvant therapy in PDAC patients post R0 or R1 resection, measured by median disease-free survival (mDFS). These objectives are clinically relevant as they aim to optimize treatment regimens and improve survival outcomes for patients with resected PDAC, a condition with historically poor prognosis.
Secondary objectives include: - Further assessing the efficacy of mFOLFIRINOX + BNT321 or mFOLFIRINOX alone as adjuvant therapy in PDAC patients post R0 or R1 resection by overall survival (OS), recurrence-free survival (RFS), and disease-free survival (DFS) rates. - Characterizing the pharmacokinetics (PK) and immunogenicity of BNT321 when co-administered with mFOLFIRINOX. - Describing the pharmacodynamic (PD) parameters of BNT321 co-administered with mFOLFIRINOX, including antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). - Assessing self-reported health-related quality of life (HRQoL) of patients receiving mFOLFIRINOX + BNT321 versus mFOLFIRINOX. - Evaluating the safety and tolerability of mFOLFIRINOX with and without BNT321 as adjuvant therapy in patients with R0 or R1 resected PDAC during Phase II.
Participants
The clinical trial involves a total of **143 participants** diagnosed with **resected pancreatic ductal adenocarcinoma**. The study population includes both male and female subjects, aged 18 years and older, who have undergone R0 or R1 resection. Participants were selected based on their ability to comply with trial requirements and their general health status, which includes an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. The trial population is characterized by individuals who have no radiologic evidence of metastatic disease and have fully recovered from surgery, making them eligible to receive chemotherapy. Lifestyle considerations include adherence to specific contraceptive measures for both male and female participants, as well as restrictions on sperm and egg donation during and after the trial. The trial does not include individuals with significant comorbidities or those unable to meet the laboratory parameter criteria. The study also involves a vulnerable population, ensuring that all participants have provided informed consent and are willing to comply with the trial's requirements.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, multicenter study to evaluate the safety, tolerability, and efficacy of mFOLFIRINOX with or without BNT321 as adjuvant therapy in patients with resected pancreatic ductal adenocarcinoma. The trial is divided into two phases: Phase I aims to assess the safety and determine the recommended dose for Phase II, while Phase II focuses on evaluating the efficacy of the treatment by measuring median disease-free survival. The trial is expected to commence recruitment on February 29, 2024, and conclude by June 30, 2031.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as histologically confirmed pancreatic ductal adenocarcinoma and a complete resection status (R0 or R1). Following successful screening, participants will be randomized and begin treatment. The trial includes regular follow-up visits to monitor safety, treatment response, and any adverse events. The end-of-study visit will occur after the completion of the treatment regimen or upon early termination.
The expected duration of participant involvement varies depending on individual response and tolerance to the treatment. Participants may be withdrawn from the study early due to reasons such as the occurrence of unacceptable adverse events, disease progression, or withdrawal of consent. The trial will adhere to rigorous safety monitoring protocols, with primary endpoints including the incidence of treatment-emergent adverse events and disease-free survival. Secondary endpoints will assess overall survival, pharmacokinetic parameters, and health-related quality of life.
Treatment
The clinical trial involves the administration of several treatments, including both experimental and comparator medications. The **experimental medication** is BNT321, a **human IgG1 monoclonal antibody against sialyl-Lewis A**, provided as a solution for infusion. This medication is administered via intravenous infusion. The dosing schedule and frequency are determined based on the phase of the trial, with the primary objective being to assess safety and determine the recommended dose for Phase II. Participant compliance is monitored through regular assessments and documentation of infusion administration.
One of the comparator treatments is **Calciumfolinat HEXAL 10 mg/ml**, a solution for injection containing **folinic acid**. This medication is administered as an intravenous infusion and serves as a detoxification agent in conjunction with cytostatic agents. The product is repackaged and relabelled by Fisher Clinical Services, with no modifications to the formulation.
Another comparator treatment is **Irinotecan HCl AqVida 20 mg/ml**, a concentrate for solution for infusion containing **irinotecan hydrochloride**. This antineoplastic agent inhibits DNA topoisomerase I and is administered via intravenous infusion. The product is also repackaged and relabelled by Fisher Clinical Services, maintaining its original formulation.
**Fluorouracil** is included as a comparator treatment, provided as a solution for injection/infusion. It acts as an antimetabolite, interfering with DNA synthesis, and is administered through intravenous infusion. Similar to other comparator treatments, it is repackaged and relabelled by Fisher Clinical Services without any changes to the product itself.
Lastly, **Oxaliplatin AqVida 5 mg/ml** is used as a comparator treatment, a concentrate for solution for infusion containing **oxaliplatin**. This antineoplastic agent disrupts DNA synthesis, leading to cytotoxic and antitumor effects. It is administered via intravenous infusion and is repackaged and relabelled by Fisher Clinical Services, with no modifications to the formulation.
Efficacy
The efficacy of the clinical trial will be assessed through a combination of primary and secondary endpoints. For Phase II, the primary endpoint is **disease-free survival (DFS)**, defined as the time from randomization to the occurrence of locoregional recurrence, distant metastasis, second primary cancer, or death from any cause, as determined by an independent central radiology assessment. Secondary endpoints include overall survival (OS), defined as the time from the first dose of trial treatment to death from any cause, and recurrence-free survival (RFS), which is the time from randomization to locoregional recurrence, distant metastasis, or death from any cause.
Additional secondary endpoints involve pharmacokinetic (PK) parameters derived from serum concentration of the investigational medicinal product (IMP), including mean area under the curve (AUC), mean maximum concentration (Cmax), and median time to maximum concentration (tmax) in Cycles 2 and 3, followed by sparse sampling through the end of the trial. The percentage of patients with detectable anti-drug antibodies (ADA) formation and antibody-dependent cell-mediated cytotoxicity (ADCC) and/or complement-dependent cytotoxicity (CDC) will also be evaluated. Patient-reported health-related quality of life (HRQoL) will be assessed using the EORTC QLQ-C30 and EORTC QLQ-Pan26 questionnaires, with changes from baseline measured at the end of Cycle 12.
Data collection will occur at specified timepoints throughout the trial, with assessments conducted using validated scales and laboratory tests. The analysis will be performed to determine the efficacy of mFOLFIRINOX with or without BNT321 as adjuvant therapy in patients with pancreatic adenocarcinoma following curative resection.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Has signed the informed consent form (ICF) before initiation of any trial-specific procedures.
- POCBP who agree to practice a highly effective form of contraception (for guidance on highly effective forms of contraception, see Section 10.5) and to require their male partners to use condoms with a spermicidal agent, starting after signing of the ICF and continuously throughout trial and for a period of 111 days after the last dose of BNT321 and for 9 months after the last oxaliplatin dose. If the highly effective method of contraception is medically contraindicated, then only the use of condoms with a spermicidal agent is acceptable (Section 4.2.3).
- Full recovery from surgery and able to receive chemotherapy.
- Has acceptable laboratory parameters including: a) absolute neutrophil count (ANC) ≥1.5x 10E9/L, b) hemoglobin ≥10.0 g/dL, c) platelet count >100,000/mm10E3, d) aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.0x upper limit of normal range (ULN), e) total bilirubin ≤ULN, f) serum creatinine ≤1.5x ULN or estimated glomerular filtration rate (eGFR) >50 mL/min, g) serum albumin >3.0 g/dL
- Patient of childbearing potential (POCBP) must have a negative urine beta human chorionic gonadotropin (βhCG) test at screening. Patients that are postmenopausal or permanently sterilized (verified by medical records; for definitions, see Section 10.5) will not be considered POCBP, and therefore are not required to undergo pregnancy testing.
- Is willing to allow collection of pharmacokinetic samples.
- POCBP who agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during trial, starting after signing of the ICF and continuously throughout trial and for a period of 3 months after the last dose of BNT321 and for 9 months after the last oxaliplatin dose.
- Agrees not to enroll in another trial of an investigational medicinal product (IMP), starting after signing of the informed consent form (ICF) and continuously until the last planned visit in this trial.
- Is >18 years of age or is deemed to be an adult per local authorities at the time of giving written informed consent.
- Willing and able to comply with scheduled visits, treatment schedule, laboratory tests, lifestyle restrictions, and other requirements of the trial.
- Has an ECOG performance status of 0 to 1.
- Men who are sexually active with a POCBP 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 during the trial, starting after signing of the ICF and continuously until 111 days after receiving the last dose of BNT321 and for 6 months after the last oxaliplatin dose.
- Has histologically or cytologically confirmed pancreatic ductal adenocarcinoma (PDAC).
- Had macroscopically complete resection (R0 or R1 resection) performed between ≥21 and ≤84 days prior to first trial medication (C1D1). Submission of tumor tissue from resection or biopsy is required.
- Has no radiologic (CT/MRI) evidence of metastatic disease, malignant ascites, or pleural effusion through an assessment obtained within 4 weeks of first trial medication (i.e., C1D1).
- Men who are willing to refrain from sperm donation, starting after signing of ICF and continuously until 111 days (one sperm cycle) after receiving the last dose of BNT321 and for 6 months after the last oxaliplatin dose.
Exclusion Criteria
- Is pregnant or breastfeeding or is planning a pregnancy or to father children during the trial or within 60 days after last treatment with the investigational medicinal product (IMP).
- Significant cardiovascular risk (past medical history of coronary stenting or myocardial infarction within 6 months, or NYHA Class III/IV, heart failure, or concurrent unstable angina) or risk factors for QT prolongation (sustained Grade 3 or higher hypokalemia, history of unstable arrhythmia, family history of long QT syndrome).
- Has pre-existing neuropathy.
- Active Hepatitis C virus infection (patients who have completed curative antiviral treatment with Hepatitis C virus viral load below the limit of quantification are allowed).
- Homozygous UGT1A1*28 mutation, if testing required by local regulations.
- Has inflammatory disease of the colon or rectum, or occlusion or sub-occlusion of the intestine or severe post-operative uncontrolled diarrhea.
- Has used any investigational medicinal product (IMP) or device within 21 days before administration of first dose of trial treatment or ongoing participation in the active treatment phase of another interventional clinical trial.
- Has a history of seropositivity for human immunodeficiency virus (HIV) with CD4+ T-cell counts <350 cells/μL and a history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections.
- Has 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 protocol-described requirements.
- Had major surgery within 3 weeks of first dose of the trial treatment, where participation in the trial could compromise the patient’s wellbeing in the opinion of the investigator.
- Has abnormal electrocardiograms (ECGs) that are clinically significant, such as Fridericia-corrected QT prolongation >470 msec (for women) and >450 msec (for men), (average of three ECGs at least 5 minutes apart).
- Has a history of anaphylactic reactions to human or humanized antibodies.
- Has serum CA19-9 >180 U/mL within 3 weeks of first treatment with trial medication (C1D1).
- Incomplete macroscopic tumor removal (R2 resection).
- Complete dihydropyrimidine dehydrogenase (DPD) deficiency, if testing required by local regulations.
- Have other known active cancer(s) likely to require treatment in the next 2 years.
- Had prior radiotherapy or systemic treatment for pancreatic ductal adenocarcinoma (PDAC).
- Has active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic anti-infective therapy that has been administered less than 2 weeks prior to the first dose of BNT321.
- Is subject to exclusion periods from another investigational trial.
- Is a vulnerable individual as per ICH E6 definition, i.e., 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.
- Known hypersensitivity to any of the excipients of the experimental product BNT321.
- Has a history/positive serology for Hepatitis B requiring active antiviral therapy.
- Received a live vaccine within 3 weeks prior to the first dose of trial treatment.
- Patients with a contraindication to receiving mFOLFIRINOX.
- Patients with active or latent tuberculosis or history of Mycobacterium tuberculosis infection currently or within the last 2 years.
- Individuals committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Denmark | Not Yet Recruiting | 29 Feb 2024 | 11 |
 France | Not Yet Recruiting | 29 Feb 2024 | 34 |
 Germany | Not Yet Recruiting | 29 Feb 2024 | 40 |
 Spain | Not Yet Recruiting | 29 Feb 2024 | 32 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Calciumfolinat HEXAL 10 mg/ml Injektionslösung | Comparator | INJEKTIONSLÖSUNG | INTRAVENOUS INFUSION | — | — | PRD1613811 |
Irinotecan HCl AqVida 20 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Comparator | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS INFUSION | — | — | PRD3022873 |
BNT321 | Test | SOLUTION FOR INFUSION | SOLUTION FOR INFUSION | — | — | PRD10700182 |
FLUOROURACIL | Comparator | — | INTRAVENOUS INFUSION | — | — | SUB07721MIG |
Oxaliplatin AqVida 5 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Comparator | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS INFUSION | — | — | PRD1874310 |